Conditions: Respiratory Syncytial Virus Infections
Allocation: NON_RANDOMIZED | Intervention model: PARALLEL
Enrollment: 7
Healthy volunteers: no

Brief summary:
The purpose of this long-term follow-up (LTFU) study is to evaluate the incidence of the clinical diagnosis of asthma and the frequency of wheezing in infants and children with respiratory syncytial virus (RSV) infection who were treated with (lumicitabine or placebo) and have completed their last planned study-related visit in a feeding Phase 2 study (64041575RSV2004).

Detailed description:
RSV is a leading cause of lower respiratory tract disease in infants. The primary hypothesis is that treatment of RSV-infected infants/children with lumicitabine (also known as JNJ-64041575 or ALS-008176) will decrease subsequent wheezing/asthma compared to placebo (looks like lumicitabine). The participants who have completed treatment course (lumicitabine/placebo) and last study visit in a previous study, 64041575RSV2004, for the treatment of RSV infection will be enrolled in this LTFU study. The main purpose of this study is to understand the impact of lumicitabine on the occurrence of asthma/wheezing in infants/children with a history of RSV infection. The participants will be assessed via monthly calls with the parents/caregivers and also at site visits at 3, 6,12 and 24 months.

Arms:
arm 1: Participants who completed the last planned study-related visit in a feeding Phase 2 study (64041575RSV2004), in which they received a regimen containing lumicitabine for the treatment of RSV infection, and who agree to participate in this follow-up study will be assessed for the incidence of the clinical diagnosis of asthma, frequency of wheezing, long-term safety of lumicitabine, frequency and type of respiratory infections and medical resource usage. arm 2: Participants who completed the last planned study-related visit in a feeding Phase 2 study (64041575RSV2004), in which they received a regimen containing placebo for the treatment of RSV infection, and who agree to participate in this follow-up study will be assessed for the incidence of the clinical diagnosis of asthma, frequency of wheezing, long-term safety of placebo, frequency and type of respiratory infections and medical resource usage.

Interventions: intervention 1: Lumicitabine intervention 2: Placebo
Intervention descriptions: intervention 1: Participants who received lumicitabine in a feeding Phase 2 study (64041575RSV2004) will be observed in this study. intervention 2: Participants who received placebo in a feeding Phase 2 study (64041575RSV2004) will be observed in this study.

Protocol document:
Prot_000.pdf: 
1
Status: Approved, Date: 30 January 2018
Janssen Research & Development*
Clinical Protocol
A Long-term Follow-up of Study 64041575RSV2004 to Evaluate the Impact of 
Lumicitabine (JNJ-64041575) on the Incidence of Asthma and/or Wheezing in Infants and 
Children with a History of Respiratory Syncytial Virus Infection
Protocol 64041575RSV2002; Phase 2b
AMENDMENT 2
Lumicitabine (JNJ-64041575, ALS-008176)
* Janssen Research & Development is a global organization that operates through different legal entities
in various countries. Therefore, the legal entity acting as the sponsor for Janssen Research &
Development studies may vary, such as, but not limited to Janssen Biotech, Inc.; Janssen Products, LP;
Janssen Biologics, BV; Janssen-Cilag International NV; Janssen Pharmaceutica NV; Janssen, Inc; Janssen
Sciences Ireland UC; or Janssen Research & Development, LLC. The term “sponsor” is used throughout
the protocol to represent these various legal entities; the sponsor is identified on the Contact Information
page that accompanies the protocol.
US sites of this study will be conducted under US Food & Drug Administration IND regulations 
(21 CFR Part 312).
EudraCT NUMBER: 2016-002095-26
Status:
Approved
Date:
30 January 2018
Prepared by:
Janssen Research & Development, a Division of Janssen Pharmaceutica NV.
EDMS number:
EDMS-ERI-116070484, 6.0
GCP Compliance: This study will be conducted in compliance with Good Clinical Practice, and applicable regulatory 
requirements. 
Confidentiality Statement
The information in this document contains trade secrets and commercial information that are privileged or confidential and may 
not be disclosed unless such disclosure is required by applicable law or regulations. In any event, persons to whom the 
information is disclosed must be informed that the information is privileged or confidential and may not be further disclosed by 
them. These restrictions on disclosure will apply equally to all future information supplied to you that is indicated as privileged or 
confidential.
NCT03332459


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Protocol History
64041575RSV2002
Document Type and
File Name
Issued Date
Comments
Initial Clinical Protocol
64041575RSV2002_Protocol
14 June 2016
-
Protocol Amendment 1
64041575RSV2002_Protocol_Amend_1
26 June 2017
For details, please refer to Amendment 1
Protocol Amendment 2
64041575RSV2002_Protocol_Amend_2
This document.
For details, please refer to Amendment 2


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TABLE OF CONTENTS
TABLE OF CONTENTS ............................................................................................................................... 3
LIST OF ATTACHMENTS............................................................................................................................ 4
LIST OF IN-TEXT TABLES.......................................................................................................................... 5
PROTOCOL AMENDMENTS....................................................................................................................... 6
SYNOPSIS.................................................................................................................................................... 8
TIME AND EVENTS SCHEDULE .............................................................................................................. 13
ABBREVIATIONS ...................................................................................................................................... 15
1.
INTRODUCTION................................................................................................................................ 16
1.1.
Background .................................................................................................................................... 17
1.2.
Overall Rationale for the Study...................................................................................................... 19
2.
OBJECTIVES, ENDPOINTS, AND HYPOTHESIS........................................................................... 19
2.1.
Objectives and Endpoints .............................................................................................................. 19
2.1.1.
Objectives ................................................................................................................................... 19
2.1.2.
Endpoints.................................................................................................................................... 20
2.2.
Hypothesis ..................................................................................................................................... 21
3.
STUDY DESIGN AND RATIONALE ................................................................................................. 21
3.1.
Overview of Study Design.............................................................................................................. 21
3.2.
Study Design Rationale.................................................................................................................. 22
4.
SUBJECT POPULATION.................................................................................................................. 22
4.1.
Inclusion Criteria ............................................................................................................................ 22
4.2.
Exclusion Criteria ........................................................................................................................... 23
5.
TREATMENT ALLOCATION AND BLINDING................................................................................. 23
6.
DOSAGE AND ADMINISTRATION .................................................................................................. 23
7.
TREATMENT COMPLIANCE............................................................................................................ 23
8.
MEDICATIONS.................................................................................................................................. 23
9.
STUDY EVALUATIONS .................................................................................................................... 24
9.1.
Study Procedures........................................................................................................................... 24
9.1.1.
Overview..................................................................................................................................... 24
9.1.2.
Entry Visit.................................................................................................................................... 24
9.1.3.
Study Period ............................................................................................................................... 25
9.2.
Clinical Evaluations........................................................................................................................ 25
9.3.
Medical Resource Utilization and Health Economics .................................................................... 26
9.4.
Safety Evaluations ......................................................................................................................... 26
9.5.
Sample Collection and Handling.................................................................................................... 26
10.
SUBJECT COMPLETION/WITHDRAWAL FROM THE STUDY...................................................... 26
10.1.
Completion ..................................................................................................................................... 26
10.2.
Withdrawal From the Study............................................................................................................ 27
11.
STATISTICAL METHODS................................................................................................................. 27
11.1.
Subject Information ........................................................................................................................ 27
11.2.
Sample Size Determination ........................................................................................................... 27


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11.3.
Clinical Analyses ............................................................................................................................ 27
11.3.1.
Primary Analysis ......................................................................................................................... 27
11.3.2.
Secondary Analysis .................................................................................................................... 28
11.4.
Medical Resource Utilization and Health Economics Analyses..................................................... 28
11.5.
Safety Analyses ............................................................................................................................. 28
11.6.
Interim Analysis.............................................................................................................................. 28
12.
ADVERSE EVENT REPORTING ...................................................................................................... 29
12.1.
Definitions ...................................................................................................................................... 29
12.1.1.
Adverse Event Definitions and Classifications ........................................................................... 29
12.1.2.
Attribution Definitions.................................................................................................................. 30
12.1.3.
Severity Criteria .......................................................................................................................... 31
12.2.
Procedures..................................................................................................................................... 31
12.2.1.
All Adverse Events...................................................................................................................... 31
12.2.2.
Serious Adverse Events ............................................................................................................. 32
12.3.
Contacting Sponsor Regarding Safety........................................................................................... 33
13.
PRODUCT QUALITY COMPLAINT HANDLING.............................................................................. 33
14.
STUDY DRUG INFORMATION......................................................................................................... 33
15.
STUDY-SPECIFIC MATERIALS....................................................................................................... 33
16.
ETHICAL ASPECTS ......................................................................................................................... 34
16.1.
Study-specific Design Considerations ........................................................................................... 34
16.2.
Regulatory Ethics Compliance....................................................................................................... 34
16.2.1.
Investigator Responsibilities ....................................................................................................... 34
16.2.2.
Independent Ethics Committee or Institutional Review Board ................................................... 34
16.2.3.
Informed Consent Form.............................................................................................................. 36
16.2.4.
Privacy of Personal Data ............................................................................................................ 37
17.
ADMINISTRATIVE REQUIREMENTS .............................................................................................. 37
17.1.
Protocol Amendments.................................................................................................................... 37
17.2.
Regulatory Documentation ............................................................................................................ 38
17.2.1.
Regulatory Approval/Notification ................................................................................................ 38
17.2.2.
Required Prestudy Documentation............................................................................................. 38
17.3.
Subject Identification, Enrollment, and Screening Logs ................................................................ 39
17.4.
Source Documentation................................................................................................................... 39
17.5.
Case Report Form Completion ...................................................................................................... 39
17.5.1.
Parent/Caregiver......................................................................................................................... 40
17.6.
Data Quality Assurance/Quality Control ........................................................................................ 40
17.7.
Record Retention ........................................................................................................................... 40
17.8.
Monitoring ...................................................................................................................................... 41
17.9.
Study Completion/Termination....................................................................................................... 42
17.9.1.
Study Completion/End of Study.................................................................................................. 42
17.9.2.
Study Termination....................................................................................................................... 42
17.10.
On-site Audits................................................................................................................................. 42
17.11.
Use of Information and Publication................................................................................................ 42
REFERENCES............................................................................................................................................ 45
INVESTIGATOR AGREEMENT ................................................................................................................. 70
LIST OF ATTACHMENTS
Attachment 1: 
Division of Microbiology and Infectious Diseases (DMID) Pediatric Toxicity 
Tables (November 2007)............................................................................................ 46


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Attachment 2: 
Standardized Paper Questionnaire for Use During Scheduled Study Site 
Visits and Monthly Phone Calls Between Study Site Visits........................................ 58
Attachment 3: 
Wheezing Parent/Caregiver Card to Be Completed Daily ......................................... 66
Attachment 4: 
Medication Parent/Caregiver Card to Be Completed Daily........................................ 68
LIST OF IN-TEXT TABLES 
Table 1:
Investigational Product and its Metabolites .............................................................................. 17


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PROTOCOL AMENDMENTS
Amendments below are listed beginning with the most recent amendment.
Amendment 2 (This document)
This amendment is considered to be nonsubstantial based on the criteria set forth in Article 10(a) of 
Directive 2001/20/EC of the European Parliament and the Council of the European Union, in that it does not 
significantly impact the safety or physical/mental integrity of subjects, nor the scientific value of the study.
The overall reason for the amendment: The overall reason for this amendment was to provide more clarity when
the clinician questionnaire needs to be completed. Furthermore, it was clarified that the entry visit needs to take 
place within 3 months after randomization in Study 64041575RSV2004 and that the study site visits need to be 
scheduled 3, 6, 12, 18, and 24 months after entry visit in Study 64041575RSV2002.
The table below gives an overview of the rationale for each change and all applicable sections.
Rationale: It was clarified that the clinician questionnaire needs to be completed during the scheduled study site
visits (entry visit and 3, 6, 12, 18, and 24 months after entry visit) and during monthly telephone calls with the 
parent/caregiver between study site visits as indicated in the Time and Events Schedule. Instructions in the paper 
questionnaire and footnote “b” of the Time and Events Schedule were updated accordingly. Furthermore, it was 
clarified that the entry visit needs to take place within 3 months after randomization in Study 64041575RSV2004 
and that the study site visits need to be scheduled 3, 6, 12, 18, and 24 months after entry visit in 
Study 64041575RSV2002.
SYNOPSIS
Time and Events Schedule
9.1.2 Entry Visit
9.1.3 Study Period
Attachment 2
Rationale: A window of ±7 days from the entry visit is allowed for the other scheduled study site visits.
Time and Events Schedule
Rationale: The protocol is aligned with the sponsor’s latest available protocol template and minor corrections were 
made, including but not limited to:
-
The classification of this study as an observational or interventional study depends on local regulation. Therefore 
the word “observational” was removed from the protocol.
Throughout the protocol
Amendment 1 (26 June 2017)
This amendment is considered to be nonsubstantial based on the criteria set forth in Article 10(a) of 
Directive 2001/20/EC of the European Parliament and the Council of the European Union, in that it does not 
significantly impact the safety or physical/mental integrity of subjects, nor the scientific value of the study.
The overall reason for the amendment: The overall reason for this amendment was to clarify that participation in 
this long-term follow-up study is optional for study sites, update the study number for which this study will be the 
long-term follow-up study (64014575RSV2004), update the introduction and background information to be in line 
with Study 64014575RSV2004, update the age of subjects participating in Study 64014575RSV2004, and update 
the planned number of subjects to be enrolled in Study 64041575RSV2004. In addition, minor editorial changes, 
clarifications, and corrections were made.


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The table below gives an overview of the rationale for each change and all applicable sections.
Rationale: Language was added to clarify that participation in this long-term follow-up study is optional for study 
sites.
SYNOPSIS
3.1 Overview of Study Design
Rationale: The study number for Study 64041575RSV2001 was changed to 64041575RSV2004. Due to significant 
changes in the study design a new protocol number was created for this study. Additional changes were also made to 
align Study 64041575RSV2002 with Study 64041575RSV2004 and included the following:

The introduction and background information was updated to be in line with Study 64041575RSV2004 and the 
updated version of the Investigator’s Brochure (Edition 7).

The age of infants and children participating in Study 64041575RSV2004 was updated from 1 to 36 months to 
≥28 days to ≤36 months, according to the 64041575RSV2004 protocol.

The planned number of subjects to be enrolled in Study 64041575RSV2004 was updated according to the 
64041575RSV2004 protocol.
Throughout the protocol
SYNOPSIS
1 INTRODUCTION
1.1 Background
11.2 Sample Size Determination
Rationale: Minor editorial changes, clarifications, and corrections were made, including but not limited to:

The generic name of the investigational product, lumicitabine, was added. The compound numbers of the 
investigational product and its metabolites were also updated to the current compound numbers.

A definition was added to explain that “previous treatment group” refers to the actual treatment (lumicitabine or 
placebo) administered in Study 64041575RSV2004.

Clarification was made that wheezing and medication parent/caregiver cards will be completed on a daily basis 
and that these cards will aid the study site personnel to complete the clinical questionnaire when they interview 
the parent/caregiver. The wheezing and medication parent/caregiver cards were added as attachments to the 
protocol.

A paper questionnaire instead of an electronic device will be used for completion of the clinical questionnaire.
Throughout the protocol
SYNOPSIS
3.1 Overview of Study Design
8 Medications
9.1 Study Procedures
11.3.1 Primary Analysis
15 STUDY-SPECIFIC MATERIALS


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SYNOPSIS
A Long-term Follow-up of Study 64041575RSV2004 to Evaluate the Impact of Lumicitabine 
(JNJ-64041575) on the Incidence of Asthma and/or Wheezing in Infants and Children with a 
History of Respiratory Syncytial Virus Infection
Lumicitabine (also known as JNJ-64041575 or ALS-008176) is a 3’,5’-bisisobutyrate prodrug of the 
cytidine nucleoside analog JNJ-63549109 (also known as ALS-008112), which is being developed as an 
orally administered antiviral therapy for the treatment of infants, children, and adults infected with 
respiratory syncytial virus (RSV) and human metapneumovirus. Once administered, lumicitabine is 
rapidly and efficiently converted by esterases to JNJ-63549109. Inside cells, JNJ-63549109 is 
subsequently
converted to the JNJ-63549109-5’-triphosphate,
JNJ-65409136
(also known as 
ALS-008136), which, as the active metabolite of the compound, is a potent and selective inhibitor of RSV 
and human metapneumovirus ribonucleic acid (RNA) polymerase activity via a classic chain termination 
mechanism. JNJ-64167896 (also known as ALS-008144), the uridine metabolite of JNJ-63549109, is the 
inactive major metabolite noted in systemic circulation.
Investigational Product and its Metabolites
Compound Name/Number
Description
Lumicitabine (JNJ-64041575, ALS-008176)
3’,5’-bisisobutyrate prodrug of JNJ-63549109
JNJ-63549109 (ALS-008112)
parent nucleoside, major metabolite of lumicitabine
JNJ-64412309 (ALS-008206)
3’-isobutyrate monoester of JNJ-63549109, minor metabolite
JNJ-64412296 (ALS-008207)
5’-isobutyrate monoester of JNJ-63549109, minor metabolite
JNJ-64167896 (ALS-008144)
uridine metabolite of JNJ-63549109, major metabolite
JNJ-65409136 (ALS-008136)
5’-triphosphate of JNJ-63549109 (NTP), intracellular 
metabolite, active
JNJ-65409123 (ALS-008137)
5’-monophosphate of JNJ-63549109, intracellular metabolite
Abbreviation: NTP: nucleoside triphosphate.
This long-term follow-up (LTFU) study will evaluate the incidence of the clinical diagnosis of asthma 
and the frequency of wheezing for at least 2 years in subjects enrolled from Study 64041575RSV2004.
OBJECTIVES, ENDPOINTS, AND HYPOTHESIS
Objectives
Primary Objectives
The primary objectives are to evaluate in infants and children who have been treated with lumicitabine or 
placebo in Study 64041575RSV2004 during the follow-up period and within 2 years after the RSV 
infection:

The incidence of the clinical diagnosis of asthma.

