Conditions: Respiratory Syncytial Virus
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 5
Healthy volunteers: no

Brief summary:
The purpose of this study is to evaluate the efficacy of rilematovir compared to placebo with respect to the time to resolution of respiratory syncytial virus (RSV) lower respiratory tract disease (LRTD) symptoms.

Detailed description:
Rilematovir is an investigational RSV specific fusion inhibitor currently in development for the treatment of RSV infection in both adult and pediatric populations. The study will include a Screening period (Day -1 to Day 1), a Treatment period (Day 1 to Day 7/8 \[depending on timing of first dose\]), and a Follow-up period (Day 8/9 to Day 35). The total study duration of the study for each participant will be up to 35 days. The study will evaluate efficacy and safety of RSV in adult outpatients (18-85 years) who are at high risk of RSV related disease progression and have at least moderate RSV disease. The efficacy assessments include evaluation with electronic patient-reported outcome (ePRO) and the safety assessments include evaluations of physical examinations, vital signs, electrocardiograms, clinical laboratory tests, and adverse events.

Arms:
arm 1: Participants will receive oral dose of rilematovir 250 milligrams (mg), twice daily (bid) for 7 days. arm 2: Participants will receive oral dose of placebo matching to rilematovir, bid for 7 days.

Interventions: intervention 1: Rilematovir intervention 2: Placebo
Intervention descriptions: intervention 1: Rilematovir 250 mg will be administered orally. intervention 2: Placebo matching to rilematovir will be administered orally.

Protocol document:
Prot_002.pdf: 
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
1
Status: Approved,  Date: 12 March 2021
Janssen Research & Development *
Clinical Protocol
A Phase 2b Randomized, Double-blind, Placebo-controlled Study to Evaluate the Efficacy 
and Safety of Rilematovir (JNJ-53718678) in Adult Outpatients with Respiratory Syncytial 
Virus (RSV) Infection who are at High Risk for RSV-related Disease Progression
PRIMROSE
Effects of Rilematovir in Adult Outpatients with RSV Infection who are at High Risk for 
RSV-related Disease Progression
Protocol 53718678RSV2008; Phase 2b
JNJ-53718678 (Rilematovir)
*Janssen Research & Development is a global organization that operates through different legal entities in
various countries. Therefore, the legal entity acting as the sponsor for Janssen Research & Development
studies may vary, such as, but not limited to Janssen Biotech, Inc.; Janssen Products, LP; Janssen
Biologics, BV; Janssen-Cilag International NV; Janssen, Inc; Janssen Pharmaceutica NV; Janssen
Sciences Ireland UC; Janssen Biopharma Inc.; or Janssen Research & Development, LLC. The term
“sponsor” is used throughout the protocol to represent these various legal entities; the sponsor is
identified on the Contact Information page that accompanies the protocol.
United States (US) sites of this study will be conducted under US Food & Drug Administration
Investigational New Drug (IND) regulations (21 CFR Part 312).
IND: IND 128973
EudraCT NUMBER: 2020-005980-30
Status:
Approved  
Date:
12 March 2021
Prepared by:
Janssen Research & Development, a division of Janssen Pharmaceutica NV
EDMS number:
EDMS-RIM-283209, 1.0
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.
NCT04978337


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Status: Approved,  Date: 12 March 2021
TABLE OF CONTENTS
TABLE OF CONTENTS ............................................................................................................................... 2
LIST OF IN-TEXT TABLES AND FIGURES................................................................................................ 5
1.
PROTOCOL SUMMARY ..................................................................................................................... 6
1.1.
Synopsis........................................................................................................................................... 6
1.2.
Schema .......................................................................................................................................... 20
1.3.
Schedule of Activities..................................................................................................................... 21
2.
INTRODUCTION................................................................................................................................ 28
2.1.
Study Rationale.............................................................................................................................. 28
2.2.
Background .................................................................................................................................... 30
2.3.
Benefit-Risk Assessment ............................................................................................................... 37
2.3.1.
Risks for Study Participation....................................................................................................... 38
2.3.1.1.
Known risks ............................................................................................................................. 38
2.3.1.2.
Potential risks .......................................................................................................................... 38
2.3.2.
Benefits for Study Participation .................................................................................................. 39
2.3.2.1.
Known benefits ........................................................................................................................ 39
2.3.2.2.
Potential benefits ..................................................................................................................... 39
2.3.3.
Benefit-Risk Assessment for Study Participation ....................................................................... 40
3.
OBJECTIVES AND ENDPOINTS ..................................................................................................... 41
4.
STUDY DESIGN ................................................................................................................................ 46
4.1.
Overall Design................................................................................................................................ 46
4.2.
Scientific Rationale for Study Design............................................................................................. 50
4.2.1.
Study-Specific Ethical Design Considerations ........................................................................... 51
4.3.
Justification for Dose...................................................................................................................... 52
4.4.
End of Study Definition................................................................................................................... 54
5.
STUDY POPULATION ...................................................................................................................... 55
5.1.
Inclusion Criteria ............................................................................................................................ 55
5.2.
Exclusion Criteria ........................................................................................................................... 58
5.3.
Lifestyle Considerations................................................................................................................. 60
5.4.
Screen Failures .............................................................................................................................. 61
6.
STUDY INTERVENTION AND CONCOMITANT THERAPY............................................................ 61
6.1.
Study Intervention(s) Administered................................................................................................ 61
6.2.
Preparation/Handling/Storage/Accountability ................................................................................ 63
6.3.
Measures to Minimize Bias: Randomization and Blinding............................................................. 64
6.4.
Study Intervention Compliance...................................................................................................... 65
6.5.
Dose Modification........................................................................................................................... 66
6.6.
Continued Access to Study Intervention After the End of the Study ............................................. 66
6.7.
Treatment of Overdose .................................................................................................................. 66
6.8.
Concomitant Therapy..................................................................................................................... 66
7.
DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT
DISCONTINUATION/WITHDRAWAL ............................................................................................... 70
7.1.
Discontinuation of Study Intervention ............................................................................................ 70
7.2.
Participant Discontinuation/Withdrawal From the Study................................................................ 71
7.2.1.
Withdrawal From the Use of Research Samples ....................................................................... 72
7.3.
Lost to Follow-up............................................................................................................................ 72
8.
STUDY ASSESSMENTS AND PROCEDURES ............................................................................... 72
8.1.
Efficacy Assessments .................................................................................................................... 76
8.1.1.
Clinical Course and Severity of RSV Infection ........................................................................... 76


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8.1.1.1.
RSV disease symptoms .......................................................................................................... 76
8.1.1.2.
Complications of RSV infection ............................................................................................... 78
8.1.1.3.
Other measures of RSV-related disease progression............................................................. 79
8.1.2.
Functioning and Health-related Quality of Life ........................................................................... 79
8.1.3.
Antiviral Activity........................................................................................................................... 82
8.1.4.
Viral Sequencing......................................................................................................................... 83
8.2.
Safety Assessments....................................................................................................................... 83
8.2.1.
Physical Examinations................................................................................................................ 84
8.2.2.
Vital Signs................................................................................................................................... 84
8.2.3.
Electrocardiograms..................................................................................................................... 84
8.2.4.
Clinical Safety Laboratory Assessments .................................................................................... 85
8.2.5.
Pregnancy Testing...................................................................................................................... 85
8.3.
Adverse Events, Serious Adverse Events, and Other Safety Reporting ....................................... 85
8.3.1.
Time Period and Frequency for Collecting Adverse Event and Serious Adverse Event 
Information.................................................................................................................................. 86
8.3.2.
Method of Detecting Adverse Events and Serious Adverse Events .......................................... 86
8.3.3.
Follow-up of Adverse Events and Serious Adverse Events ....................................................... 86
8.3.4.
Regulatory Reporting Requirements for Serious Adverse Events and Anticipated 
Events......................................................................................................................................... 87
8.3.5.
Pregnancy................................................................................................................................... 87
8.3.6.
Disease-Related Events and Disease-Related Outcomes Not Qualifying as Adverse 
Events or Serious Adverse Events ............................................................................................. 88
8.3.7.
Safety Areas of Evaluation ......................................................................................................... 88
8.3.7.1.
Safety Topic of Special Interest: Hepatobiliary effects............................................................ 88
8.3.7.2.
Cardiac events potentially related to QT prolongation ............................................................ 88
8.4.
Pharmacokinetics........................................................................................................................... 89
8.4.1.
Evaluations ................................................................................................................................. 89
8.4.2.
Analytical Procedures................................................................................................................. 90
8.4.3.
Pharmacokinetic Parameters and Evaluations........................................................................... 90
8.5.
Biomarkers ..................................................................................................................................... 91
8.6.
Detection of Baseline Presence of Other Respiratory Viruses or Bacteria.................................... 91
8.7.
Medical Resource Utilization.......................................................................................................... 91
9.
STATISTICAL CONSIDERATIONS.................................................................................................. 91
9.1.
Statistical Hypotheses.................................................................................................................... 91
9.2.
Sample Size Determination ........................................................................................................... 92
9.3.
Populations for Analysis Sets ........................................................................................................ 92
9.4.
Statistical Analyses ........................................................................................................................ 92
9.4.1.
General Considerations.............................................................................................................. 92
9.4.2.
Participant Information................................................................................................................ 93
9.4.3.
Efficacy Analysis......................................................................................................................... 93
9.4.3.1.
Primary endpoint ..................................................................................................................... 93
9.4.3.2.
Secondary clinical endpoints................................................................................................... 94
9.4.3.3.
Antiviral activity........................................................................................................................ 95
9.4.3.4.
Viral sequencing ...................................................................................................................... 95
9.4.4.
Safety Analyses .......................................................................................................................... 95
9.4.5.
Other Analyses ........................................................................................................................... 96
9.5.
Interim Analysis.............................................................................................................................. 97
9.6.
Independent Data Monitoring Committee ...................................................................................... 97
10.
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS ............................ 99
10.1.
Appendix 1: Abbreviations ............................................................................................................. 99
10.2.
Appendix 2: Clinical Laboratory Tests ......................................................................................... 101
10.3.
Appendix 3: Regulatory, Ethical, and Study Oversight Considerations....................................... 103
10.3.1.
Regulatory and Ethical Considerations .................................................................................... 103
10.3.2.
Financial Disclosure.................................................................................................................. 106
10.3.3.
Informed Consent Process ....................................................................................................... 106
10.3.4.
Data Protection ......................................................................................................................... 107


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10.3.5.
Long-Term Retention of Samples for Additional Future Research .......................................... 108
10.3.6.
Committees Structure............................................................................................................... 108
10.3.7.
Publication Policy/Dissemination of Clinical Study Data .......................................................... 108
10.3.8.
Data Quality Assurance............................................................................................................ 110
10.3.9.
Case Report Form Completion................................................................................................. 110
10.3.10.
Source Documents ................................................................................................................... 111
10.3.11.
Monitoring ................................................................................................................................. 112
10.3.12.
On-Site Audits........................................................................................................................... 112
10.3.13.
Record Retention...................................................................................................................... 113
10.3.14.
Study and Site Start and Closure ............................................................................................. 113
10.4.
Appendix 4: Adverse Events, Serious Adverse Events, Product Quality Complaints, and 
Other Safety Reporting: Definitions and Procedures for Recording, Evaluating, Follow-up, 
and Reporting............................................................................................................................... 114
10.4.1.
Adverse Event Definitions and Classifications ......................................................................... 114
10.4.2.
Attribution Definitions................................................................................................................ 115
10.4.3.
Severity Criteria ........................................................................................................................ 115
10.4.4.
Special Reporting Situations .................................................................................................... 115
10.4.5.
Procedures ............................................................................................................................... 116
10.4.6.
Product Quality Complaint Handling......................................................................................... 117
10.4.7.
Contacting Sponsor Regarding Safety, Including Product Quality........................................... 118
10.5.
Appendix 5: Contraceptive and Barrier Guidance and Collection of Pregnancy Information...... 118
10.6.
Appendix 6: Liver Safety: Suggested Actions and Follow-up Assessments................................ 121
10.7.
Appendix 7: Toxicity Tables ......................................................................................................... 122
10.8.
Appendix 8: List of Commonly Used Medications With a Known Risk of QT Prolongation 
and Torsade de Pointes............................................................................................................... 131
10.9.
Appendix 9: Anticipated Events ................................................................................................... 135
10.10.
Appendix 10: Pre-Existing Symptom Questionnaire.................................................................... 137
10.11.
Appendix 11: Respiratory Infection Intensity and Impact Questionnaire (RiiQ™)....................... 138
10.11.1.
Respiratory Infection Intensity and Impact Questionnaire (RiiQ™) Symptom Scale ............... 138
10.11.2.
Respiratory Infection Intensity and Impact Questionnaire (RiiQ™) Impact Scales.................. 139
10.12.
Appendix 12: Patient Global Impression (PGI-S) ........................................................................ 140
10.13.
Appendix 13: Patient Global Impression of Change (PGI-C)....................................................... 141
10.14.
Appendix 14: Return to Usual Activities....................................................................................... 142
10.15.
Appendix 15: Return to Usual Health........................................................................................... 143
10.16.
Appendix 16: Employment Status................................................................................................ 144
10.17.
Appendix 17: Hours Missed from Work ....................................................................................... 145
10.18.
Appendix 18: Clinician Symptom Score....................................................................................... 146
10.19.
Appendix 19: EQ-5D-5L Questionnaire ....................................................................................... 147
10.20.
Appendix 20: Guidance on Study Conduct During the COVID-19 Pandemic ............................. 150
10.21.
Appendix 21: Protocol Amendment History ................................................................................. 153
11.
REFERENCES................................................................................................................................. 154
INVESTIGATOR AGREEMENT ............................................................................................................... 156


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Status: Approved,  Date: 12 March 2021
LIST OF IN-TEXT TABLES AND FIGURES
TABLES
Table 1:
Simulated Effect of Concomitant CYP3A4 Inhibitors on Rilematovir PK Parameters.............. 53
Table 2:
Predicted Geometric Mean AUC0-24h, Cmax, Ctrough and ΔΔQTcI After Day 1 and Day 7........... 54
Table 3:
Examples of Commonly Used Medications With CYP3A4 Inhibiting and/or QT 
Prolonging Effects Which are Disallowed or Allowed Upon Coadministration with 
Rilematovir ................................................................................................................................ 69
FIGURES
Figure 1:
Schematic Overview of the Study............................................................................................. 20
Figure 2:
Timeline from RSV Sign/Symptom Onset to First Dose........................................................... 47
Figure 3:
Schedule for Collection of Bilateral Nasal Mid-Turbinate Swab Samples................................ 83


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1.
PROTOCOL SUMMARY
1.1.
Synopsis
A Phase 2b Randomized, Double-blind, Placebo-controlled Study to Evaluate the Efficacy and Safety 
of Rilematovir (JNJ-53718678) in Adult Outpatients with Respiratory Syncytial Virus (RSV) 
Infection who are at High Risk for RSV-related Disease Progression
Effects of Rilematovir in Adult Outpatients with RSV Infection who are at High Risk for RSV-related
Disease Progression
Rilematovir (JNJ-53718678) is an investigational, potent small molecule respiratory syncytial 
virus (RSV) specific fusion inhibitor belonging to the indole chemical class. Rilematovir targets 
the RSV fusion (F) protein and prevents the conformational changes of the F-protein required for 
fusion of the viral envelope with the host cell membrane and for cell-to-cell fusion, thereby 
inhibiting viral replication and syncytia formation.
OBJECTIVES AND ENDPOINTS
Objectives
Endpoints
Primary

To evaluate efficacy of rilematovir compared to 
placebo with respect to the time to resolution of 
RSV lower respiratory tract disease (LRTD)
symptoms.

Time to resolution of RSV LRTD symptoms 
(ie, cough, short of breath, wheezing, coughing 
up phlegm [sputum]) as assessed by the 
participant using the Respiratory Infection 
Intensity and Impact Questionnaire (RiiQ™)
Symptom Scale.
Definition of resolution in participants without 
pre-existing respiratory symptoms:
-
All LRTD symptoms in the RiiQ Symptom 
Scalea scored as ‘None’ (score = 0) or 
‘Mild’ (score =1) for at least 24 hours.
Definition of resolution in participants with 
pre-existing respiratory symptoms:
-
Pre-existing symptoms that were worse at 
baseline should have improved at least 
1 point on the RiiQ Symptom Scale from 
baseline for at least 24 hours; and
-
Pre-existing symptoms that were not 
worse at baseline should have not 
worsened from baseline severity for at 
least 24 hours; and
                                                
a The RiiQ Symptom scale is a four-item scale (0: no symptoms, 1: mild symptoms, 2: moderate symptoms, 3: severe 
symptoms).


JNJ-53718678 (Rilematovir)
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Status: Approved,  Date: 12 March 2021
Objectives
Endpoints
-
Symptoms that were not pre-existing at
baseline should be scored as ‘None’
(score = 0) or ‘Mild’ (score =1) on the
RiiQ Symptom Scale for at least 24 hours.
Secondary

To evaluate the effect of rilematovir compared
to placebo with respect to the incidence of
post-baseline RSV-related complications.

Proportion of participants with post-baseline
complications (ie, RSV-related pulmonary and
extrapulmonary complications).
-
Pulmonary complications: primary viral
pneumonia, bronchitis, respiratory failure,
secondary 
bacterial 
pneumonia, 
and
exacerbations 
of
underlying 
chronic
pulmonary diseases (such as chronic
obstructive pulmonary disease [COPD]
and asthma)
-
Extrapulmonary 
complications:
cardiovascular 
and 
cerebrovascular
disease events, congestive heart failure
(CHF) or exacerbation of underlying CHF,
acute exacerbation of chronic kidney
disease, 
severe 
dehydration,
decompensation of previously controlled
diabetes mellitus, and other airway
infections (eg, sinusitis).
-

To evaluate the effect of rilematovir as
compared to placebo on medical resource
utilization (MRU) with respect to respiratory
therapeutic interventions associated with RSV-
related disease progression.

Proportion of participants with new antibiotic
use, 
or 
new 
or 
increased
use
in
bronchodilator/nebulizer,
systemic 
corticosteroids, 
or 
home 
oxygen 
supplementation. 

To evaluate the effect of rilematovir as
compared to placebo on MRU with respect to
medically attended visits associated with
RSV-related disease progression.

Proportion of participants with unscheduled
outpatient clinic visits, emergency room visits
or hospitalization for respiratory infection.

To evaluate the effect of rilematovir as
compared 
to 
placebo
on 
the 
overall
RSV-related disease progression.

Proportion of participants meeting a composite
endpoint of either developing RSV-related
complications (pulmonary & extra pulmonary)
and/or 
needing 
RSV-related 
medical
attendance.

To evaluate the safety and tolerability of
rilematovir.

Safety and tolerability, as assessed by adverse
events (AEs), clinical laboratory testing,
electrocardiograms 
(ECGs), 
physical
examination, and vital signs.


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Status: Approved,  Date: 12 March 2021
Objectives
Endpoints

To evaluate the effect of rilematovir compared
to placebo on the clinical course of RSV
infection.

Change from baseline over time in severity of
the RSV LRTD symptoms as assessed by the
participant using the RiiQ™ Symptom Scale.

Time to resolution of LRTD symptoms and
2 systemic symptoms (feeling feverish and
fatigue) as assessed by the participant using the
RiiQ™ Symptom Scale.

Time to resolution of the overall RSV
symptoms (upper respiratory tract disease
[URTD] {sore throat and nasal congestion},
LRTD, and 2 systemic symptoms [feeling
feverish and fatigue]) as assessed by the
participant using the RiiQ™ Symptom Scale.

Time to resolution of all RSV symptoms as
assessed by the participant using the RiiQ™
Symptom Scale.

Time to resolution of each separate RSV LRTD
symptom as assessed by the participant using
the RiiQ™Symptom Scale.

Time to resolution of respiratory infection
symptoms as assessed by the participant using
the Patient Global Impression of RSV Severity
(PGI‑S) Scale.
Definition of resolution in participants without 
pre-existing respiratory symptoms:
−
All LRTD symptoms in the RiiQ Symptom
Scalea scored as ‘None’ (score = 0) or
‘Mild’ (score =1) for at least 24 hours.
Definition of resolution in participants with 
pre-existing respiratory symptoms:
−
Pre-existing symptoms that were worse at
baseline should have improved at least
1 point on the RiiQ Symptom Scale from
baseline for at least 24 hours; and
−
Pre-existing symptoms that were not
worse at baseline should have not
worsened from baseline severity for at
least 24 hours, and,
a The RiiQ Symptom scale is a four-item scale (0: no symptoms, 1: mild symptoms, 2: moderate symptoms, 3: severe 
symptoms).


JNJ-53718678 (Rilematovir)
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Status: Approved,  Date: 12 March 2021
Objectives
Endpoints
−
Symptoms that were not pre-existing at 
baseline should be scored as ‘None’ 
(score = 0) or ‘Mild’ (score =1) on the
RiiQ Symptom Scale for at least 24 hours.

Time to return to pre-existing health (status) for 
all RSV symptoms as assessed by the 
participant using the RiiQ™Symptom Scale.

Time to improvement in RSV disease as 
assessed by the participant using the Patient 
Global Impression of Change (PGI‑C) Scale.

To evaluate the effect of rilematovir compared 
to placebo on Health-Related Quality of Life 
(HRQOL).

Change from baseline over time for the 
HRQOL as assessed by participants using the 
EQ-5D-5L and RiiQ™Impact Scales.

Time to return to usual health as assessed by the 
participant using the ‘Adult RSV Return to 
Usual Health’ question.

Time to return to usual activities as assessed by 
the participant using the ‘Adult RSV Return to 
Usual Activities’ question.

Time to no or mild impact of RSV-related 
disease on daily activities, emotions, and social 
relationships as assessed by the participant 
using the RiiQ™ Impact Scales.

To evaluate the antiviral effect of rilematovir as 
measured by RSV viral load in bilateral nasal 
mid-turbinate swab samples by quantitative 
revers transcription polymerase chain reaction 
(qRT-PCR) assay.

Respiratory syncytial virus viral load area 
under the curve from immediately prior to first 
dose of study intervention (baseline) through 
Day 3, Day 5, Day 8.

Change from baseline over time in RSV viral 
load.

Proportion of participants with undetectable
RSV viral load at each time point that a swab is 
planned to be collected.

To evaluate the emergence of mutations in the 
viral genome potentially associated with 
resistance to rilematovir.

Post-baseline sequence changes in the RSV 
F gene.

To evaluate the pharmacokinetics (PK) of 
rilematovir. 

Pharmacokinetic
parameters of rilematovir
(ie, predose plasma concentration [Ctrough], 
maximum plasma concentration [Cmax], and
area under the curve of administration up to 12 
hours post dosing [AUC0-12h ]).


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Status: Approved,  Date: 12 March 2021
Objectives
Endpoints

To evaluate the impact of rilematovir compared 
to placebo on MRU.

Number and type of medical encounters.

Shift in any care setting (e.g. from no assistance 
to use of skilled home nurse or assisted home 
living).

Proportion 
of 
participants 
requiring 
hospitalization for respiratory or other reasons 
and duration of hospitalization (total days 
length of stay, including incidence and where 
feasible duration by wards, eg, intensive care 
unit [ICU]).

Incidence and duration of treatment-emergent 
use of antibiotics.

Incidence and duration of treatment-emergent 
new use or increased dose of systemic or 
inhaled corticosteroids and bronchodilators.

Proportion of participants with new or 
increased use of oxygen therapy.

Duration of oxygen supplementation.

Duration of selected post-baseline emergent 
(after start of study intervention) MRU.
Exploratory

To explore the relationship between antiviral 
activity and the primary and key secondary 
clinical outcomes.

Respiratory syncytial virus viral load-based 
endpoints and primary and key secondary 
clinical course endpoints.

To explore the impact of rilematovir compared 
to placebo on RSV disease-related progression 
and complications.

The proportion of participants progressing to 
ICU including the need for mechanical 
ventilation (yes or no).

All-cause mortality up to Day 35. 

To evaluate the impact of rilematovir compared 
to placebo on the clinical course of disease
using the Clinician Symptom Score (CSS).

Change from baseline over time in the CSS as 
assessed by a Clinician Questionnaire.

To explore the relationship between PK of
rilematovir
and 
pharmacodynamics 
(PD) 
(selected antiviral activity, clinical outcomes, 
and safety parameters).

Pharmacokinetic/PD 
analysis 
of 
plasma 
concentration-time data of rilematovir and 
selected clinical outcomes, antiviral activity, 
and safety parameters.

To explore the impact of rilematovir compared 
to placebo on hours missed from work (by all 
members of the participant’s household, 
including the participant, if employed).

Hours
missed from work due to the 
participant's RSV infection by all members of 
the participant’s household, including the 
participant, if employed.


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Status: Approved,  Date: 12 March 2021
Hypothesis
The primary hypothesis of this study is that rilematovir reduces the time to resolution of the RSV 
LRTD symptoms compared to placebo, as assessed by a patient-reported outcome (PRO) measure 
(RiiQTM) in adult outpatients with at least moderate RSV disease and who are at high risk for RSV 
disease-related progression.
OVERALL DESIGN
This is a Phase 2b, randomized, double-blind, placebo-controlled, multicenter study to evaluate 
efficacy, safety, and tolerability of rilematovir at a dose of 250 mg twice daily administered for 
7 days in outpatient adults (≥18 to ≤85 years of age) who are at high risk of RSV-related disease 
progression, and who have at least moderate RSV disease (LRTD) due to RSV infection. Moderate 
RSV disease is defined as having at least any 2 of the symptoms of LRTD (cough, wheeze, 
coughing up phlegm, short of breath), one of which must be scored as at least ‘moderate’ if the 
symptoms did not pre-exist before RSV onset, OR one of which must be scored worse than usual 
if the symptoms pre-existed as determined by the participant's ratings of the RiiQ Symptom Scale 
and the Pre-Existing Symptom Questionnaire in the ePRO device.
A target of 180 participants who meet all eligibility criteria will be randomized in a 2:1 ratio to 
receive 1 of the following 2 treatments:

Treatment A: rilematovir 250 mg twice daily for 7 days (n = 120)

Treatment B: placebo twice daily for 7 days (n = 60)
Randomization to study intervention treatment should occur within 72 hours after onset of any of 
the RSV symptoms or worsening of pre-existing symptoms.
High-risk condition(s) for RSV-related disease progression is defined as:

Presence of any of the underlying high-risk comorbid cardiopulmonary conditions (COPD,
asthma, or CHF) AND/OR

≥65 years of age (elderly participants)
The study population should consist of at least 50% of participants with randomization ≤48 hours 
since onset of RSV symptoms.
All study procedures will be conducted as stipulated in the Schedule of Activities of the body of 
the document.
An Independent Data Monitoring Committee will be commissioned for this study to monitor safety 
data on a regular basis.
A separate Substudy to explore the use of Biosensors for monitoring cardio-respiratory parameters 
will be performed at selected study sites in a subset of participants who provide specific consent 


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for this assessment. Details, including objectives and study design, will be described in a separate 
Substudy protocol.
A second Substudy with Qualitative Patient Interviews will be performed at selected study sites in 
a subset of participants who provide specific consent for this assessment. This Substudy will gain 
insight in the participants 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.
NUMBER OF PARTICIPANTS
A target of 180 participants who are at high risk for RSV-related disease progression will be 
randomly assigned in a 2:1 ratio (active:placebo) in this study with approximately 120 participants 
planned in the rilematovir group and approximately 60 participants in the placebo group. 
High-risk condition(s) for RSV-related disease progression is defined as:

Presence of any of the underlying high-risk comorbid cardiopulmonary conditions (COPD,
asthma, or CHF) AND/OR

≥65 years of age (elderly participants)
Randomization will be stratified by high-risk (<65 years of age with underlying high-risk comorbid 
cardiopulmonary conditions [COPD, asthma, or CHF] versus ≥65 years of age without underlying 
comorbid cardiopulmonary conditions versus ≥65 years of age with underlying comorbid 
cardiopulmonary conditions), and time since symptom onset (≤48 hours versus >48-72 hours).
INTERVENTION GROUPS AND DURATION
Eligible participants will be randomized in a 2:1 ratio to receive either Treatment A (rilematovir
250 mg twice daily) or B (matching placebo twice daily).
The study will include a screening period (Day -1 to Day 1), a Treatment Period (Day 1 to Day 7/8 
[depending on timing of first dose]), and a Follow-up Period (Day 8/9 to Day 35 [±3]). In general, 
the total study duration for each participant will be 35 (±3) days. The study is considered complete 
with the completion of the last study assessment for the last participant in the study.
Description of Interventions
Arm Name
Treatment A
Treatment B
Intervention Name
Rilematovir 
(JNJ-53718678)
Placebo
Type
Drug
Drug
Dose Formulation
Oral film-coated tablet
Oral film-coated tablet
Unit Dose Strength(s)
eq. 125-mg
Matching placebo


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Arm Name
Treatment A
Treatment B
Dosage Level(s)
250 mg bid for 7 days 
(dose reduction to 125 mg 
bid if coadministration 
with moderate or strong 
CYP3A4 inhibitors is 
started or continued during 
study intervention 
treatment)a
Matching placebo bid for 
7 days
Route of Administration
Oral
Oral
Use
Experimental
Placebo
Investigational Medicinal Product (IMP)
Yes
Yes
Non-Investigational Medicinal 
Product/Auxiliary Medicinal Product
No
No
Sourcing
Provided centrally by the sponsor
Packaging and Labeling
The oral film-coated tablets are packaged in high-
density polyethylene (HDPE) bottles with child-resistant 
screw caps with 2 g of desiccant.
Labels will contain information to meet the applicable 
regulatory requirements.
Delivery Instructions
Do not crush tablets.
All study drugs will be taken orally with a glass of 
water.
Food/Fasting Requirement
Regardless of food administration
Other Requirements
Dosing should preferably occur approximately at the 
same time each day for both intakes (AM and PM)
a Refer to the body of the document for details regarding the coadministration of moderate or strong 
CYP3A4 inhibitors during the study. Investigators must review the concomitant medications at 
screening and consult the sponsor as needed.
EFFICACY EVALUATIONS
Clinical Course and Severity of RSV Infection
The impact of rilematovir treatment on RSV disease severity and duration will be assessed by 
participants in the ePRO device using the:

RiiQ™ Symptom Scale

Pre-Existing Symptom Questionnaire

2 Patient Global Impression (PGI) questions about the overall severity and change in RSV 
disease: PGI of severity (PGI-S) and PGI of change (PGI-C) in RSV disease
The impact of rilematovir treatment on RSV disease severity will be assessed by the clinician by 
rating the severity of the RSV LRTD sign/symptoms in the study participants using the Clinician 
Symptom Score (CSS).
Clinical evaluation includes vital sign assessments (ie, body temperature, respiratory rate, 
pulse/heart rate, peripheral capillary oxygen saturation [SpO2]) and physical examination 
assessments (ie, presence of wheezing or crackles/rhonchi) as measured during site visits. Clinical 


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evaluation also includes RSV-related complications, need for respiratory therapeutic interventions
(including antibiotics), and medical attendance for respiratory infections.
Functioning and Health-related Quality of Life (HRQOL)
The impact of treatment on the degree to which RSV symptoms interfere with the participant’s 
routine functioning and HRQOL will be assessed by participants in the ePRO device using the:

Hours Missed from Work question

RiiQ™ Impact Scales

5 level EuroQol© 5 Dimension (EQ-5D-5L) questionnaire
Antiviral Activity
As an evaluation of antiviral activity, the RSV viral load in nasal secretions, obtained via a bilateral 
nasal mid-turbinate swab sample, will be measured at the central laboratory using a quantitative 
revers transcription polymerase chain reaction (qRT-PCR) assay. The qRT-PCR used to determine 
RSV viral load will also provide information on the RSV subtype. Bilateral nasal mid turbinate 
swab specimens for the determination of RSV viral load will be collected at several time points 
during the study as indicated in the Schedule of Activities of the body of the document.
PHARMACOKINETIC EVALUATIONS
Blood samples will be used to evaluate the PK of rilematovir. Pharmacokinetic parameters will be 
determined using a population PK (popPK) approach by means of nonlinear mixed-effects 
modeling. The PK/PD relationship of rilematovir exposure (area under the plasma concentration-
time curve from time 0 to 24 hours after dosing [AUC0-24h], maximum plasma concentration [Cmax], 
or minimum plasma concentration [Cmin]) with selected efficacy (change in viral load from 
baseline and clinical outcomes) and safety (including laboratory abnormalities and AEs) 
parameters will be explored. If there is any visual trend in graphical analysis, suitable models will 
be applied to describe the exposure-effect relationships. The results of the PK/PD analysis will be 
reported in a separate report.
Venous blood samples of approximately 2 mL per sample will be collected for measurement of 
plasma concentrations of rilematovir at time points indicated in the Schedule of Activities in the 
body of the document. Samples can also be used for the analysis of metabolites of rilematovir, 
excipients, protein binding, or endogenous markers for enzymes or transporters involved in the 
metabolism and distribution of rilematovir, at the discretion of the sponsor.
BIOMARKERS
Blood samples for biomarker research will be collected at time points indicated in the Schedule of 
Activities in the body of the document. and may be used for biomarker research (eg, host 
ribonucleic acid [RNA], proteins including cytokines, cellular phenotyping), on the premise that 
these markers may play a role in the treatment response, safety, or PK of rilematovir, or in 
RSV-related disease. Leftover nasal mid-turbinate swabs and blood samples collected for other 


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testing may be used as well for the same purpose. Analyses of biomarkers will be conducted at the 
sponsor’s discretion and may be reported separately from this study.
MEDICAL RESOURCE UTILIZATION
Medical resource utilization data, associated with medical encounters, will be collected in the 
electronic case report form (eCRF) by the investigator and study site personnel for all participants 
throughout the study. Protocol-mandated procedures, tests, and encounters are excluded. The data 
collected will be used to conduct secondary efficacy analyses (use of respiratory therapeutic 
interventions as well as medically attended visits) and may be used to conduct exploratory 
economic analyses. Medical Resource Utility will include:

Number and duration of medical care encounters (eg, increased nursing visits at home, 
emergency room visit).