The frequency of wheezing.
Secondary Objectives
The secondary objectives are to evaluate during the follow-up period in infants and children who have 
been treated with lumicitabine or placebo in Study 64041575RSV2004:

The frequency of wheezing over time.

The frequency of wheezing episodes over time.

The long-term safety of lumicitabine.


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
The frequency and type of respiratory infections.

Medical resource utilization.
Exploratory Objectives
The exploratory objectives are to evaluate during the follow-up period in infants and children who have 
been treated with lumicitabine or placebo in Study 64041575RSV2004:

The long-term impact of RSV and its treatment with lumicitabine or placebo on how the subject’s 
health affects normal daily activities for subjects, parents/caregivers, and other family members. 

Impact of the type of wheezing/asthma phenotypes on the frequency of wheezing and clinical 
diagnosis of asthma.
Endpoints
Primary Endpoints
The primary endpoints are:

Clinical diagnosis of asthma within the first 2 years after the RSV infection, as diagnosed by a 
physician and reported by the parent/caregiver.
All medical information needed to confirm the diagnosis of asthma needs to be collected by the 
study site personnel.

Percentage of wheezing days within the first 2 years after the RSV infection, based on information 
reported by the parent/caregiver.
Secondary Endpoints
The secondary endpoints during the follow-up period are:

Percentage of wheezing days per month after the RSV infection, based on information reported by 
the parent/caregiver.

Number of wheezing episodes after the RSV infection, based on information reported by the 
parent/caregiver.

Incidence of reportable adverse events (AEs) and serious adverse events (SAEs) among subjects, 
based on information reported by the parent/caregiver and judged by the investigator. Reportable 
AEs include AEs related to respiratory illnesses and AEs considered at least possibly related to 
lumicitabine or placebo by the investigator.

Number and type of respiratory infections among subjects, based on information reported by the 
parent/caregiver.

Medical resource utilization including the number of medical visits, emergency room visits, and 
hospitalizations, all for respiratory conditions only, based on information reported by the 
parent/caregiver.


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Exploratory Endpoints
The exploratory endpoints during the follow-up period are:

The long-term impact of RSV and its treatment with lumicitabine or placebo on how the subject’s 
health affects the normal daily activities of the subject, the parent/caregiver, and other family 
members as determined by:

The extent to which the subject’s daily activities each month were limited by the subject’s 
health.

The percentage of days each month that the parent/caregiver missed from work due to the 
subject’s health.

The extent to which the parent’s/caregiver’s productivity while at work was limited by the 
subject’s health.

The extent to which the subject’s health problems limited the parent’s/caregiver’s ability to 
engage in normal daily activities.

The extent to which the subject’s health problems impacted the parent’s/caregiver’s health.

The inability of the parent/caregiver to care for other family members due to the subject’s 
health.

The extent to which the subject’s health limited the parent’s/caregiver’s time spent with other 
family members.

The percentage of days each month that other family members missed from work due to the 
subject’s health problems.

Frequency of wheezing and clinical diagnosis of asthma by type of wheezing/asthma phenotype.
Hypothesis
No formal hypothesis testing will be performed. The hypothesis to be explored is that treatment of 
RSV-infected infants and children with lumicitabine will decrease the incidence of subsequent asthma 
and/or wheezing compared with infants and children treated with placebo.
OVERVIEW OF STUDY DESIGN
This is a global, multicenter, blinded, LTFU study to evaluate the incidence of the clinical diagnosis of
asthma and the frequency of wheezing in infants and children (otherwise healthy or with underlying 
comorbidities for severe RSV) who have completed their treatment course and their last study-related 
visit in a previous Phase 2 study, 64041575RSV2004, in which they received lumicitabine or placebo for 
the treatment of RSV infection. Subjects will be followed for at least 2 years following treatment. This 
study may be extended up to an additional 3 years (ie, total duration up to 5 years after randomization into 
Study 64041575RSV2004). Participation in this LTFU study is optional for study sites. This LTFU study 
will be offered to subjects of Study 64041575RSV2004 if their site decides to participate in this LTFU 
study.
Subjects will be enrolled within 3 months after randomization in Study 64041575RSV2004.
No study drug will be administered in this study. The parent/caregiver of the subject and the investigator 
will 
remain 
blinded 
to 
the 
study 
treatment 
(lumicitabine
or 
placebo) 
administered 
in 
Study 64041575RSV2004 until the completion of this LTFU study, including any extension period.
Assessments will be performed at the study site at enrollment in this study and at 3, 6, 12, 18, and 
24 months after entry visit in Study 64041575RSV2002. The last visit of Study 64041575RSV2004 (ie, 


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Day 28) may be combined with the entry visit of this LTFU study. The same assessments will be 
performed during monthly phone calls with the parent/caregiver between the study site visits.
An unblinded interim analysis will be performed when all subjects from the first season in 
Study 64041575RSV2004 who are enrolled in this LTFU study complete the 18 month follow-up 
assessment of this LTFU study. This interim analysis will serve to evaluate the need for an extension of 
the follow-up period.
SUBJECT POPULATION
Male or female infants and children who were previously randomized in Study 64041575RSV2004 for 
the treatment of RSV infection, who completed the planned course of the study drug and the last 
study-related visit in Study 64041575RSV2004, and whose legally acceptable representative has signed 
the informed consent form are eligible for participation in this LTFU study.
DOSAGE AND ADMINISTRATION
No study drug will be administered in this study.
CLINICAL EVALUATIONS
The study includes the following clinical evaluations:

Collection of information on the clinical diagnosis of asthma to determine the incidence of asthma.

Collection of presence of wheezing on a daily basis to determine the frequency of wheezing and 
wheezing episodes.

Collection of medical history and family history to identify risk factors for wheezing/asthma at 
baseline.

Collection of data to determine the frequency and type of respiratory infections.

Collection of data on medications used for the treatment of respiratory infections and illnesses (eg, 
bronchodilators).

Collection of data from lung function tests and allergy tests (immunoglobulin E and skin test), if 
available, as supporting documentation of the diagnosis of asthma, wheezing, and atopy.
MEDICAL RESOURCE USAGE AND HEALTH ECONOMICS
Medical resource usage (including medical visits, emergency room visits, and hospitalizations, all for 
respiratory conditions) and the impact of the subject’s health status on normal daily activities for subjects, 
parents/caregivers, and other family members will be collected throughout the course of the study.
SAFETY EVALUATIONS
The study includes the following evaluations of safety and tolerability:

Respiratory illness AEs (including subsequent RSV infections).

AEs considered at least possibly related to lumicitabine or placebo.

SAEs.
STATISTICAL METHODS
No formal power calculation has been performed, as this is an LTFU study in which infants and children 
from the previous Phase 2 study of lumicitabine (Study 64041575RSV2004) may be enrolled. The 
planned number of subjects enrolled in Study 64041575RSV2004 is up to 120 subjects on lumicitabine


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and up to 60 subjects on placebo. It is expected that approximately 35% of those subjects will participate 
in this LTFU study.
The final analysis will be done when all the subjects have completed the last planned assessment of the 
follow-up period or discontinued earlier. 
The primary endpoints in this study are the clinical diagnosis of asthma and the percentage of wheezing 
days in a subject within the first 2 years after the RSV infection, as reported by the parent/caregiver.
No statistical testing will be done. 
Estimates of the incidence of asthma will be presented together with the 95% (2-sided) confidence 
interval by previous treatment group. The previous treatment group is defined as the actual treatment 
(lumicitabine or placebo) of Study 64041575RSV2004. As a sensitivity analysis, the incidence of asthma 
will be presented for the subgroup of subjects for whom at least 12 months of follow-up data are
available.
The percentage of days with wheezing within the first 2 years after the RSV infection will be calculated 
per subject. Descriptive statistics, including 95% confidence intervals, will be presented by previous 
treatment group.
For the secondary endpoint, descriptive statistics and frequency tabulations will be used to present the 
percentage of wheezing days per month, the mean number of wheezing episodes, and the number and 
type of respiratory infections by previous treatment group.
Long-term safety of lumicitabine, medical resource utilization, and impact of the subject’s health status 
on normal daily activities for subjects, parents/caregivers, and other family members will be evaluated 
using frequency tabulations and listings by previous treatment group.


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TIME AND EVENTS SCHEDULE
Study Period
Entry Visita,b
Assessment Periodb
Months
0
3 (±7 days)
6 (±7 days)
12 (±7 days)
18 (±7 days)
24 (±7 days)
Screening/Administrative
Informed consent
X
Eligibility criteria
X
Baseline demographicsc
X
Medical and family historyc,d
X
Wheezing and medication parent/caregiver card
distribution and verificatione,f
X
X
X
X
X
X
Clinical Evaluations
Clinician questionnaireg
X
X
X
X
X
X
Monthly telephone calls between study site visitsh
Collection of data from lung function tests and 
allergy tests (immunoglobulin E and skin tests)i
X
Medical resource utilizationj
X
Medicationf
X
Safety Evaluations
Serious/reportable adverse eventsk
X
a. The entry visit needs to take place within 3 months after randomization in Study 64041575RSV2004. The last visit of Study 64041575RSV2004 (ie, Day 28) may be 
used as the entry visit for this study.
b. Assessments will be performed during study site visits (entry visit and 3, 6, 12, 18, and 24 months after entry visit in Study64041575RSV2002) and during monthly 
telephone calls with the parent/caregiver between study site visits.
c. Baseline demographics and medical/family history from the previous Phase 2 Study 64041575RSV2004 will be captured in the long-term follow-up electronic case 
report form (eCRF).
d. Medical and family history to identify risk factors for wheezing/asthma at baseline, including prenatal smoking by the subject’s mother, subject’s exposure to 
tobacco smoke, wheezing associated with symptoms of acute respiratory infections, whether the subject has siblings or attends kindergarten/day care, and personal 
and/or family history of atopy/allergy will be recorded in the eCRF.
e. Parents/caregivers will be provided with a wheezing parent/caregiver card to be completed daily. The information recorded on the wheezing parent/caregiver card 
will aid the site responsible person to complete the clinical questionnaire when interviewing the subject’s parent/caregiver. Parents/caregivers will be required to 
return the completed parent/caregiver cards to the study sites every 3 months (eg, in person or by mail/email/fax when no study site visit is scheduled).
f. Medication use will be monitored throughout the study from signing of the informed consent form until the last study-related activity. Parents/caregivers will be 
required to bring all medications to the study site visit. Additionally, parents/caregivers will be required to document on a daily basis use of all medications on a 
medication parent/caregiver card, which will serve as a reminder card to be used during the study site visits and during the monthly phone calls between the study 
site visits for recording the medication used for respiratory infections and illnesses in the eCRF by the study site personnel. Parents/caregivers will be required to 
return the completed parent/caregiver cards to the study sites every 3 months (eg, in person or by mail/email/fax when no study site visit is scheduled).
g. Collection of data on wheezing, asthma, eczema, allergic rhinitis, and impact of the subject’s health status on normal daily activities for subjects, parents/caregivers,
and other family members using a standardized questionnaire. The questionnaire should preferably be completed by the same study site responsible person, by 


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interviewing the subject’s parent/caregiver. Parents/caregivers will complete the wheezing and medication parent/caregiver cards on a daily basis, which will aid the 
study site responsible person in completing the questionnaire during the interview. Parents/caregivers will be required to return the completed parent/caregiver cards
to the study sites every 3 months (eg, in person or by mail/email/fax when no study site visit is scheduled).
h. Once per calendar month (±7 days) from the entry visit.
i.
Data from lung function tests and allergy tests (immunoglobulin E and skin test), if available, will be collected as supporting documentation of the diagnosis of 
asthma, wheezing, and atopy as reported by the parent/caregiver.
j.
Medical resource utilization will be monitored throughout the study from signing of the informed consent form until the last study-related activity and will include 
medical visits, emergency room visits, and hospitalizations, all for respiratory conditions only and will be recorded in the eCRF. Visits with each type of health care 
provider (eg, general practitioner, pediatrician, physician assistant, nurse practitioner, pulmonologist, allergist, or other) will be specified in the eCRF.
k. All reportable adverse events and serious adverse events will be monitored throughout the study from signing of the informed consent form until the last 
study-related activity and recorded in the eCRF.


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ABBREVIATIONS
AE
adverse event
CI
confidence interval
CYP
cytochrome P450
DMID
Division of Microbiology and Infectious Diseases
eCRF
electronic case report form
GCP
Good Clinical Practice
IB
Investigator’s Brochure
ICF
informed consent form
ICH
International Council for Harmonisation of Technical Requirements for Pharmaceuticals for 
Human Use
IEC
Independent Ethics Committee
IRB
Institutional Review Board
LD
loading dose
LRTI
lower respiratory tract infection
LTFU
long-term follow-up
MD
maintenance dose
NTP
nucleoside triphosphate
OAT
organic anion transporter
PK
pharmacokinetic(s)
RNA
ribonucleic acid
RSV
respiratory syncytial virus
SAE
serious adverse event
SUSAR
serious unexpected suspected adverse reaction


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1.
INTRODUCTION
Respiratory syncytial virus (RSV) is a ribonucleic acid (RNA) virus and a member of the 
Pneumoviridae family, which also includes human metapneumovirus. The RSV season occurs 
during winter months in regions with temperate climates in the Northern and Southern 
hemispheres and throughout the year or peaks semiannually in tropical regions.3
RSV causes acute lower respiratory tract infection (LRTI) and is a major cause of hospital 
admissions and death in young children worldwide. RSV is a leading cause of lower respiratory 
disease in infants.9 In 2005, an estimated 33.8 million episodes of RSV LRTI occurred 
worldwide in infants. Of these, at least 3.4 million severe cases of LRTI required hospitalization, 
and an estimated 66,000 to 199,000 deaths occurred, mostly in the developing world.9 In the 
United States, it has been estimated that annually RSV infection causes 2.1 million emergency 
room or outpatient visits, including 57,527 hospitalizations.7 Infants that are born prematurely or 
close to the RSV season and/or suffering from bronchopulmonary dysplasia or congenital heart 
disease are at the highest risk of developing severe RSV-related acute LRTI.6
RSV infection has been strongly associated with subsequent childhood asthma and wheezing, 
although the relationship has not been clearly defined.4,5 A causal relationship of RSV to 
subsequent development of asthma is supported by studies showing that the prophylactic use of 
Synagis(palivizumab) to prevent RSV infection can decrease the subsequent incidence of 
recurrent wheezing in high risk infants.2,11,12,13 In one such study, physician-diagnosed recurrent 
wheezing was observed in 6.4% and 18.9% of infants in the palivizumab-treated and -untreated 
groups, respectively (p <0.001). This difference remained significant after adjustment for known 
risk factors of recurrent wheezing (p <0.001).13 The American Academy of Pediatrics has 
however questioned the validity of these findings, describing the reduction of wheezing episodes 
among recipients of palivizumab as being statistically significant but of clinically minimal 
significance.1 A recent study in Native American infants with an efficacious anti-RSV 
monoclonal antibody (motavizumab), despite reducing RSV admission to hospital by 87%, did 
not have any impact on medically attended recurrent wheezing.10
Asthma appears to be a heterogeneous condition, with signs, symptoms, and clinical evolution 
that vary according to the patient’s disease characteristics or phenotype.4 Asthma is defined and 
diagnosed through a combination of clinical symptoms and physiologic abnormalities, generally 
without reliance upon pathologic or biologic markers. However, the physiologic definition of 
asthma is relatively nonspecific, consisting of airway hyperreactivity and airflow limitation 
during expiration, which is variable and/or reversible with bronchodilators. In many asthma 
patients, the presence of bronchial hyperreactivity is never objectively confirmed. 
Three wheezing/asthma phenotypes have been identified: early transient wheezers, non-atopic 
preschool wheezers, and atopic asthmatics/wheezers. Potential risk factors for each of these 
classic wheezing/asthma phenotypes presenting in children include prenatal smoking by the 
subject’s mother, subject’s exposure to tobacco smoke, wheezing associated with symptoms of 
acute respiratory infections, whether the subject has siblings or attends kindergarten/day care, 
personal and/or family history of atopy/allergy, and lung function.4