Number (proportion) of participants requiring hospitalization for respiratory/other reasons and 
duration of hospitalization (total days length of stay, including duration by wards; 
eg, intensive care unit). In the event of hospitalization during the study, investigators must 
make every effort to collect details of hospitalization as feasible, including the reason and 
duration of hospitalization.

Incidence of antibiotic treatment.

Any new or increased use of systemic or inhaled corticosteroids and bronchodilators use.

New or increased use of oxygen therapy.

Duration of selected post-baseline (after start of study intervention) MRU.
SAFETY EVALUATIONS
Safety and tolerability will be assessed throughout the study from signing the main informed 
consent form (ICF) until the participant’s last study-related activity. For participants having signed 
a diagnostic ICF, only procedure-related AEs will be reported.
Any clinically relevant changes occurring during the study must be recorded on the AE section of 
the eCRF. Any clinically significant abnormalities persisting at the end of the study/early 
withdrawal will be followed by the investigator until resolution or until a clinically stable condition 
is reached.
The study will include the following evaluations of safety and tolerability:

AEs, serious AEs (SAEs), and deaths.

Clinical laboratory tests (blood and urine).

ECG (12-lead).

Vital signs.

Vital signs assessments performed as part of the clinical course of RSV infection related 
assessments (body temperature, heart/pulse rate, respiratory rate, and SpO2).


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
Additional vital signs assessments: systolic blood pressure and diastolic blood pressure.

A complete physical examination (including height and body weight measurements) and
targeted physical examination.

Pregnancy.
STATISTICAL METHODS
Sample Size Determination
The study will aim to enroll approximately 180 participants in a 2:1 ratio to rilematovir 
250 mg twice daily (approximately 120 participants) and placebo (approximately 60 participants).
The sample size calculation is based on the primary efficacy endpoint, which is the time to 
resolution of RSV LRTD symptoms from randomization up to Day 35 in the intention-
to--treat-infected (ITT-i) analysis set.
With a sample size of 180 participants, there is an 80% probability to demonstrate a reduction of 
at least 20% in the primary efficacy endpoint when the true effect is 30%. As further guidance for 
the sample size of this study, the power to detect a treatment difference for the primary efficacy 
endpoint is also calculated.
An accelerated failure time (AFT) model with underlying log-normal distribution for the time to 
resolution is assumed with a median in a placebo arm of 14 days and a scale parameter of 0.8 (as 
observed in Study 51738678RSV2004). Using the Gehan-Wilcoxon test to analyze the data and 
based on the assumptions that the time to recovery is improved by 30%, that approximately 10% 
of the total enrolled participants may not be centrally confirmed RSV positive, and that 5% of 
patients may drop out of the study early before reaching resolution of their RSV LRTD symptoms, 
a sample size of 180 participants (randomized in a 2:1 ratio to rilematovir 250 mg twice daily and 
placebo) will have an estimated power of 80% as based on 10,000 simulations using a 10% 2-sided 
significance level. The power was estimated as the number of simulated studies where the 2-sided 
p value from the Gehan-Wilcoxon test was <0.1 out of the 10,000 simulated datasets.
Efficacy Parameters
Primary Endpoint
The primary endpoint is the time to resolution of RSV LRTD symptoms from initiation of study 
treatment up to Day 35 as assessed by the participant using the RiiQ™ Symptom Scale. The RSV 
LRTD symptoms are defined as the following symptoms from the RiiQ Symptom Scale: cough, 
short of breath, wheezing, and coughing up phlegm (sputum).
Resolution of RSV LRTD symptoms in participants without pre-existing conditions is reached
when all RSV LRTD symptoms in the RiiQ Symptom Scale are scored as ‘None’ (score = 0) or 
‘Mild’ (score =1) for at least 24 hours.
Resolution of RSV LRTD symptoms in participants with pre-existing conditions is reached when:


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–
Pre-existing symptoms that were worse at baseline have improved at least 1 point from
baseline for at least 24 hours; and
–
Pre-existing symptoms that were not worse at baseline have not worsened from baseline
severity for at least 24 hours; and
–
Symptoms that were not pre-existing at baseline should be scored as ‘None’ (score = 0) or
‘Mild’ (score =1) for at least 24 hours.
The primary efficacy endpoint will be estimated using an AFT model adjusted by the 
randomization factors (high-risk and time since symptom onset) and baseline RSV LRTD 
symptom domain score.
Kaplan‑Meier curves as well as Kaplan-Meier estimates of median time to resolution will also be 
provided.
Secondary Endpoint
The proportion of participants with complications (including all RSV-related pulmonary and 
extrapulmonary complications) from initiation of study treatment up to Day 35 will be analyzed 
using a logistic regression. Stratification factors will be added as covariates to the model. Similarly, 
all the secondary binary endpoints will be analyzed using a logistic regression.
All time-to-event secondary efficacy analyses will be analyzed similarly to the primary endpoint.
Changes from baseline over time as assessed by PRO questionnaires will be analyzed using a 
mixed-effect model with repeated measurements (MMRM). This analysis includes fixed 
categorical effects of treatment, randomization strata, time, and treatment-by-time interaction, as 
well as the continuous covariates of baseline score and baseline score-by-time interaction.
Antiviral Activity
Antiviral activity will be determined based on measurements of RSV viral load in nasal 
mid-turbinate swab samples by a qRT-PCR assay. These data will be analyzed graphically. For 
continuous variables, descriptive statistics (n, mean, standard deviation [SD], median, minimum, 
and maximum) will be calculated. For categorical variables, frequency tables will be presented.
Mean log10 viral load values over time will be analyzed using MMRM. Differences between 
intervention groups in viral load, and the difference in the RSV viral load AUC through Days 3, 
5, and 8 between intervention groups will be derived using appropriate contrasts deriving least 
square mean differences, including the 90% 2-sided confidence intervals.
The relationship between antiviral activity and baseline characteristics, including but not limited 
to RSV viral subtype and genotype will be explored.


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Viral Sequencing
The results of viral sequencing will be evaluated by the sponsor virologist. Pre-treatment genetic 
variations and relevant post-baseline changes in the RSV F gene (and other regions of the RSV 
genome, if applicable and on request of the sponsor virologist) will be tabulated and described. 
The effect of pre-treatment RSV F protein genetic variations and relevant post-baseline RSV F 
protein amino acid changes on antiviral response and/or clinical outcomes will be explored.
Safety Analysis
Adverse Events
The verbatim terms used in the eCRF by investigators to identify AEs will be coded using the 
Medical Dictionary for Regulatory Activities (MedDRA). Any AE occurring at or after the initial 
administration of study intervention through the end of the study is considered to be 
treatment-emergent. 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.
Clinical Laboratory Tests
Laboratory data will be summarized by type of laboratory test. Reference ranges will be used in 
the summary of laboratory data. Descriptive statistics will be calculated for each laboratory analyte 
at baseline and for observed values and changes from baseline at each scheduled time point. 
Changes from baseline results will be presented in pre- versus post-intervention cross-tabulations 
(with classes for below, within, and above normal ranges). A listing of participants with any 
laboratory results outside the reference ranges will be provided. A listing of participants with any 
markedly abnormal laboratory results will also be provided (as defined in the Appendix of the 
document).
The laboratory abnormalities will be determined according to the criteria specified in the Division 
of Microbiology and Infectious Diseases adult toxicity table (as defined in the Appendix of the 
document) and in accordance with the normal ranges of the clinical laboratory if no gradings are 
available.
Electrocardiogram
The effects on cardiovascular variables will be evaluated by means of descriptive statistics and 
frequency tabulations and pre- vs post-intervention cross-tabulations. These tables will include 
observed values and changes from baseline values (the predose ECG will be used as baseline).
Vital Signs
Descriptive statistics of respiratory rate, pulse/heart rate, SpO2, body temperature, and blood 
pressure (systolic and diastolic) will be summarized at each scheduled time point. The percentage 
of participants with values beyond clinically important limits will be summarized by treatment.


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Other Analysis
Pharmacokinetic Analyses
Pharmacokinetic analysis set of plasma concentration-time data of rilematovir will be performed 
using nonlinear mixed-effects modeling. Data may be combined with those of other selected 
studies to support a relevant structural model. Available baseline participant characteristics 
(demographics, laboratory variables, genotypes, race, etc.) will be tested as potential covariates 
affecting PK parameters. Details will be given in a PK analysis set plan and the results of the PK 
analysis set will be presented in a separate report.
Pharmacokinetic/Pharmacodynamic Analyses
Relationships of rilematovir population-derived exposure parameters with selected antiviral 
activity parameters, clinical outcomes, and safety endpoints will be explored. These relationships 
will be presented in a tabular and/or graphical display. The results of the PK/PD analysis may be 
conducted at the sponsor’s discretion and reported separately from this study.
Biomarkers Analyses
Statistical approaches to explore correlations between clinical outcome, viral load, and biomarkers 
in blood and nasal mid-turbinate swabs vary and depend on the different data types of the applied 
technology platforms, as well as on the extent of observed differences among study participants. 
Analyses may be conducted at the sponsor’s discretion and reported separately from this study.
Interim Analysis
Interim analyses may be conducted at sponsor’s discretion when at least approximately 65% of 
participants are enrolled to allow preparation towards a Phase 3 study design. The interim analysis, 
performed by the sponsor in an unblinded manner, will preferably be conducted at the end of a 
northern or southern hemisphere RSV season.


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1.2.
Schema
Figure 1:
Schematic Overview of the Study
CHF: congestive heart failure; COPD: Chronic Obstructive Pulmonary Disease; D: day; bid: twice daily; N: number of 
participants; rand: randomization; RSV: respiratory syncytial virus.
a
Patients should be randomized within 72 hours of RSV sign/symptom onset. Randomization should occur 
within 24 hours after start of screening or within 48 hours after collection of the standard-of-care sample or 
pre-screening sample used for local RSV diagnosis, whichever comes first. The randomization will be 
stratified by the following factors: high-risk (<65 years of age with underlying high-risk cardiopulmonary 
conditions [COPD, asthma, or CHF] versus ≥65 years of age without underlying high-risk conditions versus 
≥65 years of age with underlying high-risk conditions) and time since symptom onset (≤48 hours versus >48-
72 hours).
b
First study intervention administration should start as soon as possible, but no later than 4 hours after 
randomization. Participants will receive either rilematovir or matching placebo for 7 days twice daily. For 
participants who receive only 1 dose of study intervention on Day 1 (PM), dosing should continue until the 
morning of Day 8 (AM) so that all participants receive 14 consecutive doses in total.
c
If feasible and allowed by local regulations, home visits by the nursing/ study site personnel are allowed 
instead of on-site visits.
d
If feasible, and allowed per country-specific regulations, digital (eg. videocall) follow-up may be done instead 
of phone follow-up.
e
The screening and D1 predose visit should preferably be done on the same calendar day.










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g.
All participants will complete assessments from Day 1 through Day 35 as per the Schedule of Activities. On Day 28 and Day 35, all participants will be contacted 
by the study site personnel for a telephone (or other digital call, if possible) follow-up visit to assess the clinical status, MRU and to check for any AEs including
RSV-related complications. The phone follow-up visit may be replaced by an on-site visit (or home visit by the nursing/study site personnel, if feasible), at the 
discretion of the investigator, for safety follow-up in case participants had ongoing AEs or other ongoing laboratory, vital signs or ECG-related abnormalities at the 
previous visit or for practical reasons (such as return of ePRO device).
h.
Procedures performed as part of SOC within approximately 48 hours prior to screening completion (ie, randomization) may be used in determining study eligibility. 
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.
i.
Participants will be completing ePRO assessments on an electronic device. Sites will ensure participants are trained in the use of the device before completing ePRO 
assessments (ie, Employment status, RiiQSymptom and Impact ScalesPGI-S, PGI-C, Hours missed from work, return to usual activities, return to usual health, 
and EQ-5D-5L) on the device. The ePRO assessments will be completed by each participant in a language in which the participant is fluent; if no appropriate language 
version is available for the ePRO assessments, the participant should not be enrolled in this study. If a participant requires assistance entering responses in the 
electronic device, his/her spouse, partner, relative, or other caregiver or member of the study team who is trained on the use of the device and in the interview 
procedure can interview the participant and enter the participant’s responses on the electronic device on the participant’s behalf.
Note: If participant is clinically stable and there is no safety concern, it is recommended that daily ePRO entries for RiiQ symptom scale as well as scheduled on-site 
visits are performed before use of any concomitant medication(s) for symptom relief (e.g. bronchodilators, cough medication). 
j.
The Pre-Existing Symptom Questionnaire will be completed at screening after the participant completes the RiiQSymptom Scale.
k.
Assessment of inclusion criterion n°3 (RSV symptoms severity) must be performed before randomization through the evaluation of the participant’s answers to 
RiiQSymptom Scale and Pre-Existing Symptom Questionnaire.
l.
Investigator will evaluate severity of clinical signs/symptoms of RSV using the Clinician Symptom Score (CSS) questionnaire based on clinical evaluation of the 
participant at the specified on-site visits as per the Schedule of Activities. If an on-site visit is not feasible for the participant, option for home visit & evaluation by 
nursing staff under remote supervision of the physician will be allowed. At Day 28 and Day 35, phone follow-up for symptom assessment will be done.
m.
Investigator will rate severity of clinical signs/symptoms of RSV in the CSS questionnaire based on participant interview by phone (or other digital call, if possible).
n.
For all female participants of childbearing potential, a urine pregnancy test is to be performed on-site at screening and at Day 21.
o.
Follicle stimulating hormone (FSH) will be tested at screening for female participants who are amenorrheic for 12 months or less.
p.
Study site personnel will diagnose RSV locally for eligibility, using a study-specific bilateral nasal MT swab and a polymerase chain reaction (PCR)-based or other 
molecular-based diagnostic assay. They should ship the leftover specimen for any patient that is subsequently randomized. Collection of a study-specific bilateral 
nasal MT swab at screening is not required if a standard-of-care (SOC) diagnostic sample is collected within 24 hours of screening start and yields a positive RSV 
result using a molecular-based diagnostic assay.
q.
A nasal MT swab should be collected from each nostril and both swabs should be put in the same universal transport medium tube (ie, a bilateral nasal MT swab 
sample). Only at times when sampling of both nostrils is not feasible, such as in case of bleeding in one nostril, one nasal MT swab should be collected from one 
nostril (ie, the non-bleeding nostril).
r.
Randomization should occur within 24 hours after start of screening or within 48 hours after collection of the sample used for local RSV diagnosis, whichever comes 
first AND within a window of 72 hours of RSV sign/symptom onset.
s.
First study intervention administration should occur as soon as possible, but no later than 4 hours after randomization. The day of first study intervention 
administration is defined Day 1. Dosing should occur approximately every 12 hours, but the second dose may be delayed or brought forward (by maximum 4 hours) 
if the nominal timing for this dose falls in the middle of the night. Thereafter, dosing follows a regular AM/PM schedule. The study intervention can be administered 
with/without food.


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t.
Depending on the time of randomization/enrollment, participants will receive 1 dose (PM) or 2 doses (AM and PM) of study intervention on Day 1. For participants 
who receive only 1 dose of study intervention on Day 1 (PM), dosing should continue until the morning of Day 8 (AM) so that all participants receive 14 consecutive 
doses in total.
u.
On Day 1, study site personnel will hand-out to the participant all the required study intervention for dosing at home. Study site personnel will instruct participants 
on how to use and store study intervention for at home dosing.
v.
Clinical evaluation includes vital sign assessments (ie, body temperature, respiratory rate, pulse/heart rate, and peripheral capillary oxygen saturation [SpO2]) and 
targeted physical examination assessments (ie, presence of wheezing or crackels/ronchi). It is recommended that the vital signs are assessed after the participant has 
rested for at least 15 minutes. Clinical evaluation also includes evaluation of the occurrence of adverse events (AEs), RSV-related complications, and need for 
medications (including antibiotics).
w.
Only performed if the screening assessment occurred >8 hours before anticipated first dosing.
x.
In case the first dose treatment is early in the morning, a second assessment should be performed in the evening.
y.
If the participant is not employed and neither is anyone who may help them, the Hours missed from Work Questions will not be asked at any point.
z.
Only applicable if clinically indicated to evaluate a participant’s ongoing AE(s) or any clinically significant laboratory, vital sign or ECG abnormality identified on 
Day 21. (see also footnotee).
aa.
Study site personnel should collect the predose nasal MT swab as close as possible and prior to first study intervention administration. Leftover study-specific (pre) 
screening nasal MT swab specimen can serve as baseline IF this screening sample: was collected within 8 hours prior to first dose, is appropriately stored AND is 
available in sufficient volume (volume is considered sufficient if no more than 600 μL from the original sample has been used for local RSV testing and the entire 
remainder of the original sample is available). However, when local RSV diagnosis was performed using a SOC sample, then this Day 1 predose sample is required 
to be collected in any case.
bb.
Leftover nasal samples may be used for biomarker research at the discretion of the sponsor.
cc.
Bilateral nasal MT swabs will be taken preferably at approximately the same time as the predose sample taken on Day 1. During scheduled visits on Day 3, Day 8, 
Day 14 and Day 21, bilateral nasal MT swabs will be collected by a health care practitioner. On Day 2 and Day 5, bilateral nasal MT swabs are collected at home 
preferably by a health care professional and, only if not possible by a health care professional, by the participant (or his/her spouse, partner, relative, or other 
caregiver) after being properly trained by the investigator/study-site personnel. In case preferred by the participant, all bilateral nasal MT swabbing may also be 
performed at the site. Date and time of swabs collected at home need to be recorded. All participants will be given appropriate nasal MT swabs and universal transport 
medium (same supplies as those used to collect nasal samples at the sites) to collect nasal MT swabs. All swabs collected at home should be stored immediately 
between 2°C and 8°C (in the refrigerator) and brought to the site at the latest at the Day 3 and the Day 8 visit.
dd.
Return of ePRO device only applies if the device was provided to the participant by the site. Site staff will ensure return of the ePRO device is arranged for participants 
who have a phone visit at Day 35, and for any participants who discontinue/withdraw from the study.
ee.
ePRO completion compliance should be assessed daily by the study site personnel via the ePRO vendor portal. If scheduled assessments are missing from the prior 
day, the sites will contact the participant as soon as possible to identify reason for missing PRO and document reasons for missing PRO assessments in the eCRF 
based on discussion with the participant.
ff.
.
gg.
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.
hh.
A complete physical examination (including height and body weight measurements) will be performed at screening. A targeted physical examination will be 
performed at the other site visits and includes evaluation of body weight (Day 21 only), the respiratory system, nose, ear, throat, and facial and neck lymph nodes.
ii.
12-lead ECGs will be obtained at screening, Day 1, Day 3, Day 8, and Day 14. An ECG may be repeated at the discretion of the investigator to rule out erroneous 
readings or to confirm abnormal ECG findings. Presence of an abnormal QTcF interval should be confirmed by repeat ECG recording. ECGs will be obtained in a 
supine position after at least 5 minutes rest. Additional monitoring of ECG can be done (unscheduled visit), if needed in the opinion of the investigator based on the 


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overall clinical picture. If ECG was performed as part of SOC within approximately 48 hours prior to screening completion (ie, randomization) and the participant 
is clinically stable, this may be used in determining study eligibility.
jj.
ECG to be performed approximately 1 hour after administration of first study intervention.
kk.
Biochemistry blood samples at Day 8 and Day 21 will be taken, if possible, under fasted conditions (fasted for at least 10 hours).
ll.
Safety laboratory tests will be done for each participant. Samples for clinical laboratory assessments will be collected and analyzed at the central laboratory. Any 
values that indicate a potential safety concern will be assessed by the investigator and appropriate follow-up actions, including potential discontinuation from 
treatment, will be carried out.
mm. Levels of potassium and magnesium to be determined by the local and by the central laboratory. In case of confirmed hypokalemia and/or hypomagnesemia at 
screening, or at any of the visits in the study period, the levels of potassium and magnesium should be corrected also 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. Documentation of correction of electrolyte levels and the corrective measures as indicated in Section 8.3.7.2 must be 
maintained. For confirmed hypokalemia of <2.5 mEq/ L and/or hypomagnesemia of < 0.9 mEq/ L, please see Section 7.1 for study intervention discontinuation 
guidance.
nn.
Urinalysis will be performed by the central laboratory and includes dipstick analysis, and if needed microscopic examination.
oo.
Blood samples (sparse sampling) for determination of plasma concentrations of rilematovir will be collected preferable 1 hour post the first dose, or just before the 
second dose administration on Day 1, predose and approximately 1 hour post dose (first or second dose) on Day 3, and at a random time point on Day 8 for all 
participants. The following information needs to be recorded on the requisition form: date and time of study intervention administration, date and time of PK blood 
sampling, time of meal if any in the time window of 2 hours before and 2 hours after study intervention administration on the day of PK sampling. Samples can be 
used for the determination of plasma concentrations of metabolites of rilematovir, excipients, protein binding, or endogenous markers for enzymes or transporters 
involved in the metabolism and distribution of rilematovir, at the discretion of the sponsor.
pp.
A blood sample will be collected at screening, Day 3, Day 8, and Day 21 for biomarker research, including but not limited to host RNA analysis. At screening, at 
Day 3, and at Day 21 an additional blood sample will be collected for protein analysis (eg, cytokines).
qq.
All AEs and serious AEs will be collected from signing of the main ICF onwards until the last follow-up visit (end of study visit). Any clinically significant 
abnormalities persisting at the end of the study/early withdrawal will be followed by the investigator until resolution or until a clinically stable condition is reached.
rr.
Medications taken will be discussed with the investigator and recorded on the concomitant medication page of the eCRF.
Notes:
1.
Additional unscheduled visits in case of laboratory abnormalities, ECG abnormalities, need for clinical follow-up of (an) AE(s) can be scheduled at the discretion of 
the investigator.
2.
See Appendix 10.20 for guidance on study conduct during the Coronavirus Disease 2019 (COVID-19) pandemic.
3.
In case of supply issues for nasal MT swabs because of increased demand due to the COVID-19 pandemic, alternative nasal swabs instead of nasal MT swabs
may be provided for nasal sample collection for the study assessments.


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2.
INTRODUCTION
Rilematovir (JNJ-53718678) is an investigational, potent small molecule respiratory syncytial 
virus (RSV) specific fusion inhibitor belonging to the indole chemical class. Rilematovir targets 
the RSV fusion protein and prevents the conformational changes of the F-protein required for 
fusion of the viral envelope with the host cell membrane and for cell-to-cell fusion, thereby 
inhibiting viral replication and syncytia formation. Rilematovir is currently in late phase
development as treatment for RSV infection.
For the most comprehensive nonclinical and clinical information regarding rilematovir, refer to 
the latest version of the Investigator's Brochure (IB) for rilematovir (IB 2020).
The term “study intervention” throughout the protocol, refers to the administration of study 
intervention as defined in Section 6.1.
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.
The term "participant" throughout the protocol refers to the common term "subject".
2.1.
Study Rationale
Respiratory syncytial virus is a negative-stranded ribonucleic acid (RNA) virus belonging to the 
Pneumoviridae family, and is considered the most important cause of lower respiratory tract 
disease (LRTD) in infants, young children, and a common cause of acute respiratory disease in 
adults with the risk of severe infection increasing with age, as well as associated high-risk 
comorbidities (Hall CB 2001, Nair 2010). Two subtypes of RSV have been identified, ie, subtypes 
A and B, that generally co-circulate simultaneously (Falsey & Walsh 2000). The RSV season 
occurs during winter months in regions with temperate climates in the Northern and Southern 
Hemispheres and throughout the year or with peaks semi-annually in tropical regions (AAP 2006,
Bloom-Feshback 2013, Yusuf 2007).
The impact of RSV infections in adults is being increasingly recognized with the wider use of 
molecular testing of adult patients presenting with respiratory tract infections (Nam and 
Ison 2019). It has been estimated that RSV infects 3% to 10% of adults annually (Wantuch 2014). 
In the United States (US), an annual estimated 61,000-177,000 hospitalizations and 10,000-14,000 
deaths are attributable to RSV in adults ≥65 years of age (Falsey 2005). Some of the factors that 
increase susceptibility to RSV in the elderly include declining immune system function such as 
lower RSV-specific serum immunoglobulin (Ig) and nasal IgA titers (Falsey and Walsh 1998, 
Walsh 2004). In a longitudinal assessment over 12 RSV seasons in a single community (n=13,809), 
RSV was detected in 11% of outpatient adults ≥60 years of age with medically attended acute 
respiratory illness. The relative risk of a serious outcome (ie, hospitalization, emergency room 
visit, and pneumonia) was significantly increased in RSV-infected persons aged ≥75 years of age
(versus 60-64 years of age) and in those with chronic obstructive pulmonary disease (COPD) or 
congestive heart failure (CHF) (Belongia 2018). The severity of adult RSV disease is likely 


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multifactorial involving age, immune factors, and comorbid conditions (Walsh 2004, Falsey 2019, 
Malloy 2013). While RSV typically presents in adults as self-limited upper respiratory tract disease
(URTD) or LRTD, it is a significant cause of severe respiratory infection in elderly adults aged 
≥65 years of age (Duncan 2009, Falsey 2005, Jain 2015) and in adults (regardless of age) with 
underlying cardiopulmonary comorbidities such as asthma, COPD, and CHF (Duncan 2009, 
Falsey 2005, Falsey 2019).These patients may present primarily with symptoms of decompensated 
heart failure or acute exacerbation of COPD. Among elderly adults who are at risk for severe RSV 
disease, RSV infection may manifest as severe or life-threatening LRTD with pneumonia, a 
requirement for ventilatory support, and short- and long-term morbidity (Tseng 2020).
Current treatment options for RSV are generally supportive in nature, consisting of supplemental 
oxygen, intravenous fluids, and bronchodilators. No vaccines or antivirals have been approved for 
the prevention or treatment of RSV infection in adults. Aerosolized, oral, and intravenous ribavirin 
have been used selectively in RSV-infected immunocompromised adults with variable results
(Nam and Ison 2019). Due to the significant disease burden and the lack of effective treatment, the 
unmet medical need (prophylactically and therapeutically) is substantial, especially related to 
antiviral treatment in the high-risk adult population as described above.
Rilematovir is being developed for the treatment of adult patients who are at high risk of 
RSV-related disease progression and thus are considered to have a high unmet medical need. Early 
antiviral treatment of RSV infection in an outpatient setting may offer the potential to resolve the 
infection sooner and prevent or halt the progression to severe RSV disease and RSV-related 
complications.
Data from the non-hospitalized adult Phase 2a study 53718678RSV2004 indicate a trend towards 
a favorable effect of rilematovir 80 mg and 500 mg (dosed as once daily for 7 days) compared to 
placebo. In addition, the median time to resolution of Key RSV Symptoms (ie, cough, wheezing, 
coughing up phlegm [sputum], short of breath, fatigue, and feverishness) assessed by participants 
using the respiratory infection (RI) patient reported outcome (PRO) or Respiratory Infection 
Intensity and Impact Questionnaire [RiiQ]) in the subgroup of participants with ≤3 days since 
symptom onset was shorter in rilematovir 80 mg group (7.6 days) and rilematovir 500 mg group 
(8.0 days, 32% reduction compared to placebo) as compared to the placebo group (11.8 days).
In consideration of the unmet medical need in adults who are at high risk of severe RSV disease, 
this Phase 2b study will evaluate efficacy, safety, and tolerability of rilematovir compared to 
placebo in high-risk adults in an outpatient setting, presenting with symptoms consistent with at 
least 2 LRTD symptoms, one of which needs to be at least moderate or worsened in case the 
participant had pre-existing LRTD symptoms and who are randomized within a window of 
72 hours since RSV symptom onset. High risk in this study is defined as elderly adults (≥65 years
of age), or adults (≥18 to ≤65 years of age) with underlying high-risk comorbid cardiopulmonary 
conditions (COPD, asthma, or CHF). The study will be stratified at randomization by the following 
factors: high-risk (<65 years of age with underlying high-risk comorbid cardiopulmonary 
conditions [COPD, asthma, or CHF] versus ≥65 years of age without underlying high-risk 


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conditions versus ≥65 years of age with underlying high-risk comorbid cardiopulmonary 
conditions) and time since symptom onset (≤48 hours versus >48-72 hours).
Data from this Phase 2b outpatient Study 53718678RSV2008 in high-risk adults will provide 
guidance for the design of confirmatory Phase 3 studies.
2.2.
Background
Enveloped viruses like RSV have a complex membrane-fusion machinery that includes a fusion 
protein that enables the deposition of the viral nucleic acid genome into the host cells and initiates 
their replication (Colman and Lawrence 2003, Leung 2005). Rilematovir is an investigational 
RSV-specific fusion inhibitor belonging to the indole chemical class and is currently in 
development for the treatment of RSV infection in both adult and pediatric populations.
Rilematovir has demonstrated in vitro activity against a panel of viruses belonging to both the RSV 
subfamilies A and B. In addition, trends for antiviral activity and clinical benefit of rilematovir
were
demonstrated during clinical studies in healthy adults inoculated with RSV 
(Study 53718678RSV2001), in non-hospitalized adult participants naturally infected with RSV 
(Study 53718678RSV2004), and in naturally RSV-infected hospitalized pediatric participants 
(Study 53718678RSV1005 and Study 53718678RSV2002). For the most comprehensive 
nonclinical and clinical information regarding rilematovir, refer to the latest version of the IB for 
rilematovir (IB 2020).
Nonclinical Studies
Rilematovir has been extensively evaluated and characterized in both in vitro and in vivo 
pharmacological, pharmacokinetic (PK), and toxicological studies. These nonclinical in vitro and 
animal in vivo efficacy data demonstrate that rilematovir 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 rilematovir-treated Balb/C mice and neonatal lambs. No in vitro antiviral 
activity was observed for the rilematovir 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 rilematovir. Detailed results of performed 
nonclinical studies are described in the latest IB for rilematovir (IB 2020).
Clinical Studies
Human Pharmacokinetics and Product Metabolism
In the single-dose escalation part of Study 53718678RSV1001, the mean maximum plasma 
concentration (Cmax) of rilematovir increased proportionally with dose after administration of 
rilematovir doses between 25 mg and 1,000 mg under fasted conditions. Mean AUC from time of 
administration extrapolated to infinity (AUC0-∞) of rilematovir increased slightly more than 
dose-proportionally with increasing rilematovir dose from 25 mg to 1,000 mg. Median time to 
reach Cmax (tmax) was 1 hour, except for the 1,000 mg dose group, in which it was 2.5 hours. 
Similarly, mean apparent terminal elimination half-lives (t1/2term) for the different dose groups were 