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Lumicitabine (also known as JNJ-64041575 or ALS-008176) is a 3’,5’-bisisobutyrate prodrug, 
which is readily metabolized to the cytidine nucleoside analog, JNJ-63549109 (also known as 
ALS-008112). Once administered, lumicitabine is rapidly and efficiently converted by esterases 
to 
JNJ-63549109. 
Inside 
cells, 
JNJ-63549109
is 
subsequently
converted 
to 
JNJ-63549109-5’-triphosphate, JNJ-65409136 (also known as ALS-008136), which, as the 
active metabolite of the compound, is a potent and selective inhibitor of RSV and human 
metapneumovirus RNA polymerase activity via a classic chain termination mechanism. 
JNJ-64167896 (also known as ALS-008144), the uridine metabolite of JNJ-63549109, is the 
inactive major metabolite detected in systemic circulation. Table 1 gives an overview of the 
investigational product used in this study and its metabolites, including the prior and current 
compound numbers.
Table 1:
Investigational Product and its Metabolites
Compound Name/Number
Description
Lumicitabine (JNJ-64041575, ALS-008176)
3’,5’-bisisobutyrate prodrug of JNJ-63549109
JNJ-63549109 (ALS-008112)
parent nucleoside, major metabolite of lumicitabine
JNJ-64412309 (ALS-008206)
3’-isobutyrate monoester of JNJ-63549109, minor metabolite
JNJ-64412296 (ALS-008207)
5’-isobutyrate monoester of JNJ-63549109, minor metabolite
JNJ-64167896 (ALS-008144)
uridine metabolite of JNJ-63549109, major metabolite
JNJ-65409136 (ALS-008136)
5’-triphosphate of JNJ-63549109 (NTP), intracellular metabolite, 
active
JNJ-65409123 (ALS-008137)
5’-monophosphate of JNJ-63549109, intracellular metabolite
Abbreviation: NTP: nucleoside triphosphate.
For the most comprehensive nonclinical and clinical information regarding lumicitabine, refer to 
the latest version of the Investigator’s Brochure (IB).8
The term “sponsor” used throughout this document refers to the entities listed in the Contact 
Information page(s), which will be provided as a separate document.
1.1.
Background
This study is a long-term follow-up (LTFU) of Study 64041575RSV2004, which evaluates the 
antiviral activity, clinical outcomes, safety, tolerability, and pharmacokinetics (PK) of orally 
administered lumicitabine regimens in infants and children aged ≥28 days to ≤36 months 
hospitalized with RSV infection
in Study 64041575RSV2004
whose parents/caregivers 
consented for participation in the LTFU study. This LTFU study, Study 64041575RSV2002, will 
follow these infants and children for at least 2 years after completion of their treatment course 
and their final visit of Study 64041575RSV2004 to evaluate the incidence of the clinical 
diagnosis of asthma and the frequency of wheezing.
A summary of the major findings from nonclinical and clinical studies available at the time of 
initial protocol writing is presented below. Please refer to the IB for more details.8
Nonclinical Studies
The antiviral activity and selectivity of the parent nucleoside JNJ-63549109 and its prodrug, 
lumicitabine, were demonstrated in vitro using a combination of cell-based RSV infectious and 
subgenomic replicon reporter systems, together with cell-extracted replicase and recombinant 


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RSV polymerase L–P complex. In vivo, lumicitabine was evaluated in the African Green 
monkey model of RSV infection. 
The nonclinical safety profiles for lumicitabine and JNJ-63549109 have been established in 
multiple in vitro and in vivo studies. In general, lumicitabine was well tolerated in adult rats and 
dogs for 14 days with no mortality or overt signs of toxicity when administered orally twice 
daily. In juvenile toxicity studies, doses of 1,000 mg/kg/day caused overt toxicity in both rats and 
dogs (JNJ-63549109 area under the concentration time curve from time zero to 24 hours 
postdose of ≥300,000 and ≥1,375,000 ng.h/mL in rats and dogs, respectively).
In studies investigating the PK and metabolism profile, the prodrug, lumicitabine, was rapidly 
and efficiently converted to the parent nucleoside, JNJ-63549109, following both intravenous 
and oral administration in all species studied. Lumicitabine exhibited high systemic clearance 
and short half-life. JNJ-64167896, the uridine metabolite of JNJ-63549109, was a major 
metabolite noted in systemic circulation in monkeys, but not in other species.
Lumicitabine and its major metabolites are predicted to have low potential for cytochrome P450 
(CYP)- and transporter-mediated drug-drug interactions, with the possible exception of strong 
organic anion transporter (OAT) 3 inhibitors.   
Clinical Studies
The efficacy of lumicitabine in naturally infected populations has not been demonstrated; 
however, efficacy has been assessed in healthy adult subjects infected with RSV in a human 
challenge model (Study ALS-8176-502). In this study, in 62 healthy adult subjects inoculated 
with RSV and treated with lumicitabine or placebo, data demonstrated that maintenance doses 
(MDs) of 150 to 500 mg lumicitabine, following a 750 mg loading dose (LD), resulted in rapid, 
substantial declines in RSV viral load with an accompanying comparable improvement in signs 
and symptoms of RSV infection compared with placebo-treated subjects.
Data from 6 Phase 1/2a studies (ALS-8176-501, ALS-8176-502, ALS-8176-504, ALS-8176-509, 
64041575RSV1001 [ALS-8176-511], and 64041575RSV1003) in healthy adult subjects 
(N=234), indicate that lumicitabine was well tolerated and that no safety concerns were 
identified after receiving lumicitabine as single doses up to 3,000 mg or as multiple doses up to 
750 mg twice daily on Day 1 followed by up to 500 mg MD (twice daily, every 12 hours) for up 
to 13 days. 
As of 20 April 2017, there have been 2 hematologic serious adverse events (SAEs) of 
pancytopenia and neutropenia reported in the ongoing clinical studies in hospitalized adult or 
pediatric subjects with RSV infection, respectively. In addition, there has been 1 non-serious 
Grade 4 hematologic adverse event (AE) (neutropenia, laboratory Grade 4) in the terminated 
Study ALS-8176-510 in an adult hospitalized subject with RSV infection. The safety data for all 
3 studies have been regularly reviewed by unblinded Independent Data Monitoring Committee, 
which have identified no potential safety concerns. Factors other than treatment with 
lumicitabine, including underlying RSV infection, are more likely to have contributed to these 
serious/severe hematologic AEs. However, a potential contribution of lumicitabine cannot be 
excluded. The risk-benefit assessment for the continued development of lumicitabine remains 


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favorable given the population targeted (hospitalized subjects) and the lack of available treatment 
for RSV infection. 
1.2.
Overall Rationale for the Study
Given the anticipated effect of lumicitabine treatment on RSV viral kinetics and clinical 
symptoms (see Section 1), the potential impact on subsequent wheezing and asthma is of interest. 
This study will therefore evaluate the long-term impact of treatment of RSV infection with 
lumicitabine on the subsequent development of wheezing or asthma.
2.
OBJECTIVES, ENDPOINTS, AND HYPOTHESIS
2.1.
Objectives and Endpoints
2.1.1.
Objectives
Primary Objectives
The primary objectives are to evaluate in infants and children who have been treated with 
lumicitabine or placebo in Study 64041575RSV2004 during the follow-up period and within 
2 years after the RSV infection:

The incidence of the clinical diagnosis of asthma.

The frequency of wheezing.
Secondary Objectives
The secondary objectives are to evaluate during the follow-up period in infants and children who 
have been treated with lumicitabine or placebo in Study 64041575RSV2004:

The frequency of wheezing over time.

The frequency of wheezing episodes over time.

The long-term safety of lumicitabine.

The frequency and type of respiratory infections.

Medical resource utilization.
Exploratory Objectives
The exploratory objectives are to evaluate during the follow-up period in infants and children 
who have been treated with lumicitabine or placebo in Study 64041575RSV2004:

The long-term impact of RSV and its treatment with lumicitabine or placebo on how the 
subject’s health affects normal daily activities for subjects, parents/caregivers, and other 
family members. 

Impact of the type of wheezing/asthma phenotypes on the frequency of wheezing and 
clinical diagnosis of asthma.


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2.1.2.
Endpoints
Primary Endpoints
The primary endpoints are:

Clinical diagnosis of asthma within the first 2 years after the RSV infection, as diagnosed by 
a physician and reported by the parent/caregiver.
All medical information needed to confirm the diagnosis of asthma needs to be collected by 
the study site personnel.

Percentage of wheezing days within the first 2 years after the RSV infection, based on 
information reported by the parent/caregiver.
Secondary Endpoints
The secondary endpoints during the follow-up period are:

Percentage of wheezing days per month after the RSV infection, based on information 
reported by the parent/caregiver.

Number of wheezing episodes after the RSV infection, based on information reported by the 
parent/caregiver.

Incidence of reportable AEs and SAEs among subjects, based on information reported by 
the parent/caregiver and judged by the investigator. Reportable AEs include AEs related to 
respiratory illnesses and AEs considered at least possibly related to lumicitabine or placebo 
by the investigator.

Number and type of respiratory infections among subjects, based on information reported by 
the parent/caregiver.

Medical resource utilization including the number of medical visits, emergency room visits, 
and hospitalizations, all for respiratory conditions only, based on information reported by 
the parent/caregiver.
Exploratory Endpoints
The exploratory endpoints during the follow-up period are:

The long-term impact of RSV and its treatment with lumicitabine or placebo on how the 
subject’s health affects the normal daily activities of the subject, the parent/caregiver, and 
other family members as determined by:

The extent to which the subject’s daily activities each month were limited by the 
subject’s health.

The percentage of days each month that the parent/caregiver missed from work due to 
the subject’s health.

The extent to which the parent’s/caregiver’s productivity while at work was limited by 
the subject’s health.


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
The extent to which the subject’s health problems limited the parent’s/caregiver’s 
ability to engage in normal daily activities.

The extent to which the subject’s health problems impacted the parent’s/caregiver’s 
health.

The inability of the parent/caregiver to care for other family members due to the 
subject’s health.

The extent to which the subject’s health limited the parent’s/caregiver’s time spent with 
other family members.

The percentage of days each month that other family members missed from work due to 
the subject’s health problems.

Frequency of wheezing and clinical diagnosis of asthma by type of wheezing/asthma 
phenotype.
Refer to Section 9 for evaluations related to endpoints.
2.2.
Hypothesis
No formal hypothesis testing will be performed. The hypothesis to be explored is that treatment 
of RSV-infected infants and children with lumicitabine will decrease the incidence of subsequent 
asthma and/or wheezing compared with infants and children treated with placebo.
3.
STUDY DESIGN AND RATIONALE
3.1.
Overview of Study Design
This is a global multicenter, blinded, LTFU study to evaluate the incidence of the clinical 
diagnosis of asthma and the frequency of wheezing in infants and children (otherwise healthy or 
with underlying comorbidities for severe RSV) who have completed their treatment course and 
their last planned study-related visit in a previous Phase 2 study, 64041575RSV2004, in which 
they received lumicitabine or placebo for the treatment of RSV infection. Subjects will be 
followed for at least 2 years following treatment. Participation in this LTFU study is optional for 
study sites. This LTFU study will be offered to subjects of Study 64041575RSV2004 if their site 
decides to participate in the LTFU.
No study drug will be administered in this study. Subjects may be enrolled within 3 months after 
randomization in Study 64041575RSV2004. Assessments will be performed at the time points 
specified in the Time and Events Schedule. The last visit of Study 64041575RSV2004 (ie, 
Day 28) may be combined with the entry visit of this LTFU study.
Parents/caregivers will be provided with a wheezing parent/caregiver card and a medication 
parent/caregiver card, both of which should be completed on a daily basis. These 
parent/caregiver cards will serve as reminder cards when a study site responsible person 
interviews the subject’s parent/caregiver in order to complete a standardized paper questionnaire. 
The questionnaire will be completed by a study site responsible person at each study site visit as 
noted in the Time and Events Schedule and during a monthly telephone call (calendar month 
±7 days) between study site visits (see Section 9.1.3).


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An unblinded interim analysis will be performed when all subjects from the first season in 
Study 64041575RSV2004 who are enrolled in this LTFU study complete the 18 months 
follow-up assessment of this LTFU study. Sites and the parents/caregivers of subjects will 
remain blinded. This interim analysis will serve to evaluate the need for an extension of the 
follow-up period (see Section 11.6).
The planned total study duration for each subject will be 24 months unless the decision is taken 
to extend the duration of follow-up in this study, based on the interim analysis.
3.2.
Study Design Rationale
This study is a LTFU study in subjects who received lumicitabine or placebo in
Study 64041575RSV2004.
4.
SUBJECT POPULATION
The inclusion and exclusion criteria for enrolling subjects in this study are described in the 
following 2 subsections. If there is a question about the inclusion or exclusion criteria below, the 
investigator must consult with the appropriate sponsor representative and resolve any issues 
before enrolling a subject in the study. Waivers are not allowed. 
4.1.
Inclusion Criteria
Each potential subject must satisfy all of the following criteria to be enrolled in the study:
1.
Male or female infants
and children who were
previously randomized in 
Study 64041575RSV2004 for the treatment of RSV infection and who completed the 
planned 
course 
of 
the 
study 
drug 
and 
the 
last 
study-related 
visit
of 
Study 64041575RSV2004.
2.
The subject’s legally acceptable representative must sign an informed consent form 
(ICF) indicating that he or she understands the purpose of, and procedures required for, 
the study and is willing for the subject to participate in the study.


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4.2.
Exclusion Criteria
Any potential subject who meets any of the following criteria will be excluded from participating 
in the study:
1.
The subject’s legally acceptable representative, ie, parent/legal guardian/caregiver, is 
not able to maintain reliable communication with the investigator.
2.
Any condition for which, in the opinion of the investigator, participation would not be
in the best interest of the subject (eg, compromise the well-being) or that could prevent,
limit, or confound the protocol-specified assessments.
5.
TREATMENT ALLOCATION AND BLINDING
The parent/caregiver of subjects who enroll in this study and their investigators will remain 
blinded to the study treatment (lumicitabine or placebo) administered in the previous 
Study 64041575RSV2004 until the completion of this LTFU study, including any extension 
period.
6.
DOSAGE AND ADMINISTRATION
Not applicable as no study drug will be administered in this study.
7.
TREATMENT COMPLIANCE
Not applicable as no study drug will be administered in this study.
8.
MEDICATIONS
There are no medication restrictions in this study.
Medication use will be monitored throughout the study from signing of the ICF until the last 
study-related activity. Parents/caregivers will be required to bring all medications to the study 
site visit. Additionally, parents/caregivers will be required to document on a daily basis use of 
medication on a medication parent/caregiver card (see Attachment 4), which will serve as a 
reminder card to be used during the study site visits and monthly phone calls between study site 
visits for recording the medication used for respiratory infections and illnesses on the 
Concomitant Medication page of the electronic case report form (eCRF) by the study site 
personnel.
Parents/caregivers will be required to return the completed parent/caregiver cards to the study 
sites every 3 months (eg, in person or by mail/email/fax when no study site visit is scheduled).


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9.
STUDY EVALUATIONS
9.1.
Study Procedures
9.1.1.
Overview
The Time and Events Schedule summarizes the frequency and timing of clinical and safety 
assessments.
No blood sampling will be performed in this study.
9.1.2.
Entry Visit
Screening can be performed as soon as it is confirmed that the subject participated in 
Study 64041575RSV2004 and completed the planned course of the study drug and the last 
study-related visit. Subjects may be enrolled within 3 months after randomization in 
Study 64041575RSV2004. The last visit of Study 64041575RSV2004 (ie, Day 28) may be 
combined with the entry visit of this LTFU study (Study 64041575RSV2002).
At the entry visit, after signing the ICF, the overall eligibility of the subject to participate in the 
study will be assessed. 
Baseline 
demographics 
and 
medical/family 
history 
from 
the 
previous 
Phase 2 
Study 64041575RSV2004 will be captured in the LTFU (Study 64041575RSV2002) eCRF. 
Medical and family history to identify risk factors for wheezing/asthma at baseline, including 
prenatal smoking by the subject’s mother, subject’s exposure to tobacco smoke, wheezing 
associated with symptoms of acute respiratory infections, whether the subject has siblings or 
attends kindergarten/day care, and personal and/or family history of atopy/allergy will be 
recorded in the eCRF.
Parents/caregivers will be provided with the medication and wheezing parent/caregiver cards, 
both of which need to be completed on a daily basis (see Attachment 3 and Attachment 4).
During the entry visit, a clinical questionnaire (see Attachment 2) needs to be completed by a
study site responsible person, by interviewing the subject’s parent/caregiver, to collect the 
following information:

Wheezing.

Diagnosis of asthma, eczema, and allergic rhinitis. All medical information needed to 
confirm the diagnosis of asthma, eczema, and allergic rhinitis needs to be collected by the 
study site personnel.