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observed. Based upon data from Study 53718678RSV1004 in healthy Japanese adult men and 
Study 53718678RSV1001, Cmax and AUC0-∞for rilematovir were similar between Caucasian and 
Japanese participants.
In the multiple dose escalation part of Study 53718678RSV1001 in adult participants under fed 
conditions, predose plasma concentrations (Ctrough) reached steady state after 1 day of treatment 
with rilematovir. On Day 8, rilematovir exposure expressed as mean Ctrough, minimum plasma 
concentration (Cmin), Cmax and AUC from time of administration up to 24 hours post dosing 
(AUC0-24h) demonstrated a dose-proportional increase with increasing rilematovir dose from 
250 mg every 24 hours (q24h) to 500 mg q24h . Fluctuation was lower for the 250 mg twice daily
regimen compared with the 500 mg once daily regimen. For the 500 mg q24h dose group, mean 
C24h values of rilematovir were similar between Day 1 and Day 8, while Cmax and AUC0-24h were 
1.15- and 1.16-fold higher at Day 8. For the 250 mg every 12 hours (q12h) dose group, mean C12h, 
Cmax and AUC from time of administration up to 12 hours post dosing (AUC0-12h) of rilematovir
were increased 1.53-, 1.42-, and 1.53-fold, respectively, on Day 8 compared with Day 1. The mean 
total amount of rilematovir excreted in urine over the dosing interval at steady state was low; mean 
renal clearance was very low, and similar between dose regimens.
In study 53718678RSV2001 in adult participants, the PK profile of rilematovir at multiple doses 
of 75 mg, 200 mg, and 500 mg once daily for 7 days was evaluated in healthy adult participants 
inoculated with RSV-A Memphis 37b virus. The PK results from this study were consistent with 
those from corresponding regimens in Study 53718678RSV1001, indicating that viral infection 
did not affect the PK of rilematovir.
Results from the mass balance Study 53718678RSV1008 demonstrated that rilematovir was the 
major circulating entity in plasma (44% to 47%), with M12 and M37 being the most abundant 
metabolites at 17-22% and 9.73% of AUC from time of administration up to 96 hours post dosing 
(AUC0-96h) of total radioactivity (TR), respectively; M19, M5, and glucuronide metabolites (M8 
and M9) represented 5%, 4%, and 1% (each), respectively. Most of TR was recovered in feces 
(71%) and urine (20%), with unchanged drug representing 10% to 16% and 1%, respectively.
A population PK (popPK) model for rilematovir has been developed using data from
Study 53718678RSV1001 in healthy adults. 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).
Results from Study 53718678RSV2004 in RSV-infected adult patients demonstrate that the 
popPK model provides an adequate description of the majority of the data, although with higher 
than expected levels for Ctrough, Cmax, and AUC0-24h. The mean standard deviation (SD) Day 7 
AUC0-24h and Ctrough following administration of 500 mg rilematovir in this study (N=16) were 
38,800 (16,600) ng.hr/mL and 698 ng/mL (546), respectively, compared to 26,520 
(7,520) ng.hr/mL and 334 (197) ng/mL, respectively, observed in Study 53718678RSV2001 
(N=17). The mean (SD) Day 1 and Day 7 AUC0-24h and Ctrough following administration of 80 mg 
rilematovir in this study (N=16) were 4,190 (987) and 5,820 (2,360) ng.hr/mL and 67.6 (40.9) and 


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101 (82.2) ng/mL, respectively. The mean (SD) Day 1 and Day 7 AUC0-24h and Ctrough following 
administration of 500 mg rilematovir in this study (N=16) were 27,600 (7,550) and 38,800 
(16,600) ng.hr/mL and 454 (270) and 698 (546) ng/mL, respectively. The Day 7 exposure was 
therefore higher than in Study 53718678RSV2001. The mean (SD) Day 1 and Day 7 Cmax after 
80 mg rilematovir were 399 (58.9) ng/mL (N=23) and 498 (89.9) ng/mL (N=20), respectively, and 
2,500 (426) ng/mL (N=17) and 3,150 (800) ng/mL (N=16), respectively, after 500 mg rilematovir.
Effect of Food
In Study 53718678RSV1001, mean Cmax of rilematovir was approximately 35% lower and median 
tmax increased from 1 hour to 3.5 hours when rilematovir was administered under fed conditions 
compared with fasted conditions. Mean AUC0-of rilematovir was slightly lower (93%) when 
rilematovir was administered under fed conditions compared with fasted conditions. The PK 
results from the study part evaluating a single dose (500 mg) of the oral suspension in Study 
53718678RSV1007, demonstrated that AUC0-∞and Cmax of rilematovir were 5% and 35%, 
respectively, lower when the oral suspension was administered under fed conditions compared to 
fasted conditions. The mean fed/fasted ratio was 95% for AUC0-. Therefore, rilematovir can be 
taken with or without food.
Bioavailability of the Rilematovir Oral Suspension and Oral Film-Coated Tablet.
The interim PK results from Study 53718678RSV1007, demonstrated similar bioavailability of
several oral concept suspension formulations compared to the oral solution formulation.
The PK results for the oral suspension G001 demonstrated similar bioavailability compared to the 
oral solution formulation (G024), with a relative bioavailability of ~109% (Cmax) and ~104% 
(AUC) under fasted conditions and a relative bioavailability of ~65% (Cmax) and ~95% (AUCinf) 
under fed conditions.
The PK results for the oral suspension reconstituted from powder G015 (concept formulation) and 
solvent G010 demonstrated similar bioavailability compared to the oral solution formulation 
(G024), with a relative bioavailability of ~110% (Cmax) and ~99% (AUC) under fasted conditions 
and a relative bioavailability of ~57% (Cmax) and ~100% (AUC) under fed conditions.
The interim PK results from Study 53718678RSV1011 demonstrated similar bioavailability of the 
oral solid concept formulation compared to the oral suspension formulation (provided as powder 
G007 + solvent G005). In part 1 of Study 53718678RSV1011, a new oral solid concept formulation 
of rilematovir was evaluated in a 3-way crossover design for assessment of the bioavailability 
relative to the oral suspension (G007 powder + G005 solvent) and food effect in 24 healthy adult 
participants.


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The PK results for the oral solid concept formulation G033 demonstrated similar bioavailability 
compared to the oral suspension formulation (G007 powder + G005 solvent), with a relative 
bioavailability of ~91% (Cmax) and ~98% (AUC) under fasted conditions and a relative 
bioavailability of ~72% (Cmax) and ~94% (AUC) under fed conditions. The ~30% reduction in 
Cmax under fed conditions for the solid concept formulation is similar to the food effect with the 
oral suspension (33-43% reduction; analyzed in Parts 6 & 7 of Study 53718678RSV1007).
The oral solid concept G033 is the formulation to be administered in this study, further referred to 
as oral film-coated tablet.
Drug-Drug Interactions
Based on in vitro data, rilematovir 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 rilematovir will likely not be 
hepatic uptake-limited or sensitive to interactions with hepatic uptake inhibitors.
The potential effect of rilematovir on the PK of sensitive CYP substrates was evaluated in the 
drug-drug interaction Study 53718678RSV1002. In this study, the drug interaction potential of 
rilematovir 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 rilematovir 500 mg once daily
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 rilematovir and a weak induction of CYP3A4 activity 
after repeated administration of rilematovir. Overall, at steady state of rilematovir, the exposure of
midazolam is hardly affected by rilematovir due to the combined CYP3A4 inhibitory and inductive 
effect described. In Study 53718678RSV1002, rilematovir had no clinically significant effect on 
CYP2C9 and CYP1A2. Single and multiple doses of rilematovir reduced the plasma exposure of 
fexofenadine. The observed decrease in exposure of fexofenadine after coadministration of a single 
dose of rilematovir is due to the inhibition of OATP1A2, an uptake transporter located in the gut; 
further reduction of the fexofenadine exposure after repeated dosing of rilematovir, was likely due 
to induction of P-gp. Please see Section 6.8 for prohibitions related to concomitant use of specific 
inhibitors or inducers of CYP3A4 enzymes.
In Study 53718678RSV1006, rilematovir was coadministered with itraconazole (a strong CYP3A4 
and P-gp inhibitor) and with rifampicin (an inducer of CYP3A4, glucuronyl transferase, and P-gp, 
and an inhibitor of OATP). AUC0-of rilematovir increased approximately 3-fold upon 
coadministration with itraconazole 200 mg once daily. After coadministration of rilematovir with 
a single dose of rifampicin, no significant change in the total exposure of rilematovir was observed, 
suggesting the OATP transporter is not involved in the disposition of rilematovir. However, 
repeated administration of rifampicin 600 mg once daily decreased the exposure of rilematovir, 
primarily due to induction of CYP3A4.


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Efficacy
In a challenge model for RSV infection in healthy adults (Study 53718678RSV2001), exposure to
rilematovir resulted in a reduction of viral load over time in all rilematovir 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 associated with lower clinical symptom scores and mucus production.
The Phase 2 pilot Study 53718678RSV2004 explored the antiviral activity, clinical outcomes, 
safety, tolerability, and PK of rilematovir at two dose levels (80 and 500 mg q.d for 7 days) in non-
hospitalized adult participants (with or without high-risk conditions for RSV-related disease 
progression) naturally infected with RSV.
There were 72 participants randomized and dosed, of whom 66 (91.7%) had PCR-confirmed RSV 
infection at baseline, comprising the intent-to-treat-infected (ITT-i) analysis set. Results of this
study in adult non-hospitalized RSV-infected participants demonstrated an improvement in 
clinical course of RSV disease:

No clear effect of rilematovir 80 mg and 500 mg versus placebo was observed on RSV 
viral load over time in both mean nasal RSV RNA viral load AUC and change from 
baseline analyses. However, from Day 2 through Day 8, the proportion of participants with 
undetectable RSV RNA viral load was higher in the rilematovir 500 mg group compared 
to the rilematovir 80 mg group and the placebo group. At Day 8 (end of treatment phase), 
81.3% of participants in the rilematovir 500 mg group had undetectable RSV RNA by 
quantitative reverse transcription polymerase chain reaction (qRT-PCR), compared to 
42.1% and 47.4% in the rilematovir 80 mg and placebo groups, respectively. The time to 
first confirmed undetectable nasal RSV RNA was favorable for the rilematovir 500 mg 
group; the median Kaplan-Meier (KM) estimate was 5.9 days in the rilematovir 500 mg 
group, 8.0 days in the rilematovir 80 mg group, and 7.5 days in the placebo group. In 
general, a similar trend was observed in the subgroup of participants with ≤3 days since
symptom onset.

The overall median KM estimate for time to resolution of key RSV Symptoms (ie, cough, 
wheezing, coughing up phlegm (sputum), short of breath, fatigue, and feverishness 
assessed by participants using RiiQ was 7.6 days in the rilematovir 80 mg group, 7.1 days 
in the rilematovir 500 mg group, and 9.6 days in the placebo group. The median KM 
estimate in the subgroup of participants with ≤3 days since symptom onset was 7.6 days in 
the rilematovir 80 mg group, 8.0 days in the rilematovir 500 mg group, and 11.8 days in 
the placebo group. The median KM estimate in the subgroup of participants with 
>3 to 5 days since symptom onset was 8.5 days in the rilematovir 80 mg group, 5.1 days 
in the rilematovir 500 mg group, and 5.0 days in the placebo group.
Overall, data from this study indicate a trend towards a favorable effect of rilematovir 80 mg and 
500 mg (dosed once daily for 7 days) compared to placebo, especially in the subgroup of 
participants ≤3 days since symptom onset. In addition, the median time to resolution of Key RSV 


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Symptoms in the subgroup of participants with ≤3 days since symptom onset was shorter after 
rilematovir 80 mg and 500 mg treatment compared to placebo.
Trends in benefits for clinical course outcomes and antiviral effects were observed in interim 
analyses of a study in RSV-infected pediatric participants. For more details, refer to the latest 
version of the IB for rilematovir (IB 2020).
Safety and Tolerability
Based on the available clinical data, no adverse events (AEs) or clinically significant laboratory 
abnormalities, abnormalities in vital signs parameters, electrocardiogram (ECG) abnormalities, or 
physical examination findings indicative of a safety concern have been identified.
Study 53718678RSV1009
In Study 53718678RSV1009, the effect of rilematovir on the cardiac repolarization interval in 
healthy adult participants was evaluated with dosing up to 4,500 mg. Part 1 of the study was the 
dose escalation part; based on the PK and safety results of Part 1, the supratherapeutic dose of 
4,500 mg was selected for Part 2 of the study, the thorough QT (TQT) part. Exposure-response 
analysis was performed to determine the relationship between the concentrations of rilematovir 
and QT/QTc interval changes extracted from Holter monitor ECG data. Based on this analysis, an 
important potential risk of QT interval prolongation was identified for rilematovir. The 
model-predicted mean placebo-corrected change from baseline for the individual-corrected QTc 
(ΔΔQTcI) (90% confidence interval [CI]) at the observed geometric mean of the Cmax of the effect 
compartment concentration following a single dose of 500 mg (2,165 ng/mL) and 4,500 mg 
(10,153 ng/mL) rilematovir was 4.8 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. Based on exposure-response analysis, an important potential risk of QT
interval prolongation was identified for rilematovir. For more details on the analysis, refer to the 
latest version of the IB for rilematovir (IB 2020). A change to a twice daily dosing regimen and 
several other mitigation measures to safeguard the participants have been implemented.
Study 53718678RSV1009 demonstrated that a single dose of rilematovir 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 rilematovir, 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 rilematovir, 50.0%, 83.3%, and 83.3%, respectively, 
experienced at least 1 AE as compared to 55.6% of participants who received placebo. Diarrhea, 
nausea, and headache were more frequently observed in participants who received rilematovir
compared to participants who received placebo.


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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 rilematovir
(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 rilematovir 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 rilematovir, 
22 (88.0%) participants after receiving 4,500 mg rilematovir, 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 rilematovir compared to participants who received 500 mg of rilematovir, placebo, or 
400 mg of moxifloxacin.
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).
Study 53718678RSV2001
Study 53718678RSV2001 evaluated the antiviral activity, safety, and PK of rilematovir against 
RSV infection in the RSV challenge model in healthy adult participants. Overall, the oral solution 
formulation was generally safe and well tolerated. No SAEs or deaths were reported during the 
study. No treatment-emergent adverse events (TEAEs) with severity Grade 3 or higher were 
observed during the treatment phase. During follow-up, 1 participant in the placebo group was 
reported with a Grade 3 increased lipase, which was reported as an AE. Three participants 
permanently discontinued the study due to a TEAE: 2 participants were reported with an ECG 
change (one Grade 2 AE [abnormally high QRS duration, QRS =126 ms] in the 75 mg rilematovir
group and one Grade 1 AE [no specific change] in the 200 mg rilematovir group) and 1 participant 
(placebo group) was reported with a Grade 2 AE urticaria.
Eight (53.3%) participants in the 75 mg rilematovir group, 13 (76.5%) participants in the 200 mg 
rilematovir group, 13 (72.2%) participants in the 500 mg rilematovir group, and 9 (56.3%) 
participants in the placebo group were reported with at least one TEAE during the treatment phase, 
which were all either Grade 1 or Grade 2 in severity. The most frequently reported TEAEs 
(>2 participants in any treatment group) during the treatment phase were diarrhea, increased blood 


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cholesterol, increased low density lipoprotein, and epistaxis. For diarrhea there was a trend for 
dose relationship. However, it was also observed in the placebo-treated group and was considered 
related to the amount of 2-hydroxypropyl-beta-cyclodextrin (HP-β-CD) (both rilematovir and 
placebo solutions contain 30% HP-β-CD as an excipient) administered, which is a known 
emollient and has been correlated with increased incidences of diarrhea as main AE.
ECG abnormalities were infrequently reported, and results were generally consistent with those 
observed in the pooled Phase 1 studies. Graded and non-graded laboratory abnormalities were 
generally consistent with those observed in the pooled Phase 1 dataset.
Altogether, rilematovir was generally safe and well tolerated. No relation was noted between the 
incidence of AEs and the dose level and/or the dose regimen of rilematovir. No safety signal was 
identified.
Study 53718678RSV2004
Results from Study 537186578RSV2004 demonstrated that rilematovir was generally safe and 
well tolerated in RSV-infected non-hospitalized adults. No new safety signal was identified.
There were no deaths, no treatment-emergent (S)AEs, and no AEs of severity Grade 3 or 4 in the 
study, except for 1 (4.2%) participant in the placebo group, who was reported with an AE of 
severity Grade 3 (bacterial infection). Overall, 37.5%, 75.0%, and 62.5% of participants in the 
rilematovir 500 mg group, in the rilematovir 80 mg group, and in the placebo group, respectively, 
experienced at least 1 TEAE, of which diarrhea was the most frequently reported TEAE. This AE 
occurred at similar incidences in all treatment groups and at similar incidences as observed in 
earlier studies with the same oral solution. This is likely due to the hydroxypropyl-β-cyclodextrin 
content (30%) in the oral solution used in this trial for both active and placebo. The oral suspension 
formulation used in ongoing and future trials does not contain this excipient. Six participants 
discontinued study intervention prematurely due to the following AEs: diarrhea (1 participant in 
the placebo group and 3 participants in the rilematovir 500 mg group, of whom 2 also discontinued 
study participation), abdominal discomfort (1 participant in the rilematovir 80 mg group), and 
urticaria (1 participant in the rilematovir 80 mg group).
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.
2.3.
Benefit-Risk Assessment
More detailed information about the known and expected benefits and risks of rilematovir can be 
found in the current IB (IB 2020).


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2.3.1.
Risks for Study Participation
2.3.1.1.
Known risks
No formal adverse drug reaction analysis has yet been conducted for rilematovir. No adverse drug 
reactions or known risks associated with rilematovir have been identified.
2.3.1.2.
Potential risks
All therapies have the potential to cause adverse drug reactions.
According to the latest IB update, a total of 345 adult participants and 192 pediatric participants 
received at least 1 dose of rilematovir. Of the 345 adult participants, 251 received at least one dose 
of rilematovir 500 mg. In total, 92 pediatric participants received multiple 500 mg adult dose 
equivalents (IB 2020).
Please refer to Section 2.2 for details on the reported AEs and laboratory/ECG abnormalities in 
the studies conducted to date.
Based upon the available clinical data, no risk related to the hepatobiliary system was identified. 
However, given the hepatobiliary-related nonclinical findings and because the amount of clinical 
data are limited, the sponsor considers hepatobiliary effects to be a safety topic of special interest 
and hepatobiliary function will be monitored by routine hepatic function tests during clinical 
studies.
In the TQT Study 53718678RSV1009 (healthy adults), the important potential risk of QT interval 
prolongation with rilematovir administration was identified after administration of the 4,500 mg 
supratherapeutic dose. Based on exposure-response analysis, with a single dose of 1,000 mg 
rilematovir the QTc interval prolongation is predicted to remain below the 10 msec threshold of 
regulatory concern;(see Section 2.2 and the IB [IB 2020]) for more information). The dose regimen 
(see Section 4.3) for this study was selected in consideration of this potential risk. Several other 
measures to safeguard the participants (see Section 2.3.3) have also been implemented
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.
Available clinical safety data do not indicate any safety signal or concern with regard to the 
cardiovascular system (Section 2.2).
Study procedures such as blood sampling carry a potential risk (eg, pain, discomfort, hematoma) 
to the participant.
The evaluation of rilematovir antiviral activity and sequencing requires bilateral nasal 
mid-turbinate swabbing. However, this is a minimally invasive assessment that at most results in 


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some short-term discomfort for the participant and is usually well tolerated, though occasionally 
nasal bleeding can occur. Examples of other AEs that may occur, but are not considered severe, 
are coughing, gagging, nausea, and vomiting.
2.3.2.
Benefits for Study Participation
2.3.2.1.
Known benefits
Proof-of-concept antiviral effect was established in adult healthy volunteers challenged with a 
laboratory strain of RSV (Study 53718678RSV2001) (Section 2.2).
In the ongoing pediatric Study 53718678RSV2002, the interim analysis (data cut-off 
02 January 2020) data demonstrated a trend towards an antiviral effect of rilematovir in
hospitalized children ≥28 days of age and ≤3 years of age with RSV disease compared to placebo, 
with more pronounced effects in the subgroup with symptom onset ≤3 days compared to the 
subgroup with symptom onset >3-5 days to randomization.
In the adult Study 53718678RSV2004, the interim analysis (data cut-off 23 September 2019) data 
demonstrated positive trends for time to first confirmed RSV undetectability for rilematovir 
compared to placebo. Effects appeared greater in the subgroup of participants with symptom onset
≤3 days compared to the subgroup with symptom onset >3-5 days to randomization.
However, the clinical benefit of this compound remains to be established.
2.3.2.2.
Potential benefits
An increasing age (elderly; ≥65 years of age or more) and/or the presence of underlying high-risk 
cardiopulmonary comorbidity (COPD, asthma, or CHF) have been clearly defined as high-risk 
factors for severe illness and hospitalizations in RSV-infected adults. The high-risk adults 
participating in this study may have a benefit regarding the clinical course of their RSV infection. 
Treatment with rilematovir could reduce the severity and duration of RSV signs and their impact 
on functioning, reduce the effect of RSV infection on physiologic parameters, reduce the risk of 
progression to more severe disease and complications, reduce the need for and duration of 
supportive care (eg, oxygen supplementation), and accelerate the participants’ return to pre-RSV 
health status.
Study intervention will be provided in addition to, not in replacement of, standard-of-care (SOC) 
supportive and symptomatic therapy.
In Study 53718678RSV2004, data demonstrated a positive trend for time to symptom resolution 
of key RSV Symptoms for rilematovir compared to placebo. Effects appeared greater in the 
subgroup of participants with symptom onset ≤3 days compared to the subgroup with symptom 
onset >3-5 days to randomization.
In the ongoing pediatric Study 53718678RSV2002, the interim analysis (data cut-off 
02 January 2020) data demonstrated a trend towards an improvement in the clinical course of RSV 
disease in children ≥28 days and ≤3 years of age with RSV disease of rilematovir compared to 


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placebo, with more pronounced effects in the subgroup with symptom onset ≤3 days compared to 
the subgroup with symptom onset >3-5 days to randomization.
2.3.3.
Benefit-Risk Assessment for Study Participation
Currently the only available treatment for RSV in immunocompetent adults is supportive and 
symptomatic care (se 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:

Antiviral effect proof-of-concept was established in adult healthy volunteers challenged with 
a laboratory strain of RSV (study 53718678RSV2001) and in RSV-infected pediatric 
participants (study 53718678RSV1005). Additionally, data from an interim analysis of 
Study 53718678RSV2002 in RSV-infected pediatric participants showed benefits for clinical 
course outcomes and antiviral effects (Section 2.2).

Data from the 53718678RSV2004 analysis in adult outpatients showed a trend for an antiviral 
effect as well a trend to improvement in the RSV clinical course outcomes (Section 2.2).

No safety concerns were identified in Study 53718678RSV2004 in non-hospitalized adult 
participants infected with RSV (Section 2.2).

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 rilematovir 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.

Utilization of study intervention discontinuation and withdrawal criteria specific to QTcF 
interval changes (see Section 7.1 and 7.2).

Safety surveillance in this study will monitor standard safety parameters associated with 
investigational drug development (see Section 8.2) and safety topics of interest for
rilematovir (see Section 8.3.6) as part of the study assessments.

Utilization of results from diagnostic testing (swab) performed as part of SOC.

The establishment of an Independent Data Monitoring Committee (IDMC) (see 
Section 9.6) to monitor data on a regular basis to ensure continuing safety of the 
participants enrolled in this study (see Sections 8.2 and 8.3).

In view of the identified important potential risk of QT interval prolongation (see Section 2.2, 
TQT Study 53718678RSV1009), the following measures have been implemented to minimize 
the potential risk to participants:


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
The selection of the 250 mg twice daily dose regimen which, relative to the respective 
once daily dose regimens for which no safety concern was identified, will minimize Cmax
while still maintaining AUC and increasing Ctrough (see Section 4.3). For participants 
co-administered with moderate or strong CYP3A4 inhibitors (with the exception of 
posaconazole and ketoconazole), the dose will be reduced to 125 mg twice daily (see 
Sections 4.3, 6.1, 6.5 and 6.8).

Specific cardiovascular and ECG-based criteria for eligibility assessment (see Section 5.1
and 5.2).

Close monitoring of the use of concomitant medications will be conducted regularly (see 
Section 6.8).

Regular ECG monitoring will be performed at screening and several timepoints during 
the study, including an ECG around tmax on Day 1 and Day 3 (steady state). 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 Schedule of Activities and Section 8.3.7.2).

Close monitoring of potassium and magnesium will be done. Levels of potassium and 
magnesium will be determined by the local as well as the central laboratory. In case of 
confirmed hypokalemia and/or hypomagnesemia at screening, or at any of the visits in 
the study period, the levels of potassium and magnesium should be corrected also taking 
into account any underlying condition and as soon as possible to prevent cardiac 
disturbances (see Section 8.3.7.2). Appropriate clinical management per local SOC 
(including but not limited to checking the corrected values at the local laboratory) may 
be required. Documentation of correction of electrolyte levels and the corrective 
measures as indicated in Section 8.3.7.2 must be maintained. For confirmed hypokalemia 
of <2.5 mEq/ L and/or hypomagnesemia of < 0.9 mEq/ L, participant study intervention 
will be discontinued (Section 7.1)

Specific toxicity management for confirmed QTcF interval value ≥500 ms (see Section
8.3.7.2).

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 of this study, the potential 
risks identified in association with rilematovir are justified by the anticipated benefits that may be 
afforded to adult participants with RSV who are at high risk for RSV-related disease progression.
3.
OBJECTIVES AND ENDPOINTS
Objectives
Endpoints
Primary

To evaluate efficacy of rilematovir compared to 
placebo with respect to the time to resolution of 
respiratory syncytial virus (RSV) lower 
respiratory tract disease (LRTD) symptoms.

Time to resolution of RSV LRTD symptoms 
(ie, cough, short of breath, wheezing, coughing 
up phlegm [sputum]) as assessed by the 
participant using the Respiratory Infection 


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Objectives
Endpoints
Intensity and Impact Questionnaire (RiiQ™ 
Symptom Scale).
Definition of resolution in participants without 
pre-existing respiratory symptoms:
-
All LRTD symptoms in the RiiQ Symptom 
Scalea scored as ‘None’ (score = 0) or 
‘Mild’ (score =1) for at least 24 hours.
Definition of resolution in participants with 
pre-existing respiratory symptoms:
-
Pre-existing symptoms that were worse at 
baseline should have improved at least 
1 point on the RiiQ Symptom Scale from 
baseline for at least 24 hours; and
-
Pre-existing symptoms that were not 
worse at baseline should have not 
worsened from baseline severity for at 
least 24 hours; and
-
Symptoms that were not pre-existing at 
baseline should be scored as ‘None’ 
(score = 0) or ‘Mild’ (score =1) on the
RiiQ Symptom Scale for at least 24 hours.
Secondary

To evaluate the effect of rilematovir compared 
to placebo with respect to the incidence of 
post-baseline RSV-related complications.

Proportion of participants with post-baseline 
complications (ie, RSV-related pulmonary and 
extrapulmonary complications).
-
Pulmonary complications: primary viral 
pneumonia, bronchitis, respiratory failure, 
secondary 
bacterial 
pneumonia, 
and 
exacerbations 
of 
underlying 
chronic 
pulmonary diseases (such as chronic 
obstructive pulmonary disease [COPD]
and asthma).
-
Extrapulmonary 
complications: 
cardiovascular 
and 
cerebrovascular 
disease events, CHF or exacerbation of 
underlying CHF, acute exacerbation of 
chronic 
kidney 
disease, 
severe 
dehydration, 
decompensation 
of 
                                                
a The RiiQ Symptom scale is a four item scale (0: no symptoms, 1: mild symptoms, 2: moderate symptoms, 3: severe 
symptoms).


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Objectives
Endpoints
previously controlled diabetes mellitus, 
and other airway infections (eg, sinusitis).

To evaluate the effect of rilematovir as 
compared to placebo on medical resource 
utilization (MRU) with respect to respiratory
therapeutic interventions associated with RSV-
related disease progression.

Proportion of participants with new antibiotic 
use, 
or 
new 
or 
increased
use
in 
bronchodilator/nebulizer,
systemic 
corticosteroids, 
or 
home 
oxygen 
supplementation. 

To evaluate the effect of rilematovir as 
compared to placebo on MRU with respect to 
medically attended visits associated with
RSV-related disease progression.

Proportion of participants with unscheduled 
outpatient clinic visits, emergency room visits 
or hospitalization for respiratory infection.

To evaluate the effect of rilematovir as
compared to placebo on the overall RSV-
related disease progression.

Proportion of participants meeting a composite 
endpoint of either developing RSV-related 
complications (pulmonary & extra pulmonary)
and/or 
needing
RSV-related 
medical 
attendance.

To evaluate the safety and tolerability of 
rilematovir.

Safety and tolerability, as assessed by AEs, 
clinical laboratory testing, electrocardiograms 
(ECGs), physical examination, and vital signs.

To evaluate the effect of rilematovir compared 
to placebo on the clinical course of RSV 
infection.

Change from baseline over time in severity of 
the RSV LRTD symptoms as assessed by the 
participant using the RiiQ™ Symptom Scale.

Time to resolution of LRTD symptoms and 
2 systemic symptoms (feeling feverish and 
fatigue) as assessed by the participant using the 
RiiQ™ Symptom Scale.

Time to resolution of the overall RSV 
symptoms (URTD [sore throat and nasal 
congestion], LRTD, and 2 systemic symptoms
[feeling feverish and fatigue]) as assessed by 
the participant using the RiiQ™ Symptom 
Scale.

Time to resolution of all RSV symptoms as 
assessed by the participant using the RiiQ™ 
Symptom Scale.

Time to resolution of each separate RSV LRTD 
symptom as assessed by the participant using 
the RiiQ™Symptom Scale.

Time to resolution of respiratory infection 
symptoms as assessed by the participant using 


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Objectives
Endpoints
the Patient Global Impression of RSV Severity 
(PGI‑S) Scale.
Definition of resolution in participants without 
pre-existing respiratory symptoms:
−
All LRTD symptoms in the RiiQ Symptom 
Scalea scored as ‘None’ (score = 0) or 
‘Mild’ (score =1) for at least 24 hours.
Definition of resolution in participants with 
pre-existing respiratory symptoms:
−
Pre-existing symptoms that were worse at 
baseline should have improved at least 
1 point on the RiiQ Symptom Scale from 
baseline for at least 24 hours; and
−
Pre-existing symptoms that were not 
worse at baseline should have not 
worsened from baseline severity for at 
least 24 hours, and,
−
Symptoms that were not pre-existing at 
baseline should be scored as ‘None’ 
(score = 0) or ‘Mild’ (score =1) on the
RiiQ Symptom Scale for at least 24 hours.

Time to return to pre-existing health (status) for 
all RSV symptoms as assessed by the 
participant using the RiiQ™Symptom Scale.