Impact
of the subject’s health status on normal daily
activities for subjects, 
parents/caregivers, and other family members.
This questionnaire will capture information since the last study visit:

If the entry visit of Study 64041575RSV2002 coincides with the last visit of 
Study 64041575RSV2004 (ie, Day 28), the “last study visit” in the questionnaire refers to 


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the Day 14 visit in Study 64041575RSV2004. Any recalled events in the questionnaire will 
be related to this time period.

If the entry visit of Study 64041575RSV2002 takes place after the last visit of Study 
64041575RSV2004 (ie, Day 28), the “last study visit” in the questionnaire refers to the 
Day 28 visit in Study 64041575RSV2004. Any recalled events in the questionnaire will be 
in the last 30 days or less (if the entry visit to last study visit of Study 64041575RSV2004 is 
less than 30 days).
9.1.3.
Study Period
No study drug will be administered.
The medical follow-up of the subjects will be performed according to the local standard of care
during the assessment period. 
At each study site visit (3, 6, 12, 18, and 24 months after entry visit) as noted in the 
Time and Events Schedule and during a monthly telephone call (calendar month ±7 days), a 
clinical questionnaire (see Attachment 2) will be completed by a study site responsible person, 
by interviewing the subject’s parent/caregiver, to collect the following information:

Wheezing.
The parent/caregiver will be provided with a wheezing parent/caregiver card to be 
completed daily (see Attachment 3) which will aid the site responsible person in completing
the questionnaire.

Diagnosis of asthma, eczema, and allergic rhinitis. All medical information needed to 
confirm the diagnosis of asthma, eczema, and allergic rhinitis needs to be collected by the 
study site personnel.

Impact
of the subject’s health status on normal daily
activities for subjects, 
parents/caregivers, and other family members.
Medical resource utilization data will be collected throughout the study.
Parents/caregivers will also be provided with a medication parent/caregiver card to record 
medication use on a daily basis (see Attachment 4). 
Parents/caregivers will be required to return the completed wheezing and medication 
parent/caregiver cards to the study sites every 3 months (eg, in person or by mail/email/fax when 
no study site visit is scheduled).
9.2.
Clinical Evaluations
The study includes the following clinical evaluations:

Collection of information on the clinical diagnosis of asthma to determine the incidence of 
asthma.

Collection of presence of wheezing on a daily basis to determine the frequency of wheezing 
and wheezing episodes.


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
Collection of medical history and family history to identify risk factors for wheezing/asthma 
at baseline.

Collection of data to determine the frequency and type of respiratory infections.

Collection of data on medications used for the treatment of respiratory infections and 
illnesses (eg, bronchodilators).

Collection of data from lung function tests and allergy tests (immunoglobulin E and skin 
test), if available, as supporting documentation of the diagnosis of asthma, wheezing, and 
atopy.
9.3.
Medical Resource Utilization and Health Economics
Medical resource usage (including medical visits, emergency room visits, and hospitalizations, 
all for respiratory conditions) and the impact of the subject’s health status on normal daily
activities for subjects, parents/caregivers, and other family members will be collected throughout 
the course of the study.
9.4.
Safety Evaluations
Any SAEs or reportable AEs occurring during the study must be recorded on the AE section of 
the eCRF.
The following AEs will be considered reportable (within the context of this study):

Respiratory illness AEs, including subsequent RSV infections.

AEs considered at least possibly related to lumicitabine or placebo.

SAEs (defined in Section 12.1.1).
The study will include the following evaluations of safety and tolerability according to the time 
points provided in the Time and Events Schedule.
Adverse Events
Reportable AEs will be reported by the subject’s parent/caregiver (or the subject’s legally
acceptable representative) for the duration of the study. 
Any reportable AEs persisting at the end of the study will be followed by the investigator until 
resolution or until a clinically stable endpoint is reached.
9.5.
Sample Collection and Handling
No safety or PK blood sampling will be performed.
10.
SUBJECT COMPLETION/WITHDRAWAL FROM THE STUDY
10.1.
Completion
A subject will be considered to have completed the study if he or she has completed assessments 
at Month 24 of the assessment period (or until the last assessment, if the study is extended).


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10.2.
Withdrawal From the Study
A subject will be automatically withdrawn from the study for any of the following reasons:

Lost to follow-up.

Withdrawal of consent.

Death.
If a subject is lost to follow-up, every reasonable effort must be made by the study site personnel 
to contact the parent/caregiver and determine the reason for withdrawal. The measures taken to 
follow up must be documented.
When a subject is withdrawn by his/her parent(s)/caregiver(s) before completing the study, the 
reason for withdrawal is to be documented in the eCRF and in the source document. 
11.
STATISTICAL METHODS
Statistical analyses will be performed by a qualified vendor under the supervision/responsibility 
of the sponsor.
11.1.
Subject Information
All subjects whose parent/caregiver provides informed consent will be included in the analysis. 
Demographics and other baseline characteristics will be summarized descriptively.
11.2.
Sample Size Determination
No formal power calculation has been performed, as this is an LTFU study in which infants and 
children from the previous Phase 2 study of lumicitabine (Study 64041575RSV2004) may be 
enrolled.
The planned number of subjects enrolled in Study 64041575RSV2004 is up to 120 subjects on 
lumicitabine and up to 60 subjects on placebo. It is expected that approximately 35% of those 
subjects will participate in this LTFU study.
11.3.
Clinical Analyses
The final analysis will be done when all the subjects have completed the last planned assessment 
of this LTFU study or discontinued earlier.
11.3.1.
Primary Analysis
The primary endpoints in this study are the clinical diagnosis of asthma and the percentage of 
wheezing days in a subject within the first 2 years after the RSV infection, as reported by the 
parent/caregiver.
No statistical testing will be done.
Estimates of the incidence of asthma will be presented together with the 95% (2-sided) 
confidence interval (CI) by previous treatment group. The previous treatment group is defined as 


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the actual treatment of the Study 64041575RSV2004. As a sensitivity analysis, the incidence of 
asthma will be presented for the subgroup of subjects for whom at least 12 months of follow-up 
data are available.
The percentage of days with wheezing within the first 2 years after the RSV infection will be 
calculated per subject. Descriptive statistics, including 95% CIs, will be presented by previous 
treatment group.
11.3.2.
Secondary Analysis
Descriptive statistics and frequency tabulations will be used to present the percentage of 
wheezing days per month, the mean number of wheezing episodes, and the number and type of 
respiratory infections by previous treatment group.
As a sensitivity analysis, 2 different imputations for missing data will be performed:

Missing values will be replaced with the mean of the previous and subsequent month of the 
subject. When values at the end of the second follow-up year are missing, these missing 
values will be replaced by the mean of the previous month and the same month of the 
previous year. Thus, missing values will be replaced by values that are completely 
dependent on observations of the same subject.

Missing values will be imputed by the mean of non-missing values of other subjects during 
the same month of the same follow-up year of the same treatment group. Thus, with this 
approach, missing values will be replaced by values that are independent of observations 
from the same subject.
11.4.
Medical Resource Utilization and Health Economics Analyses 
Medical resource utilization will be evaluated using frequency tabulations and listings by 
previous treatment group.
The impact of the subject’s health status on normal daily
activities
for subjects, 
parents/caregivers, and other family members will be evaluated using frequency tabulations and 
listings by previous treatment group.
11.5.
Safety Analyses
Adverse Events
The verbatim terms used in the eCRF by investigators to identify the reportable AEs and SAEs 
will be coded using the Medical Dictionary for Regulatory Activities. For each reportable AE 
and SAE, the percentage of subjects who experience at least 1 occurrence of the given event will 
be summarized by previous treatment group. In addition, comparisons between previous 
treatment groups will be provided if appropriate.
11.6.
Interim Analysis 
An unblinded interim analysis will be performed when all subjects from the first season in 
Study 64041575RSV2004 who are enrolled in this LTFU study complete the 18 month 


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follow-up assessment of this LTFU study. This interim analysis will serve to evaluate the need 
for an extension of the follow-up period. The interim analysis will use all available data; the 
results will be presented by previous treatment group, using descriptive statistics.
Based on this interim review, the study may be extended up to an additional 3 years (ie, total 
duration up to 5 years after randomization into Study 64041575RSV2004). In the event that the 
study is extended, the parents/caregivers of subjects will be required to provide additional 
informed consent.
Additional interim analyses may be performed for regulatory purposes.
12.
ADVERSE EVENT REPORTING
Timely, accurate, and complete reporting and analysis of safety information from clinical studies 
are crucial for the protection of subjects, investigators, and the sponsor, and are mandated by 
regulatory agencies worldwide. The sponsor has established standard operating procedures in 
conformity with regulatory requirements worldwide to ensure appropriate reporting of safety 
information; all clinical studies conducted by the sponsor or its affiliates will be conducted in 
accordance with those procedures.
Method of Detecting AEs and SAEs
Care will be taken not to introduce bias when detecting AEs or SAEs. Open-ended and 
nonleading verbal questioning of the parent/caregiver of the subject is the preferred method to 
inquire about AE occurrence.
12.1.
Definitions
12.1.1.
Adverse Event Definitions and Classifications
Adverse Event
An AE is any untoward medical occurrence in a clinical study subject administered a medicinal 
(investigational or non-investigational) product. An AE does not necessarily have a causal 
relationship with the treatment. An AE can therefore be any unfavorable and unintended sign 
(including an abnormal finding), symptom, or disease temporally associated with the use of a 
medicinal (investigational or non-investigational) product, whether or not related to that 
medicinal (investigational or non-investigational) product. (Definition per International Council 
for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use [ICH]).
This includes any occurrence that is new in onset or aggravated in severity or frequency from the 
baseline condition.
Note: The sponsor collects AEs starting with the signing of the ICF to the last study-related 
activity. In this study, only reportable AEs (respiratory illness AEs and AEs considered at least 
possibly related to lumicitabine or placebo) and SAEs will be recorded.


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Any AEs reported in Study 64041575RSV2004 ongoing at the entry visit of this LTFU study 
will be considered part of the subject’s medical history. If the AE worsens during this study and 
is a reportable AE or SAE, it will be reported as also occurring in the LTFU study.
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 subject was at risk of death at the time of the event. It does not refer to an event that 
hypothetically might have caused death if it were more severe).

Requires inpatient hospitalization or prolongation of existing hospitalization.

Results in persistent or significant disability/incapacity.

Is a congenital anomaly/birth defect.

Is a suspected transmission of any infectious agent via a medicinal product.

Is medically important*.
*Medical and scientific judgment should be exercised in deciding whether expedited reporting is 
also appropriate in other situations, such as important medical events that may not be 
immediately life-threatening or result in death or hospitalization but may jeopardize the subject 
or may require intervention to prevent one of the other outcomes listed in the definition above. 
These should usually be considered serious.
If a serious and unexpected AE occurs for which there is evidence suggesting a causal 
relationship between the study drug administered in Study 64041575RSV2004 and the event (eg, 
death from anaphylaxis), the event must be reported as a serious unexpected suspected adverse 
reaction (SUSAR) 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 lumicitabine, the expectedness of an AE will be 
determined by whether or not it is listed in the IB.8
Adverse Event Associated With the Use of the Drug
An AE is considered associated (ie, at least possibly related) with the use of the drug if the 
attribution is possible, probable, or very likely by the definitions listed in Section 12.1.2.
12.1.2.
Attribution Definitions
Not Related
An AE that is not related to the use of the drug administered in Study 64041575RSV2004.


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Doubtful
An AE for which an alternative explanation is more likely, eg, medication use, concomitant 
disease(s), or the relationship in time suggests that a causal relationship is unlikely.
Possible
An AE that might be due to the use of the drug administered in Study 64041575RSV2004. An 
alternative explanation, eg, medication use, concomitant disease(s), is inconclusive. The 
relationship in time is reasonable; therefore, the causal relationship cannot be excluded.
Probable
An AE that might be due to the use of the drug administered in Study 64041575RSV2004. The 
relationship in time is suggestive (eg, confirmed by dechallenge). An alternative explanation is 
less likely, eg, medication use, concomitant disease(s).
Very Likely
An AE that is listed as a possible adverse reaction and cannot be reasonably explained by an 
alternative explanation, eg, medication use, concomitant disease(s). The relationship in time is 
very suggestive (eg, it is confirmed by dechallenge and rechallenge).
12.1.3.
Severity Criteria
An assessment of severity grade will be made using the Division of Microbiology and Infectious 
Diseases (DMID) categorical descriptors; for abnormalities NOT found elsewhere in the toxicity 
tables (see Attachment 1) the scale below is to be used for the estimation of severity:
GRADE 1
Mild: 
Transient 
of 
mild 
discomfort 
(<48 
hours); 
no 
medical 
intervention/therapy required.
GRADE 2
Moderate: Mild to moderate limitation in activity, some assistance may be 
needed; no or minimal medical intervention/therapy required.
GRADE 3
Severe: Marked limitation in activity, some assistance usually required; 
medical intervention/therapy required, hospitalizations possible.
GRADE 4
Life-threatening or death: Extreme limitation in activity, significant 
assistance required; significant medical intervention/therapy required, 
hospitalization (or hospice) care probable.
12.2.
Procedures
12.2.1.
All Adverse Events
All reportable AEs and SAEs will be reported from the time a signed and dated ICF is obtained 
until completion of the subject’s last study-related procedure, which may include contact for 


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follow-up of safety. SAEs, including those spontaneously reported to the investigator, must be 
reported using the SAE Form.
All events that meet the definition of an SAE will be reported as SAEs.
All SAEs and reportable AEs must be recorded using medical terminology in the source 
document and the eCRF. Whenever possible, diagnoses should be given when signs and 
symptoms are due to a common etiology (eg, cough, runny nose, sneezing, sore throat, and head 
congestion should be reported as “upper respiratory infection”). Investigators must record in the 
eCRF their opinion concerning the relationship of the AE to the study drug administered in 
Study 64041575RSV2004. All measures required for AE management must be recorded in the 
source document and reported according to sponsor instructions.
The sponsor assumes responsibility for appropriate reporting of AEs to the regulatory authorities. 
The sponsor will also report to the investigator (and the head of the investigational institute 
where required) all SUSARs. The investigator (or sponsor where required) must report SUSARs 
to the appropriate Independent Ethics Committee/Institutional Review Board (IEC/IRB) that 
approved the protocol unless otherwise required and documented by the IEC/IRB.
For all studies with an outpatient phase, including open-label studies, the subject’s 
parent/caregiver 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 subject is participating in a clinical study.

Investigator’s name and 24-hour contact telephone number.

Local sponsor’s name and 24-hour contact telephone number (for medical personnel only).

Site number.

Subject number.
12.2.2.
Serious Adverse Events
All SAEs occurring during the study must be reported to the appropriate sponsor contact person 
by study site personnel within 24 hours of their knowledge of the event.
Information regarding SAEs will be transmitted to the sponsor using the SAE Form, which must 
be completed and signed 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 made by facsimile (fax).
All SAEs that have not resolved by the end of the study, or that have not resolved upon 
discontinuation of the subject’s participation in the study, must be followed until any of the 
following occurs:

The event resolves.


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
The event stabilizes.

The event returns to baseline, if a baseline value/status is available.

The event can be attributed to agents other than the study drug administered in
Study 64041575RSV2004 or to factors unrelated to study conduct.

It becomes unlikely that any additional information can be obtained (subject or health care 
practitioner refusal to provide additional information, lost to follow-up after demonstration 
of due diligence with follow-up efforts).
Suspected transmission of an infectious agent by a medicinal product will be reported as an SAE. 
Any event requiring hospitalization (or prolongation of hospitalization) that occurs during the 
course of the subject’s participation in a study must be reported as an SAE, except 
hospitalizations for the following:

Hospitalizations not intended to treat an acute illness or AE (eg, social reasons such as 
pending placement in long-term care facility).

Surgery or procedure planned before entry into the study (must be documented in the 
eCRF). Note: Hospitalizations that were planned before the signing of the ICF, and where 
the underlying condition for which the hospitalization was planned has not worsened, will 
not be considered SAEs. Any AE that results in a prolongation of the originally planned 
hospitalization is to be reported as a new SAE.
12.3.
Contacting Sponsor Regarding Safety
The names (and corresponding telephone numbers) of the individuals who should be contacted 
regarding safety issues or questions regarding the study are listed in the Contact Information 
page(s), which will be provided as a separate document.
13.
PRODUCT QUALITY COMPLAINT HANDLING
Not applicable as no study drug will be administered in this study.
14.
STUDY DRUG INFORMATION
Not applicable as no study drug will be administered in this study.
15.
STUDY-SPECIFIC MATERIALS
The investigator will be provided with the following:

Lumicitabine IB and addenda (if applicable).

Contact Information page(s).

Electronic data capture manual/eCRF completion guidelines.

Parent/caregiver card for wheezing and medications, including instructions.

Clinical paper questionnaire, including instructions.


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16.
ETHICAL ASPECTS
16.1.
Study-specific Design Considerations
The potential subject’s legally acceptable representative will be fully informed of the risks and 
requirements of the study and, during the study, subject’s parent/caregiver will be given any new 
information that may affect their decision to continue participation. They will be told that their 
consent to participate in the study is voluntary and may be withdrawn at any time with no reason 
given and without penalty or loss of benefits to which they would otherwise be entitled. Only 
subjects whose parent/caregiver is fully able to understand the risks, benefits, and potential AEs 
of the study, and provide their consent voluntarily will be enrolled.
When referring to the signing of the ICF, the terms legal guardian and legally acceptable 
representative refer to the legally appointed guardian of the subject with authority to authorize 
participation in research. For each subject, his or her parent (both parents, if available or if 
required according to local regulations) or a legally acceptable representative(s), as required by 
local regulations, must give written consent (permission) according to local requirements after 
the nature of the study has been fully explained and before the performance of any study-related 
assessments. For the purposes of this study, all references to subjects who have provided consent 
(and assent as applicable) refer to the subjects and his or her parent or the subject’s legal 
guardian(s) or legally acceptable representative(s) who have provided consent according to this 
process. 
16.2.
Regulatory Ethics Compliance
16.2.1.
Investigator Responsibilities
The investigator is responsible for ensuring that the study is performed in accordance with the 
protocol, current ICH guidelines on Good Clinical Practice (GCP), and applicable regulatory and 
country-specific requirements.
GCP is an international ethical and scientific quality standard for designing, conducting, 
recording, and reporting studies that involve the participation of human subjects. Compliance 
with this standard provides public assurance that the rights, safety, and well-being of study 
subjects are protected, consistent with the principles that originated in the Declaration of 
Helsinki, and that the study data are credible.
16.2.2.
Independent Ethics Committee or Institutional Review Board
Before the start of the study, the investigator (or sponsor where required) will provide the 
IEC/IRB with current and complete copies of the following documents (as required by local 
regulations):

Final protocol and, if applicable, amendments.

Sponsor-approved ICF (and any other written materials to be provided to the subject’s
parent/caregiver).

IB (or equivalent information) and amendments/addenda.


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
Sponsor-approved subject recruiting materials.

Information on compensation for study-related injuries or payment to subjects for 
participation in the study, if applicable.

Investigator’s curriculum vitae or equivalent information (unless not required, as 
documented by the IEC/IRB).

Information regarding funding, name of the sponsor, institutional affiliations, other potential 
conflicts of interest, and incentives for subjects.

Written information provided to subject’s parent/caregiver.

Any other documents that the IEC/IRB requests to fulfill its obligation.
This study will be undertaken only after the IEC/IRB has given full approval of the final 
protocol, amendments (if any, excluding the ones that are purely administrative, with no 
consequences for subjects, data, or study conduct, unless required locally), the ICF, applicable 
recruiting materials, and subject compensation programs, and the sponsor has received a copy of 
this approval. This approval letter must be dated and must clearly identify the IEC/IRB and the 
documents being approved.
During the study, the investigator (or sponsor where required) will send the following documents 
and updates to the IEC/IRB for their review and approval, where appropriate:

Protocol amendments (excluding the ones that are purely administrative, with no 
consequences for subjects, data, or study conduct).

Revision(s) to ICF and any other written materials to be provided to subjects.

If applicable, new or revised subject recruiting materials approved by the sponsor.

Revisions to compensation for study-related injuries or payment to subjects for participation 
in the study, if applicable.

New edition(s) of the IB and amendments/addenda.

Summaries of the status of the study at intervals stipulated in guidelines of the IEC/IRB (at 
least annually).

Reports of AEs that are serious, unlisted/unexpected, and associated with the study drug
administered in Study 64041575RSV2004.

New information that may adversely affect the safety of the subjects or the conduct of the 
study.

Deviations from or changes to the protocol to eliminate immediate hazards to the subjects.

Report of deaths of subjects under the investigator’s care.

Notification if a new investigator is responsible for the study at the site.

Development Safety Update Report and Line Listings, where applicable.

Any other requirements of the IEC/IRB.


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For all protocol amendments (excluding the ones that are purely administrative, with no 
consequences for subjects, data, or study conduct), the amendment and applicable ICF revisions 
must be submitted promptly to the IEC/IRB for review and approval before implementation of 
the change(s).
At least once a year, the IEC/IRB will be asked to review and reapprove this study, where 
required.
At the end of the study, the investigator (or sponsor where required) will notify the IEC/IRB 
about the study completion (if applicable, the notification will be submitted through the head of 
investigational institution).
16.2.3.
Informed Consent Form
Each legally acceptable representative must give written consent according to local requirements 
after the nature of the study has been fully explained. The ICF must be signed before 
performance of any study-related activity. The ICF that is used must be approved by both the 
sponsor and the reviewing IEC/IRB, and be in a language that the parent/caregiver can read and 
understand. The informed consent should be in accordance with principles that originated in the 
Declaration of Helsinki, current ICH and GCP guidelines, applicable regulatory requirements, 
and sponsor policy.
Before enrollment in the study, the investigator or an authorized member of the study site 
personnel must explain to the parent/caregiver of potential subjects or their legally acceptable 
representatives the aims, methods, reasonably anticipated benefits, and potential hazards of the 
study, and any discomfort participation in the study may entail. Subjects’ legally acceptable 
representatives will be informed that subject participation is voluntary and that they may 
withdraw consent to participate at any time. They will be informed that choosing not to 
participate will not affect the care the subject will receive for the treatment of his or her disease. 
Finally, they will be told that the investigator will maintain a subject identification register for 
the purposes of LTFU, if needed, and that their records may be accessed by health authorities 
and authorized sponsor personnel without violating the confidentiality of the subject, to the 
extent permitted by the applicable law(s) or regulations. By signing the ICF the subject’s legally 
acceptable representative is authorizing such access, which includes permission to obtain 
information about his or her survival status. It also denotes that the subject’s legally acceptable 
representative agrees to allow his or her study physician to re-contact the subject for the purpose 
of obtaining consent for additional safety evaluations, and subsequent disease-related treatments, 
if needed.
The subject’s legally acceptable representative will be given sufficient time to read the ICF and 
the opportunity to ask questions. After this explanation and before entry into the study, consent 
should be appropriately recorded by means of the subject’s legally acceptable representative’s 
personally dated signature. After having obtained the consent, a copy of the ICF must be given to 
the subject’s legally acceptable representative.


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If the subject’s legally acceptable representative is unable to read or write, an impartial witness 
should be present for the entire informed consent process (which includes reading and explaining 
all written information) and should personally date and sign the ICF after the oral consent of the 
subject’s legally acceptable representative is obtained.
16.2.4.
Privacy of Personal Data
The collection and processing of personal data from subjects enrolled in this study will be 
limited to those data that are necessary to fulfill the objectives of the study.
These data must be collected and processed with adequate precautions to ensure confidentiality 
and compliance with applicable data privacy protection laws and regulations. Appropriate 
technical and organizational measures to protect the personal data against unauthorized 
disclosures or access, accidental or unlawful destruction, or accidental loss or alteration must be 
put in place. Sponsor personnel whose responsibilities require access to personal data agree to 
keep the identity of subjects confidential.
The informed consent obtained from the subject’s legally acceptable representative includes 
explicit consent for the processing of personal data and for the investigator/institution to allow 
direct access to his or her original medical records (source data/documents) for study-related 
monitoring, audit, IEC/IRB review, and regulatory inspection. This consent also addresses the 
transfer of the data to other entities and to other countries.
The subject’s legally acceptable representative has the right to request through the investigator 
access to the subject’s personal data and the right to request rectification of any data that are not 
correct or complete. Reasonable steps will be taken to respond to such a request, taking into 
consideration the nature of the request, the conditions of the study, and the applicable laws and 
regulations.
17.
ADMINISTRATIVE REQUIREMENTS
17.1.
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 subjects, 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) involves 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 


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departure from the protocol. In all cases, contact with the sponsor must be made as soon as 
possible to discuss the situation and agree on an appropriate course of action. The data recorded 
in the eCRF and source documents will reflect any departure from the protocol, and the source 
documents will describe this departure and the circumstances requiring it.
Waivers for inclusion and exclusion criteria are not permitted.
17.2.
Regulatory Documentation
17.2.1.
Regulatory Approval/Notification
This protocol and any amendment(s) must be submitted to the appropriate regulatory authorities 
in each respective country, if applicable. A study may not be initiated until all local regulatory 
requirements are met.
17.2.2.
Required Prestudy Documentation
The following documents must be provided to the sponsor before the first study procedure:

Protocol and amendment(s), if any, signed and dated by the principal investigator.

A copy of the dated and signed (or sealed, where appropriate per local regulations), written 
IEC/IRB approval of the protocol, amendments, ICF, any recruiting materials and, if 
applicable, subject compensation programs. This approval must clearly identify the specific 
protocol by title and number and must be signed (or sealed, where appropriate per local 
regulations) by the chairman or authorized designee.

Name and address of the IEC/IRB, including a current list of the IEC/IRB members and 
their function, with a statement that it is organized and operates according to GCP and the 
applicable laws and regulations. If accompanied by a letter of explanation, or equivalent, 
from the IEC/IRB, a general statement may be substituted for this list. If an investigator or a 
member of the study site personnel is a member of the IEC/IRB, documentation must be 
obtained to state that this person did not participate in the deliberations or in the 
vote/opinion of the study.

Regulatory authority approval or notification, if applicable.

Signed and dated statement of investigator (eg, Form FDA 1572), if applicable.

Documentation of investigator qualifications (eg, curriculum vitae).

Completed investigator financial disclosure form from the principal investigator, where 
required.

Signed and dated clinical study agreement, which includes the financial agreement.

Any other documentation required by local regulations.
The following documents must be provided to the sponsor before enrollment of the first subject:

Completed investigator financial disclosure forms from all subinvestigators.

Documentation of subinvestigator qualifications (eg, curriculum vitae).


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17.3.
Subject Identification, Enrollment, and Screening Logs
The investigator agrees to complete a subject identification and enrollment log to permit easy 
identification of each subject during and after the study. This document will be reviewed by the 
sponsor study site contact for completeness.
The subject identification and enrollment log will be treated as confidential and will be filed by 
the investigator in the study file. To ensure subject confidentiality, no copy will be made. All 
reports and communications relating to the study will identify subjects by subject identification 
and date of birth. In cases where the subject is not randomized into the study, the date seen and 
date of birth will be used.
The investigator must also complete a subject screening log, which reports on all subjects who 
were seen to determine eligibility for inclusion in the study.
17.4.
Source Documentation
At a minimum, source documents consistent in the type and level of detail with those commonly 
recorded at the study site as a basis for standard medical care must be available for the following: 
subject identification, eligibility, and study identification; study discussion and date of signed 
informed consent; dates of visits; results of safety and clinical evaluation parameters as required 
by the protocol; record of all SAEs and reportable AEs; medication; and date of study 
completion and reason for early withdrawal from the study, if applicable. 
The author of an entry in the source documents should be identifiable.
Specific details required as source data for the study and source data collection methods will be 
reviewed with the investigator before the study and will be described in the monitoring 
guidelines (or other equivalent document).
Data collected during the phone calls and study site visits can be recorded directly into the eCRF 
and the paper questionnaire, and will be considered the source data.
17.5.
Case Report Form Completion
Case report forms are prepared and provided by the sponsor for each subject in electronic format. 
All eCRF entries, corrections, and alterations must be made by the investigator or authorized 
study site personnel. The investigator must verify that all data entries in the eCRF are accurate 
and correct.
The study data will be transcribed by study site personnel from the source documents onto an 
eCRF, if applicable. Study-specific data will be transmitted in a secure manner to the sponsor.
Worksheets may be used for the capture of some data to facilitate completion of the eCRF. Any 
such worksheets will become part of the subject’s source documents. Data must be entered into 
the eCRF in English. The eCRF must be completed as soon as possible after an assessment and 
the forms should be available for review at the next scheduled monitoring visit.


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All subjective measurements 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 tool. If corrections to an 
eCRF are needed after the initial entry into the eCRF, this can be done in either of the following 
ways:

Investigator and study site personnel can make corrections in the electronic data capture tool 
at their own initiative or as a response to an auto query (generated by the electronic data 
capture tool).

Sponsor or sponsor delegate can generate a query for resolution by the investigator and 
study site personnel.
17.5.1.
Parent/Caregiver
The subject’s parent/caregiver with routine and frequent experience caring for the subject will 
provide information about the subject’s status and symptoms and all other information required 
during clinical interviews conducted by the study site responsible person at the time points noted 
in the Time and Events Schedule.
17.6.
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, and periodic monitoring visits by the sponsor.
Guidelines for eCRF completion will be provided and reviewed with study site personnel before 
the start of the study. 
The sponsor will review eCRFs for accuracy and completeness during on-site monitoring visits 
and after transmission to the sponsor; any discrepancies will be resolved with the investigator or 
designee, as appropriate. After upload of the data into the study database they will be verified for 
accuracy and consistency with the data sources.
17.7.
Record Retention
In compliance with the ICH/GCP guidelines, the investigator/institution will maintain all eCRF 
and all source documents that support the data collected from each subject, as well as all study 
documents as specified in ICH/GCP Section 8, Essential Documents for the Conduct of a 
Clinical Trial, and all study documents as specified by the applicable regulatory requirement(s). 
The investigator/institution will take measures to prevent accidental or premature destruction of 
these documents.
Essential documents must be retained until at least 2 years after the last approval of a marketing 
application in an ICH region and until there are no pending or contemplated marketing 
applications in an ICH region, or until at least 2 years have elapsed since the formal 
discontinuation of clinical development of the investigational product. These documents will be 


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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.
17.8.
Monitoring
The sponsor will use a combination of monitoring techniques as specified in the monitoring 
guidelines, 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 
postinitiation visit will be made as soon as possible after enrollment has begun. At these visits, 
the monitor will compare data entered into, including but not limited to, the eCRF with the 
source documents (eg, hospital/clinic/physician’s office medical records); a sample may be 
reviewed. The nature and location of all source documents will be identified to ensure that all 
sources of original data required to complete the eCRF are known to the sponsor and 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.


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17.9.
Study Completion/Termination
17.9.1.
Study Completion/End of Study
The study is considered completed with the last scheduled study assessment (including any 
extension period) for the last subject participating in the study. The final data from the study site 
will be sent to the sponsor (or designee) after completion of the final subject assessment at that 
study site, in the time frame specified in the Clinical Trial Agreement.
17.9.2.
Study Termination
The sponsor reserves the right to close a 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.

Discontinuation of further study drug development.
17.10. On-site Audits
Representatives of the sponsor’s clinical quality assurance department may visit the study site at 
any time during or after completion of the study to conduct an audit of the study in compliance 
with regulatory guidelines and company policy. These audits will require access to all study
records, including source documents, for inspection. Subject privacy must, however, be 
respected. The investigator and study site personnel are responsible for being present and 
available for consultation during routinely scheduled study site audit visits conducted by the 
sponsor or its designees. 
Similar auditing procedures may also be conducted by agents of any regulatory body, either as 
part of a national GCP compliance program or to review the results of this study in support of a 
regulatory submission. The investigator should immediately notify the sponsor if he or she has 
been contacted by a regulatory agency concerning an upcoming inspection.
17.11. Use of Information and Publication
All information, including but not limited to, information regarding lumicitabine or the sponsor’s 
operations (eg, patent application, formulas, manufacturing processes, basic scientific data, prior 
clinical data, formulation information) supplied by the sponsor to the investigator and not 
previously published and any data generated as a result of this study are considered confidential 
and remain the sole property of the sponsor. The investigator agrees to maintain this information 


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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 lumicitabine, 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 any analyses 
performed after the clinical study report has been issued will be reported in a separate report and 
will not require a revision of the clinical study report. Study subject identifiers will not be used in 
publication of results. Any work created in connection with performance of the study and 
contained in the data that can benefit from copyright protection (except any publication by the 
investigator as provided for below) shall be the property of the sponsor as author and owner of 
copyright in such work.
Consistent with Good Publication Practices and International Committee of Medical Journal 
Editors guidelines, the sponsor shall have the right to publish such primary (multicenter) data 
and information without approval from the investigator. The investigator has the right to publish 
study site-specific data after the primary data are published. If an investigator wishes to publish 
information from the study, a copy of the manuscript must be provided to the sponsor for review 
at least 60 days before submission for publication or presentation. Expedited reviews will be 
arranged for abstracts, poster presentations, or other materials. If requested by the sponsor in 
writing, the investigator will withhold such publication for up to an additional 60 days to allow 
for filing of a patent application. In the event that issues arise regarding scientific integrity or 
regulatory compliance, the sponsor will review these issues with the investigator. The sponsor 
will not mandate modifications to scientific content and does not have the right to suppress 
information. For multicenter study designs and substudy approaches, secondary results generally 
should not be published before the primary endpoints of a study have been published. Similarly, 
investigators will recognize the integrity of a multicenter study by not submitting for publication 
data derived from the individual study site until the combined results from the completed study
have been submitted for publication, within 18 months of the availability of the final data (tables, 
listings, graphs), or the sponsor confirms there will be no multicenter study publication. 
Authorship of publications resulting from this study will be based on the guidelines on 
authorship, such as those described in the ICMJE Recommendations for the Conduct, Reporting, 
Editing and Publication of Scholarly Work in Medical Journals, which state that the named 
authors must have made a significant contribution to the design of the study or analysis and 
interpretation of the data, provided critical review of the paper, and given final approval of the 
final version.