Time to improvement in RSV disease as 
assessed by the participant using the Patient 
Global Impression of Change (PGI‑C) Scale.

To evaluate the effect of rilematovir compared 
to placebo on Health-Related Quality of Life 
(HRQOL).

Change from baseline over time for the 
HRQOL as assessed by participants using the 
EQ-5D-5L and RiiQ™Impact Scales.

Time to return to usual health as assessed by the 
participant using the ‘Adult RSV Return to 
Usual Health’ question.

Time to return to usual activities as assessed by 
the participant using the ‘Adult RSV Return to 
Usual Activities’ question.

Time to no or mild impact of RSV-related 
disease on daily activities, emotions, and social 
                                                
a The RiiQ Symptom scale is a four item scale (0: no symptoms, 1: mild symptoms, 2: moderate symptoms, 3: severe 
symptoms).


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Objectives
Endpoints
relationships as assessed by the participant 
using the RiiQ™ Impact Scales.

To evaluate the antiviral effect of rilematovir as 
measured by RSV viral load in bilateral nasal 
mid-turbinate swab samples by quantitative 
reverse transcription polymerase chain 
reaction (qRT-PCR) assay.

RSV viral load area under the curve from 
immediately prior to first dose of study 
intervention (baseline) through Day 3, Day 5, 
Day 8.

Change from baseline over time in RSV viral 
load.

Proportion of participants with undetectable
RSV viral load at each time point that a swab is 
planned to be collected.

To evaluate the emergence of mutations in the 
viral genome potentially associated with 
resistance to rilematovir.

Post-baseline sequence changes in the RSV 
F gene.

To evaluate the pharmacokinetics (PK) of 
rilematovir. 

Pharmacokinetic parameters of rilematovir (ie, 
Ctrough, Cmax, and AUC0-12h).

To evaluate the impact of rilematovir compared 
to placebo on MRU.

Number and type of medical encounters.

Shift in any care setting (e.g. from no assistance 
to use of skilled home nurse or assisted home 
living).

Proportion 
of 
participants 
requiring 
hospitalization for respiratory or other reasons 
and duration of hospitalization (total days 
length of stay, including incidence and where 
feasible duration by wards, eg, intensive care 
unit [ICU]).

Incidence and duration of treatment-emergent 
use of antibiotics.

Incidence and duration of treatment-emergent 
new use or increased dose of systemic or 
inhaled corticosteroids and bronchodilators.

Proportion of participants with new or 
increased use of oxygen therapy.

Duration of oxygen supplementation.

Duration of selected post-baseline emergent 
(after start of study intervention) MRU.
Exploratory

To explore the relationship between antiviral 
activity and the primary and key secondary 
clinical outcomes.

Respiratory syncytial virus viral load-based 
endpoints and primary and key secondary 
clinical course endpoints.


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Objectives
Endpoints

To explore the impact of rilematovir compared 
to placebo on RSV disease-related progression 
and complications.

The proportion of participants progressing to 
ICU including the need for
mechanical 
ventilation (yes or no).

All-cause mortality up to Day 35. 

To evaluate the impact of rilematovir compared 
to placebo on the clinical course of disease
using the Clinician Symptom Score (CSS).

Change from baseline over time in the CSS as 
assessed by a Clinician Questionnaire.

To explore the relationship between PK of 
rilematovir
and 
pharmacodynamics 
(PD) 
(selected antiviral activity, clinical outcomes, 
and safety parameters).

Pharmacokinetic/PD 
analysis 
of 
plasma 
concentration-time data of rilematovir and 
selected clinical outcomes, antiviral activity, 
and safety parameters.

To explore the impact of rilematovir compared 
to placebo on hours missed from work (by all 
members of the participant’s household, 
including the participant, if employed).

Hours
missed from work due to the 
participant's RSV infection by all members of 
the participant’s household, including the 
participant, if employed.
Refer to Section 8 for evaluations related to endpoints.
HYPOTHESIS
The primary hypothesis of this study is that rilematovir reduces the time to resolution of the RSV 
LRTD symptoms compared to placebo, as assessed by a PRO measure (RiiQTM) in adult 
outpatients with at least moderate RSV disease and who are at high risk for RSV disease-related
progression.
4.
STUDY DESIGN
4.1.
Overall Design
This is a Phase 2b, randomized, double-blind, placebo-controlled, multicenter study to evaluate 
efficacy, safety, and tolerability of rilematovir at a dose of 250 mg twice daily administered for 
7 days in outpatient adults (≥18 to ≤85 years of age) who are at high risk of RSV-related disease
progression, and who have at least moderate RSV disease (LRTD) due to RSV infection. Moderate 
RSV disease is defined as having at least any 2 of the symptoms of LRTD (cough, wheeze, 
coughing up phlegm, short of breath), one of which must be scored as at least ‘moderate’ if the 
symptoms did not pre-exist before RSV onset, OR one of which must be scored worse than usual 
if the symptoms pre-existed as determined by the participant's ratings of the RiiQ Symptom Scale 
and the Pre-Existing Symptom Questionnaire in the ePRO device.
A target of 180 participants who are at high risk for RSV-related disease progression will be 
randomly assigned in a 2:1 ratio (active:placebo) in this study with approximately 120 participants 
planned in the rilematovir group and approximately 60 participants in the placebo group. 
Randomization to study intervention treatment should occur within 72 hours after onset of any of 
the RSV symptoms or worsening of pre-existing symptoms.


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High-risk condition(s) for RSV-related disease progression is defined as:

Presence of any of the underlying high-risk comorbid cardiopulmonary conditions (COPD, 
asthma, or CHF) AND/OR

≥65 years of age (elderly participants)
Randomization will be stratified by high-risk (<65 years of age with underlying high-risk comorbid 
cardiopulmonary conditions ([COPD, asthma, or CHF] versus ≥65 years of age without underlying 
comorbid cardiopulmonary conditions versus ≥65 years of age with underlying comorbid 
cardiopulmonary conditions), and time since symptom onset (≤48 hours versus >48-72 hours). 
The study population should consist of at least 50% of participants with randomization ≤48 hours 
since onset of RSV symptoms. Efforts will be made to include all races and gender. 
Figure 2:
Timeline from RSV Sign/Symptom Onset to First Dose
ICF = informed consent form; RSV = respiratory syncytial virus; SOC = standard-of-care.
Participants who meet all eligibility criteria will be randomized in a 2:1 ratio to receive 1 of the 
following 2 treatments:

Treatment A: rilematovir 250 mg twice daily for 7 days (n = 120)

Treatment B: placebo twice daily for 7 days (n = 60)
The study will include a screening period (Day -1 to Day 1), a Treatment Period (Day 1 to Day 7/8
[depending on timing of first dose]), and a Follow-up Period (Day 8/9 to Day 35 [±3]). In general, 
the total study duration for each participant will be 35 (±3) days. The study is considered complete 
with the completion of the last study assessment for the last participant in the study.
Study participants will be identified when they present for medical care with symptoms suggesting 
a diagnosis of RSV infection (eg, nasal congestion, sore throat, dry cough, wheezing, coughing up 
phlegm [sputum], short of breath , fever and fatigue [tiredness]). Participants must have at least 
2 LRTD symptoms, at least one of which is considered of moderate severity as evaluated by the 
RiiQ Symptom Scale at screening or worsened if the LRTD symptoms were pre-existing based on 


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the Pre-RSV symptom questionnaire. Screening should be completed as soon as possible. During 
screening, a bilateral nasal mid-turbinate swab will be collected for local diagnosis of RSV 
infection preferably using a PCR-based or other molecular-based diagnostic assay. For any patient 
that is subsequently randomized, the leftover from this sample will be used for central testing of
RSV viral load and viral sequencing. However, collection of a study-specific bilateral nasal 
mid-turbinate (MT) swab at screening is not required if a SOC diagnostic sample is collected 
within 24 hours of screening start and yields a positive RSV result using a molecular-based 
diagnostic assay.
Study interventions will be administered orally. Study intervention administration should start as 
soon as possible, but no later than 4 hours after randomization. Randomization must occur within 
a window of 72 hours of RSV symptom onset (Figure 2). The first dose of study intervention will 
be administered before the participant leaves the site. On Day 1, study-site personnel will provide 
to the participant all the required study intervention for dosing at home. Study site personnel will 
instruct participants on how to use and store study intervention for at home dosing.
All participants will complete assessments from Day 1 till the Day 35 visit as stipulated in the
Schedule of Activities. Participants will be required to have a study visit at the study site on Day 3, 
Day 8 (+1), Day 14 (±1), and Day 21 (±3). If feasible and allowed per local regulations, a home 
visit by the home nursing/ study site personnel can be scheduled in situations where the participant 
is not able to attend on-site due to medical condition or other care situation.
On Day 28 (±3) and Day 35 (±3), all participants will be contacted by the study site personnel for 
a telephone follow-up visit (or other digital call, if possible) to assess the clinical status and medical 
resource utilization (MRU) and to check for any AEs including RSV-related complications. 
Participants might be requested, at the discretion of the investigator, to have a safety follow-up 
visit at the site on Day 28 (±3) and Day 35 (±3) in case participants had ongoing AEs or other 
ongoing laboratory, vital signs or ECG-related abnormalities at the previous visit.
Patient-reported outcomes will be done throughout the study as stipulated in the Schedule of 
Activities (see Section 8.1).
Evaluation of clinical assessment of the RSV clinical course will be explored using a Clinician 
Symptom Score (CSS) based on the Clinician Questionnaire at timepoints as stipulated in the 
Schedule of Activities. This is a respiratory symptom score based on clinician interview of the 
participant to evaluate RSV LRTD symptom severity and to determine the degree of improvement 
following study intervention.
One of the secondary efficacy endpoints is the incidence of treatment-emergent complications 
associated with RSV. RSV-related complications (pulmonary and extra pulmonary) will be 
identified by the treating investigator based on protocol guided definition of complications and the 
required clinical data.
Medical resource utilization will be assessed (see Section 8.7).


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Safety and tolerability, including AEs, laboratory assessments, ECGs, physical examination, and 
vital signs will be assessed throughout the study from signing of the main informed consent form 
(ICF) until the participant’s last study-related activity (see Section 8.2). For participants having 
signed only a diagnostic ICF, only procedure-related AEs will be reported.
A bilateral nasal mid-turbinate swab will be taken on Day 1 (predose) for the central laboratory 
confirmation of RSV infection, determination of RSV viral load (and RSV subtype), determination 
of the presence of other respiratory viruses or bacteria and viral sequencing. This sample is not to 
be collected if a study-specific screening bilateral nasal mid-turbinate swab was taken within 
8 hours before the first dosing, in which case the leftover of that sample can serve as the baseline 
predose sample, provided that the sample was stored appropriately and sufficient sample volume
is available (volume is considered sufficient if no more than 600 μL from the original sample has 
been used for local RSV testing and the entire remainder of the original sample is available). 
However, when a local RSV diagnosis was performed using a SOC sample, then this Day 1 predose 
sample is required to be collected in any case. In addition, bilateral nasal mid-turbinate swabs for 
RSV viral load quantification and viral sequencing will be collected throughout the study
(Section 8.1.3).
Pharmacokinetic assessments during the study will be based on sparse sampling and will be 
performed using a popPK model (Section 8.4).
Blood samples collected for biomarker research (eg, RNA, proteins including cytokines, cellular 
phenotyping) may be analyzed at the sponsor’s discretion on the premise that these markers may 
play a role in the treatment response, safety or PK of rilematovir, or RSV-related disease. Leftover 
nasal mid-turbinate swabs and blood samples collected for other testing may be used as well for 
the same purpose (see Section 8.5).
The presence of other respiratory viruses or bacteria in nasal swabs will be assessed (see 
Section 8.6).
A separate Substudy to explore the use of Biosensors for monitoring cardio-respiratory parameters 
will be performed at selected study sites in a subset of participants who provide specific consent 
for this assessment. Details, including objectives and study design, will be described in a separate 
Substudy protocol.
A second Substudy with Qualitative Patient Interviews will be performed at selected study sites in 
a subset of participants who provide specific consent for this assessment. This Substudy will gain 
insight in the participants 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.
Interim analyses may be conducted at the sponsor’s discretion when at least approximately 65% 
of participants are enrolled to review futility as well as clinical outcome trends to allow (or initiate) 
preparation towards a Phase 3 study design. The interim analysis will preferably be conducted at 
the end of a northern or southern hemisphere RSV season (Section 9.5).


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An IDMC will be commissioned for this study to monitor safety data on a regular basis (see 
Section 9.6)
Participants who prematurely discontinue study intervention for any reason (except withdrawal of 
consent) are recommended to remain compliant to all study-related procedures including timely 
completion of all the efficacy assessments (e.g., RiiQ/other PRO questionnaires) up to Day 35. 
Participants who withdraw consent to participate in the study during the treatment or follow-up 
phase will be offered an optional Safety Follow-up visit which will consist of the same assessments 
as at the Final Study Visit (Day 35).
When participants are hospitalized during the course of the study, the reason for hospitalization 
should be recorded and every effort should be made by the investigator to perform all the 
assessments as indicated in the Schedule of Activities, if practically feasible.
See Appendix 10.20 for guidance on study conduct during the Coronavirus Disease 2019
(COVID-19) pandemic.
A diagram of the study design is provided in Section 1.2.
4.2.
Scientific Rationale for Study Design
Study Population
The study population targets immunocompetent adult participants ≥18 to ≤85 years of age 
diagnosed with RSV infection in an outpatient setting who are at high risk for RSV-related disease 
progression.
While RSV typically presents in adults as self-limited URTD or LRTD, it is a significant cause of 
severe respiratory infection in elderly adults aged ≥65 years of age (Duncan 2009, Falsey 2005, 
Jain 2015) and in adults (regardless of age) with underlying cardiopulmonary comorbidities such 
as asthma, COPD, and CHF (Duncan 2009, Falsey 2005, Falsey 2019). Among elderly adults who 
are at risk for severe RSV disease, RSV infection may manifest as severe, life-threatening LRTD 
with pneumonia, requirement for ventilatory support, and short- and long-term morbidity (Tseng 
2020). In the US, an annual estimated 61,000-177,000 hospitalizations and 10,000-14,000 deaths 
are attributable to RSV in adults ≥65 years of age (Falsey 2005). In a longitudinal assessment over 
12 RSV seasons in a single outpatient community (n=13,809), the relative risk of a serious outcome 
(ie, hospitalization, emergency room visit, and pneumonia) was significantly increased in 
RSV-infected persons aged ≥75 years of age (versus 60-64 years of age) and in those with COPD 
or CHF (Belongia 2018).
Current treatment options for RSV are generally supportive in nature, consisting of supplemental 
oxygen, intravenous fluids, and bronchodilators. No vaccines or antivirals have been approved for 
the prevention or treatment of RSV infection in adults. Aerosolized, oral, and intravenous ribavirin 
have been used selectively in RSV-infected immunocompromised adults with variable results 
(Nam and Ison 2019). Due to the significant disease burden and the lack of effective treatment, the 


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unmet medical need (prophylactically and therapeutically) is substantial, especially related to 
antiviral treatment in the high-risk adult population as described above.
Blinding, Control, Study Phase/Periods, Intervention Groups
A placebo control will be used to establish the frequency and magnitude of changes in clinical and 
virologic endpoints that may occur in the absence of active intervention. The use of a placebo 
control will allow for any AEs or laboratory abnormalities observed during the course of the study 
to be evaluated properly, ie, to differentiate between events potentially related to the use of 
rilematovir versus those related to the underlying disease. In addition, no approved treatments are 
available to allow comparison.
Randomization will be used to minimize bias in the assignment of participants to intervention 
groups, to increase the likelihood that known and unknown participant attributes (eg, demographic 
and baseline characteristics) are evenly balanced across intervention groups, and to enhance the 
validity of statistical comparisons across intervention groups. Blinded intervention will be used to 
reduce potential bias during data collection and evaluation of clinical endpoints.
Eligible participants will be randomized in a 2:1 ratio to receive either Treatment A (rilematovir
250 mg twice daily) or B (matching placebo twice daily).
Stratification Factors
Randomization will be stratified by high-risk (<65 years of age with underlying high-risk comorbid 
cardiopulmonary conditions [COPD, asthma, or CHF] versus ≥65 years of age without underlying 
comorbid cardiopulmonary conditions versus ≥65 years of age with underlying comorbid 
cardiopulmonary conditions), and time since symptom onset (≤48 hours versus >48-72 hours). The 
study population should consist of at least 50% of participants with randomization ≤48 hours since 
onset of RSV symptoms.
Study and Dosing Duration
A twice daily dosing regimen for 7 days (14 consecutive doses) is employed as data have shown 
that the duration of viral shedding after RSV infection is at least that long. Seven days was also 
the duration of dosing in the healthy volunteer challenge study in adults (study 
53718678RSV2001), in the completed study 53718678RSV1005 in pediatric participants, the pilot 
Phase 
2a 
study 
in 
adults 
(Study 53718678RSV2004), 
and 
in 
the 
ongoing 
Study 53718678RSV2002 in RSV-infected pediatric participants, in which rilematovir was 
generally safe and well tolerated (see Section 2.2).
Interim Analysis
Refer to Section 9.5.
4.2.1.
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 


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participation. They will be told that their consent to participate in the study is voluntary and may be 
withdrawn at any time with no reason given and without penalty or loss of benefits to which 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 voluntarily 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.
The total blood volume (maximum approximately 80 mL) to be collected is considered to be 
acceptable over this time period from the population in this study.
4.3.
Justification for Dose
Participants will be administered 250 mg rilematovir twice daily for 7 days. Co-administration of 
moderate or strong CYP3A4 inhibitors will require dose reduction of rilematovir to 125 mg twice 
daily for 7 days. Co-administration with certain strong CYP3A4 inhibitors such as posaconazole 
or ketoconazole is however not allowed in this study. Please refer to Section 2.2 for details on the 
interaction with CYP3A4 inhibitors and Section 6.8 for details on CYP3A4 inhibitors that are 
allowed but require dose adjustment.
In the Phase 2a Study 53718678RSV2004, 2 dose levels of 500 mg and 80 mg once daily were 
investigated compared to placebo. The choice of the dosing regimens in that study was based on 
the results of the human challenge Study 53718678RSV2001, in which target engagement for 
rilematovir was demonstrated in immunocompetent adults inoculated with RSV-A Memphis 37b.
In Study 53718678RSV2001, exposure to rilematovir resulted in a reduction of viral load over 
time in all 3 rilematovir dose groups (75, 200, and 500 mg once daily) as compared to the placebo 
group, without an apparent exposure-antiviral effect relationship. The protein-adjusted 90% 
effective concentration (paEC90) of rilematovir against the RSV-A rgRSV224 strain was calculated 
as 41 ng/mL. The doses of 75, 200, and 500 mg once daily had mean Ctrough levels of 50, 85, and 
334 ng/mL, respectively, and were all above the paEC90. Since all dose regimens were generally 
safe and well tolerated, the highest dose of 500 mg once daily was selected for subsequent adult 
studies to minimize the risk of development of drug resistance and to ensure the highest potential 
for antiviral effect. Doses of 500 mg once daily provide trough levels of at least 8- to 13-fold 
greater (~300 to 550 ng/mL, as observed in Studies 53718678RSV1001 and 53718678RSV2001) 
than paEC90 levels.
Adult Study 53718678RSV2004 confirmed the appropriateness of the 500 mg once daily dose in 
terms of trends of favorable antiviral and clinical effects. The results in adult participants infected 
with RSV demonstrated better clinical outcome with the 500 mg rilematovir once daily dose 
compared to the 80 mg rilematovir once daily dose.
However, due to exposure (Cmax)-related important potential risk of QT interval prolongation
identified from the analysis of the TQT Study 53718678RSV1009 (see Section 2.2), the sponsor 
has performed additional modeling to evaluate alternative dose and dosing regimens, which would 
allow to maintain the plasma concentration (Ctrough) at effective levels and maintain AUC exposure 
while reducing the Cmax, to mitigate this potential risk. The updated popPK model is suitable for 


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PK simulations to adequately predict Cmax, AUC, and Ctrough after single and multiple doses of 
rilematovir.
The physiologically-based pharmacokinetic (PBPK) model developed to assess the potential 
drug-drug interactions with rilematovir 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 rilematovir following dosing (Table 1). 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 1:
Simulated Effect of Concomitant CYP3A4 Inhibitors on Rilematovir PK Parameters
PK Parameter
Strong CYP3A4 Inhibitorsa
Moderate CYP3A4 Inhibitorsb
Cmax single dose 
1.5-fold 
1.5-fold
AUC0-24h single dose 
3-fold 
2-fold
Cmax multiple doses 
1.5-fold 
1.5-fold
AUC0-24h 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 doses 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.
The PBPK model was used to simulate the PK parameters for rilematovir following a multiple 
125 mg twice daily dose in the presence of strong CYP3A4 inhibitors (200 mg twice daily
voriconazole, 500 mg twice daily clarithromycin, or 400 mg twice daily posaconazole) in healthy 
participants. Concomitant administration of voriconazole, clarithromycin, and posaconazole 
resulted in a 2.80, 2.88, and 4.73-fold increase, respectively, in steady state AUC0-24h values and a 
1.77, 1.82, and 2.48-fold increase, respectively, in Cmax,ss of rilematovir.
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 2.


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Table 2:
Predicted Geometric Mean AUC0-24h, Cmax, Ctrough and ΔΔQTcI After Day 1 and Day 7
PK Parameters
250 mg bid
125 mg bid + moderate 
CYP3A4 inhibitorsa
125 mg bid + strong 
CYP3A4 inhibitorsb
AUC0-24h Day 1 (ng hr/mL) 
24,700
23,300
35,000/40,800b
AUC0-24h Day 7 (ng hr/mL) 
40,700
35,800
44,800/62,700b
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, Ctrough: predose plasma concentration, CI: confidence 
interval, Cmax: maximum plasma concentration, CYP: cytochrome P450, PK: pharmacokinetic(s), PBPK: 
physiologically-based pharmacokinetic(s).
a. Based on PBPK modeling.
b. Based on single dose PK results of 53718678RSV1006.
In study 53718678RSV1001, the 250 mg twice daily regimen provided Ctrough levels that are 
somewhat higher than those observed with the 500 mg once daily regimen (mean [SD] Ctrough
levels on Day 7 of 550 [477] ng/mL and 643 [126] ng/mL [n=6] for 500 mg once daily and 250 
mg twice daily, respectively). The dose regimen of 250 mg twice daily provides similar exposure 
levels (AUC0-24h), higher Ctrough levels and lower Cmax levels compared to the 500 mg once daily
regimen, which should translate to at least similar efficacy of rilematovir 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 7-day dosing regimen of 250 mg twice daily is selected for the adult Phase 2b study. 
The dose is to be reduced to 125 mg twice daily when patients are co-administered or may require 
initiation of moderate to strong CYP3A4 inhibitors, including macrolide antibiotics and 
antifungals, which are important in the population with high risk of RSV-related disease 
progression and complications. Co-administration with posaconazole or ketoconazole is not 
allowed in this study The upper limit of the 90% CI for ΔΔQTcI for the twice daily regimen in 
combination with moderate or strong CYP3A4 inhibitors remains below 10 ms for each of the 
groups (Table 2).
Overall, based on all currently available data, it is anticipated that the selected twice daily dosing 
of rilematovir will be in the therapeutic range for adults, ensuring the highest potential antiviral 
effect while minimizing the risk of development of resistance (by 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).
4.4.
End of Study Definition
End of Study Definition
The end of study is considered as the last 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 


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of the final participant visit at that study site, in the time frame specified in the Clinical Trial 
Agreement.
Study Completion Definition
A participant will be considered to have completed the study if he or she has completed dosing 
and has completed assessments at Day 35 (±3 days) of the double-blind phase.
5.
STUDY POPULATION
Screening for eligible participants will be performed as soon as possible after presentation to the 
healthcare facility, such that participants are randomized within 72 hours of RSV symptom onset.
Treatment is initiated as soon as possible, but no later than 4 hours after randomization.
The inclusion and exclusion criteria for enrolling participants in this study are described below. If 
there is a question about these criteria, the investigator must consult with the appropriate sponsor 
representative and resolve any issues before enrolling a participant in the study. Waivers are not 
allowed.
For a discussion of the statistical considerations of participant selection, refer to Section 9.2.
5.1.
Inclusion Criteria
Each potential participant must satisfy all the following criteria to be enrolled in the study:
Age
1.
18 (or the legal age of consent in the jurisdiction in which the study is taking place) to 
85 years of age, inclusive.
Type of Participant and Disease Characteristic
2.
Presentation to the healthcare facility with symptoms suggestive of a diagnosis of acute 
RSV infection and have at least any 2 of the following symptoms of LRTD, one of which 
must be scored as at least ‘moderate’ if the symptoms did not pre-exist before RSV onset, 
OR one of which is scored worse than usual if the symptoms pre-existed as determined 
by the participant's ratings of the RiiQ Symptom Scale and the Pre-Existing Symptom 
Questionnaire in the ePRO device.
LRTD symptoms: cough, wheezing, short of breath, coughing up phlegm (sputum).
3.
Tested positive for RSV infection using a molecular-based diagnostic assay (PCR or 
other) on a bilateral nasal mid-turbinate swab sample as part of the study-specific 
screening assessment or on a respiratory tract sample as part of SOC testing (collected 
within 24 hour prior to start of screening).


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4.
Participants must have at least one of the following high-risk conditions that predispose 
them to RSV-related disease progression:
a.
Age ≥65 years
b.
CHF
c.
COPD
d.
Asthma.
5. 
Randomized to study intervention treatment within 72 hours after onset of any of the RSV 
symptoms or worsening of pre-existing symptoms.
Onset of symptoms is defined as the time the participant becomes aware of the first sign 
and/or symptom or worsening of sign and/or symptom consistent with a viral infection. 
Efforts should be made to determine the time of onset of symptoms as accurately as 
possible (in relation to routine daily activities).
Note: The study intervention administration should start as soon as possible, but no later 
than 4 hours after randomization.
6.
Not be hospitalized during screening. Emergency room or hospital observation status for 
an anticipated duration of <24 hours are not considered as hospitalization.
7.
Except for the RSV-related disease, the participant must be medically stable based on 
physical examination, medical history, vital signs, and 12-lead ECG performed at 
screening. Any abnormalities must be consistent with the underlying illness (RSV disease 
and/or comorbid 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.
8.
The participant must have been assessed per local public health practice and considered 
not to have severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection 
during this respiratory infection.
Sex and Contraceptive/Barrier Requirements
9.
A woman must be (as defined in Appendix 10.5)
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 


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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. The investigator should evaluate the potential
for contraceptive method failure (eg, noncompliance, recently initiated) 
in relationship to the first dose of study intervention. Examples of highly 
effective methods of contraception are in Appendix 10.5.
o
Have a negative urine pregnancy test (β-human chorionic gonadotropin 
[β-hCG]) at screening.
10.
A woman must agree not to donate eggs (ova, oocytes) or freeze for future use for the 
purposes of assisted reproduction during the study and for a period of 30 days after the 
last dose of study intervention.
11.
From Day 1 during the study and for 90 days after receiving the last dose of study 
intervention, a male participant must wear a condom when engaging in any activity that 
allows for passage of ejaculate to another person. Male participants should also be advised 
of the benefit for a female partner to use a highly effective method of contraception as 
condom may break or leak.
Note: Contraceptive (birth control) use by participants should be consistent with local 
regulations regarding the acceptable methods of contraception for those participating in 
clinical studies.
12.
A male participant must agree not to donate sperm for the purpose of reproduction during 
the study and for a minimum 90 days after receiving the last dose of study intervention.
Informed Consent
13.
Must sign an ICF 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 ICF for the study, participants may specifically allow for 
the collection and testing of study-specific bilateral nasal mid-turbinate swabs by signing 
the pre-screening (diagnostic) ICF. This is not applicable if a positive RSV diagnostic 
result, based on a local SOC sample collected within 24 hours prior to start of screening, 
is available and used for determining study eligibility.
14.
Willing and able to adhere to the lifestyle restrictions specified in this protocol (see 
Section 5.3).


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5.2.
Exclusion Criteria
Any potential participant who meets any of the following criteria will be excluded from 
participating in the study:
Medical Conditions
1.
History of or concurrent disease (with the exception of COPD, asthma, CHF), or 
clinically significant findings during screening or medical history, physical 
examination, laboratory testing, vital signs, ECG recording, for which, in the opinion 
of the investigator, participation would not be in the best interest of the participant 
(eg, compromise the well-being).
2.
Any condition that could prevent, limit, or confound the protocol-specified assessments 
(eg. participant is unable to understand and answer questions in one of the official 
language versions provided for the PRO assessments to participate in the study or is 
illiterate).
3.
Known allergies, hypersensitivity, or intolerance to rilematovir or to any of the 
excipients of rilematovir or placebo formulation (refer to the IB; IB 2020).
4.
Presence of clinically significant heart arrhythmias, uncontrolled, unstable atrial 
arrhythmia, or sustained ventricular arrhythmia.
5.
Unstable angina pectoris or myocardial infarction within 30 days prior to screening 
(inclusive).
6.
Recent history (<2 months before screening) of clinically relevant electrolyte disorders 
related to hypokalemia and/or hypomagnesemia, as per investigator assessment, that
have not been adequately managed.
7.
Confirmed corrected QT (QTcF) interval >450 ms per the machine read ECG parameter 
result at screening. Presence of an abnormal QTcF interval should be confirmed by 
repeat ECG recording during screening.
8.
Presence of repetitive ventricular premature contractions (>10/min), second (Type II or 
Mobitz Type II) or third-degree heart block, or incomplete or complete left bundle 
branch block, or complete right bundle branch block per the machine read ECG results 
at screening. Presence of any of the above abnormalities should be confirmed by repeat 
ECG recording during screening.
9.
Other clinically significant abnormal ECG findings not consistent with the underlying 
condition in the study population, as judged by the investigator based on the machine 
read ECG results at screening.
10.
Participants who are considered by the investigator to be immunocompromised within 
the past 12 months, whether due to underlying medical condition (eg, malignancy or 


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genetic disorder other than immunoglobulin A deficiency, or human immunodeficiency 
virus [HIV] infection, eg, CD4+ count <200 cells/mm3) or medical therapy (eg, 
medications other than corticosteroids for the treatment of COPD or asthma 
exacerbations, chemotherapy, radiation, stem cell or solid organ transplant).
11.
Participant has known or suspected (from medical history or participant examination) 
chronic or acute hepatitis B or C infection.
12.
The participant has had either:
a) Confirmed SARS-CoV-2 infection (test positive) during the four weeks prior to 
randomization,
OR
b) Close contact with a person with COVID-19 (test confirmed or suspected 
SARS-CoV-2 infection) within 14 days prior to randomization.
13.
Participants 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.
14.
Participants unwilling to undergo bilateral nasal mid-turbinate swab procedures or with 
any physical abnormality which limits the ability to collect regular nasal specimens.
15.
Participant had major surgery (eg, requiring general anesthesia) within 28 days before 
screening, or will not have fully recovered from surgery, or has surgery planned during 
the time the participant is expected to participate in the study.
Note: Participants with planned surgical procedures to be conducted under local 
anesthesia may participate.
16.
Living in institutional care or assisted living facility and also receiving acute care 
management for any respiratory condition.
Note: Institutional care refers to a place of residence that provides nursing supervised 
assistance with activities of daily living, healthcare, and rehabilitation.
Prior/Concomitant Therapy
17.
Taken any disallowed therapies as noted in Section 6.8 before the planned first dose of 
study intervention.
Prior/Concurrent Clinical Study Experience
18.
Received an investigational intervention (including investigational vaccines) or used an 
invasive investigational medical device within 30 days before the planned first dose of 
study intervention or is currently enrolled in an investigational study.