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Registration of Clinical Studies and Disclosure of Results
The sponsor will register and disclose the existence of and the results of clinical studies as 
required by law.


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REFERENCES
1.
American Academy of Pediatrics Technical report: Updated guidance for palivizumab prophylaxis among 
infants and young children at increased risk of hospitalization for respiratory syncytial virus infection. 
Pediatrics. 2014;134:e620-e638.
2.
Blanken MO, Rovers MM, Molenaar JM, et al. Respiratory syncytial virus and recurrent wheeze in healthy 
preterm infants. N Engl J Med. 2013;368(19):1791-1799.
3.
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(2):e54445.
4.
Castro-Rodriguez JA, Garcia-Marcos L. Wheezing and asthma in childhood: An epidemiology approach. 
Allergol et Immunopathol. 2008;36(5):280-290.
5.
Feldman AS, He Y, Moore ML, et al. Toward primary prevention of asthma. Reviewing the evidence for 
early-life respiratory viral infections as modifiable risk factors to prevent childhood asthma. Am J Respir Crit 
Care Med. 2015;191:34-44.
6.
Feltes TF, Sondheimer HM. Palivizumab and the prevention of respiratory syncytial virus illness in pediatric
patients with congenital heart disease. Expert Opin Biol Ther. 2007;7(9):1471-1480.
7.
Hall CB, Weinberg GA, Iwane MK, et al. The burden of respiratory syncytial virus infection in young children. 
N Engl J Med. 2009;360(6):588-598.
8.
Lumicitabine Investigator’s Brochure Edition 7, June 2017.
9.
Nair H, Nokes DJ, Gessner BD, et al. Global burden of acute lower respiratory infections due to respiratory 
syncytial virus in young children: a systematic review and meta-analysis. Lancet. 2010;375(9725):1545-1555.
10. O’Brien KL, Chandran A, Weatherholtz R, et al. Efficacy of motavizumab for the prevention of respiratory 
syncytial virus disease in healthy Native American infants; a phase 3 randomized double-blind 
placebo-controlled trial. Lancet Infect Dis. 2015;15(12):1398-408.
11. Simoes EA, Groothuis JR, Carbonell-Estrany X, et al, for the Palivizumab Long-term Respiratory Outcomes 
Study Group. Palivizumab prophylaxis, respiratory syncytial virus, and subsequent recurrent wheezing. J 
Pediatr. 2007;151(1):34-42.
12. Simoes EA, Carbonell-Estrany X, Rieger CH, et al, for the Palivizumab Long-term Respiratory Outcomes 
Study Group. The effect of respiratory syncytial virus on subsequent recurrent wheezing in atopic and nonatopic 
children. J Allergy Clin Immunol. 2010;126:256-262.
13. Yoshihara S, Kusuda S, Mochizuki H, et al, for the C-CREW Investigators. Effect of palivizumab prophylaxis 
on subsequent recurrent wheezing in preterm infants. Pediatrics. 2013;132(5):811-818.
14. 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(7):1077-1090.


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Attachment 1: Division of Microbiology and Infectious Diseases (DMID) Pediatric Toxicity Tables 
(November 2007)
DIVISION OF MICROBIOLOGY AND INFECTIOUS 
DISEASES (DMID) PEDIATRIC TOXICITY TABLES 
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 or death*: Extreme limitation in activity, significant 
assistance required; significant medical intervention/therapy required, 
hospitalization or hospice care probable 
* The draft DMID pediatric toxicity tables characterize death as a Grade 5 event, for the 
purposes of this study the sponsor will categorize events into 4 grades and has included 
death with life-threatening in the Grade 4 category.
SERIOUS OR LIFE-THREATENING ADVERSE EVENTS
ANY clinical event deemed by the clinician to be serious or life-threatening should be 
considered a grade 4 event. Clinical events considered to be serious or life-threatening include, 
but are not limited to: seizures, coma, tetany, diabetic ketoacidosis, disseminated intravascular 
coagulation, diffuse petechiae, paralysis, acute psychosis, and severe depression.
COMMENTS REGARDING THE USE OF THESE TABLES

Standardized and commonly used toxicity tables (Division of AIDS, NCI’s Common 
Toxicity Criteria [CTC], and WHO) have been adapted for use by the DMID and modified 
to better meet the needs of participants in DMID trials. 

For parameters not included in the following Toxicity Tables, sites should refer to the 
“Guide For Estimating Severity Grade” located above. 


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
Criteria are generally grouped by body system. 

Some protocols may have additional protocol-specific grading criteria, which will supersede 
the use of these tables for specified criteria.


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


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


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


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


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Approved, Date: 30 January 2018
DIVISION OF MICROBIOLOGY AND INFECTIOUS 
DISEASES (DMID) PEDIATRIC TOXICITY TABLES 
NOVEMBER 2007
(Older than 3 months of age)
GASTROINTESTINAL (continued)
Grade 1
Grade 2
Grade 3
Grade 4
Constipation 
Slight change in 
the consistency/
frequency of 
stool
Hard, dry stools 
with a change in 
frequency
Abdominal pain
Distention and 
vomiting
Nausea 
Mild
Moderate -
decreased oral 
intake
Severe - little 
oral intake
Unable to ingest 
food or fluid for 
more than 24 hours
Vomiting 
1 episode/day
2-3 episodes/day
4-6 episodes/day
Greater than 
6 episodes per day 
or intractable 
vomiting


Lumicitabine (JNJ-64041575, ALS-008176)  
Clinical Protocol 64041575RSV2002 Amendment 2
53
Approved, Date: 30 January 2018
DIVISION OF MICROBIOLOGY AND INFECTIOUS 
DISEASES (DMID) PEDIATRIC TOXICITY TABLES 
NOVEMBER 2007
(Older than 3 months of age)
ELECTROLYTES
Grade 1
Grade 2
Grade 3
Grade 4
CREATININE
3 months - 2 years of 
age 
0.6 - 0.8 x ULN
0.9 - 1.1 x ULN
1.2 - 1.5 x ULN
>1.5 x ULN
2 years - 12 years of 
age 
0.7 - 1.0 x ULN
1.1 - 1.6 x ULN
1.7 - 2.0 x ULN
>2.0 x ULN
Older than 12 years of 
age 
1.0 - 1.7 x ULN
1.8 - 2.4 x ULN
2.5 - 3.5 x ULN
>3.5 x ULN
Hypernatremia 
-
<145 - 149 
mEq/L
150 - 155 
mEq/L
>155 mEq/L or 
abnormal sodium AND 
mental status changes
Hyponatremia 
-
130 - 135 
mEq/L
129 - 124 
mEq/L
<124 mEq/L or 
abnormal sodium AND 
mental status changes
Hyperkalemia 
5.0 - 5.9 mEq/L
6.0 - 6.4 mEq/L
6.5 - 7.0 mEq/L
>7.0 mEq/L or abnormal 
potassium AND cardiac 
arrhythmia
Hypokalemia 
3.0 - 3.5 mEq/L
2.5 - 2.9 mEq/L
2.0 - 2.4 mEq/L
<2.0 mEq/L or abnormal 
potassium AND cardiac 
arrhythmia
Hypercalcemia 
10.5 - 11.2
mg/dL
11.3 - 11.9 
mg/dL
12.0 - 12.9 
mg/dL
>13.0 mg/dL
Hypocalcemia 
7.8 - 8.4 mg/dL
7.0 - 7.7 mg/dL
6.0 - 6.9 mg/dL
<6.0 mg/dL
Hypomagnesemia 
1.2 - 1.4 mEq/L
0.9 - 1.1 mEq/L
0.6 - 0.8 mEq/L
<0.6 mEq/L or abnormal 
magnesium AND 
cardiac arrhythmia
Hypoglycemia 
55 - 65 mg/dL
40 - 54 mg/dL
30 - 39 mg/dL
<30 mg/dL or abnormal 
glucose AND mental 
status changes
Hyperglycemia 
116 - 159 
mg/dL
160 - 249 
mg/dL
250 - 400 
mg/dL
>400 mg/dL or 
ketoacidosis
Proteinuria 
Tr-1+ or <150 
mg/day
2+ or 150 - 499 
mg/day
3+ or 500 -
1000 mg/day
4+ or Nephrotic 
syndrome >1000 
mg/day
Hematuria 
Microscopic 
<25 cells/hpf
Microscopic 
>25 cells/hpf
----
Gross hematuria


Lumicitabine (JNJ-64041575, ALS-008176)  
Clinical Protocol 64041575RSV2002 Amendment 2
54
Approved, Date: 30 January 2018
DIVISION OF MICROBIOLOGY AND INFECTIOUS 
DISEASES (DMID) PEDIATRIC TOXICITY TABLES 
NOVEMBER 2007
(Older than 3 months of age)
ELECTROLYTES (continued)
Grade 1
Grade 2
Grade 3
Grade 4
Hypernatremia 
-
<145 - 149 
mEq/L
150 - 155 mEq/L
>155 mEq/L or 
abnormal sodium 
AND mental 
status changes
Hyponatremia 
-
130 - 135 mEq/L
129 - 124 mEq/L
<124 mEq/L or 
abnormal sodium 
AND mental 
status changes
Hyperkalemia 
5.0 - 5.9 mEq/L
6.0 - 6.4 mEq/L
6.5 - 7.0 mEq/L
>7.0 mEq/L or 
abnormal 
potassium AND 
cardiac 
arrhythmia
Hypokalemia 
3.0 - 3.5 mEq/L
2.5 - 2.9 mEq/L
2.0 - 2.4 mEq/L
<2.0 mEq/L or 
abnormal 
potassium AND 
cardiac 
arrhythmia
Hypercalcemia 
10.5 - 11.2
mg/dL
11.3 - 11.9 
mg/dL
12.0 - 12.9 
mg/dL
>13.0 mg/dL
Hypocalcemia 
7.8 - 8.4 mg/dL
7.0 - 7.7 mg/dL
6.0 - 6.9 mg/dL
<6.0 mg/dL
Hypomagnesemia 
1.2 - 1.4 mEq/L
0.9 - 1.1 mEq/L
0.6 - 0.8 mEq/L
<0.6 mEq/L or 
abnormal 
magnesium AND 
cardiac 
arrhythmia
Hypoglycemia 
55 - 65 mg/dL
40 - 54 mg/dL
30 - 39 mg/dL
<30 mg/dL or 
abnormal glucose 
AND mental 
status changes
Hyperglycemia 
116 - 159 mg/dL
160 - 249 mg/dL
250 - 400 mg/dL
>400 mg/dL or 
ketoacidosis
Proteinuria 
Tr-1+ or <150 
mg/day
2+ or 150 - 499 
mg/day
3+ or 500 - 1000 
mg/day
4+ or Nephrotic 
syndrome >1000 
mg/day
Hematuria 
Microscopic <25 
cells/hpf
Microscopic >25 
cells/hpf
-
Gross hematuria


Lumicitabine (JNJ-64041575, ALS-008176)  
Clinical Protocol 64041575RSV2002 Amendment 2
55
Approved, Date: 30 January 2018
DIVISION OF MICROBIOLOGY AND INFECTIOUS 
DISEASES (DMID) PEDIATRIC TOXICITY TABLES 
NOVEMBER 2007
(Older than 3 months of age)
CENTRAL NERVOUS SYSTEM (CNS)
Grade 1
Grade 2
Grade 3
Grade 4
Generalized CNS 
symptoms
-
-
Dizziness
Hypotonic, 
hyporesponsive 
episodes;
seizures; 
apnea/bradycardia;
inconsolable crying 
>3 hrs
Headache 
Mild
Moderate, 
responds to non-
narcotic analgesia
Moderate to 
severe, responds 
to narcotic 
analgesia
Intractable
Level of activity 
-
Slightly irritable 
OR slightly 
subdued
Very irritable OR 
lethargic
Inconsolable OR 
obtunded
Visual 
-
Blurriness, 
diplopia, or 
horizontal 
nystagmus of 
<1 hour duration, 
with spontaneous 
resolution
More than 
1 episode of 
Grade 2 
symptoms per 
week, or an 
episode of 
Grade 2 
symptoms lasting 
more than 1 hour 
with spontaneous 
resolution by 
4 hours or 
vertical 
nystagmus
Decrease in visual 
acuity, visual field 
deficit, or oculogyric 
crisis
Myelopathy 
-
None
None
Myelopathic/spinal 
cord symptoms, such 
as: pyramidal tract 
weakness and 
disinhibition, sensory 
level, loss of 
proprioception, 
bladder/bowel 
dysfunction


Lumicitabine (JNJ-64041575, ALS-008176)  
Clinical Protocol 64041575RSV2002 Amendment 2
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Approved, Date: 30 January 2018
DIVISION OF MICROBIOLOGY AND INFECTIOUS 
DISEASES (DMID) PEDIATRIC TOXICITY TABLES 
NOVEMBER 2007
(Older than 3 months of age)
PERIPHERAL NERVOUS SYSTEM
Grade 1
Grade 2
Grade 3
Grade 4
Neuropathy/lower 
motor neuropathy 
-
Mild transient 
paresthesia only
Persistent or 
progressive 
paresthesias, 
burning sensation 
in feet, or mild 
dysesthesia; no 
weakness; mild to 
moderate deep 
tendon reflex 
changes; no 
sensory loss
Onset of 
significant 
weakness, 
decrease or loss 
of DTRs, sensory 
loss in “stocking 
glove”
distribution, 
radicular sensory 
loss, multiple 
cranial nerve 
involvement; 
bladder or bowel 
dysfunction, 
fasciculations, 
respiratory 
embarrassment 
from chest wall 
weakness.
Myopathy or 
neuromuscular junction 
impairment 
Normal or mild 
(<2 x ULN) CPK 
elevation
Mild proximal 
weakness and/or 
atrophy not 
affecting gross 
motor function. 
Mild myalgias, 
+/- mild CPK 
elevation (<2 x 
ULN)
Proximal muscle 
weakness and/or 
atrophy affecting 
motor function 
+/- CPK 
elevation; or 
severe myalgias 
with CPK >2 x 
ULN
Onset of 
myasthenia-like 
symptoms 
(fatigable 
weakness with 
external, variable 
ophthalmoplegia 
and/or ptosis), or 
neuromuscular 
junction blockade
(acute paralysis) 
symptoms


Lumicitabine (JNJ-64041575, ALS-008176)  
Clinical Protocol 64041575RSV2002 Amendment 2
57
Approved, Date: 30 January 2018
DIVISION OF MICROBIOLOGY AND INFECTIOUS 
DISEASES (DMID) PEDIATRIC TOXICITY TABLES 
NOVEMBER 2007
(Older than 3 months of age)
OTHER
Grade 1
Grade 2
Grade 3
Grade 4
Allergy 
Pruritus without 
rash
Pruritic rash
Mild urticaria
Severe urticaria 
anaphylaxis, 
angioedema
Drug fever (rectal) 
-
38.5 - 40.0C
101.3 / 104.0 F
Greater than 
40.0C
Greater than 
104.0F
Sustained fever: 
Equal or greater 
than 40.0C 
(104.0F) for 
longer than 
5 days
Cutaneous 
Localized rash
Diffuse 
maculopapular
rash
Generalized 
urticaria
Stevens-Johnson 
Syndrome or 
erythema 
multiforme
Stomatitis 
Mild discomfort
Painful, difficulty 
swallowing, but 
able to eat and 
drink
Painful: unable to 
swallow solids
Painful: Unable 
to swallow 
liquids; requires 
IV fluids
Clinical symptoms not 
otherwise specified in 
this table 
No therapy; 
monitor 
condition
May require 
minimal 
intervention and 
monitoring
Requires medical 
care and possible 
hospitalization
Requires active 
medical 
intervention, 
hospitalization, 
or hospice care
Laboratory values not 
otherwise specified in 
this table 
Abnormal, but 
requiring no 
immediate 
intervention; 
follow
Sufficiently 
abnormal to 
require 
evaluation as to 
causality and 
perhaps mild 
therapeutic 
intervention, but 
not of sufficient 
severity to 
warrant 
immediate 
changes in study 
drug
Sufficiently 
severe to require 
evaluation and 
treatment, 
including at least 
temporary 
suspension of 
study drug
Life-threatening 
severity; requires 
immediate 
evaluation, 
treatment, and 
usually 
hospitalization; 
study drug must 
be stopped 
immediately and 
should not be 
restarted until the 
abnormality is 
clearly felt to be 
caused by some 
other mechanism 
than study drug


Lumicitabine (JNJ-64041575, ALS-008176)  
Clinical Protocol 64041575RSV2002 Amendment 2
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Approved, Date: 30 January 2018
Attachment 2: Standardized Paper Questionnaire for Use During Scheduled Study Site Visits and 
Monthly Phone Calls Between Study Site Visits
A Long-term Follow-up of Study 64041575RSV2004 to 
Evaluate the Impact of Lumicitabine on the Incidence of 
Asthma and/or Wheezing in Infants and Children with a 
History of Respiratory Syncytial Virus Infection
Protocol Number: 64041575RSV2002
Standardized Questionnaire for Use During Scheduled Study Site Visits
and Monthly Phone Calls Between Study Site Visits


Lumicitabine (JNJ-64041575, ALS-008176)  
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Approved, Date: 30 January 2018
General Instructions for the Study Site

The questionnaire needs to be completed in its entirety by the study site through 
parent/caregiver interviews during scheduled study site visits (entry visit, 3, 6, 12, 18, and 
24 months) and monthly phone calls between study site visits.