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Note: COVID-19 vaccines with Emergency authorized approvals are not considered 
investigational.
19.
Participant with current or planned participation in another clinical study where study 
intervention/investigational device is being administered while participating in the 
current study.
Other Exclusions
20.
Employee of the 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 
family members of the employees or the investigator.
21.
Women who are pregnant or breastfeeding.
22.
Plans to father a child while enrolled in this study or within 90 days after the last dose 
of study intervention.
23.
Any condition for which, in the opinion of the investigator, participation would not be 
in the best interest of the participant (eg, compromise the well-being) or that could 
prevent, limit, or confound the protocol-specified assessments.
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 describes options for retesting. The required source 
documentation to support meeting the enrollment criteria are noted in Appendix 10.3.
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.
Concurrent administration of medications/use of licensed devices is allowed as 
supportive therapy per local SOC, as long as the medication/licensed device will not 
affect the participant’s participation in the study and is in accordance with allowed 
concomitant therapy. 
COVID-19 vaccine administration during study period: As side effects due to 
vaccination may impact the evaluation of the clinical evolution of RSV symptoms, it is 
recommended that administration of a COVID-19 vaccine be timed to occur after study 
completion or at least two weeks after the last dose of study medication. Investigator 
discretion 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 as well as the follow up can continue as scheduled.  


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Refer to Section 6.8 for details regarding prohibited and restricted therapy during the 
study.
2.
Participants may not consume food or beverages containing grapefruit juice during 
rilematovir dosing period.
3.
Agree to be compliant with the completion of the ePROs per the required schedule.
4.
Agree to follow all requirements that must be met during the study as noted in the 
Inclusion and Exclusion Criteria (eg, contraceptive requirements).
5.4.
Screen Failures
Participant Identification, Enrollment, and Screening Logs
The investigator agrees to complete a participant identification and enrollment log to permit easy 
identification of each participant during and after the study. This document will be reviewed by 
the sponsor study site contact for completeness.
The participant identification and enrollment log will be treated as confidential and will be filed 
by the investigator in the study file. To ensure participant confidentiality, no copy will be made. 
All reports and communications relating to the study will identify participants by participant 
identification and age at initial informed consent. In cases where the participant is not randomized 
into the study, the date seen and age at initial informed consent will be used.
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
rescreened, but not in the same acute respiratory infection episode in case RSV(-) diagnosis was 
the reason for screen failure.
6.
STUDY INTERVENTION AND CONCOMITANT THERAPY
6.1.
Study Intervention(s) Administered
Eligible participants will be randomized in a 2:1 ratio (active:placebo) to receive either rilematovir
or placebo for 7 days twice daily (14 consecutive doses).
Study interventions will be administered orally. Study intervention administration should start as 
soon as possible, but no later than 4 hours after randomization. Randomization must occur within 
a window of 72 hours of RSV symptom onset. For analysis purposes, the day of first study 
intervention administration will be considered Day 1.
Description of Interventions
Arm Name
Treatment A
Treatment B
Intervention Name
Rilematovir 
(JNJ-53718678)
Placebo
Type
Drug
Drug


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Arm Name
Treatment A
Treatment B
Dose Formulation
Oral film-coated tablet
Oral film-coated tablet
Unit Dose Strength(s)
eq. 125-mg
Matching placebo
Dosage Level(s)
250 mg twice daily (bid)
for 7 days (dose reduction 
to 125 mg bid if 
coadministration with 
moderate or strong 
CYP3A4 inhibitors is 
started or continued during 
study intervention 
treatment)a
Matching placebo bid for 
7 days
Route of Administration
Oral
Oral
Use
Experimental
Placebo
Investigational Medicinal Product (IMP)
Yes
Yes
Non-Investigational Medicinal 
Product/Auxiliary Medicinal Product
No
No
Sourcing
Provided centrally by the sponsor
Packaging and Labeling
The oral film-coated tablets are packaged in high-
density polyethylene (HDPE) bottles with child-resistant 
screw caps with 2 g of desiccant.
Labels will contain information to meet the applicable 
regulatory requirements.
Delivery Instructions
Do not crush tablets.
All study drugs will be taken orally with a glass of 
water.
Food/Fasting Requirement
Regardless of food administration
Other Requirements
Dosing should preferably occur approximately at the 
same time each day for both intakes (AM and PM)
a Refer to Section 6.8 for details regarding the coadministration of moderate or strong CYP3A4 
inhibitors during the study. Investigators must review the concomitant medications at screening and 
consult the sponsor as needed.
Rilematovir will be administered as an eq. 125-mg (G033, containing 143.75 mg of 
JNJ-53718678-ZCL, hemi-tartrate, equivalent to 125 mg JNJ-53718678-AAA, the free form drug 
substance) or placebo (G037) oral film-coated tablet.
Rilematovir oral film-coated tablets will be manufactured and provided under the responsibility of 
the sponsor. The rilematovir film-coated tablets contain the following excipients: hypromellose 
2910 15 mPa.s, sodium laurilsulfate, lactose monohydrate, croscarmellose sodium, silicified 
microcrystalline cellulose, silica (colloidal anhydrous), magnesium stearate, coating powder 
yellow and purified water (removed during processing). The matching placebo film-coated tablets 
contain the following excipients: lactose monohydrate, croscarmellose sodium, silicified 
microcrystalline cellulose, silica (colloidal anhydrous), magnesium stearate, coating powder 
yellow and purified water (removed during processing).
Dosing Instructions


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Rilematovir will be dosed as 250 mg twice daily for 7 days. In case coadministration 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 twice daily. Note: Coadministration with 
posaconazole or ketoconazole is not allowed in this study (see Section 6.8).
Depending on the time of randomization/enrollment, participants will receive 1 dose (PM) or 
2 doses (AM and PM) of study intervention on Day 1. Administration of the second dose may be 
delayed or brought forward (by maximum of 4 hours) only if the nominal timing for this second 
dose falls in the middle of the night; thereafter, further dosing will follow a regular AM/PM dosing 
schedule. For participants who receive only 1 dose of study intervention on Day 1 (PM), dosing 
should continue until the morning of Day 8 (AM) so that all participants receive 14 consecutive 
doses in total.
Dosing should occur approximately every 12 hours at approximately the same time each day. The 
study intervention can be administered with/without food. In case a dose was missed, the dose 
should be given as soon as possible but within 6 hours after the scheduled time. If more than 
6 hours have elapsed, the dose should be skipped, and the next dose should be taken at the next 
scheduled time point per the initial dosing schedule. In case of vomiting >6 hours after dosing or 
in case of no visual confirmation of tablet in the vomit, the participant should not be re-dosed.
The first dose of study intervention will be administered before the participant leaves the site on 
Day 1. The date and time of study intervention administration must be captured in the source 
documents and the electronic case report form (eCRF). Study site personnel will instruct 
participants on how to store study intervention for at-home use as indicated for this protocol.
For a definition of study intervention overdose, refer to Section 6.7.
6.2.
Preparation/Handling/Storage/Accountability
Preparation/Handling/Storage
All study intervention must be stored as specified on the label.
Refer to the pharmacy manual or study site investigational product and procedures manual for 
additional guidance on study intervention handling and storage.
Accountability
The investigator is responsible for ensuring that all study intervention received at the site is 
inventoried and accounted for throughout the study. The first dose of study intervention dispensed 
to the participant at Day 1 must be documented on the intervention accountability form. For doses 
administered at home, 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. 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.


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At the study site, study intervention must be handled in strict accordance with the protocol and the 
container label, and must be stored at the study site in a limited-access area or in a locked cabinet 
under appropriate environmental conditions. Unused study intervention, and study intervention 
returned by the 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.
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 intervention (Treatments A or B; 2:1 ratio [active: placebo] randomization) groups based 
on a computer-generated randomization schedule prepared before the study by or under the 
supervision of the sponsor. Randomization will be stratified by high-risk (<65 years of age with 
underlying high-risk comorbid cardiopulmonary conditions [COPD, asthma, or CHF] versus 
≥65 years of age without underlying comorbid cardiopulmonary conditions versus ≥65 years of 
age with underlying comorbid cardiopulmonary conditions), and time since symptom onset 
(≤48 hours versus >48-72 hours). The study population should consist of at least 50% of 
participants with randomization ≤48 hours since onset of RSV symptoms. To ensure the 
enrollment of participants with randomization ≤48 hours since onset of RSV symptoms of a 
minimum of approximately 50% of all participants, a cap (at a maximum of 50%; ie 
90 participants) on the enrollment of the participants with randomization >48-72 hours since onset 
of RSV symptoms will be applied.
The interactive web response system (IWRS) will assign a unique intervention code, which will 
dictate the intervention assignment and matching study intervention kit for the participant. The 
requestor must use his or her own user identification and personal identification number when 
contacting the IWRS and will then give the relevant participant details to uniquely identify the 
participant.


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Blinding
The investigator will not be provided with randomization codes. The codes will be maintained 
within the IWRS, which has the functionality to allow the investigator to break the blind for an 
individual participant.
Data that may potentially unblind the intervention assignment (ie, rilematovir plasma 
concentrations) will be handled with special care to ensure that the integrity of the blind is 
maintained and the potential for bias is minimized. This can include making special provisions, 
such as segregating the data in question from view by the investigators, clinical team, or others as 
appropriate until the time of database lock and unblinding.
Under normal circumstances, the blind should not be broken until all participants have completed 
the study and the database is finalized. The investigator may in an emergency determine the 
identity of the intervention by contacting the IWRS. While the responsibility to break the 
intervention code in emergency situations resides solely with the investigator, it is recommended 
that the investigator contact the sponsor or its designee if possible, to discuss the particular 
situation, before breaking the blind. Telephone contact with the sponsor or its designee will be 
available 24 hours per day, 7 days per week. In the event the blind is broken, the sponsor must be 
informed as soon as possible. The date and reason for the unblinding must be documented in the 
appropriate section of the case report form eCRF. The documentation received from the IWRS
indicating the code break must be retained with the participant's source documents in a secure 
manner.
Participants who have had their intervention assignment unblinded will be asked to return for 
scheduled evaluations.
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.
6.4.
Study Intervention Compliance
At the screening/predose visit, study site personnel will instruct participants on how to use and 
store study intervention for at home dosing. Participants will be provided with study intervention 
for daily use at home and will be requested to document date and time of intakes.
During the course of the study, the investigator or designated study site personnel will be 
responsible for ensuring the participants are compliant with taking in the study intervention, and 
for providing additional instruction to reeducate any participant who is not compliant with taking 
in the study intervention.
Participants will be asked to return the remainder of the study intervention and/or empty packaging 
to the site on the Day 8 visit for compliance checking (including count of any study drug returned). 


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Discrepancies will be discussed with the participant and date and time of study drug intakes 
recorded in the source documents and the eCRF.
The study intervention will be administered orally.
Missed doses of rilematovir or placebo will be recorded in the source documents and the eCRF.
6.5.
Dose Modification
Any dose/dosage adjustment should be overseen by medically qualified study site personnel 
(principal or subinvestigator unless an immediate safety risk appears to be present).
No dose modification is allowed unless coadministration of the class of strong or moderate 
CYP3A4 inhibitors is started or continued during study intervention treatment, in which case the 
dose of rilematovir needs to be adjusted to 125 mg twice daily (see Sections 6.1, 4.3, and 6.8).
Note: Coadministration of posaconazole or ketoconazole is not allowed in this study.
6.6.
Continued Access to Study Intervention After the End of the Study
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.
6.7.
Treatment of Overdose
For this study, any dose of rilematovir greater than the total daily dose within a 24-hour time period
will be considered an overdose. The sponsor does not recommend specific treatment for an 
overdose.
In the event of an overdose, the investigator or treating physician should:

Contact the Medical Monitor immediately.

Closely monitor the participant for AE/SAE, ECG and laboratory abnormalities until
rilematovir can no longer be detected systemically (at least 3 days).

Document the quantity of the excess dose as well as the duration of the overdosing in the 
eCRF.
6.8.
Concomitant Therapy
Concomitant medications and supportive therapies (prescription or over-the-counter medications, 
including vaccines, vitamins, herbal supplements; non-pharmacologic therapies such as electrical 
stimulation, acupuncture, special diets, exercise regimens, or other specific categories of interest) 
different from the study intervention must be recorded in the eCRF. Recorded information will 
include a description of the type of drug/therapy, treatment duration (dates of treatment start and 
stop), dosing regimen, route of administration, and indication. Modification of an effective 
pre-existing therapy should not be made for the explicit purpose of entering a participant into the 
study; however, if a participant has received acute doses of a prohibited drug, switching to an 
alternative drug chosen at the discretion of the investigator will be allowed.


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Participants will be required to document the use of concomitant medication in the participants 
notes from signing of the main ICF until the last study visit, which will serve as source document 
for the study site personnel to complete the eCRF.
Allowed Medications
Participants
can receive medications
such as acetaminophen/paracetamol, non-steroidal 
anti-inflammatory drugs, leukotriene antagonists, or antihistamines, considering their respective 
package insert, at the investigator’s discretion prior to and during the study.
Prescription medications intended to treat the symptoms/sequelae of the RSV infection are 
permitted, including:

Inhaled β-agonists or anticholinergics (also permitted as maintenance therapy for the 
underlying asthma or COPD);

Inhaled corticosteroids and, to a certain extent, systemic corticosteroids (see below);

Oral/intravenous/intramuscular antibiotics such as β-lactams and macrolides.
Note: The temporary use of over-the-counter medications in the 14 days prior to randomization 
and during the study is permitted. The use of vitamins and mineral supplements is also permitted.
Prescription medications, known to be moderate or strong inhibitors of CYP3A4 enzymes that are 
allowed but require rilematovir dose adjustment as described in Section 6.1, are listed in Table 3.
As side effects due to seasonal (eg. flu) or other routine (eg. pneumococcal) vaccinations may 
impact the clinical evolution of RSV symptoms, it is recommended that administration of these 
vaccines be timed to occur after study completion or at least two weeks after the last dose of study 
medication. Investigator discretion 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 as well as the follow up can continue as scheduled.
Disallowed Medications
The following medications are not permitted during the study and for the time period prior to 
screening as noted:

Herbal supplements with active metabolic enzyme inducing components (eg, St-John’s Wort) 
within 21 days or 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.

Any investigational vaccine, including investigational RSV vaccines, at any time prior to and 
during the study.
Note: COVID-19 vaccines with Emergency authorized approvals are not considered 
investigational.


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
Systemic corticosteroids if used for >7 consecutive days immediately prior to screening at 
doses higher than 20 mg/day of prednisone or equivalent (unless indicated to treat underlying 
COPD/asthma). Participants meeting the eligibility criteria at screening but requiring 
initiation or increased doses of systemic corticosteroids (>20 mg/day of prednisone or 
equivalent) for a prolonged period (>7 consecutive days) during the study due to the 
underlying conditions are allowed to continue participation in the study.

Prescription 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 QTc interval meets the 
eligibility criteria, however, the use of these medications cannot be initiated at screening 
and/or during the study intervention treatment period (see Table 3 and Appendix 10.8).

The following prescription medications within 14 days prior to screening and during the study:
−
Prescription medications intended to prevent or treat the RSV infection itself (eg, 
inhaled/oral ribavirin, intravenous RSV immunoglobulin). Prescription medications 
intended to treat the symptoms/sequelae of the RSV infection are permitted.

Prescription medications which are known to be a moderate or strong inhibitor of 
CYP3A4 enzymes, with the exception of posaconazole and ketoconazole), are only 
permitted during the study period if accompanied by a dose reduction of rilematovir 
(125 mg twice daily dose) as listed in Table 3.

Prescription medications which are known to be a strong inducer of CYP3A4 enzymes
as listed in Table 3.

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.

Palivizumab, within 5 half-lives (approximately 100 days) prior to screening.

Any other investigational drug within 30 days or 5 elimination half-lives of that drug 
(whichever is longer) prior to screening and during the study.

Prior exposure to rilematovir at the time of screening.
The sponsor must be notified in advance (or as soon as possible thereafter) of any instances in 
which prohibited therapies are administered.


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Table 3:
Examples of Commonly Used Medications With CYP3A4 Inhibiting and/or QT Prolonging Effects Which are Disallowed or Allowed Upon
Coadministration with Rilematovir
Drug Class
CYP3A4 Inhibitors
Allowed with Dose Reductiona
QT Prolonging Drugs
Allowed with Restrictionsb
CYP3A4 Inhibitors
+ QT Prolonging Drugs
Allowed with Dose Reduction and 
Restrictionsc
CYP3A4 Inhibitors/Inducers +/-
QT Prolonging Effects
Disallowedd
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
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 (see Appendix 10.8).
a.
Dose reduction required in case of coadministration of rilematovir with strong or moderate CYP3A4 inhibitors (see Section 6.1).
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 require dose adjustment (see Section 6.1). However, the use of these medications cannot be initiated 
at screening and/or during the study intervention treatment period.
d.
Disallowed within 14 days prior to screening and during the study.


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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 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 QTc interval value >500 ms at any scheduled visit, per the 
machine read parameter result. Confirmation needs to be obtained immediately by another 
machine read ECG locally at the site.

The participant is reported with laboratory abnormality of hypokalemia of <2.5 mEq/ L and/or 
hypomagnesemia of < 0.9 mEq/L in samples taken at screening or any time during the study 
intervention treatment period, confirmed in a repeat test done locally, to be performed within 
24 hours of the result being available at the site.

The participant is reported with laboratory abnormality of alanine transaminase (ALT)
increase ≥3 x upper limit of normal (ULN) in samples taken at any time during the study 
intervention treatment period and met the liver safety management discontinuation criteria 
(see Appendix 10.6).

The participant is reported with any other laboratory abnormality of Grade 3 or 4 (except for 
Grade 3 or 4 elevations of triglycerides, low density lipoprotein cholesterol, and/or 
cholesterol), considered as possibly related to study intervention and confirmed in a repeat 
test done locally, to be performed within 48 hours of the result being available at the site.

The participant is poorly compliant with completing ePRO questionnaires, preferably after 
evaluation and discussion between the investigator and the sponsor.

The randomization code is broken by the investigator or the study-site personnel.

Lost to follow-up.

Sponsor’s decision to terminate the study.
If a participant prematurely discontinues study intervention treatment for any reason, he or she is 
recommended to remain compliant to all study-related procedures including timely completion of 
all the efficacy assessments (e.g., RiiQ/other PRO questionnaires) up to Day 35 (see Schedule of 
Activities). 
When participants are hospitalized during the course of the study, the reason for hospitalization 
should be recorded and every effort should be made by the investigator to perform all the 
assessments as indicated in the Schedule of Activities, if practically feasible.


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If the reason for discontinuation of study intervention is full withdrawal of consent, 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 entered to ensure sufficient 
evaluable participants for the primary analysis.
7.2.
Participant Discontinuation/Withdrawal From the Study
A participant will be withdrawn from the study for any of the following reasons:

Lost to follow-up.

Withdrawal of consent.

Death.

The participant is poorly compliant with completing ePRO questionnaires, preferably after 
evaluation and discussion between the investigator and the sponsor.

The participant is poorly compliant with other study procedures, study intervention 
administration, visits, and assessments, preferably after evaluation and discussion between the 
investigator and sponsor.

Decision by the sponsor to stop or cancel the study.

Decision by the investigator to withdraw participant.

Decision by local regulatory authorities or Independent Ethics Committee (IEC)/ Institutional 
Review Board (IRB) to stop or cancel the study.
If a participant is lost to follow-up, every reasonable effort must be made by the study-site 
personnel to contact the participant and determine the reason for discontinuation/withdrawal. The 
measures taken to follow-up must be documented.
If a participant however withdraws consent to further continue in the study, he or she will also be 
offered an optional Safety Follow-up Visit. The optional follow-up visit will occur the day of 
consent withdrawal or the day after and will consist of the same assessments as the Final Study 
visit (Day 35). 
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 withdrawal of consent for further study participation, then no additional assessments are 
allowed.
Withdrawal of Consent
A participant declining to return for scheduled visits does not necessarily constitute withdrawal of 
consent. Alternate follow-up mechanisms that the participant agreed to when signing the consent 
form apply (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.


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In case the participant withdraws consent during the treatment or follow-up phase, an optional 
Safety Follow-up visit will be offered.
7.2.1.
Withdrawal From the Use of Research Samples
Withdrawal From the Use of Samples in Future Research
The participant may withdraw consent for use of samples for research (refer to Long-Term 
Retention of Samples for Additional Future Research in Appendix 10.3). In such a case, samples 
will be destroyed after they are no longer needed for the clinical study. Details of the sample 
retention for research are presented in the main ICF.
7.3.
Lost to Follow-up
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.
Should a study site close, eg, for operational, financial, or other reasons, and the investigator cannot 
reach the participant to inform them, their contact information will be transferred to another study 
site.
8.
STUDY ASSESSMENTS AND PROCEDURES
Overview
The Schedule of Activities summarizes the frequency and timing of efficacy, safety, and 
PK/pharmacodynamic (PD) measurements, as well as PRO, biomarker analysis, and MRU, 
applicable to this study.


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Clinical course and severity of RSV infection will be assessed through different measures (see 
Section 8.1.1). Severity and evolution of symptoms will be assessed using the RSV symptom 
assessments described in Section 8.1.1.1. Progression of RSV disease will be assessed using a 
complication endpoint (8.1.1.2). Health-related quality of life (HRQOL) and functioning 
assessments reported by participants are described in Section 8.1.2. Furthermore, assessment of 
antiviral activity and viral sequencing is described in Sections 8.1.3 and 8.1.4, respectively.
If a participant is clinically stable and there is no safety concern, it is recommended that ePRO 
assessments as well as scheduled on-site visits are performed before use of any concomitant 
medication(s) for symptom relief (e.g. bronchodilators, cough medication). 
If multiple assessments are scheduled for the same timepoint, it is recommended that procedures 
be performed in the following sequence: ePRO, ECG, vital signs, bilateral nasal mid-turbinate 
swab, blood sampling, physical examination, and CSS. It is recommended that the vital signs are 
assessed after the participant has rested for at least 15 minutes. Urine and blood collections for PK 
and PD assessments should be kept as close to the specified time as possible. Actual dates and 
times of assessments will be recorded in the source documentation and eCRF. Repeat or 
unscheduled samples may be taken for safety reasons or for technical issues with the samples.
All ePRO assessments should preferentially be conducted/completed before any tests, procedures, 
or other consultations to prevent influencing participant responses, except for the screening 
assessment, which can take place after investigator assessment of eligibility. Refer to the ePRO 
completion guidelines for instructions on the administration of ePROs.
As ePRO assessments are required for the primary efficacy evaluation, if no translation is available 
in a language in which the participant is fluent, the participant cannot be enrolled in the study.
The ePRO device (this can be provided by the site to the participants at screening, or participants
can bring their own device) will be used to record participant’s ratings of the severity of their 
symptoms and changes in their functioning and HRQOL every day (once daily or twice daily), as 
specified in the Schedule of Activities. Electronic PRO assessments will be completed by all 
participants on the ePRO device, in a language in which the participant is fluent. Translations have 
been performed for all PRO assessments using recommended best practices for PRO research
(Wild 2009).
The investigator/study personnel will provide sufficient information (included in the study manual
and participant information guide) to enable the participants to complete the ePRO on the device 
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 ePRO device) on 
how to enter responses to questions on the ePRO device. If a participant requires assistance 
entering responses in the ePRO device, a caregiver or member of the study team who is trained 
can interview the participant and enter the participant’s responses on the ePRO device on the 
participant’s behalf.


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ePRO completion compliance should be assessed daily by the study site personnel via the ePRO 
vendor portal. If scheduled assessments are missing from the prior day, the sites will contact the 
participant to identify reason for missing PRO and document reasons for missing PRO assessments 
in the eCRF based on discussion with the participant.
On Day 28, all participants will be contacted by the study site personnel for a telephone follow-up 
visit to assess the clinical status and MRU and to check for any AEs including RSV-related 
complications.
On Day 35 (ie, the last study-related visit), a telephone follow-up will be performed with all 
participants to assess the clinical status and MRU and check for RSV-related complications. In 
addition, they will be asked to return the ePRO device to the site by courier in case no visit is 
planned. Alternatively, if an on-site visit is required, the ePRO device can be returned at the study 
visit.
In case participants have ongoing AEs or other ongoing laboratory, vital signs or ECG-related 
abnormalities at time of the Day 28 and Day 35 follow-up visit, participants might be requested, 
at the discretion of the investigator, to have a safety follow-up visit at the site if feasible (see 
Section 9.4.4 for more details on safety assessments).
Medications taken will be discussed with the investigator and recorded on the concomitant 
medication page of the eCRF.
Safety and tolerability, including AEs, laboratory assessments, ECGs, vital signs, and physical 
examination will be assessed throughout the study from signing of the main ICF until the 
participant’s last study-related activity (see Section 8.2).
Pharmacokinetic assessments during the study will be based on sparse sampling and will be 
performed using a popPK model (see Section 8.4).
Blood samples collected for biomarker research may be used for biomarker research analyses (see 
Section 8.5).
The presence of other respiratory viruses or bacteria in the nasal mid-turbinate swab samples will 
be assessed as described in Section 8.6.
Medical resource utilization data will be collected. Refer to Section 8.7 for details.
Sample Collection and Handling
The actual dates and times of sample collection must be recorded in the eCRF or laboratory 
requisition form.
Refer to the Schedule 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 


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must be under the specified, and where applicable, controlled temperature conditions as indicated 
in the laboratory manual.
Blood Sample Collection and Handling
The maximum amount of blood drawn from each participant in this study over the duration of the 
study (maximum approximately 60 mL) is considered to be acceptable for the population in this 
study. 
Repeat or unscheduled samples may be taken for safety reasons or for technical issues with the 
samples. This could increase the total blood volume.
Nasal Sample Collection and Handling
For the evaluation of antiviral activity, the RSV viral load in bilateral nasal mid-turbinate swabs 
will be measured at the central laboratory using a qRT-PCR assay (see Section 8.1.3). Viral 
sequencing will also be performed on the bilateral nasal mid-turbinate swabs (see Section 8.1.4). 
Only nasal mid-turbinate swabs provided for this study may be used. Other swabs are not 
acceptable for specimen collection as they may inhibit recovery of the pathogens. Note that in case 
of supply issues for nasal mid-turbinate swabs because of increased demand due to the COVID-
19 pandemic, alternative nasal swabs instead of nasal mid-turbinate swabs may be provided for 
nasal sample collection for the study assessments.
The presence of viral (other than RSV) or bacterial co-pathogens will be assessed in the bilateral 
nasal mid-turbinate swab sample by using multiplex PCR at the central laboratory (see 
Section 8.6).
Refer to the Schedule of Activities for the timing and frequency of all sample collections.
Study-Specific Materials
The investigator will be provided with the following supplies:

Rilematovir JNJ-53718678 IB and any addenda.

Laboratory manual.

IWRS Manual.

ePRO instruction/training guidelines.

Electronic device for ePRO assessments.

eCRF completion guidelines.

Specimen collection kits for PK, safety blood and urine samples, and bilateral nasal 
mid-turbinate swabs together with universal transport medium tubes (for use on-site and at 
home).

Materials for transport of nasal swab samples taken at home (eg, cool packs, biohazard packs, 
…).


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
Contact information page(s).

ECG machine and manual.
8.1.
Efficacy Assessments

The PRO instrument will be provided in the local language(s) in accordance with local 
guidelines.

The PRO and AE data will not be reconciled with one another.
8.1.1.
Clinical Course and Severity of RSV Infection
Clinical evaluation includes vital sign assessments (ie, body temperature, respiratory rate, 
pulse/heart rate, peripheral capillary oxygen saturation [SpO2]) and physical examination
assessments (ie, presence of wheezing or crackles/rhonchi) as measured during site visits. Clinical 
evaluation also includes evaluation of the occurrence of AEs, RSV-related complications, and need 
for medications (including antibiotics).
Furthermore, the following evaluations of the clinical course of RSV infection will be performed 
for all participants, according to the time points indicated in the Schedule of Activities.
8.1.1.1.
RSV disease symptoms
All participants will assess the severity and/or duration of symptoms of RSV disease in the ePRO 
device using the RiiQ™ Symptom Scale (see Appendix 10.11.1), the Pre-Existing Symptom 
Questionnaire (see Appendix 10.10), and 2 Patient Global Impression (PGI) questions about the 
overall severity and change in RSV disease: PGI of severity (PGI-S) (see Appendix 10.12) and 
PGI of change (PGI-C) in RSV disease (see Appendix 10.13). In addition, the investigator will 
evaluate participants to complete the CSS questionnaire (see Appendix 10.18).
RiiQ™ Symptom Scale
To evaluate the impact of rilematovir treatment on RSV disease severity and duration, participants 
will rate the severity of the 13 most common symptoms in adults (Falsey and Walsh 2000) by 
completing the RiiQSymptom Scale and rating the worst severity of their RSV symptoms from 
screening/baseline through the Day 14 visit for the past 12 hours twice daily (AM/PM), and from 
Day 15 through Day 35 once daily for the past 24 hours on the ePRO device.
Participants rate each RSV symptom on a scale from None (0), Mild (1), Moderate (2), to
Severe (3):

6 Respiratory Tract Symptoms:

URTD symptoms: sore throat and nasal congestion

LRTD symptoms: cough, wheezing, coughing up phlegm (sputum), and short of breath

7 Systemic Symptoms: headache, feeling feverish, body aches and pains, fatigue (tiredness),
neck pain, interrupted sleep, and loss of appetite.


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The RiiQSymptom Scale is one of 4 scales in the RiiQ, a 29-item PRO measure developed 
for evaluating severity of symptoms of an acute respiratory infection (RiiQSymptom Scale) and 
the impact of a respiratory infection on 3 domains of functioning and HRQOL (RiiQImpact 
Scales). Additional information on the 3 RiiQImpact Scales is provided in Section 8.1.2.
Evidence from the analysis of a longer symptom assessment used in a Phase 2 study identified 
7 Key RSV Symptoms that were most informative about severity and recovery from RSV 
symptoms in a small study of adults treated in a community setting (Study 53718678RSV2004). 
Those analyses confirmed that collection of other symptoms beyond the 7 Key RSV Symptoms 
provided little or no additional information about time to recovery of moderate to severe symptoms 
of RSV disease. The same Key RSV Symptoms were best able to differentiate mild from moderate 
or severe RSV disease reported by older adult participants who developed RSV infection during 
an RSV vaccine study (Yu 2020).
Symptoms in the RiiQSymptom Scale will be evaluated individually, as 2 subscales 
(Respiratory Tract Symptoms and Systemic Symptoms) and as the 7 Key RSV Symptoms. 
Analyses will evaluate mean scores and recovery to pre-existing severity levels based on 
symptoms reported at screening on the Pre-Existing Symptom Questionnaire.
Pre-Existing Symptom Questionnaire
The Pre-Existing Symptom Questionnaire was adapted from the RiiQSymptom Scale for this 
study to enable evaluation of recovery from an RSV infection in adults with chronic comorbid 
illness that include respiratory or systemic symptoms similar to those caused by an RSV infection.
It consists of the same 13 symptoms as assessed in the RiiQSymptom Scale but asks participants 
to describe only those symptoms present prior to the onset of their current illness due to RSV
infection (see Appendix 10.10). Participants will complete the Pre-Existing Symptom 
Questionnaire at screening after they complete the RiiQSymptom Scale to enable evaluation of 
eligibility for the study and efficacy of treatment.
Patient Global Impression of RSV
Patient Global Impression of Severity (PGI-S) is a global rating of how severe the participant’s
respiratory infection symptoms at their worst scored that day on a 1-point ordinal scale with 
responses ranging from No symptoms today (0) to Very Severe (4) (see Appendix 10.12). It will 
be used not only to provide a general impression from the participant’s perspective on the severity 
of RSV disease, but also to establish guides for interpreting how much change on other PRO 
endpoints can be considered clinically meaningful (Revicki 2008).
Participants will rate the severity of their RSV-related disease using the PGI-S once daily from 
screening/baseline through the Day 35 visit.
Patient Global Impression of Change in Severity (PGI-C) is a single item PRO aimed to capture 
the participant’s perceptions of improvement or deterioration in the severity of RSV symptoms 
compared to before the participant started taking the study intervention, important for monitoring 


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when a clinically important change in the participant’s health has occurred based on the 
participant’s own perspective. A simple 7-point ordinal response scale for the PGI-C provides a 
range from much better (3), about the same (0), to much worse (-3) (see Appendix 10.13).
Clinician Symptom Score
The RSV2008 study aims to evaluate the treatment effect of rilematovir in participants with 
moderate RSV disease and are enrolled based on the presentation of at least 2 LRTD symptoms, 
one of which needs to be at least moderate due to RSV infection. The CSS was therefore adapted 
to focus on the LRTD signs/symptoms and will be studied as an exploratory study objective (see 
Appendix 10.18).
To evaluate the impact of rilematovir treatment on RSV disease severity, clinicians will rate the 
severity of the RSV LRTD sign/symptoms in the study participants by completing the CSS 
questionnaire from screening/baseline through Day 35 as specified in the Schedule of Activities.
Five RSV LRTD sign/symptoms will be rated on a scale from None (0), Mild (1), Moderate (2), 
to Severe (3):

Cough, short of breath, wheezing, coughing up phlegm (sputum), presence of 
rales/rhonchi/crackles
This clinician rated assessment of RSV disease severity will be based on the information on an 
individual participant (history, underlying comorbidity, baseline disease characteristics), overall 
clinical evaluation as well as interview of the participants on their symptoms. During each 
assessment, clinician will select the level that most accurately describes the severity of the 
participant’s symptoms. The clinician then indicates the score for each item in the ‘score’ column 
provided.
8.1.1.2.
Complications of RSV infection
Treatment comparisons will evaluate the potential of rilematovir to reduce the incidence and 
severity of complications with onset after treatment initiation that are associated with RSV disease.
Complications (including all RSV-related pulmonary and extrapulmonary complications) will be 
determined based on predefined criteria taking into account the investigator’s assessment of 
available clinical data (eg, chest X-ray results, lab results) and will be documented as AEs in the 
eCRF.

Pulmonary complications are defined as:

Primary viral pneumonia: a progressive event involving the lower respiratory tract with 
bilateral and/or diffuse radiological findings. No bacterial agent is identified in sputum 
cultures.

Bronchitis.

Respiratory failure: defined as either hypoxemic respiratory failure characterized by an 
arterial oxygen tension (PaO2) lower than 60 mmHg with a normal or low arterial carbon 


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dioxide tension (PaCO2), or hypercapnic respiratory failure characterized by a PaCO2
higher than 50 mmHg.

Secondary bacterial pneumonia (including pneumonia attributable to unusual pathogens): 
a clinical event compatible with lower respiratory tract involvement, with lobar infiltrates 
on radiological studies and/or microbiological isolate of a bacterial pathogen, including 
unusual pathogens in sputum cultures.

Exacerbations of underlying chronic pulmonary diseases such as COPD and asthma: 
participants with documented medical history of COPD or asthma with a sudden 
worsening of symptoms and deteriorating respiratory function (the latter as evidenced by 
worsening hypoxia, tachypnea, etc.). The event must start before a full recovery from the 
RSV infection occurred.

Extrapulmonary complications are defined as:

Cardiovascular and cerebrovascular disease events (eg, myocardial infarction, atrial 
fibrillation, stroke).

Acute heart failure or exacerbation of underlying CHF: participants with documented 
medical history of CHF with a sudden worsening of symptoms and deteriorating 
respiratory function.

Acute exacerbation of chronic kidney disease (CKD).

Severe dehydration.

Decompensation of previously controlled diabetes mellitus.

Other respiratory infections.
8.1.1.3.
Other measures of RSV-related disease progression
Respiratory therapeutic interventions associated with RSV-related disease progression after the 
start of rilematovir treatment will be evaluated by the proportion of participants with new antibiotic 
use, or new or increased use in bronchodilator/nebulizer, systemic corticosteroids, or home oxygen 
supplementation up to Day 35. In addition, any medical attendance for the respiratory infection 
after the start of rilematovir will be assessed by the proportion of participants with unscheduled 
outpatient clinic visits, emergency room visits or hospitalization for respiratory infection (MARIs)
during the study period up to Day 35.
8.1.2.
Functioning and Health-related Quality of Life
Although RSV disease usually resolves within a few weeks, the morbidity caused by respiratory 
and systemic symptoms can make it difficult for people to do things they would ordinarily do, and 
cause worry about how long the illness will last and how much they are dependent on or burdening 
others close to them (Osborne 2011, Scott 2018).
The impact of treatment on the degree to which RSV symptoms interfere with the participant’s 
routine functioning and HRQOL will be assessed by all participants in the ePRO device using the 
the Hours Missed from Work question (see Appendix 10.17; this question will only be asked if the 
participant or on other member of his household is employed [see Appendix 10.16]), the RiiQ™ 


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Impact Scales (see Appendix 10.11.2),
the Return to Usual activities question (see 
Appendix 10.14), the Return to Usual Health question (see Appendix 10.15), and the 5-level 
EuroQol© 5-Dimension (EQ-5D-5L) questionnaire (see Appendix 10.19), at the timepoints 
specified in the Schedule of Activities.
Hours Missed from Work
Participants who indicate during the first Day 1 assessment that at least one person in their 
household was employed will be asked to report the total number of hours missed from work by 
all members of the participant’s household, including the participant, due to RSV (see 
Appendix 10.16 and Appendix 10.17). The participant will complete this question on the ePRO 
device at the timepoints specified in the Schedule of Activities. This question was created for this 
study to help address the paucity of information on the impact RSV in adults on hours missed from 
work.
Respiratory syncytial virus, like most acute respiratory infections, can result in debilitating illness 
that causes patients or their family members who care for them to miss time from work (Tsai 2014).
Much of the research on the impact of RSV on work loss and productivity has focused more on 
the parents of young children with RSV. In adults, high risk of severe RSV disease is well 
documented for older adults who may no longer be in the workforce but may require support from 
a family member during their illness has not been extensively studied (Falsey and Walsh 2000). 
However, one study of 10 healthy hospital staff with natural RSV infections found that 8 of 10 
missed work for an average of 6 days due to their RSV disease (Hall WE 1978). Until recently, 
diagnostic testing in adults to discriminate viral pathogens has generally been limited to screening 
for influenza. As testing for COVID-19 and other viruses increases, the research on work-related 
impact of RSV in adults is expected to increase. Evidence from the current study is expected to 
add to this growing body of evidence of the economic burden of RSV disease on patients and their 
families.
RSV-specific HRQOL
To understand the impact of an acute episode of RSV infection on participant’s daily lives, 
participants will report on their functioning and disease specific HRQOL using the 3 
RiiQ™Impact Scales (see Appendix 10.11.2):

RiiQ™ Impact on Daily Activities Scale (RiiQ-DAS) that asks about any difficulty that 
participants may have had performing 7 activities of daily living (get out of bed, prepare
meals, perform usual activities, leave the home, concentrate on tasks, take care of self, and go 
out of the room you are in) using the response options No difficulty (0), Some difficulty (1), 
Moderate difficulty (2), and Great difficulty (3).

RiiQ™ Impact on Emotions Scale (RiiQ-IES) that asks participants to report on impacts 
to 4 specific moods and emotions (irritable, helpless, worried, and frustrated) using the 
response options Not at all (0), Somewhat (1), Moderately (2), and Extremely (3).


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
RiiQ™ Impact on Others Scale (RiiQ-IOS) that asks participants to indicate the extent to 
which they have been concerned about 5 specific social and interpersonal impacts (people 
worrying about you, being a burden, people being annoyed with you, needing to depend on 
people, and people having to do extra things for you) using the response options Not at all 
concerned (0), Somewhat concerned (1), Moderately concerned (2), and Extremely 
concerned (3).
The RiiQImpact Scales can be administered individually or together with or without the RiiQ
Symptom Scale as required for the study setting. Each scale takes less than 2 minutes to complete.
Evidence to support the adequacy of the development and validation of these scales for studies in 
adults with influenza-like illness has been described (Osborne 2011) and their use for 
understanding the impact of influenza on older adults has been reported (van Essen 2014).
Participants will complete the RiiQ™ Impact Scales on the ePRO device once daily in the evening 
(PM) from Day 1 (as close as possible and before the first study intervention administration) 
through the Day 35 visit.
Analyses will evaluate change over time in RiiQ™ Impact Scale scores computed as the mean of 
the items for each scale.
Generic HRQOL and Health Utilities
To enable comparison of the impact of RSV treatment on HRQOL as compared to HRQOL 
reported in the general population or in treatments for other medical conditions, participants will 
rate their HRQOL using the generic EQ-5D-5L at baseline, Day 3, Day 14, and Day 21 visits (see 
Schedule of Activities and Appendix 10.19). The EQ-5D-5L takes only 2-3 minutes to complete.
EQ-5D-5L was developed to be applicable to a wide range of health conditions and treatments as 
a brief, simple assessment of health status. It includes 6 cognitively undemanding questions that 
provide a profile on 5 HRQOL domains: Mobility, Self-Care, Usual Activities, Pain/Discomfort, 
and Anxiety/Depression. Domains can be analyzed descriptively as separate outcomes or 
combined in a single index of health status that can be used in the clinical and economic evaluation 
of health care. In addition, EQ-5D-5L contains a visual analog scale (VAS) asking participants 
‘how good or bad is your health TODAY’ on a scale with endpoints labeled ‘the best health you 
can imagine’ and ‘the worst health you can imagine’ that provides a quantitative measure of overall 
health as judged by the individual participants (Reenan 2015).
EQ-5D-5L is designed for self-completion either on electronic devices or using paper-and-pencil 
questionnaires and can be administered as an interview either face-to-face or by telephone. 
Instructions to participants are included in the questionnaire, and separate instructions for 
interview administration are provided.


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8.1.3.
Antiviral Activity
As an evaluation of antiviral activity, the RSV viral load in nasal secretions, obtained via a bilateral
nasal mid-turbinate swab sample, will be measured at the central laboratory using a qRT-PCR 
assay. The qRT-PCR used to determine RSV viral load will also provide information on the RSV 
subtype. Bilateral nasal mid-turbinate swab specimens for the determination of RSV viral load will 
be collected at several time points during the study as indicated in the Schedule of Activities. A
nasal mid-turbinate swab should be collected from each nostril and both swabs should be put in 
the same universal transport medium tube (ie, a bilateral nasal mid-turbinate swab sample). Only 
at times when sampling of both nostrils is not feasible, such as in case of bleeding in one nostril, 
one nasal mid-turbinate swab should be collected from one nostril (ie, the non-bleeding nostril).
The baseline bilateral nasal mid-turbinate swab should be collected as close as possible and prior 
to the first administration of study intervention (on Day 1). If a study-specific screening bilateral 
nasal mid-turbinate swab was collected within 8 hours prior to dosing, the leftover of that sample 
can serve as the baseline predose sample, provided that the study-specific screening bilateral nasal 
mid-turbinate swab sample was stored appropriately and has sufficient sample volume available
(volume is considered sufficient if no more than 600 μL from the original sample has been used 
for local RSV testing and the entire remainder of the original sample is available). Only in such 
case, no additional sample needs to be collected at Day 1 predose. The next swabs should be 
collected preferably at approximately the same time as on Day 1 each day (see Schedule of 
Activities). During scheduled visits on Day 3, Day 8, Day 14 and Day 21, bilateral nasal 
mid-turbinate swabs will be collected by a health care practitioner. On Day 2 and Day 5, bilateral 
mid-turbinate nasal swabs are collected at home preferably by a health care practitioner and, only 
if not possible by an health care practitioner, by the participant (or his/her spouse, partner, relative, 
or other caregiver) after being properly trained by the investigator/study-site personnel (Figure 3). 
In case preferred by the participant, all bilateral mid-turbinate swabbing may also be performed at 
the site. The collection of these nasal swabs and date and time of sampling should be recorded for 
all participants in the eCRF. All participants will be given appropriate nasal mid-turbinate swabs 
and universal transport medium (same supplies as those used to collect nasal samples at the sites) 
to collect nasal mid-turbinate swabs. All swabs collected at home should be stored immediately 
between 2°C and 8°C (in the refrigerator) and brought to the site at the latest at the Day 3 and the 
Day 8 visit.


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Figure 3:
Schedule for Collection of Bilateral Nasal Mid-Turbinate Swab Samples
D: Day, hrs: hours, min: minimum, MT: mid-turbinate, RSV: respiratory syncytial virus, SOC: standard-of-care.
Additional information about the collection, handling, and shipment of biologic samples can be 
found in the laboratory manual.
Changes in viral load will be evaluated but will not be reported as AEs.
8.1.4.
Viral Sequencing
Viral resistance will be monitored by sequencing of the RSV F gene in all baseline samples and in 
post-baseline samples upon request of the sponsor’s protocol virologist. Other regions of the RSV 
genome may also be sequenced at the request of the sponsor’s virologist. Sequencing results may 
be presented in a separate report. Sequencing data will not be reported to the investigators.
Changes in viral sequence will be evaluated but will not be reported as AEs.
8.2.
Safety Assessments
Details regarding the IDMC are provided in Committees Structure in Appendix 10.3. The PRO 
and AE data will not be reconciled with one another.
Adverse events will be reported and followed by the investigator as specified in Section 8.3 and 
Appendix 10.4.
Any clinically relevant changes occurring during the study must be recorded on the AE section of 
the eCRF.


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Any clinically significant abnormalities persisting at the end of the study/early withdrawal will be 
followed by the investigator until resolution or until a clinically stable condition is reached.
The study will include the following evaluations of safety and tolerability according to the time 
points provided in the Schedule of Activities.
8.2.1.
Physical Examinations
A complete physical examination (including height and body weight measurements) will be 
performed at screening. A targeted physical examination will be performed at the other site visits 
(see Schedule of Activities) and includes evaluation of body weight (Day 21 only), the respiratory 
system, nose, ear, throat, and facial and neck lymph nodes.
Any clinically relevant changes occurring during the study must be recorded in the AE section of 
the eCRF. Clinically relevant findings present at screening will be reported as medical history, any 
worsening of these findings during the study must be reported as an AE.
8.2.2.
Vital Signs
Body temperature, pulse/heart rate, respiratory rate, and SpO2 will be assessed as part of the 
clinical parameters (see Section 8.1.1). Additional vital signs assessments include systolic blood 
pressure and diastolic blood pressure. It is recommended that the vital signs are assessed after the 
participant has rested for at least 15 minutes.
Blood pressure and pulse/heart rate measurements will be assessed in a sitting or supine position 
(same position at each measurement) with a completely automated device. Manual techniques will 
be used only if an automated device is not available.
8.2.3.
Electrocardiograms
Twelve-lead ECGs will be collected at the time points specified in the Schedule of Activities and 
when clinically indicated or to confirm abnormal ECG findings.
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 multiple assessments are scheduled for the same time point as ECG recording, the procedures 
should be performed in the following order: ePRO, ECG(s), vital signs, bilateral nasal mid-
turbinate swab, blood sampling, physical examination, and CSS.
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.


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For eligibility determination, the machine read ECG results, printed on the ECG device print-out 
of the ECG tracing, will be used. 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 8.3.7.2). 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 
the results have become available. Evaluation of clinical relevance should be done on confirmed 
results.
8.2.4.
Clinical Safety Laboratory Assessments
Blood samples for serum chemistry and hematology and a urine sample for urinalysis will be 
collected as noted in Appendix 10.2. 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 CRF. The laboratory reports must be filed with the source documents. If a participant has a 
laboratory abnormality that meets the liver safety management discontinuation criteria (see 
Appendix 10.6), the participant should be permanently discontinued from the study intervention 
and the study. If a participant has any other Grade 3 or Grade 4 laboratory abnormality during the 
treatment period, confirmation needs to be obtained by a repeat test (local lab), to be performed 
within 48 hours of the result being available at the site. Please refer to the study intervention 
discontinuation guidance in Section 7.1.
8.2.5.
Pregnancy Testing
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 (see Schedule of Activities).
8.3.
Adverse Events, Serious Adverse Events, and Other Safety Reporting
Timely, accurate, and complete reporting and analysis of safety information, including AEs, SAEs, 
and product quality complaint (PQC), from clinical studies are crucial for the protection of 
participants, investigators, and the sponsor, and are mandated by regulatory agencies worldwide. 
The sponsor has established Standard Operating Procedures in conformity with regulatory 
requirements worldwide to ensure appropriate reporting of safety information; all clinical studies 
conducted by the sponsor or its affiliates will be conducted in accordance with those procedures.
Adverse events will be reported by the participant (or, when appropriate, by a caregiver, surrogate, 
or the participant's legally acceptable representative) for the duration of the study.
Complications associated with RSV disease as listed in Section 8.1.1.2 are considered events of 
interest. Additional data related to these events are collected when available and will be captured 
separately in the eCRF.


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Anticipated events for this study are defined in Appendix 10.9 and will be recorded and reported 
as described in Section 8.3.4.
Further details on AEs, SAEs, and PQC can be found in Appendix 10.4.
8.3.1.
Time Period and Frequency for Collecting Adverse Event and Serious 
Adverse Event Information
All Adverse Events
All AEs and special reporting situations, whether serious or non-serious, will be reported from the 
time a signed and dated ICF is obtained until completion of the participant's last study-related 
procedure, which may include contact for follow-up of safety. Anticipated events will be recorded 
and reported as described in Appendix 10.9.
For participants having signed a diagnostic ICF only (ie, who do not enroll in the study by signing 
the main ICF), only study procedure-related AEs will be reported.
Serious Adverse Events
All SAEs, as well as PQC, occurring during the study must be reported to the appropriate sponsor 
contact person by study site personnel within 24 hours of their knowledge of the event.
Serious adverse events, including those spontaneously reported to the investigator within 30 days
after the last dose of study intervention, must be reported using the SAE form. The sponsor will 
evaluate any safety information that is spontaneously reported by an investigator beyond the time 
frame specified in the protocol.
Information regarding SAEs will be transmitted to the sponsor using the Serious Adverse Event 
Form and Safety Report Form of the CRF, which must be completed and reviewed by a physician 
from the study site, and transmitted to the sponsor within 24 hours. The initial and follow-up 
reports of an SAE should be transmitted electronically or by facsimile (fax). Telephone reporting 
should be the exception and the reporter should be asked to complete the appropriate form(s) first.
8.3.2.
Method of Detecting Adverse Events and Serious Adverse Events
Care will be taken not to introduce bias when detecting AEs or SAEs. Open-ended and nonleading 
verbal questioning of the participant is the preferred method to inquire about AE occurrence.
8.3.3.
Follow-up of Adverse Events and Serious Adverse Events
The investigator is obligated to perform or arrange for the conduct of supplemental measurements 
and evaluations as medically indicated to elucidate the nature and causality of the AE, SAE, or 
PQC as fully as possible. This may include additional laboratory tests or investigations, 
histopathological examinations, or consultation with other health care professionals.
Adverse events including those related to pregnancy outcomes will be followed by the investigator 
as specified in Appendix 10.4.


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8.3.4.
Regulatory Reporting Requirements for Serious Adverse Events and 
Anticipated Events
The sponsor assumes responsibility for appropriate reporting of AEs to the regulatory authorities. 
The sponsor will also report to the investigator (and the head of the investigational institute where 
required) all suspected unexpected serious adverse reactions (SUSARs). The investigator (or 
sponsor where required) must report SUSARs to the appropriate IEC/IRB that approved the 
protocol unless otherwise required and documented by the IEC/IRB. A SUSAR will be reported 
to regulatory authorities unblinded. Participating investigators and IEC/IRB will receive a blinded 
SUSAR summary, unless otherwise specified.
An anticipated event is an AE (serious or non-serious) that commonly occurs in the study 
population independent of exposure to the drug under investigation. For the purposes of this study 
the SAEs that will be considered anticipated events are listed in Appendix 10.9.
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 intervention group than in the 
control group and the sponsor concludes there is a reasonable possibility that the drug under 
investigation caused the anticipated event.
The plan for monitoring and analyzing the anticipated events is specified in a separate Anticipated 
Events Safety Monitoring Plan. The assessment of causality will be made by the sponsor’s 
unblinded safety assessment Committee.
The sponsor assumes responsibility for appropriate reporting of the listed anticipated events 
according to the requirements of the countries in which the studies are conducted.
8.3.5.
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 SAEs and must be reported using an SAE reporting form. Any participant who becomes 
pregnant during the study must be promptly withdrawn from the study and discontinue further 
study intervention.
Because the study intervention 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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8.3.6.
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.
The terms “disease progression” and “complication of RSV” should not be recorded as an AE or 
SAE term; instead, signs and symptoms of clinical sequelae resulting from disease progression 
(including complications) will be reported as AE or SAE terms (refer to AE Definitions and 
Classifications in Appendix 10.4).
8.3.7.
Safety Areas of Evaluation
8.3.7.1.
Safety Topic of Special Interest: Hepatobiliary effects
Refer to Appendix 10.2 for protocol-required safety laboratory assessments. The severity grade of 
laboratory abnormalities in liver function tests is assessed using the criteria specified in the 
Division of Microbiology and Infectious Diseases (DMID) Toxicity Table (see Appendix 10.7).
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-glutamyl transferase [GGT]) 
may be performed at the discretion of the investigator, during unscheduled visits.
A liver safety management plan is implemented which is based on screening results after the 
laboratory results become available to the site (see Appendix 10.6).
For any Grade 3 or 4 laboratory abnormalities that occurred at Day 7/8, and Day 21 visits, 
participants should have a confirmatory measurement via the central lab, preferably within 48 
hours after the laboratory results become available to the site. For confirmed Grade 3 or 4 
laboratory abnormalities, participants should be followed until resolution (return to baseline) or 
stabilization of liver enzymes (ALT, aspartate aminotransferase [AST], bilirubin) elevation.
During the study, these assessments will be captured as unscheduled assessments/visits.
8.3.7.2.
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 as per the Schedule of Activities.
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 QTc value. Confirmation 
needs to be obtained immediately by another ECG machine read, locally at the site (see 
Section 7.1).
For participants with a confirmed QTc interval value >500 ms, the following measures should be 
taken:

The cardiac event must be reported to the sponsor within 24 hours.


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
The investigator should request urgent cardiology referral, within 24 hours if possible.

Clinical evaluation including safety biochemistry (such as electrolytes), assessment of the use 
of concomitant QT prolonging drugs, and evaluation for the presence of any structural heart 
disease must be conducted. Levels of potassium and magnesium to be determined by the local 
and by the central laboratory at the timepoint specified in the Schedule of Activities.

In case of hypokalemia and/or hypomagnesemia at screening or at any of the visits in the study 
period, the levels of potassium and magnesium should be corrected by 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 (central ECG) 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 and/or 
hypomagnesemia of <0.9 mEq/L in samples taken at screening or any time during the study 
intervention treatment period, following measures should be taken:  

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 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.
Pharmacokinetics
Blood samples will be used to evaluate the PK of rilematovir. Pharmacokinetic parameters will be 
determined using a popPK approach by means of nonlinear mixed-effects modeling. 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. Participant confidentiality will be maintained.
8.4.1.
Evaluations
Venous blood samples of approximately 2 mL per sample will be collected for measurement of 
plasma concentrations of rilematovir at time points indicated in the Schedule of Activities. 
Samples can also be used for the analysis of metabolites of rilematovir, excipients, protein binding,


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or endogenous markers for enzymes or transporters involved in the metabolism and distribution of 
rilematovir, at the discretion of the sponsor.
The following times need to be recorded: actual dates and times of study intervention
administration on the day of the visit and the previous and the next day and actual dates and times 
of PK blood sampling. In addition, it should be documented whether the study intervention 
administration (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).
8.4.2.
Analytical Procedures
Pharmacokinetics
Plasma samples will be analyzed to determine concentrations of rilematovir and/or metabolites as 
applicable
using 
a 
validated, 
specific, 
and 
sensitive 
liquid 
chromatography-mass 
spectrometry/mass spectrometry method by or under the supervision of the sponsor.
8.4.3.
Pharmacokinetic Parameters and Evaluations
Parameters
Population PK analysis of plasma concentration-time data of rilematovir will be performed using 
nonlinear mixed-effects modeling. Based on the individual concentration-time data, using the 
actual dose taken and the actual sampling times, PK parameters and exposure information of 
rilematovir will be derived using popPK modeling, including, but not limited to: AUC, Ctrough, and 
possibly Cmax. Baseline covariates (eg, body weight, age, sex, creatinine clearance, race) may be 
included in the model, if relevant. Other PK parameters may be determined at the discretion of the 
sponsor if deemed useful to evaluate the PK of the analytes in scope. Data may be combined with 
those of other selected studies (ie, Phase 1 and 2 studies) to support a relevant structural model. 
The results of the popPK analysis will be reported in a separate report.
Data will be listed for all participants with available plasma concentrations per treatment arm. 
Participants will be excluded from the PK analysis if their data do not allow for accurate 
assessment of the PK (eg, incomplete administration of the study intervention, missing information 
of dosing and sampling times, concentration data not sufficient for PK parameter calculation).
All concentrations below the lowest quantifiable concentration or missing data will be labeled as 
such in the concentration database. All participants and samples excluded from the analysis will 
be clearly documented in a separate PK report.
Pharmacokinetic/Pharmacodynamic Evaluations
The PK/PD relationship of rilematovir exposure (AUC0-24h, Cmax, or Cmin) with selected efficacy 
(change in viral load from baseline and clinical outcomes) and safety (including laboratory 
abnormalities and AEs) parameters will be explored. If there is any visual trend in graphical 
analysis, suitable models will be applied to describe the exposure-effect relationships. The results 
of the PK/PD analysis will be reported in a separate report.


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8.5.
Biomarkers
Blood samples for biomarker research will be collected at time points indicated in the Schedule of 
Activities and may be used for biomarker research (eg, host RNA, proteins including cytokines, 
cellular phenotyping), on the premise that these markers may play a role in the treatment response, 
safety or PK of rilematovir, or in RSV-related disease. Leftover nasal mid-turbinate swabs and 
blood samples collected for other testing may be used as well for the same purpose. Analyses of 
biomarkers will be conducted at the sponsor’s discretion and may be reported separately from this 
study.
8.6.
Detection of Baseline Presence of Other Respiratory Viruses or Bacteria
The presence of other respiratory viruses (other than RSV) or bacteria will be assessed in the 
bilateral nasal mid-turbinate swab sample collected at baseline (Day 1 predose or screening) by 
multiplex PCR at the central laboratory. Bilateral nasal mid-turbinate swabs from other time points 
may also be analyzed for detection of other respiratory viruses or bacteria, if deemed necessary.
8.7.
Medical Resource Utilization
Medical resource utilization data, associated with medical encounters, will be collected in the 
eCRF by the investigator and study site personnel for all participants throughout the study. 
Protocol-mandated procedures, tests, and encounters are excluded. The data collected will be used 
to conduct secondary efficacy analyses (use of respiratory therapeutic interventions as well as 
medically attended visits) and may be used to conduct exploratory economic analyses. Medical 
resource utilization will include:

Number and duration of medical care encounters (eg, increased nursing visits at home, 
emergency room [ER] visit).

Number (proportion) of participants requiring hospitalization for respiratory/other reasons and 
duration of hospitalization (total days length of stay, including duration by wards; eg, ICU).
In the event of hospitalization during the study, investigators must make every effort to collect 
details of hospitalization as feasible, including the reason and duration of hospitalization.

Incidence of antibiotic treatment.

Any new or increased use of systemic or inhaled corticosteroids and bronchodilators use.

New or increased use of oxygen therapy.

Duration of selected post-baseline (after start of study intervention) MRU.
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, safety, PK and PK/PD data 
are outlined below. Specific details will be provided in the Statistical Analysis Plan (SAP).
9.1.
Statistical Hypotheses
As this an exploratory, hypothesis-generating study, no formal statistical testing will be performed.


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9.2.
Sample Size Determination
The study will aim to enroll approximately 180 participants in a 2:1 ratio to rilematovir 
250 mg twice daily (approximately 120 participants) and placebo (approximately 60 participants).
The sample size calculation is based on the primary efficacy endpoint, which is the time to 
resolution of RSV LRTD symptoms from randomization up to Day 35 in the ITT-i analysis set.
With a sample size of 180 participants, there is an 80% probability to demonstrate a reduction of 
at least 20% in the primary efficacy endpoint when the true effect is 30%. As further guidance for 
the sample size of this study, the power to detect a treatment difference for the primary efficacy 
endpoint is also calculated.
An AFT model with underlying log-normal distribution for the time to resolution is assumed with 
a median in a placebo arm of 14 days and a scale parameter of 0.8 (as observed in 
Study 51738678RSV2004). Using the Gehan-Wilcoxon test to analyze the data and based on the 
assumptions that the time to recovery is improved by 30%, that approximately 10% of the total 
enrolled participants may not be centrally confirmed RSV positive, and that 5% of patients may 
drop out of the study early before reaching resolution of their RSV LRTD symptoms, a sample 
size of 180 participants (randomized in a 2:1 ratio to rilematovir 250 mg twice daily and placebo) 
will have an estimated power of 80% as based on 10,000 simulations using a 10% 2-sided 
significance level. The power was estimated as the number of simulated studies where the 2-sided 
p value from the Gehan-Wilcoxon test was <0.1 out of the 10,000 simulated datasets.
9.3.
Populations for Analysis Sets
For purposes of analysis, the following analysis sets are defined:
Analysis Sets
Description
Enrolled
All participants who sign the main ICF.
Randomized
All participants who were randomized in the study.
ITT-i
All participants who were randomized and treated (at least one dose) and had RSV infection 
confirmed by central laboratory analysis. Participants with confirmed SARS-CoV-2 infection 
(positive test by central laboratory analysis) are excluded. This analysis set will be used for 
the analysis of efficacy endpoints, as randomized.
Safety
All participants who took at least 1 dose of study intervention. This analysis set will be used 
for the analysis of safety endpoints, as treated. 
Pharmacokinetic
All participants in the ITT-i set. Participants will be excluded from the PK analysis set if
their data do not allow for accurate assessment of the PK parameters (eg, incomplete 
administration of the study intervention; missing information of dosing and sampling times).
9.4.
Statistical Analyses
9.4.1.
General Considerations
The SAP 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.