When referring to wheezing, eczema, and allergic rhinitis with the parent/caregiver, please 
use simple terminology provided in the definitions section (see below).

Records need to be obtained from the subject’s doctor or health care provider to confirm 
the diagnosis of asthma, eczema, and allergic rhinitis.

Please keep completed questionnaires and wheezing/medication parent/caregiver cards as 
part of the study file.
Definitions
Wheezing: whistling sounds in the chest
Eczema: dry, itchy, scaly patches on the skin
Allergic rhinitis: inflammation of the nasal passages due to allergies


Lumicitabine (JNJ-64041575, ALS-008176)  
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Approved, Date: 30 January 2018
Date of current interview: __/__/____ (DD/MM/YYYY)
Patient ID: _____________
Section A: Questions About Wheezing 
Definition of wheezing: whistling sounds in the chest
Please remind the parent/caregiver that the date of last interview was:
__/__/____ (DD/MM/YYYY)
1.
Since the last study site visit/telephone call, did the child have any wheezing?
 No
go straight to Section B
 Yes
a. Please provide the days of wheezing and missing days of wheezing in the 
calendar below. 
___/____ (Month/Year)
Monday
Tuesday
Wednesday
Thursday
Friday
Saturday
Sunday


Lumicitabine (JNJ-64041575, ALS-008176)  
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Approved, Date: 30 January 2018
Section B: Questions About Asthma
Important note for the study site: If on a previous questionnaire, the parent/caregiver 
indicated that the child has been diagnosed with asthma, please proceed to Section C.
Please remind the parent/caregiver that the date of last interview was:
__/__/____ (DD/MM/YYYY)
1.
Since the last study site visit/telephone call, has the child been diagnosed with asthma 
by a doctor or health care provider?
 No
 Yes
a. When was the child diagnosed with asthma by a doctor or health care 
provider?
Date of asthma diagnosis: __/__/____ (DD/MM/YYYY)
Section C: Questions About Eczema
Important note for the study site: If on a previous questionnaire, the parent/caregiver 
indicated that the child has been diagnosed with eczema, please proceed to Section D.
Definition of eczema: dry, itchy, scaly patches on the skin
Please remind the parent/caregiver that the date of last interview was:
__/__/____ (DD/MM/YYYY)
1.
Since the last study site visit/telephone call, has the child been diagnosed with eczema
by a doctor or health care provider?
 No
 Yes
a. When was the child diagnosed with eczema by a doctor or health care 
provider?
Date of eczema diagnosis: __/__/____ (DD/MM/YYYY)


Lumicitabine (JNJ-64041575, ALS-008176)  
Clinical Protocol 64041575RSV2002 Amendment 2
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Approved, Date: 30 January 2018
Section D: Questions About Allergic Rhinitis
Important note for the study site: If on a previous questionnaire, the parent/caregiver 
indicated that the child has been diagnosed with allergic rhinitis, please proceed to Section E.
Definition of allergic rhinitis: inflammation of the nasal passages due to allergies and 
characterized by episodes of sneezing, stuffy nose, often accompanied by itching of the eyes 
and nose.
Please remind the parent/caregiver that the date of last interview was:
__/__/____ (DD/MM/YYYY)
1.
Since the last study site visit/telephone call, has the child been diagnosed with 
allergic rhinitis by a doctor or health care provider?
 No
 Yes
a. When was the child diagnosed with allergic rhinitis by a doctor or health care 
provider?
Date of allergic rhinitis diagnosis: __/__/____ (DD/MM/YYYY)


Lumicitabine (JNJ-64041575, ALS-008176)  
Clinical Protocol 64041575RSV2002 Amendment 2
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Approved, Date: 30 January 2018
Section E: Questions of the Impact of the Child’s Health on the Parent/Caregiver and Family
1. Is the parent/caregiver currently in paid employment?
 No  
a. Is the parent/caregiver currently not employed because of the child’s health 
problems?
 No
 Yes
 Yes  
a. Since the date of the last study site visit/telephone call, how many days did the 
parent/caregiver miss from work because of the child’s health problems?
Total number of days missed from work because of the child’s health problems: 
____ days
b. Since the date of the last study site visit/telephone call, how much did the 
child’s health problems affect the ability of the parent/caregiver to be 
productive on the job (eg, complete tasks on time, get to work on time, pay 
attention when at work)? If your child’s health, affected work only a little, 
instruct the parent/caregiver to choose a low number. Please circle a number 
below based on the response from parent/caregiver.                           
Child’s health had 
no effect on 
parent’s/caregiver’s 
work productivity
Child’s health 
completely prevented 
the parent/caregiver 
from being productive at 
work
0
1
2
3
4
5
6
7
8
9
10
2. Since the date of the last study site visit/telephone call, how much has the child’s 
health problems affected the parent’s/caregiver’s availability to perform normal daily 
activities (other than work for pay)? By normal daily activities we mean the usual 
activities you perform, such as working around the house, gardening, shopping, 
childcare, exercising, studying, etc. If the child’s health problem affected activities only 
a little, instruct the parent/caregiver to choose a low number. Please circle a number 
below based on the response from parent/caregiver.      
Child’s health had 
no effect on 
parent’s/caregiver’s 
normal daily 
activities
Child’s health 
completely prevented 
parent/caregiver from 
doing normal daily 
activities
0
1
2
3
4
5
6
7
8
9
10


Lumicitabine (JNJ-64041575, ALS-008176)  
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Approved, Date: 30 January 2018
3. Since the date of the last study site visit/telephone call, how much has the child’s 
health affected the child’s usual activities? If the child’s health had little effect on the 
child’s usual activities, instruct the patient/caregiver to choose a low number. Please 
circle a number below based on the response from parent/caregiver.
Child’s health had 
no effect on the 
child’s usual 
activities
Child’s health severely 
limited the child’s usual 
activities
0
1
2
3
4
5
6
7
8
9
10
4. Since the date of the last study site visit/telephone call, how much has the child’s 
health affected the parent’s/caregiver’s health? If the child’s health problem had little 
effect on the parent’s/caregiver’s health, instruct the patient/caregiver to choose a 
low number. Please circle a number below based on the response from 
parent/caregiver.
Child’s health had 
no effect on the 
parent’s/caregiver’s 
health
Child’s health caused 
severe health problems 
for the parent/caregiver
0
1
2
3
4
5
6
7
8
9
10
5. Since the date of the last study site visit/telephone call, has the child’s health made it 
difficult for the caregiver to care for other family members?
 No
 Yes
6. Since the date of the last study site visit/telephone call, how often did the child’s 
health limit the amount of time the parent/caregiver spent with other family 
members?
 Rarely or never limited time
 Occasionally limited time 
 Often limited time
 Most of the time or always limited time 
7. Since the date of the last study site visit/telephone call, how many days did other 
family members miss from work because of the child’s health problems (eg, to stay 
home to care for the child or other family members, to take time off to take the child 
for medical visits, etc.)?  
Total number of days that family members missed from work because of the child’s 
health problems: ____ days


Lumicitabine (JNJ-64041575, ALS-008176)  
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Approved, Date: 30 January 2018
General Reminders for the Parent/Caregiver for the Next Study Site Visit/Telephone Call

Please remind the parent/caregiver to bring all medications and medication card to the 
scheduled study site visits and telephone calls in order to be able to capture the medication 
history.

Please remind the parent/caregiver to bring the wheezing card to the scheduled study site 
visits and telephone calls in order to be able to capture the days of wheezing.

Please remind the parent/caregiver to bring the wheezing and medication card every 
3 months to the site according to local procedures (eg, by mail, by scan/email, in person, 
etc.).
End of questionnaire


Lumicitabine (JNJ-64041575, ALS-008176)  
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Approved, Date: 30 January 2018
Attachment 3: Wheezing Parent/Caregiver Card to Be Completed Daily
FRONT
Wheezing card for: ________________ (name of the child)
January 2018
Monday
Tuesday
Wednesday Thursday
Friday
Saturday
Sunday
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31


Lumicitabine (JNJ-64041575, ALS-008176)  
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Approved, Date: 30 January 2018
BACK
How to use the wheezing card

This card is to help you remember which days your child had wheezing; that is a day when you heard 
whistling sounds in the child’s chest during breathing. 

Each day at bedtime:
o
If the child had wheezing that day, put a “1” in the box for the date.
o
If the child did not have wheezing that day, put a “0” in the box for the date.
How to read the wheezing card during the phone calls with the study coordinator

Provide the days the child had wheezing since the last study site visit/phone call.

Provide the days the child had no wheezing since the last study site visit/phone call.
Please bring all wheezing cards with you to the study site visits/phone calls! Please also bring the wheezing 
cards every 3 months to the study site according to local procedures (eg, by mail, by scan/email, in person, 
etc.)!
In case of questions about the study or the wheezing card, please call:

Name:
_______________________________

Phone number:
_______________________________


Lumicitabine (JNJ-64041575, ALS-008176)  
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Approved, Date: 30 January 2018
Attachment 4: Medication Parent/Caregiver Card to Be Completed Daily 
FRONT
Medication card for:______________________ (name of the child)
Medication 
(Generic 
Name)
Indication
Route 
Dose 
Strength
Frequency
Start date 
(DD/MM/YYY
Y)
Stop date 
(DD/MM/YYY
Y)
Error! Not a valid link.


Lumicitabine (JNJ-64041575, ALS-008176)  
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BACK
How to use the medication card

Write all medications prescribed to your child

For each medication, you need to include the medication name (generic name), indication, route, dose, strength, frequency, 
start date and stop date.
o
The indication represents the reason for treatment (for example wheezing, asthma, eczema, allergic rhinitis, 
headache, etc.).
o
The route represents the way the medication is administered to your child (for example oral, inhaled [administered 
by mask], topical [applied on skin], etc.).
o
The dose represents the number of pills, capsules, puffs, milliliter, teaspoons, tablespoons, etc. that your child has to 
take every time the medication is given to your child (for example, 2 pills, 5 mililiters, 1 teaspoon).
o
The strength represents the amount (for example, how many mg) per pill, capsule, milliliter, etc. (for example, 20 mg 
pill, or 15 mg per milliliter).
o
The frequency represents how often the medication is to be given to your child (for example, every 8 hours, every 12 
hours, once a day, etc.).
o
The start date represents the date when the first dose was given to your child.
o
The stop date represents the date when the last dose was given to your child.

Use one medication card per calendar month. 
o
If your child has been prescribed many medications in a given month, please use the necessary number of medication 
cards in order to collect all the medications.
Please bring all medications and all medication cards with you to the study site visits/phone calls! Please also bring the 
medication cards every 3 months to the study site according to local procedures (eg, by mail, by scan/email, in person, etc.) !
In case of questions about the study or the medication card, please call:

Name:
_______________________________

Phone number:
_______________________________


Lumicitabine (JNJ-64041575, ALS-008176)  
Clinical Protocol 64041575RSV2002 Amendment 2
70
Approved, Date: 30 January 2018
INVESTIGATOR AGREEMENT
I have read this protocol and agree that it contains all necessary details for carrying out this study. I will 
conduct the study as outlined herein and will complete the study within the time designated.
I will provide copies of the protocol and all pertinent information to all individuals responsible to me who 
assist in the conduct of this study. I will discuss this material with them to ensure that they are fully 
informed regarding the study drug, the conduct of the study, and the obligations of confidentiality.
Coordinating Investigator (where required):
Name (typed or printed):
Institution and Address:
Signature:
Date:
(Day Month Year)
Principal (Site) Investigator:
Name (typed or printed):
Institution and Address:
Telephone Number:
Signature:
Date:
(Day Month Year)
Sponsor’s Responsible Medical Officer:
Name (typed or printed):
Guy De La Rosa
Institution:
Janssen Research & Development 
Signature:
electronic signature appended at the end of the protocol
Date:
(Day Month Year)
Note: If the address or telephone number of the investigator changes during the course of the study, written 
notification will be provided by the investigator to the sponsor, and a protocol amendment will not be required.


 
 
SIGNATURES 
 
 
 
 
Signed by  
Date  
 
Justification  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Guy De la rosa
31Jan2018, 07:18:42 AM, UTC
Document Approval

SAP_001.pdf: 
1
Approved, Date: 11 May 2020
Janssen Research & Development 
Statistical Analysis Plan
A Long-term Follow-up of Study 64041575RSV2004 to Evaluate the Impact of 
Lumicitabine (JNJ-64041575) on the Incidence of Asthma and/or Wheezing in Infants and 
Children with a History of Respiratory Syncytial Virus Infection
Protocol 64041575RSV2002; Phase 2b
Lumicitabine (JNJ-64041575, ALS-008176)
Status:
Approved
Date:
11 May 2020
Prepared by:
Mingbo Suo (SGS Belgium), Iris Tokka (SGS Belgium), Annemie Buelens (Jansen 
R&D), Hein Fennema (Jansen R&D)
Document No.: EDMS-ERI-156034150
Compliance: The study described in this report was performed according to the principles of Good Clinical Practice (GCP). 
Confidentiality Statement
The information in this document contains trade secrets and commercial information that are privileged or confidential and 
may not be disclosed unless such disclosure is required by applicable law or regulations. In any event, persons to whom the 
information is disclosed must be informed that the information is privileged or confidential and may not be further disclosed
by them. These restrictions on disclosure will apply equally to all future information supplied to you that is indicated as 
privileged or confidential.
NCT03332459


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TABLE OF CONTENTS
TABLE OF CONTENTS ............................................................................................................................... 2
AMENDMENT HISTORY.............................................................................................................................. 3
ABBREVIATIONS ........................................................................................................................................ 3
1.
INTRODUCTION.................................................................................................................................. 4
1.1.
Trial Objectives ................................................................................................................................ 4
1.2.
Trial Design ...................................................................................................................................... 4
1.3.
Statistical Hypotheses for Trial Objectives....................................................................................... 5
1.4.
Sample Size Justification ................................................................................................................. 5
1.5.
Randomization and Blinding ............................................................................................................ 5
2.
GENERAL ANALYSIS DEFINITIONS ................................................................................................ 6
2.1.
Visit Windows and Phase definition................................................................................................. 6
2.2.
Pooling Algorithm for Analysis Centers............................................................................................ 6
2.3.
Analysis Sets.................................................................................................................................... 6
2.3.1.
All Enrolled Analysis Set............................................................................................................... 6
2.4.
Definition of Subgroups and Subsets............................................................................................... 6
2.5.
Study Day and Relative Day ............................................................................................................ 6
2.6.
Baseline ........................................................................................................................................... 6
3.
INTERIM ANALYSIS ........................................................................................................................... 7
4.
SUBJECT INFORMATION.................................................................................................................. 7
4.1.
Demographics and Baseline Characteristics ................................................................................... 7
4.2.
Disposition Information..................................................................................................................... 8
4.3.
Protocol Deviations .......................................................................................................................... 8
4.4.
Medications ...................................................................................................................................... 8
4.5.
Preplanned Surgeries/Procedures................................................................................................... 8
5.
EFFICACY ........................................................................................................................................... 9
5.1.
Primary Efficacy Endpoint(s)............................................................................................................ 9
5.1.1.
Definition....................................................................................................................................... 9
5.1.2.
Estimand....................................................................................................................................... 9
5.1.3.
Analysis Methods.......................................................................................................................... 9
5.2.
Major Secondary Endpoints............................................................................................................. 9
5.2.1.
Definition....................................................................................................................................... 9
5.2.2.
Analysis Methods........................................................................................................................ 10
5.3.
Exploratory Endpoints.................................................................................................................... 11
5.3.1.
Definition..................................................................................................................................... 11
5.3.2.
Analysis Methods........................................................................................................................ 12
6.
SAFETY............................................................................................................................................. 13
6.1.
Reportable Adverse Events ........................................................................................................... 13
6.1.1.
Definitions ................................................................................................................................... 13
6.1.2.
Analysis Methods........................................................................................................................ 13
7.
MEDICAL RESOURCE UTILIZATION.............................................................................................. 14
7.1.
Definition ........................................................................................................................................ 14
7.2.
Analysis Methods ........................................................................................................................... 14
REFERENCES............................................................................................................................................ 15


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AMENDMENT HISTORY
Not applicable.
ABBREVIATIONS
AE
adverse event
BMI
body mass index
CI
confidence interval
eCRF
electronic case report form
LTFU
long-term follow-up
MedDRA
medical dictionary for regulatory activities
PRESORS
pediatric RSV electronic severity and outcomes rating scale
RSV
respiratory syncytial virus
SAE
serious adverse event
SAP
statistical analysis plan
WHO-DD
World Health Organization drug dictionary


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1.
INTRODUCTION
This statistical analysis plan (SAP) contains definitions of analysis sets, derived variables and 
statistical methods for the analysis of safety for the final analysis of Study 64041575RSV2002 and 
should be considered in conjunction with the clinical trial protocol.2
1.1.
Trial Objectives
Primary Objectives
The primary objectives are to evaluate in infants and children who have been treated with 
lumicitabine or placebo in Study 64041575RSV20041 during the follow-up period and within 2 
years after the RSV infection:

The incidence of the clinical diagnosis of asthma.