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9.4.2.
Participant Information
For all participants who received at least 1 dose of study intervention, descriptive statistics will be 
provided (safety analysis set).
All demographic (eg, age, height, weight, race, gender), other initial participant characteristics 
(physical examination, medical and surgical history, concomitant diseases), and RSV disease 
characteristics (eg, subtype, time since symptom onset) will be tabulated and analyzed 
descriptively by intervention group.
9.4.3.
Efficacy Analysis
The primary analysis set for the efficacy analyses will be the ITT-i.
9.4.3.1.
Primary endpoint
The primary endpoint is the time to resolution of RSV LRTD symptoms from initiation of study 
treatment up to Day 35 as assessed by the participant using the RiiQ™ Symptom Scale. The RSV 
LRTD symptoms are defined as the following symptoms from the RiiQ Symptom Scale: cough, 
short of breath, wheezing, and coughing up phlegm (sputum).
Resolution of RSV LRTD symptoms in participants without pre-existing conditions is reached
when all RSV LRTD symptoms in the RiiQ Symptom Scale are scored as ‘None’ (score = 0) or 
‘Mild’ (score =1) for at least 24 hours.
Resolution of RSV LRTD symptoms in participants with pre-existing conditions is reached when:
–
Pre-existing symptoms that were worse at baseline have improved at least 1 point from 
baseline for at least 24 hours; and
–
Pre-existing symptoms that were not worse at baseline have not worsened from baseline 
severity for at least 24 hours; and
–
Symptoms that were not pre-existing at baseline should be scored as ‘None’ (score = 0) or 
‘Mild’ (score =1) for at least 24 hours.
The primary efficacy endpoint will be estimated using an AFT model adjusted by the 
randomization factors (high-risk and time since symptom onset) and baseline RSV LRTD 
symptom domain score. 
Kaplan‑Meier curves as well as KM estimates of median time to resolution will also be provided.
9.4.3.1.1.
Estimand
The primary estimand attributes are as follows:

Population: outpatient adults (≥18 to ≤85 years of age) who are at high risk of RSV-
related disease progression, with at least 2 LRTD symptoms due to RSV infection, with 
at least one of which needs to be at least moderate (if symptom did not pre-exist before 


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RSV onset), or is scored worse than usual (if symptom pre-existed before RSV onset) 
with time since symptom onset ≤72 hours, with RSV infection (based on local 
laboratory analysis), without SARS-CoV-2 infection (based on clinical diagnosis 
and/or local laboratory analysis). High-risk condition(s) for RSV-related disease 
progression is defined as:

Presence of any of the underlying high-risk comorbid cardiopulmonary conditions 
(COPD, asthma, or CHF) AND/OR

≥65 years of age (elderly participants).
A. Study intervention:

Rilematovir + SOC

Placebo + SOC
B. Variable: time to resolution of RSV LRTD symptoms from initiation of study treatment up to 
Day 35.
C. Summary measure: ratio of treatment medians.
D. Intercurrent events and corresponding strategies:
Treatment discontinuation 
Treatment policy strategy
Death
Composite strategy
Hospitalization
Treatment policy strategy
Major protocol deviation: missing more than 
4 doses
Treatment policy strategy
Major protocol deviation: Use of prohibited 
medication
Treatment policy strategy
Use of symptomatic medication (e.g. 
bronchodilators): started or changed during 
treatment phase
Composite strategy
Respiratory viral co-infections (e.g. co-
infection with SARS-CoV-2 (as per local 
laboratory, but not confirmed by central 
laboratory) 
Treatment policy strategy
COVID-19 vaccination
Treatment policy strategy
9.4.3.2.
Secondary clinical endpoints
The proportion of participants with complications (including all RSV-related pulmonary and 
extrapulmonary complications) from initiation of study treatment up to Day 35 will be analyzed 
using a logistic regression. Stratification factors will be added as covariates to the model. Similarly, 
all the secondary binary endpoints will be analyzed using a logistic regression.


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All time-to-event secondary efficacy analyses will be analyzed similarly to the primary endpoint.
Changes from baseline over time as assessed by PRO questionnaires will be analyzed using a 
mixed-effect model with repeated measurements (MMRM). This analysis includes fixed 
categorical effects of treatment, randomization strata, time and treatment-by-time interaction, as 
well as the continuous covariates of baseline score and baseline score-by-time interaction.
9.4.3.3.
Antiviral activity
Antiviral activity will be determined based on measurements of RSV viral load in nasal 
mid-turbinate swab samples by a qRT-PCR assay. These data will be analyzed graphically. For 
continuous variables, descriptive statistics (n, mean, SD, median, minimum, and maximum) will 
be calculated. For categorical variables, frequency tables will be presented.
Mean log10 viral load values over time will be analyzed using MMRM. Differences between 
intervention groups in viral load, and the difference in the RSV viral load AUC through Days 3, 
5, and 8 between intervention groups will be derived using appropriate contrasts deriving least 
square mean differences, including the 90% 2-sided confidence intervals.
The relationship between antiviral activity and baseline characteristics, including but not limited 
to RSV viral subtype and genotype will be explored.
9.4.3.4.
Viral sequencing
The results of viral sequencing will be evaluated by the sponsor virologist. Pre-treatment genetic 
variations and relevant post-baseline changes in the RSV F gene (and other regions of the RSV 
genome, if applicable and on request of the sponsor virologist) will be tabulated and described. 
The effect of pre-treatment RSV F protein genetic variations and relevant post-baseline RSV F 
protein amino acid changes on antiviral response and/or clinical outcomes will be explored.
9.4.4.
Safety Analyses
Safety data will be presented descriptively. For safety, baseline is defined as the last assessment 
prior to the first administration 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). Any AE occurring at or after the initial 
administration of study intervention through the end of the study is considered to be 
treatment-emergent. 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, or who experience a severe or 
an SAE.


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Clinical Laboratory Tests
Laboratory data will be summarized by type of laboratory test. Reference ranges will be used in 
the summary of laboratory data. Descriptive statistics will be calculated for each laboratory analyte 
at baseline and for observed values and changes from baseline at each scheduled time point. 
Changes from baseline results will be presented in pre- versus post-intervention cross-tabulations 
(with classes for below, within, and above normal ranges). A listing of participants with any 
laboratory results outside the reference ranges will be provided. A listing of participants with any 
markedly abnormal laboratory results will also be provided (as defined in Appendix 10.7).
The laboratory abnormalities will be determined according to the criteria specified in the DMID 
adult toxicity table (as defined in Appendix 10.7) and in accordance with the normal ranges of the 
clinical laboratory if no gradings are available.
Electrocardiogram
The effects on cardiovascular variables will be evaluated by means of descriptive statistics and 
frequency tabulations and pre- vs post-intervention cross-tabulations. These tables will include 
observed values and changes from baseline values (the predose ECG will be used as baseline).
The ECG variables that will be analyzed are heart/pulse rate, PR interval, QRS interval, QT 
interval, and corrected QT (QTc) interval using the following correction methods: QT corrected 
according to Bazett's formula (QTcB), QT corrected according to Fridericia's formula (QTcF) 
(Bazett 1920, Hodges 1983, ICH 2005, Sagie 1992).
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.
The percentage of participants with ECG abnormalities will be tabulated by treatment.
Vital Signs
Descriptive statistics of respiratory rate, pulse/heart rate, SpO2, body temperature, and blood 
pressure (systolic and diastolic) will be summarized at each scheduled time point. The percentage 
of participants with values beyond clinically important limits will be summarized by treatment.
9.4.5.
Other Analyses
Pharmacokinetic Analyses
Pharmacokinetic analysis set of plasma concentration-time data of rilematovir will be performed 
using nonlinear mixed-effects modeling. Data may be combined with those of other selected 
studies to support a relevant structural model. Available baseline participant characteristics 


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(demographics, laboratory variables, genotypes, race, etc.) will be tested as potential covariates 
affecting PK parameters. Details will be given in a PK analysis set plan and the results of the PK 
analysis set will be presented in a separate report.
A snapshot date for PK samples to be analyzed will be defined, if required. Samples collected 
before this date will be analyzed for rilematovir and included in the PK analysis set. Samples 
collected after the snapshot date will be analyzed at a later date and may be included in a PK re-
analysis set when they become available after database lock.
Data will be listed for all participants with available plasma concentrations per intervention group. 
Participants will be excluded from the PK analysis if their data do not allow for accurate 
assessment of the PK (eg, incomplete administration of the study intervention; missing information 
of dosing and sampling times; concentration data not sufficient for PK parameter calculation).
All concentrations below the lowest quantifiable concentration or missing data will be labeled as 
such in the concentration database. All participants and samples excluded from the analysis will 
be clearly documented in the study report.
For each intervention group, descriptive statistics, including arithmetic mean, SD, coefficient of 
variation, median, minimum, and maximum will be calculated for all individual derived PK 
parameters (ie, Ctrough, Cmax, and AUC0-12h) including exposure information of rilematovir, and, if 
applicable, of metabolites and/or endogenous markers.
Pharmacokinetic/Pharmacodynamic Analyses
Relationships of rilematovir population-derived exposure parameters with selected antiviral 
activity parameters, clinical outcomes, and safety endpoints will be explored. These relationships 
will be presented in a tabular and/or graphical display. The results of the PK/PD analysis may be 
conducted at the sponsor’s discretion and reported separately from this study.
Biomarkers Analyses
Statistical approaches to explore correlations between clinical outcome, viral load, and biomarkers 
in blood and nasal mid-turbinate swabs vary and depend on the different data types of the applied 
technology platforms, as well as on the extent of observed differences among study participants. 
Analyses may be conducted at the sponsor’s discretion and reported separately from this study.
9.5.
Interim Analysis
An interim analysis may be conducted at sponsor’s discretion when at least approximately 65% of 
participants are enrolled to allow preparation towards a Phase 3 study design. The interim analysis, 
performed by the sponsor in an unblinded manner, will preferably be conducted at the end of a 
northern or southern hemisphere RSV season.
9.6.
Independent Data Monitoring Committee
An IDMC will be established as noted in Committees Structure in Section 10.3.6.


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An IDMC will be established to monitor and review clinical safety 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. After the review, the IDMC will provide 
recommendations regarding the continuation of the study 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.


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10.
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS
10.1.
Appendix 1: Abbreviations
∆∆QTcI
placebo-corrected change from baseline for the individual-corrected QTc
AE
adverse event
AFT
accelerated failure time
ALT
alanine aminotransaminase
AST
aspartate aminotransferase
AUC
area under the curve
AUC0-12h
AUC from time of administration up to 12 hours post dosing
AUC0-24h
AUC from time of administration up to 24 hours post dosing
AUC0-96h
AUC from time of administration up to 96 hours post dosing
AUC0-∞
AUC from time of administration extrapolated to infinity
bid
bis in die; twice daily
CHF
congestive heart failure
CI
confidence interval
CKD
chronic kidney disease
Cmax
maximum plasma concentration
Cmin
minimum plasma concentration
COPD
chronic obstructive pulmonary disease
COVID-19
Coronavirus Disease 2019
CRF
case report form(s) (paper or electronic as appropriate for this study)
CSS
Clinician Symptom Score
Ctrough
predose plasma concentration
CYP
cytochrome P450
ECG
electrocardiogram
eDC
electronic data capture
ER
emergency room
EQ-5D
EuroQol© 5-Dimension
F
fusion
FOIA
Freedom of Information Act
FSH
follicle stimulating hormone
GCP
Good Clinical Practice
HIV
human immunodeficiency virus
HP-β-CD
2-hydroxypropyl-beta-cyclodextrin
HRQOL
health-related quality of life
ICF
informed consent form
ICH
International Council for Harmonisation
IDMC
Independent Data Monitoring Committee
IEC
Independent Ethics Committee
IMP
Investigational Medicinal Product
IRB
Institutional Review Board
ITT-i
intent-to-treat-infected
IWRS
interactive web response system
KM
Kaplan-Meier
LRTD
lower respiratory tract disease
MMRM
mixed-effects model with repeated measurements
MRU
medical resource utilization
OATP
organic anion transporting polypeptide
PaCO2
arterial carbon dioxide tension
paEC90
protein-adjusted 90% effective concentration
PBPK
physiologically-based pharmacokinetic(s)
PCR
polymerase chain reaction
PD
pharmacodynamic(s)
PGI-C
Patient Global Impression of Change
PGI-S
Patient Global Impression of Severity
P-gp
P glycoprotein


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PK
pharmacokinetic(s)
popPK
population pharmacokinetic
PQC
Product Quality Complaint
PRO
patient-reported outcome(s) (paper or electronic as appropriate for this study)
qd
quaque die; once daily
q24h
every 24 hours
qRT-PCR
quantitative reverse transcription polymerase chain reaction
QTcF
QT interval corrected using Fridericia's formula
RiiQ™
Respiratory Infection Intensity and Impact Questionnaire
RNA
ribonucleic acid
RSV
respiratory syncytial virus
SAE
serious adverse event
SAP
statistical analysis plan
SARS-CoV-2
severe acute respiratory syndrome coronavirus 2
SD
standard deviation
SOC
standard-of-care
SpO2
peripheral capillary oxygen saturation
SUSAR
suspected unexpected serious adverse reaction
tmax
median time to reach maximum plasma concentration
TEAE
treatment-emergent adverse event
ULN
upper limit of normal
URTD
upper respiratory tract disease
US
United States
VAS
visual analog scale
Definitions of Terms
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.
Other 
Screening Tests

Urine pregnancy testing for women of childbearing potential only

Serology testing for HIV-1 and -2, hepatitis A, B & C

At screening, FSH will be tested for female participants who are amenorrheic for 
12 months or less.


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


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


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


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At least once a year, the IEC/IRB will be asked to review and reapprove this study, where required.
At the end of the study, the investigator (or sponsor where required) will notify the IEC/IRB about 
the study completion (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 4.2.1, Study-Specific Ethical Design 
Considerations.
Other Ethical Considerations
For study-specific ethical design considerations, refer to Section 4.2.1.
10.3.2.
Financial Disclosure
Investigators and subinvestigators will provide the sponsor with sufficient, accurate financial 
information in accordance with local regulations to allow the sponsor to submit complete and 
accurate financial certification or disclosure statements to the appropriate regulatory authorities. 
Investigators are responsible for providing information on financial interests during the course of 
the study and for 1 year after completion of the study.
Refer to Required Prestudy Documentation (above) and contracts for details on financial 
disclosure.
10.3.3.
Informed Consent Process
Each participant must give written consent according to local requirements after the nature of the 
study has been fully explained. The ICF(s) must be signed before performance of any study-related 
activity. The ICF(s) that is/are used must be approved by both the sponsor and by the reviewing 
IEC/IRB and be in a language that the participant can read and understand. The informed consent 
should be in accordance with principles that originated in the Declaration of Helsinki, current ICH 
and GCP guidelines, applicable regulatory requirements, and sponsor policy.
Prior to signing the main consent form for the study, participants may specifically allow for the 
collection and testing of nasal mid-turbinate swabs by signing the pre-screening (diagnostic) ICF 
if such testing is not SOC at the investigational site.
Before enrollment in the study, the investigator or an authorized member of the study site personnel 
must explain to potential participants 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 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 


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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 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 should be appropriately recorded 
by means of the participant's personally dated signature. After having obtained the consent, a copy 
of the ICF must be given to the participant.
10.3.4.
Data Protection
Privacy of Personal Data
The collection and processing of personal data from participants enrolled in this study will be 
limited to those data that are necessary to fulfill the objectives of the study.
These data must be collected and processed with adequate precautions to ensure confidentiality 
and compliance with applicable data privacy protection laws and regulations. Appropriate 
technical and organizational measures to protect the personal data against unauthorized disclosures 
or access, accidental or unlawful destruction, or accidental loss or alteration must be put in place. 
Sponsor personnel whose responsibilities require access to personal data agree to keep the identity 
of participants confidential.
The informed consent obtained from the participant includes explicit consent for the processing of 
personal data and for the investigator/institution to allow direct access to his or her original medical 
records (source data/documents) for study-related monitoring, audit, IEC/IRB review, and 
regulatory inspection. This consent also addresses the transfer of the data to other entities and to 
other countries.
The participant 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 research is not conducted under standards appropriate for the return of data to 
participants. In addition, the sponsor cannot make decisions as to the significance of any findings 
resulting from exploratory research. Therefore, exploratory research data will not be returned to 
participants or investigators, unless required by law or local regulations. Privacy and 
confidentiality of data generated in the future on stored samples will be protected by the same 
standards applicable to all other clinical data.


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10.3.5.
Long-Term Retention of Samples for Additional Future Research
Samples collected in this study may be stored for up to 15 years (or according to local regulations) 
for additional research. Samples will only be used to understand rilematovir, to understand RSV 
infection, to understand differential intervention responders, and to develop tests/assays related to
rilematovir and RSV infection. The research may begin at any time during the study or the post-
study storage period.
Stored samples will be coded throughout the sample storage and analysis process and will not be 
labeled with personal identifiers. Participants may withdraw their consent for their samples to be 
stored for research (refer to Section 7.2.1).
10.3.6.
Committees Structure
Independent Data Monitoring Committee
An IDMC will be established to monitor and review data for the study in an unblinded manner on 
a regular basis to ensure the continuing safety of the participants enrolled in this study. The 
Committee will meet periodically to review the safety data. After the review, the IDMC will 
provide recommendations regarding the continuation of the study 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.
The IDMC will consist of at least 3 members, including one medical expert in respiratory 
infectious diseases, one cardiovascular expert knowledgeable about ECG readings, and at least one 
statistician knowledgeable about statistical methods for clinical studies and sequential analysis of 
study data. One of these individuals will chair the Committee. The IDMC responsibilities, 
authorities, and procedures will be documented in the IDMC Charter.
The committee will meet periodically to review the safety data. After the review, the IDMC will 
make recommendations regarding the continuation of the study. At any point during the study, the 
IDMC has the option to recommend modifications to the study conduct and/or to the safety 
assessments to the Sponsor Committee to ensure the safety of enrolled participants.
Sponsor Committee
A Sponsor Committee, consisting of senior sponsor personnel not involved in the conduct of the 
study, will be established and will be responsible for decision making, considering the IDMC 
recommendations, and will communicate these decisions to the study team. Details are provided 
in the IDMC Charter.
10.3.7.
Publication Policy/Dissemination of Clinical Study Data
All information, including but not limited to information regarding rilematovir or the sponsor's 
operations (eg, patent application, formulas, manufacturing processes, basic scientific data, prior 
clinical data, formulation information) supplied by the sponsor to the investigator and not 
previously published, and any data, including exploratory biomarker research data, generated as a 
result of this study, are considered confidential and remain the sole property of the sponsor. The 


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investigator agrees to maintain this information in confidence and use this information only to 
accomplish this study and will not use it for other purposes without the sponsor's prior written 
consent.
The investigator understands that the information developed in the study will be used by the 
sponsor in connection with the continued development of rilematovir, and thus may be disclosed 
as required to other clinical investigators or regulatory agencies. To permit the information derived 
from the clinical studies to be used, the investigator is obligated to provide the sponsor with all 
data obtained in the study.
The results of the study will be reported in a Clinical Study Report generated by the sponsor and 
will contain data from all study sites that participated in the study as per protocol. Recruitment 
performance or specific expertise related to the nature and the key assessment parameters of the 
study will be used to determine a coordinating investigator for the study. Results of exploratory 
biomarker analyses performed after the Clinical Study Report has been issued will be reported in 
a separate report and will not require a revision of the Clinical Study Report.
Study participant identifiers will not be used in publication of results. Any work created in 
connection with performance of the study and contained in the data that can benefit from copyright 
protection (except any publication by the investigator as provided for below) shall be the property 
of the sponsor as author and owner of copyright in such work.
Consistent with Good Publication Practices and International Committee of Medical Journal 
Editors (ICMJE) guidelines, the sponsor shall have the right to publish such primary (multicenter) 
data and information without approval from the investigator. The investigator has the right to 
publish study site-specific data after the primary data are published. If an investigator wishes to 
publish information from the study, a copy of the manuscript must be provided to the sponsor for 
review at least 60 days before submission for publication or presentation. Expedited reviews will 
be arranged for abstracts, poster presentations, or other materials. If requested by the sponsor in 
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 


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version to be published; and agreed to be accountable for all aspects of the work in ensuring that 
questions related to the accuracy or integrity of any part of the work are appropriately investigated 
and resolved.
Registration of Clinical Studies and Disclosure of Results
The sponsor will register and disclose the existence of and the results of clinical studies as required 
by law. The disclosure of the final study results will be performed after the end of study in order 
to ensure the statistical analyses are relevant.
10.3.8.
Data Quality Assurance
Data Quality Assurance/Quality Control
Steps to be taken to ensure the accuracy and reliability of data include the selection of qualified 
investigators and appropriate study sites, review of protocol procedures with the investigator and 
study site personnel before the study, periodic monitoring visits by the sponsor, direct transmission 
of clinical laboratory data from a central laboratory, and ECG and ePRO 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 
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.
10.3.9.
Case Report Form Completion
Case report forms are prepared and provided by the sponsor for each participant in electronic 
format. All data relating to the study must be recorded in 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 CRF 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 electronic data capture (eDC) tool. If corrections to 
the eCRF are needed after the initial entry into the eCRF, this can be done in either of the following 
ways:


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
Investigator and study site personnel can make corrections in the eDC tool at their own 
initiative or as a response to an auto query (generated by the eDC tool).

Sponsor or sponsor delegate can generate a query for resolution by the investigator and study 
site personnel.
10.3.10.
Source Documents
At a minimum, source documents consistent in the type and level of detail with that commonly 
recorded at the study site as a basis for standard medical care must be available for the following: 
participant identification, eligibility, and study identification; study discussion and date of signed 
informed consent; dates of visits; results of safety and efficacy parameters as required by the 
protocol; record of all AEs and follow-up of AEs; concomitant medication; intervention
receipt/dispensing/return records; study intervention administration information; and date of study 
completion and reason for early discontinuation of study intervention or withdrawal from the 
study, if applicable.
The author of an entry in the source documents should be identifiable. Given that patient-reported 
outcomes (PROs) are reports of a patient's health condition that come directly from the patient, 
without interpretation by a clinician or anyone else, the responses to PRO measures entered by 
trial participants into source records cannot be overridden by the study site personnel or 
investigators.
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 another equivalent document).
The following data will be recorded directly into the CRF 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
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.


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10.3.11.
Monitoring
The sponsor will use a combination of monitoring techniques: central, remote, or on-site 
monitoring to monitor this study.
The sponsor will perform on-site monitoring visits as frequently as necessary. The monitor will 
record dates of the visits in a study site visit log that will be kept at the study site. The first post-
initiation visit will be made as soon as possible after enrollment has begun. At these visits, the 
monitor will compare 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 
CRF are known to the sponsor and study site personnel and are accessible for verification by the 
sponsor study site contact. If electronic records are maintained at the study site, the method of 
verification must be discussed with the study site personnel.
Direct access to source documents (medical records) must be allowed for the purpose of verifying 
that the recorded data are consistent with the original source data. Findings from this review will 
be discussed with the study site personnel. The sponsor expects that, during monitoring visits, the 
relevant study site personnel will be available, the source documents will be accessible, and a 
suitable environment will be provided for review of study-related documents. The monitor will 
meet with the investigator on a regular basis during the study to provide feedback on the study 
conduct.
In addition to on-site monitoring visits, remote contacts can occur. It is expected that during these 
remote contacts, study site personnel will be available to provide an update on the progress of the 
study at the site.
Central monitoring will take place for data identified by the sponsor as requiring central review.
10.3.12.
On-Site Audits
Representatives of the sponsor's clinical quality assurance department may visit the study site at 
any time during or after completion of the study to conduct an audit of the study in compliance 
with regulatory guidelines and company policy. These audits will require access to all study 
records, including source documents, for inspection. Participant privacy must, however, be 
respected. The investigator and 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.


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10.3.13.
Record Retention
In compliance with the ICH/GCP guidelines, the investigator/institution will maintain all CRF and 
all source documents that support the data collected from each participant, as well as all study 
documents as specified in ICH/GCP Section 8, Essential Documents for the Conduct of a Clinical 
Trial, and all study documents as specified by the applicable regulatory requirement(s). The 
investigator/institution will take measures to prevent accidental or premature destruction of these 
documents.
Essential documents must be retained until at least 2 years after the last approval of a marketing 
application in an ICH region and until there are no pending or contemplated marketing applications 
in an ICH region or until at least 2 years have elapsed since the formal discontinuation of clinical 
development of the investigational product. These documents will be retained for a longer period 
if required by the applicable regulatory requirements or by an agreement with the sponsor. It is the 
responsibility of the sponsor to inform the investigator/institution as to when these documents no 
longer need to be retained.
If the responsible investigator retires, relocates, or for other reasons withdraws from the 
responsibility of keeping the study records, custody must be transferred to a person who will accept 
the responsibility. The sponsor must be notified in writing of the name and address of the new 
custodian. Under no circumstance shall the investigator relocate or dispose of any study documents 
before having obtained written approval from the sponsor.
If it becomes necessary for the sponsor or the appropriate regulatory authority to review any 
documentation relating to this study, the investigator/institution must permit access to such reports.
10.3.14.
Study and Site Start and Closure
First Act of Recruitment
The first site open is considered the first act of recruitment and it becomes the study start date.
Study/Site 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


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
Inadequate recruitment of participants by the investigator

Discontinuation of further study intervention development
10.4.
Appendix 4: Adverse Events, Serious Adverse Events, Product Quality 
Complaints, and Other Safety Reporting: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting
10.4.1.
Adverse Event Definitions and Classifications
Adverse Event
An AE is any untoward medical occurrence in a clinical study participant administered a 
pharmaceutical (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 ICF (refer to All Adverse Events
under Section 8.3.1, Time Period and Frequency for Collecting Adverse Events and Serious 
Adverse Events Information, for time of last AE recording).
Serious Adverse Event
An SAE based on ICH and European Union Guidelines on Pharmacovigilance for Medicinal 
Products for Human Use is any untoward medical occurrence that at any dose:

Results in death

Is life-threatening
(The participant was at risk of death at the time of the event. It does not refer to an event that 
hypothetically might have caused death if it were more severe)

Requires inpatient hospitalization or prolongation of existing hospitalization

Results in persistent or significant disability/incapacity

Is a congenital anomaly/birth defect

Is a suspected transmission of any infectious agent via a medicinal product

Is Medically Important*
*Medical and scientific judgment should be exercised in deciding whether expedited reporting is 
also appropriate in other situations, such as important medical events that may not be immediately 
life-threatening or result in death or hospitalization but may jeopardize the participant or may 


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require intervention to prevent one of the other outcomes listed in the definition above. These 
should usually be considered serious.
If a serious and unexpected AE occurs for which there is evidence suggesting a causal relationship 
between the study intervention and the event (eg, death from anaphylaxis), the event must be 
reported as a serious and unexpected suspected adverse reaction even if it is a component of the 
study endpoint (eg, all-cause mortality).
Unlisted (Unexpected) Adverse Event/Reference Safety Information
An AE is considered unlisted if the nature or severity is not consistent with the applicable product 
reference safety information. For rilematovir, the expectedness of an AE will be determined by 
whether or not it is listed in the IB (IB 2020).
10.4.2.
Attribution Definitions
Assessment of Causality
The causal relationship to study intervention is determined by the investigator. The following 
selection should be used to assess all AEs.
Related
There is a reasonable causal relationship between study intervention administration and the AE.
Not Related
There is not a reasonable causal relationship between study intervention administration and the 
AE.
The term "reasonable causal relationship" means there is evidence to support a causal relationship.
10.4.3.
Severity Criteria
An assessment of severity Grade will be made using the following general categorical descriptors:
Mild: Awareness of symptoms that are easily tolerated, causing minimal discomfort and not 
interfering with everyday activities.
Moderate: Sufficient discomfort is present to cause interference with normal activity.
Severe: Extreme distress, causing significant impairment of functioning or incapacitation. 
Prevents normal everyday activities.
The investigator should use clinical judgment in assessing the severity of events not directly 
experienced by the participant (eg, laboratory abnormalities).
10.4.4.
Special Reporting Situations
Safety events of interest on a sponsor study intervention in an interventional study that may require 
expedited reporting or safety evaluation include, but are not limited to:


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
Overdose of a sponsor study intervention

Suspected abuse/misuse of a sponsor study intervention

Accidental or occupational exposure to a sponsor study intervention

Medication error, intercepted medication error, or potential medication error involving a 
Johnson & Johnson medicinal product (with or without patient exposure to the Johnson & 
Johnson medicinal product, eg, product name confusion, product label confusion, intercepted 
prescribing or dispensing errors)

Exposure to a sponsor study intervention from breastfeeding
Special reporting situations should be recorded in the eCRF. Any special reporting situation that 
meets the criteria of an SAE should be recorded on the SAE page of the eCRF.
10.4.5.
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 CRF. 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 CRF their opinion concerning the relationship of the 
AE to study therapy. All measures required for AE management must be recorded in the source 
document and reported according to sponsor instructions.
For all studies with an outpatient phase, including open-label studies, the participant must be 
provided with a "wallet (study) card" and instructed to carry this card with them for the duration 
of the study indicating the following:

Study number

Statement, in the local language(s), that the participant is participating in a clinical study

Investigator's name and 24-hour contact telephone number

Local sponsor's name and 24-hour contact telephone number (for medical personnel only)

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 the 
participant's discontinuation from the study, must be followed until any of the following occurs:

The event resolves

The event stabilizes


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
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 an SAE.
Any event requiring hospitalization (or prolongation of hospitalization) that occurs during 
participation in the study must be reported as an SAE, except hospitalizations for the following:

Hospitalizations not intended to treat an acute illness or AE (eg, social reasons such as pending 
placement in long-term care facility).

Surgery or procedure planned before entry into the study (must be documented in the eCRF). 
Note: Hospitalizations that were planned before the signing of the ICF, and where the 
underlying condition for which the hospitalization was planned has not worsened, will not be 
considered SAEs. Any AE that results in a prolongation of the originally planned 
hospitalization is to be reported as a new SAE.
The terms "disease progression" and complication of RSV should not be recorded as an AE 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 (refer to Adverse 
Event Definitions and Classifications in Appendix 10.4).
Information regarding SAEs will be transmitted to the sponsor using an SAE reporting form and 
safety report form of the CRF, which must be completed and reviewed by a physician from the 
study site, and transmitted in a secure manner to the sponsor within 24 hours. The initial and 
follow-up reports of an SAE should be transmitted in a secure manner electronically or by 
facsimile (fax). Telephone reporting should be the exception and the reporter should be asked to 
complete the appropriate form(s) first.
10.4.6.
Product Quality Complaint Handling
Definition
A PQC is defined as any suspicion of a product defect related to manufacturing, labeling, or 
packaging, ie, any dissatisfaction relative to the identity, quality, durability, reliability, or
performance of a distributed product, including its labeling, drug delivery system, or package 
integrity. A PQC may have an impact on the safety and efficacy of the product. In addition, it 
includes any technical complaints, defined as any complaint that indicates a potential quality issue 
during manufacturing, packaging, release testing, stability monitoring, dose preparation, storage 
or distribution of the product or the drug delivery system.


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Procedures
All initial PQCs must be reported to the sponsor by the study site personnel within 24 hours after 
being made aware of the event.
A sample of the suspected product should be maintained under the correct storage conditions until 
a shipment request is received from the sponsor.
10.4.7.
Contacting Sponsor Regarding Safety, Including Product Quality
The names (and corresponding telephone numbers) of the individuals who should be contacted 
regarding safety issues, PQC, or questions regarding the study are listed in the Contact Information 
page(s), which will be provided as a separate document.
10.5.
Appendix 5: Contraceptive and Barrier Guidance and Collection of 
Pregnancy Information
Participants must follow contraceptive measures as outlined in Section 5.1. Pregnancy information 
will be collected and reported as noted in Section 8.3.5, and Appendix 10.5.
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 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 (for the purpose of this study)
Permanent sterilization methods include hysterectomy, bilateral salpingectomy, and bilateral 
oophorectomy.
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.


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Contraceptive (birth control) use by men or women should be consistent with local regulations 
regarding the acceptable methods of contraception for those participating in clinical studies.
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.
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)

Intrauterine hormone-releasing system (IUS)

Bilateral tubal occlusion/ligation without reversal operation

Vasectomized Azoospermic partner (vasectomized or due to medical cause)
(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)


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
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 intervention, which may 
reduce the efficacy of the contraceptive method. In addition, consider if the hormonal contraception 
may interact with the study intervention.
c) Male condom and female condom should not be used together (due to risk of failure with friction).


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10.6.
Appendix 6: Liver Safety: Suggested Actions and Follow-up Assessments
A. STOPPING ALGORITHM
ALT ONLY: Study intervention will be discontinued for a participant if liver chemistry 
stopping criteria are met.
Phase 2 Liver Chemistry Stopping Criteria and Increased Monitoring Algorithm
Abbreviations: ALT = alanine transaminase; INR = international normalized ratio; SAE = serious adverse event; 
ULN = upper limit of normal, Tbili = Total bilirubin.


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10.7.
Appendix 7: Toxicity Tables
DIVISION OF MICROBIOLOGY AND INFECTIOUS DISEASES (DMID) ADULT 
TOXICITY TABLE (NIAID 2007) – 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 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 dysrythmia;
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; ECG 
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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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


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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%
cannot work
unable to care for self


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10.8.
Appendix 8: List of Commonly Used Medications With a Known Risk of QT 
Prolongation and Torsade de Pointes
Investigators must refer to the list of medications with known risk available at 
https://www.crediblemeds.org/pdftemp/pdf/CombinedList.pdf (see copy below). Investigators 
must check regularly for any additions or updates to the list below.


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10.9.
Appendix 9: Anticipated Events
An anticipated event is an AE (serious or non-serious) that commonly occurs as a consequence of 
the underlying disease or condition under investigation (disease-related) or background regimen.
For the purposes of this study, the following events will be considered as anticipated events in the 
target population (adults with RSV infection including those at high risk for RSV-related disease 
progression and complications):

Respiratory System
−
Primary viral pneumonia
−
Secondary bacterial pneumonia (including pneumonia attributable to unusual 
pathogens)
−
Bronchitis or other LRTD leading to hospitalization
−
Other infections (eg, sinusitis, otitis) leading to hospitalization
−
Respiratory failure including acute respiratory distress syndrome
−
Worsening of asthma, asthma attack
−
Exacerbations of COPD
−
Pulmonary edema
−
Pulmonary embolism
−
Lung malignancies

Cardiovascular/Circulatory System
−
Myocardial infarction
−
Atrial Fibrillation
−
Hypertension
−
Bradycardia
−
Syncope (for other reasons than Torsades de Pointes)
−
Transient ischemic attack
−
Exacerbations of CHF

Nervous System
−
Stroke
−
Mental status changes

Digestive System:
−
Liver stasis
−
Colon malignancies

Urinary System
−
Acute exacerbation of CKD leading to hospitalization

Endocrine System
−
Decompensation of previously controlled diabetes mellitus leading to hospitalization

Skeletal System Function
−
Fractures (hip fractures most common)

Reproductive System
−
Breast malignancies


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Reporting of Anticipated Events
These AEs will be captured on the eCRF and in the database, and will be reported to the sponsor 
as described in Section 8.3 and Appendix 10.4. Any anticipated event that meets SAE criteria will 
be reported to the sponsor within the appropriate timeline as described in Section 8.3.4. The 
sponsor assumes responsibility for appropriate reporting of the listed anticipated events according 
to the requirements of the countries in which the studies are conducted.
If based on an aggregate review, it is determined that an anticipated event is possibly related to the
study intervention, the sponsor will report these events in an expedited manner.
Statistical Analysis
Details of the statistical analysis of anticipated events, including the frequency of review and 
threshold to trigger an aggregate analysis of anticipated events will be provided in a separate 
Anticipated Events Safety Monitoring Plan.


CCI
CCI






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10.12. Appendix 12: Patient Global Impression (PGI-S)
Patient Global Impression of Severityi
Overall, how severe were your respiratory infection symptoms today? (select one)
No symptoms today
Mild
Moderate
Severe
Very Severe
i(Do not translate) Source: adapted from the FLU-PRO User Manual for RSV.


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10.13. Appendix 13: Patient Global Impression of Change (PGI-C)
Adult RSV Patient Global Impression of Changea
Compared with how you felt before you started taking the study medication, how are your 
respiratory infection symptoms now? (select one)
Much better
Somewhat better
A little better
About the same
A little worse
Somewhat worse
Much worse
                                                
a Do not translate:  Source: adapted from the FLU-PRO User Manual for RSV infection.  


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10.14. Appendix 14: Return to Usual Activities
Adult RSV Return to Usual Activitiesi
Have you returned to your usual activities today? (select one)
Yes
No
i(Do not translate) Source: adapted from the FLU-PRO User Manual for RSV infection.


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10.15. Appendix 15: Return to Usual Health
Adult RSV Return to Usual Healthi
Have you returned to your usual health today? (select one)
Yes
No
i(Do not translate) Source: adapted from the FLU-PRO User Manual for RSV infection.


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10.16. Appendix 16: Employment Status
Employment statusi
How would you describe your employment status now? (select one)
Employed full-time (working at least 30 hours per week)
Employed part-time (working less than 30 hours per week)
Not currently employed full-time or part-time
Is there anyone who helps you when you are ill who is employed full-time or part-time? (select one)
Yes
No
_
i (Do not translate) Source: developed for collection during screening or baseline assessment to 
determine whether patient will be asked to report hours missed from work in the ePRO during treatment 
and follow-up for 53718678RSV2008 adult outpatient RSV treatment study in high-risk adults.


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10.17. Appendix 17: Hours Missed from Work
Hours missed from worki
Hours missed from Work
When you are ill with a respiratory infection, sometimes you must take time off from work to 
recover from your illness or to avoid infecting other people where you work. People who help 
you when you are ill also may need to take time off from work to do things that you cannot do 
due to your illness.
What is the total number of hours of work that you or people who help you missed due to your 
respiratory infection in the past 24 hours?
____ total hours missed from workii
Do not translate:
I For protocol only: Source: question developed for JNJ53718678 RSV2008. Do not include on ePRO 
application.
ii For ePRO implementation only: use range of 0-100 hours for accepted responses.


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10.18. Appendix 18: Clinician Symptom Score
Participant ID :-------------------------- Age:------------- Visit Day/Date:------------------------
Instruction: Based on all the information on an individual participant (history, underlying comorbidity, 
baseline disease characteristics), overall clinical evaluation as well as interview of the participants on their 
symptoms, please rate with check mark the presence and severity of the following LRTD sign/symptoms
LRTD Symptom Scoring 
Level 
0 (None)
1 (Mild)
2 (Moderate)
3 (Severe)
Cough
No Cough
Just noticeable.
-Occasional mild, 
isolated cough
Bothersome 
sometimes, not 
interfering with other 
activities.
-Moderate, 
paroxysmal cough
Bothersome 
most of the 
time, 
interfering with 
other activities
- Severe, 
strenuous 
cough, with or 
without chest 
discomfort
Sputum 
production
No sputum
Just noticeable
Bothersome 
sometimes, not 
interfering with other 
activities
Bothersome 
most of the 
time,
interfering with 
other activities
Shortness of 
breath/dyspnea
No episode of 
shortness of 
breath or dyspnea
May have brief 
episodes.
Or Breathless 
while 
exercise/walking 
at fast pace, 
walking uphill
May have increased 
episodes
Or Breathless 
walking at own pace
May have 
severe episodes
Or Breathless 
at rest, while 
talking, 
changing dress
Wheezing
No wheezing
Terminal 
expiration or only 
with stethoscope
Entire expiration or 
audible on expiration 
without stethoscope
Inspiration and 
expiration 
without 
stethoscope
Rales/Ronchi/Crac
kles/other lung 
sounds
No findings of 
rales/ronchi/crack
les
-
Scattered wheeze or 
ronchi
Widespread 
wheeze or 
ronchi, rales, 
dyspnea or 
signs of 
consolidation


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10.19. Appendix 19:
EQ-5D-5L Questionnaire
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 

USA (English) © 2009 EuroQol Group. EQ-5D™ is a trade mark of the EuroQol Group


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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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10.20. Appendix 20: Guidance on Study Conduct During the COVID-19 Pandemic
It is recognized that the Coronavirus Disease 2019 (COVID-19) 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 is providing options for study-
related participant management in the event of disruption to the conduct of the study. This guidance 
does not supersede any local or government requirements or the clinical judgment of the 
investigator to protect the health and well-being of participants and study site personnel. If, at any 
time, a participant’s safety is considered to be at risk, study intervention will be discontinued, and 
study follow-up will be conducted.
Scheduled visits that cannot be conducted in person at the study site will be performed to the extent 
possible remotely/virtually or delayed until such time that on-site visits can be resumed. At each 
contact, participants will be interviewed to collect safety data. Key efficacy endpoint assessments 
should be performed if required and as feasible. Participants 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 via COVID-19 Appendix after consultation with the participant, 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 
eCRF.
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, the investigator should contact the sponsor’s 
responsible medical officer to discuss plans for study intervention and follow-up. Modifications 
made to the study conduct as a result of the COVID-19 pandemic should be summarized in the 
Clinical Study Report.
GUIDANCE SPECIFIC TO THIS PROTOCOL

These emergency provisions are meant to ensure participant safety on study while site 
capabilities are compromised by COVID-19 related restrictions. As restrictions are lifted 
and the acute phase of the COVID-19 pandemic resolves, the original protocol procedures 
should take preference.

Virtual visits, missed assessments/visits, and out-of-window visits will be labeled with the 
prefix “COVID-19-related” in the eCRF/eSource by the site personnel where needed.

COVID-19 vaccination during study period:


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o
No change in risk to participant or any interaction with study intervention that 
could compromise the safety and wellbeing of participants is anticipated. 
o
As side effects due to vaccination may impact the evaluation of the clinical 
evolution of RSV symptoms, it is recommended that administration of a 
COVID-19 vaccine be timed to occur after study completion or at least two 
weeks after the last dose of study medication. 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. 
o
Participant must inform the site if he/she is scheduled to receive an approved 
COVID-19 vaccine (prophylaxis) during the study period. Documentation of
vaccination must be recorded in the participant eCRF.

Participant Visits/Assessments:
−
In case home visits cannot be performed (either due to institute policy or due to 
local regulations), such study assessments that can be performed virtually are 
accepted.
−
There are some assessments that could be conducted virtually via telephone (or 
other digital options, if possible) with participants’ parent(s)/caregiver(s) in their 
homes. This methodology can only be used in accordance with applicable 
(including local) laws, regulations, guidelines, and procedures. Please note, the visit 
windows included in the Schedule of Activities are still applicable. It must be 
documented in the eCRF and in the participants’ source documents when a visit 
occurs virtually due to COVID-19.
−
The study assessments that require investigator judgment should be conducted by 
a qualified site member identified on the site delegation log.
−
If required, nasal mid-turbinate swab can be stored at home and picked up by study 
site personnel or courier.
−
In case home visits cannot be performed, nasal mid-turbinate swabs, if required as 
per the Schedule of Activities, may be collected by the participant (or his/her 
spouse, partner, relative, or other caregiver). Training and written instructions to 
collect the nasal mid-turbinate swab will be provided to the participant (or his/her 
spouse, partner, relative, or other caregiver).

On-site Monitoring Visits:
−
In case on-site monitoring visits are not possible due to local regulations, 
restrictions and guidance, the Site Manager will conduct site monitoring visits and 
activities remotely. Additional on-site monitoring visits may be needed in the future 
to catch up on source data verification. Remote source data verification of 


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electronic records might be performed if possible and only if allowed by 
local/national regulations, restrictions, and guidance.
−
During the COVID-19 pandemic and at the impacted sites, clinical Site GCP Audits 
with direct impact/engagement from the clinical investigator team would not be 
conducted to comply with national, local and/or organizational social distancing 
restrictions. Additional quality assurance activities such as remote audits or focused 
review of study-related documents may take place with limited impact/engagement 
if possible.
−
In all cases, the written main ICF will be obtained prior to any study-specific 
assessment.


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10.21. Appendix 21: Protocol Amendment History
This is an original protocol.


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11.
REFERENCES
1.
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Diagnosis and Management of Bronchiolitis. Pediatrics. 2006;118:1774-1793.
2.
Bazett HC. An analysis of the time-relationship of electrocardiograms. Heart. 1920;7:353-380.
3.
Belongia EA, King JP, Kieke BA, et al. Clinical features, severity, and incidence of RSV illness during 
12 consecutive seasons in a community cohort of adults ≥60 years old. Open Forum Infectious Disease. 
2018;5(12):1-10.
4.
Bloom-Feshbach K, Alonso WJ, Charu V, et al. Latitudinal variations in seasonal activity of influenza and 
respiratory syncytial virus (RSV): A global comparative review. PLoS ONE. 2013;8:e54445.
5.
Colman PM, Lawrence MC. The structural biology of type I viral membrane fusion. Nat. Rev. Mol. Cell Biol. 
2003; 4(4):309-319.
6.
Duncan CB, Walsh EE, Peterson DR, et al. Risk factors for respiratory failure associated with respiratory 
syncytial virus infection in adults. J Infect Dis. 2009;200:1242-1246.
7.
Falsey AR, Walsh EE. Relationship of serum antibody to risk of respiratory syncytial virus infection in elderly 
adults. J Infect Dis. 1998; 177:463–466.
8.
Falsey AR, Walsh EE. Respiratory syncytial virus infection in adults. Clin Microbiol Rev. 2000;13(3):371 384.
9.
Falsey AR, Hennessey PA, Formica MA, Cox C, Walsh EE. Respiratory syncytial virus infection in elderly 
and high-risk adults. N Eng J Med. 2005;352(17):1749-1759.
10.
Falsey AR, Walsh EE, Esser MT, Shoemaker K, Yu L, Griffin MP. Respiratory syncytial virus-associated 
illness in adults with advanced chronic obstructive pulmonary disease and/or congestive heart failure. J Med 
Virol. 2019 Jan;91(1):65-71.
11.
Hall WJ, Hall CB, Speers DM. Respiratory syncytial virus infection in adults: clinical, virologic, and serial 
pulmonary function studies. Ann. Intern. Med. 1978;88:203–205.
12.
Hall CB. Respiratory syncytial virus and parainfluenza virus. N Engl J Med. 2001;344:1917–1928.
13.
Hodges M, Salerno D, Erlien D. Bazett’s QT correction reviewed: evidence that a linear QT correction for 
heart rate is better. J Am Coll Cardiol. 1983;1:694.
14.
International Council for Harmonisation of Technical Requirements for Registration of Pharmaceuticals for 
Human Use. ICH Harmonized Tripartite Guideline E14: Clinical evaluation of QT/QTc interval prolongation 
and proarrhythmic potential for non-antiarrhythmic drugs. ICH 12 May 2005.
15.
Investigator's Brochure (IB) JNJ-53718678, Edition 07. Janssen Research & Development (July 2020).
16.
Jain S, Self WH, Wunderink RG, et al, CDC EPIC Study Team. Community-Acquired Pneumonia Requiring 
Hospitalization among U.S. Adults. N Engl J Med. 2015;373:415-427.
17.
Leung AK, Kellner JD, Davies HD. Respiratory Syncytial Virus bronchiolitis. J Natl Med Assoc. 
2005;97:1708-1713.
18.
Levey AS, Stevens LA. Estimating GFR Using the CKD Epidemiology Collaboration (CKD-EPI) Creatinine 
Equation: More Accurate GFR Estimates, Lower CKD Prevalence Estimates, and Better Risk Predictions. Am 
J Kidney Dis. 2010;55:622–627.
19.
Malloy AM, Falsey AR, Ruckwardt TJ. Consequences of immature and senescent immune responses for 
infection with respiratory syncytial virus. Curr Top Microbiol Immunol. 2013;372:211-31.
20.
Nair H, Nokes JD, Gessner BD, et al. Global burden of acute lower respiratory infections due to respiratory 
syncytial virus in young children: a systematic review and meta-analysis. Lancet. 2010;375:1545-1555.
21.
Nam HH and Ison M. Respiratory syncytial virus infection in adults. BMJ. 2019;366:l5021.
22.
National Institute of Allergy and Infectious Diseases. Division of Microbiology and Infectious Diseases 
(DMID) Adult toxicity tables. November 2007 (draft). Available at: 
https://www.niaid nih.gov/sites/default/files/dmidadulttox.pdf. Accessed on 15 January 2021.


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23.
Osborne RH, Norquist JM, Elsworth GR, et al. Development and validation of the Influenza Intensity and 
Impact Questionnaire (FluiiQ™). Value Health. 2011;14(5):687-699.
24.
Reenan M, Janssen B. EQ-5D manual: EQ-5D-5L User Guide: Basic Information on How to Use the 
EQ-5D-5L. Version 2.1. April 2015.
25.
Revicki D, Hays RD, Cella D, Sloan J. Recommended methods for determining responsiveness and minimally 
important differences for patient-reported outcomes. J Clinical Epidemiology. 2008;61:102-109.
26.
Sagie A, Larson MG, Goldberg RJ, Bengston JR, Levy D. An improved method for adjusting the QT interval 
for heart rate (the Framingham Heart Study). Am J Cardiol. 1992;70:797-801.
27.
Scott JA, Sully K, Tatlock S, Ireland A, Arbuckle R. PIN129 - Adapting influenza patient-reported outcomes 
(PRO) measures to monitor respiratory syncytial virus (RSV) symptom severity in adults: Qualitative evidence 
of key concepts and content validity. Value in Health. 2018:21(S3);S242.
28.
Tsai Y. Zhou, Kim IK. The burden of influenza-like illness in the US workforce. Occupational Medicine. 
2014;64(5):341–347.
29.
Tseng HF, Sy LS, Ackerson B, Solano Z, Slezak J, Luo Y, Fischetti CA, Shinde V. Severe Morbidity and 
Short- and Mid- to Long-term Mortality in Older Adults Hospitalized with Respiratory Syncytial Virus 
Infection. J Infect Dis. 2020;222(8):1298-1310.
30.
van Essen GA, Beran J, Devaster JM, et al. Influenza symptoms and their impact on elderly adults: randomized 
trial of AS03-adjuvanted or non-adjuvanted inactivated trivalent seasonal influenza vaccines. Influenza Other 
Respir Viruses. 2014;8(4):452-462.
31.
Walsh EE, Peterson DR, Falsey AR. Risk factors for severe respiratory syncytial virus infection in elderly 
persons. J Infect Dis. 2004;189:233–238.
32.
Wantuch EA, Poonja S, Helfrich R, et al. Adults hospitalized for respiratory syncytial virus infections have 
high morbidity, mortality rates. The Hospitalist. 2014(10). Available at: https://www.the-
hospitalist.org/hospitalist/article/122774/infectious-diseases/adults-hospitalized-respiratory-syncytial-virus. 
Accessed on 20 March 2020.
33.
Wild D, Eremenco S, Mear I, et al. Multinational trials - Recommendations on the translations required, 
approaches to using the same language in different countries, and the approaches to support pooling the data: 
The ISPOR patient-reported outcomes translation and linguistic validation good research practices task force 
report. Value in Health. 2009;12(4):430-444.
34.
Yusuf S, Piedimonte G, Auais A, et al. The relationship of meteorological conditions to the epidemic activity 
of respiratory syncytial virus. Epidemiol Infect. 2007;135:1077-1090.



SAP_003.pdf: 
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
1
Status: Approved, Date: 24 May 2022
Janssen Research & Development
Statistical Analysis Plan
A Phase 2b Randomized, Double-blind, Placebo-controlled Study to Evaluate the Efficacy 
and Safety of Rilematovir (JNJ-53718678) in Adult Outpatients with Respiratory Syncytial 
Virus (RSV) Infection who are at High Risk for RSV-related Disease Progression
PRIMROSE
Effects of Rilematovir in Adult Outpatients with RSV Infection who are at High Risk for 
RSV-related Disease Progression
Protocol 53718678RSV2008; Phase 2b
JNJ-53718678 (rilematovir)
Status:
Approved
Date:
24 May 2022
Prepared by:
Janssen Research & Development, a division of Janssen Pharmaceutica NV
Document No.: EDMS-RIM-436373, 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.
NCT04978337


JNJ-53718678 (Rilematovir)
Statistical Analysis Plan 53718678RSV2008
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Status: Approved, Date: 24 May 2022
TABLE OF CONTENTS
TABLE OF CONTENTS ............................................................................................................................... 2
VERSION HISTORY..................................................................................................................................... 3
1.
INTRODUCTION.................................................................................................................................. 4
1.1.
Objectives and Endpoints ................................................................................................................ 4
1.2.
Study Design.................................................................................................................................... 9
2.
STATISTICAL HYPOTHESES.......................................................................................................... 10
3.
SAMPLE SIZE DETERMINATION.................................................................................................... 10
4.
POPULATIONS (ANALYSIS SETS) FOR ANALYSIS..................................................................... 11
5.
STATISTICAL ANALYSES............................................................................................................... 11
5.1.
General Considerations ................................................................................................................. 11
5.1.1.
Phase Definitions........................................................................................................................ 11
5.1.2.
Baseline ...................................................................................................................................... 11
5.1.3.
Relative Day ............................................................................................................................... 11
5.1.4.
Visit Windows ............................................................................................................................. 12
5.1.5.
Data Handling Rules for RSV RNA Viral Load ........................................................................... 12
5.2.
Participant Dispositions.................................................................................................................. 12
5.3.
Primary Endpoint Analysis ............................................................................................................. 13
5.4.
Secondary Endpoint(s) Analysis .................................................................................................... 14
5.5.
Exploratory Endpoint(s) Analysis ................................................................................................... 15
5.6.
Safety Analyses ............................................................................................................................. 15
5.6.1.
Extent of Exposure ..................................................................................................................... 15
5.6.2.
Adverse Events........................................................................................................................... 15
5.6.3.
Additional Safety Assessments .................................................................................................. 15
5.6.3.1.
Clinical Laboratory Tests......................................................................................................... 15
5.6.3.2.
Vital Signs and Physical Examination Findings....................................................................... 16
5.6.3.3.
Electrocardiogram ................................................................................................................... 16
5.7.
Other Analyses............................................................................................................................... 17
5.7.1.
Virology....................................................................................................................................... 17
5.8.
Interim Analyses............................................................................................................................. 18
6.
SUPPORTING DOCUMENTATION .................................................................................................. 18
6.1.
Appendix 1 List of Abbreviations.................................................................................................... 18
6.2.
Appendix 2 Changes to Protocol-Planned Analyses ..................................................................... 19
6.3.
Appendix 3 Demographics and Baseline Characteristics.............................................................. 19
6.3.1.
Presence of other respiratory viruses or bacteria....................................................................... 20
6.4.
Appendix 4 Protocol Deviations ..................................................................................................... 21
6.5.
Appendix 5 Prior and Concomitant Medications............................................................................ 21
6.5.1.
Specific Prior Therapy ................................................................................................................ 21
6.6.
Appendix 6 Medical History ........................................................................................................... 21
6.7.
Appendix 7 Intervention Compliance ............................................................................................. 22
6.8.
Appendix 8 Adverse Events of Special Interest............................................................................. 22
6.9.
Appendix 9 Medications of Special Interest................................................................................... 22
6.10.
Appendix 10 Laboratory Toxicity Grading...................................................................................... 22
6.11.
Appendix 11 Pre-Existing Symptom Questionnaire....................................................................... 23
6.12.
Appendix 12 Respiratory Infection Intensity and Impact Questionnaire (RiiQ™) Symptom 
Scale .............................................................................................................................................. 24
7.
REFERENCES................................................................................................................................... 24


JNJ-53718678 (Rilematovir)
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VERSION HISTORY
Table 1:
SAP Version History Summary
SAP Version
Approval Date
Change
Rationale
1
24 May 2022
Not Applicable
Initial release












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1.2.
Study Design
This is a Phase 2b, randomized, double-blind, placebo-controlled, multicenter study to evaluate 
efficacy, safety, and tolerability of rilematovir at a dose of 250 mg twice daily administered for 
7 days in outpatient adults (≥18 to ≤85 years of age) who have at least moderate RSV disease 
(LRTD) due to RSV infection, and who are at high risk of RSV-related disease progression. 
Moderate RSV disease is defined as having at least any 2 of the symptoms of LRTD (cough, 
wheeze, coughing up phlegm, short of breath), at least one of which must be scored as at least 
‘moderate’ if the symptoms did not pre-exist before RSV onset, and/or at least one of which 
must be scored worse than usual if the symptoms pre-existed as determined by the participant's 
ratings of the RiiQ™Symptom Scale and the Pre-Existing Symptom Questionnaire in the 
electronic Patient Report Outcome (ePRO) device.
A target of 180 participants who are at high risk for RSV-related disease progression is planned
in this study. Participants are randomized in a 2:1 ratio (active:placebo) with approximately 120 
participants planned in the rilematovir group and approximately 60 participants in the placebo 
group. Randomization to study intervention treatment should occur within 72 hours after onset of 
any of the RSV symptoms or worsening of pre-existing symptoms.
High-risk condition(s) for RSV-related disease progression is defined as:

Presence of any of the underlying high-risk comorbid cardiopulmonary conditions (COPD, 
asthma, or CHF) AND/OR

≥65 years of age (elderly participants).
Randomization is stratified by high-risk (<65 years of age with underlying high-risk comorbid 
cardiopulmonary conditions [COPD, asthma, or CHF] versus ≥65 years of age without 
underlying comorbid cardiopulmonary conditions versus ≥65 years of age with underlying 
comorbid cardiopulmonary conditions), and time since symptom onset (≤48 hours versus >48-72
hours). 
The study population should consist of at least 50% of participants with randomization ≤48 hours 
since onset of RSV symptoms.
Participants who meet all eligibility criteria are randomized in a 2:1 ratio to receive 1 of the 
following 2 treatments:

Treatment A: rilematovir 250 mg twice daily for 7 days (n = 120)
with dose reduction to 125 mg twice daily if coadministration with moderate or 
strong CYP3A4 inhibitors is started or continued during study intervention treatment
– for more information, see Section 6. Study Intervention and Concomitant Therapy
of the study protocol.

Treatment B: matched placebo twice daily for 7 days (n = 60).


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The study includes a Screening Period (Day -1 to Day 1), a Treatment Period (Day 1 to Day 7/8
[depending on timing of first dose]), and a Follow-up Period (Day 8/9 to Day 35 [±3]). In 
general, the total study duration for each participant is 35 (±3) days.
Study interventions is administered orally. Study intervention administration should start as soon 
as possible, but no later than 4 hours after randomization. Randomization must occur within a 
window of 72 hours of RSV symptom onset.
A diagram of the study design is provided in Figure 1.
Figure 1:
Schematic overview of the study
More information about the study can be found in the protocol, Section 4.1 Overall Design.
2.
STATISTICAL HYPOTHESES
As this is an exploratory, hypothesis-generating study, no formal statistical testing was planned.
For exploratory purposes, the primary hypothesis of this study is that rilematovir reduces the 
time to resolution of the RSV LRTD symptoms compared to placebo, as assessed by a PRO
measure (RiiQTM Symptom Scale) in adult outpatients with at least moderate RSV disease and 
who are at high risk for RSV disease related progression.
3.
SAMPLE SIZE DETERMINATION
The study aims to enroll approximately 180 participants in a 2:1 ratio to rilematovir 
250 mg twice
daily
(approximately
120 participants) and placebo (approximately 60 
participants).
The sample size calculation is based on the primary efficacy endpoint, which is the time to 
resolution of RSV LRTD symptoms from initiation of treatment to Day 35 in the Intent-to-Treat 
infected (ITT-i) analysis set.
With a sample size of 180 participants, there is an 80% probability to demonstrate a reduction of 
at least 20% in the primary efficacy endpoint when the true effect is 30%. As further guidance 


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for the sample size of this study, the power to detect a treatment difference for the primary 
efficacy endpoint is also calculated.
An accelerated failure time (AFT) model with underlying log-normal distribution for the time to 
resolution is assumed with a median in a placebo arm of 14 days and a scale parameter of 0.8 (as 
observed in Study 53718678RSV2004). Using the Gehan-Wilcoxon test to analyze the data and 
based on the assumptions that the time to recovery is improved by 30%, that approximately 10% 
of the total enrolled participants may not be centrally confirmed RSV positive, and that 5% of 
patients may drop out of the study early before reaching resolution of their RSV LRTD 
symptoms, a sample size of 180 participants (randomized in a 2:1 ratio to rilematovir 250 mg 
twice daily and placebo) will have an estimated power of 80% as based on 10,000 simulations 
using a 10% 2-sided significance level. The power was estimated as the number of simulated 
studies where the 2-sided p-value from the Gehan-Wilcoxon test was <0.1 out of the 10,000 
simulated datasets.
4.
POPULATIONS (ANALYSIS SETS) FOR ANALYSIS
Patient profiles will be produced for all participants who signed the main Informed Consent 
Form (ICF) and who were randomized in the study, regardless of being treated or not.
In addition, patient profiles including limited information: ie, demographic and safety data, will
also be produced for participants who signed the pre-screening (diagnostic) ICF and experienced 
a study procedure-related Adverse Event (AE), even if participant was not randomized.
5.
STATISTICAL ANALYSES
5.1.
General Considerations
No efficacy and safety summary analyses will be performed and only listings will be generated
for each participant.
Clinical data will be reported through patient profiles, which will be produced using SAS®
version 9.4 (or higher). 
5.1.1.
Phase Definitions
Not applicable
5.1.2.
Baseline
Not applicable
5.1.3.
Relative Day
Study Day 1 is the reference day and defined as the date of first dose of study intervention intake
(there is no ‘Day 0’). All efficacy and safety assessments at all visits will be assigned a day
relative to this date.

The relative day for visits before Day 1 will be defined as:


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Relative day = visit date – reference date

The relative day for visits on or after Day 1 will be defined as:
Relative day = visit date – reference date+1
5.1.4.
Visit Windows
All values collected for the parameters listed below will be considered based on their actual date 
and time.
5.1.5.
Data Handling Rules for RSV RNA Viral Load
For reporting purposes, the log10 qRT-PCR viral load will be imputed with the midpoint on the 
log scale between the limit of detection (LOD) and lower limit of quantification (LLOQ) of the 
RSV qRT-PCR assay when the result is ‘target detected’ (TD) but non-quantifiable.

For the RSV-A qRT-PCR assay, the LOD is 620 copies/mL and the LLOQ is 
1000 copies/mL, a result that is TD will be imputed with 2.90 log10 copies/mL.

For the RSV-B qRT-PCR assay, the LOD is 80 copies/mL and the LLOQ is 250 copies/mL, 
a result that is TD will be imputed with 2.15 log10 copies/mL.
When the result is ‘target not detected’ (TND) (i.e., below the LOD), for both RSV A and RSV 
B the value of TND will be imputed with 0 log10 copies/mL. 
For the overall reporting of viral load, all the viral load results of the RSV type with which the 
participant has been infected will be used.
In case of co-infection with both subtypes RSV A and B, the rules below will be applied for the 
overall analyses of viral load from the time the co-infection is detected (i.e., result of TD or 
>LLOQ):

In case of two quantifiable results: the log10 of the sum of the RSV A and RSV B results in 
copies/mL will be used.

In case of a quantifiable result and a TD/TND result: use the imputed TD/TND on the 
copies/mL scale value and then use the log10 of the sum of the imputed value and the 
quantifiable result.

In case of two TD results, or one TD and one TND result: use the imputed TD/TND on the 
copies/mL scale values and then use the log10 of the sum of the imputed values.

In case of two TND results: impute as 0 log10.
5.2.
Participant Dispositions
Table 3 presents a list of the disposition information variables that will be reported in the patient 
profiles. The randomization listing will be included as appendix in the CSR.












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Status: Approved, Date: 24 May 2022
5.8.
Interim Analyses
Not applicable.
6.
SUPPORTING DOCUMENTATION
6.1.
Appendix 1 List of Abbreviations
AE
adverse event
AFT
accelerated failure time
ALT/SGPT
alanine aminotransferase
AST/SGOT
aspartate aminotransferase
AUC
area under the curve
BL
Baseline
BMI
body mass index
bpm
beats per minute
CHF
congestive heart failure
Cmax
maximum concentration
COPD
chronic obstructive pulmonary disease
CSR
Clinical Study Report
CSS
Clinician Symptom Score
DMID
Division of Microbiology and Infectious Diseases
ECG
electrocardiogram
eCRF
electronic case report form
EPR-3
Expert panel report 3
ePRO
Electronic Patient Report Outcome
EQ-5D-5L
5 level EuroQol© 5 Dimension (EQ-5D-5L) questionnaire
F
Fusion
GOLD
Global initiative for chronic obstructive lung disease
HRQOL
Health-Related Quality of Life
ICF
Informed consent form
ICU
intensive care unit
ITT-i
Intent-to-Treat infected
IWRS
interactive web response system
LLOQ
lower limit of quantification
LOD
limit of detection
LRTD
lower respiratory tract disease
MedDRA
Medical Dictionary for Regulatory Activities
mL
milliliters
mmHg
millimeters of mercury
MRU
medical resource utilization
ms
milliseconds
NAEPP
National asthma education and prevention program
NGS
next-generation sequencing
PGI‑C
Patient Global Impression of Change
PGI‑S
Patient Global Impression of RSV Severity
PK
pharmacokinetic(s)
PK/PD
pharmacokinetic/pharmacodynamics










CCI