The frequency of wheezing.
Secondary Objectives
The secondary objectives are to evaluate during the follow-up period in infants and children who 
have been treated with lumicitabine or placebo in Study 64041575RSV2004:

The frequency of wheezing over time.

The frequency of wheezing episodes over time.

The long-term safety of lumicitabine.

The frequency and type of respiratory infections.

Medical resource utilization.
Exploratory Objectives
The exploratory objectives are to evaluate during the follow-up period in infants and children who 
have been treated with lumicitabine or placebo in Study 64041575RSV2004:

The long-term impact of RSV and its treatment with lumicitabine or placebo on how the 
subject’s health affects normal daily activities for subjects, parents/caregivers, and other 
family members.

Impact of the type of wheezing/asthma phenotypes on the frequency of wheezing and 
clinical diagnosis of asthma.
1.2.
Trial Design
This is a global, multicenter, blinded, LTFU study to evaluate the incidence of the clinical 
diagnosis of asthma and the frequency of wheezing in infants and children (otherwise healthy or 
with underlying comorbidities for severe RSV) who have completed their treatment course and
their last study-related visit in a previous Phase 2 study, 64041575RSV2004, in which they 
received lumicitabine or placebo for the treatment of RSV infection. Subjects will be followed for 
at least 2 years following treatment. This study may be extended up to an additional 3 years (i.e., 
total duration up to 5 years after randomization into Study 64041575RSV2004). Participation in 
this LTFU study is optional for study sites. This LTFU study will be offered to subjects of Study 
64041575RSV2004 if their site decides to participate in this LTFU study.
Subjects will be enrolled within 3 months after randomization in Study 64041575RSV2004.


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No study drug will be administered in this study. The parent/caregiver of the subject and the 
investigator will remain blinded to the study treatment (lumicitabine or placebo) administered in
Study 64041575RSV2004 until the completion of this LTFU study, including any extension 
period.
Assessments will be performed at the study site at enrollment in this study and at 3, 6, 12, 18, and
24 months after randomization in Study 64041575RSV2004. The last visit of Study 
64041575RSV2004 may be combined with the entry visit of this LTFU study. The same 
assessments will be performed during monthly phone calls with the parent/caregiver between the 
study site visits.
More details can be found in the Time-and-Event schedule in the study protocol.
1.3.
Statistical Hypotheses for Trial Objectives
No formal hypothesis testing will be performed. The hypothesis to be explored is that treatment of
RSV-infected infants and children with lumicitabine will decrease the incidence of subsequent 
asthma and/or wheezing compared with infants and children treated with placebo.
1.4.
Sample Size Justification
No formal power calculation has been performed, as this is an LTFU study in which infants and 
children from the previous Phase 2 study of lumicitabine (Study 64041575RSV2004) may be 
enrolled.
The planned number of subjects enrolled in Study 64041575RSV2004 is up to 120 subjects on 
lumicitabine and up to 60 subjects on placebo. It was expected that approximately 35% of those 
subjects were to participate in this LTFU study.
1.5.
Randomization and Blinding
Randomization is not applicable in this study since it is the LTFU of Study 64041575RSV2004.
The parent/caregiver of subjects who enroll in this study and their investigators were to remain 
blinded to the study treatment (lumicitabine or placebo) administered in the previous Study 
64041575RSV2004 until the completion of this LTFU study, including any extension period.


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2.
GENERAL ANALYSIS DEFINITIONS
2.1.
Visit Windows and Phase definition
As this is a LTFU of Study 64041575RSV2004, only 1 analysis phase will be defined (see Table 
1). The reference is the date of informed consent in study 64041575RSV2002.
Table 1: Trial Phase
Trial Phase
Trial Phase
(Numeric 
Version)
Start Date
End Date
Long Term Follow Up
1
00:00 of the date of signing 
the informed consent
Trial termination date (date of last 
contact) with timestamp 23:59
For assigning assessments, the visit schedule as reported in the database will be used.
If a subject has a missing visit, the data will be set to missing and will not be imputed. 
Information of an unscheduled visit will be merged with the scheduled visit, meaning that any 
information will be added to scheduled visit data.
2.2.
Pooling Algorithm for Analysis Centers
No pooling algorithm for analysis centers will be specified.
2.3.
Analysis Sets
2.3.1.
All Enrolled Analysis Set
The All Enrolled analysis set includes all subjects who were enrolled in this LTFU study. The All 
Enrolled set will be analyzed as treated. 
2.4.
Definition of Subgroups and Subsets
As study 64041575RSV2002 only included 7 subjects, no subgroups or subsets will be defined.
2.5.
Study Day and Relative Day
The reference day is the date of informed consent in study 64041575RSV2002. All assessments 
will be assigned a day relative to this day.
The relative day for a visit is defined as:
Visit day - (informed consent in study 64041575RSV2002) +1
For the monthly reports, the visit schedule will be based on the entry dates of each monthly report; 
the entry of the first report is the Screening visit, and each subsequent entry is considered as the 
next Monthly report (starting with Month 2, reflecting the time since the RSV event).
2.6.
Baseline 
The baseline as defined in study 64041575RSV2004 will be used in the presentation of 
demographics and disease characteristics. A footnote will indicate that the data are used from study
64041575RSV2004.


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3.
INTERIM ANALYSIS
An unblinded interim analysis was to be performed when all subjects from the first season in Study 
64041575RSV2004 who are enrolled in this LTFU study complete the 18-month follow-up 
assessment of this LTFU study. This interim analysis was to serve an evaluation of the need for an 
extension of the follow-up period. The interim analysis was not performed as the project was 
stopped and due to the limited sample size, an extension of the follow-up period was not deemed 
useful for the objectives of this trial.
4.
SUBJECT INFORMATION
Subject information will be analyzed on the All Enrolled set, defined as the subjects that enrolled 
in the 64041575RSV2002 study (i.e., signed informed consent). 
4.1.
Demographics and Baseline Characteristics
In this study (where no treatment is given), treatment will be used in summaries, where the 
treatment of RSV2004 will be presented. All demographics and baseline characteristics will be 
summarized overall and by treatment group. Descriptive statistics and frequency distribution will 
be provided for respectively the continuous and categorical parameters below. These data will be 
taken for the All Enrolled set from the data of the 64041575RSV2004 study, and at the time of 
enrollment in that study (eg age reported here is the age at the time of the index event).
Demographic parameters [to be inherited from the 64041575RSV2004 study]:
-
Sex (Male, Female)
-
Race (White, Black or African American, Asian, American Indian or Alaska 
Native, Native Hawaiian or Other Pacific Islander). If multiple race categories are 
indicated, the Race is recorded as 'Multiple'.
-
Ethnicity (Hispanic or Latino, Not Hispanic or Latino)
-
Country 
-
Geographic region (based on country: North America [to include Puerto Rico], 
Europe, South America, Asia-Pacific) 
-
Region (Japan, non-Japan) Note: Japan region only includes subjects indicated as 
Japanese on the eCRF.
-
Age (months)
-
Age category [≥28 days to <24 months, ≥24 to <=36 months]
-
Weight at baseline (kg)
-
Height at baseline (cm)
-
BMI at baseline (kg/m2) = Weight at baseline (kg) / (Height at baseline (m))2
(rounded to 1 decimal)
-
Gestational age at birth (Weeks)
-
Prenatal smoking by the mother (yes, no)
-
Exposure to tobacco smoke at home (yes, no)
-
Contact with other children (yes, no)
-
Attending day care (yes, no)
-
Breastfeeding (yes, no)


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Baseline disease characteristics
-
Wheezing associated with symptoms of acute respiratory infections (yes, no)
-
Personal or family history of atopy/allergy (yes, no) 
[to be inherited from the 64041575RSV2004 study]:
-
Duration of RSV symptoms from onset till time of randomization (days)
-
Duration of RSV symptoms from onset till time of randomization (days)
categories (≤3 days; >3 days to ≤5 days)
-
Presence comorbid conditions (yes, no) 
-
Number of subjects with one of following comorbid conditions: 
o
prematurity at birth [subject’s gestational age was <37 weeks; for infants 
<1 year old at randomization], 
o
bronchopulmonary dysplasia, 
o
congenital heart disease, 
o
other congenital diseases, 
o
Down syndrome, 
o
neuromuscular impairment, or 
o
cystic fibrosis
-
Baseline RSV subtype (Type A, Type B, Type A+B)
-
Receiving Supplemental Oxygen (yes, no)
-
Reasons for hospitalization (PRESORS question 1) 
4.2.
Disposition Information
The number of subjects in the following disposition categories will be summarized throughout the 
study by treatment group and overall:

Subjects who completed and discontinued the trial, with the reasons of discontinuation

Subjects per analysis visit in the trial
4.3.
Protocol Deviations
Only major protocol deviations will be defined in this trial. All major protocol deviations will be 
listed, including the deviations to the inclusion-exclusion criteria, and the violations to the 
prohibitions and restrictions, if any. A tabulation of the number and percentage of subjects per 
major protocol deviation will be provided.
4.4.
Medications
Medications will be coded using the [World Health Organization Drug Dictionary (WHO-DD)] in 
the version current at database lock. Summaries of medications (number and percent of subjects) 
will be presented by treatment group.
4.5.
Preplanned Surgeries/Procedures
A tabulation and listing of the preplanned surgeries/procedures requiring hospitalization will be 
made.


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5.
EFFICACY
5.1.
Primary Efficacy Endpoint(s)
5.1.1.
Definition
The primary endpoints are:
1. Clinical diagnosis of asthma within the first 2 years after the RSV infection, as diagnosed 
by a physician and reported by the parent/caregiver. This will be derived based on the 
completed study questionnaires at each visit/telephone call until the final visit. It is either 
“Yes” or “No”.
2. The percentage of wheezing days in a subject within the first 2 years after the RSV infection
will be calculated as:
Percentage of wheezing days = 
number of wheezing days
day of study completion −day of informed consent + 1 ∗100
The percentage will be rounded to the nearest integer. Number of wheezing days is the sum 
of all days that were reported in the Monthly visit reports. The day of informed consent is 
the informed consent of the RSV2002 study.
5.1.2.
Estimand
The incidence of asthma will be evaluated descriptively as the difference in proportions of subjects 
with clinical diagnosis within the first 2 years after the RSV infection for the lumicitabine versus
the placebo treatment.
5.1.3.
Analysis Methods
The proportions of subjects with clinical diagnosis of asthma within the first 2 years after the RSV 
infection will be presented descriptively by previous treatment group, together with the 95% (2-
sided) confidence intervals using the Wilson method.
The percentage of days with wheezing within the first 2 years after the RSV infection will be 
presented descriptively by previous treatment group, including 95% CIs.
5.2.
Major Secondary Endpoints
5.2.1.
Definition
The definitions of these endpoints are given in Table 2. While the clinical trial protocol mentions 
two methods for imputing missing data, these methods will not be performed as based on the 
limited number of subjects enrolled in the study these analyses would not be meaningful.
Consecutive wheezing episodes will be combined.
Step 1: Combination of wheezing episodes
Consecutive wheezing episodes are defined as episodes of the same subject with the start date of 
an episode is exactly 1 day after the end date of the preceding episode (or same date). Wheezing 


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episodes can only be combined into one and the same episode if the start and stop dates are 
complete.
Step 2: Allocation of wheezing episodes to intervals. For analysis of incidence over time the 
wheezing episodes will be allocated into the analysis visits (intervals), using the start date of the 
episode. For the analysis of prevalence over time, the wheezing episodes will be counted in each
interval it overlaps, using the available start and end date information.
Table 2: Calculations (Secondary Endpoints)
Parameter
Definition
Percentage of wheezing days per month
Percentage of wheezing days per month as based on Visit variable in 
the database using information reported by the parent/caregiver. The 
nominator is the number of Days reported in that period with 
wheezing, using last day – first day + 1 for reported days of 
wheezing. The fraction is multiplied by 100% and rounded to the 
nearest integer.
Number of wheezing episodes per month
Number of wheezing episodes during each month, after combination 
of the consecutive episodes, as based on information reported by the 
parent/caregiver. A wheezing episode is defined as the presence of 
wheezing for ≥1 day that started during the episode. If an episode is 
present but started in the previous episode it will not be counted. 
Number of wheezing episodes within the 
first 2 years after the RSV infection
Number of wheezing episodes recorded between informed consent 
and the last day in the trial for completed subjects. It is the sum of 
the number of wheezing episodes across Months.
Incidence of reportable AEs and SAEs,
including AEs related to respiratory 
illnesses and AEs considered at least 
possibly related to lumicitabine or placebo
by the investigator.
These incidences are defined as the number of AEs overall and by 
category divided by the 2 year reporting period. Each AE is counted 
as reported. The unit will be ‘per month/during the first 2 years’. In 
case the subject did not report on the full 24 months the divisor will 
be adapted to nearest number of months participating.
Number of respiratory infections per 
subject during study participation
The total number of respiratory infections of each subject. The unit 
will be ‘during study participation’. The respiratory infection AE 
terms (AEDECOD) will be determined based on medical review and 
reported overall and by Preferred Term.
Medical resource utilization including the 
number of medical visits, emergency room 
visits, and hospitalizations, all for 
respiratory conditions only, based on 
information reported by the 
parent/caregiver.
Total number of medical visits, emergency room visits, and 
hospitalizations, as reported by the parent/caregiver. The number will 
be given overall and by relationship to respiratory conditions, as 
based on medical review.
5.2.2.
Analysis Methods
Descriptive statistics will be used to present the percentage of wheezing days and the number of 
wheezing episodes per Month. Frequency tabulations will be used to summarize the number and 
type of respiratory infections per subject by previous treatment group.
Listings will be provided showing the reported information on wheezing and respiratory infections 
together with the derived efficacy parameters above. A summary will be provided for respiratory 
infections:


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-
any respiratory infections,
-
serious respiratory infections,
-
deaths due to respiratory infections,
-
respiratory infections by toxicity grade,
-
respiratory infections at least possibly related to study medication,
-
serious respiratory infections that were at least possibly related to study medication
Listings will be provided for all respiratory infections.
5.3.
Exploratory Endpoints
5.3.1.
Definition
For the exploratory endpoints the data will be presented using for each subject a row for each 
month (based on the assignment in the database), and columns presenting the data to each 
subsequent question of the interview. 
The same lay-out will be used to provide summary statistics for endpoints as defined below by 
treatment group and study Month. The definitions of these endpoints are given in Table 3. 
Parameters will be assigned to the monthly visits based on the assignment in the database.
Table 3: Calculations and Conversion Formulae (Exploratory Endpoints)
Measurement
Calculation
Subject’s daily activities limited by the
subject’s health per Month
The parent/caregiver reports that they are not working due to the 
child’s health problems. The answer to Questionnaire section E 
question 1. The result will be either “Yes” or “No” and will be 
calculated for Screening and each Month as based on the assignment in 
the database.
Percentage of days per Month the 
parent/caregiver missed from work due 
to the subject’s health
This is only calculated for parents/caregivers that were working, OR not 
working due to the child’s health problems. If the parent is not working 
due to the child’s health problems this is set to 100%. In all other cases 
total number of days missed from work because of the child’s health 
problems, divided by the end date - start date +1 of the reported Month
x100% and rounded to the nearest integer. The answer to Questionnaire 
section E question 1. 
Parent’s/caregiver’s productivity at work 
limited by the subject’s health per Month
This is only calculated for parents/caregivers that were working. The 
extent to which the parent’s/caregiver’s productivity while at work was 
limited by the subject’s health per Month. The answer to Questionnaire 
section E question 1b.
Subject’s health problems limited the 
parent’s/caregiver’s ability to engage in 
normal daily activities per Month
The extent to which the subject’s health problems limited the 
parent’s/caregiver’s ability to engage in normal daily activities per 
Month. The answer to Questionnaire section E question 2.
How much the child’s health has affected 
the child’s usual activities per Month
The extent to which the child’s health affected the child’s usual 
activities per Month. The answer to Questionnaire section E question 3.
Impact of the subject’s health problems
on the parent’s/caregiver’s health per 
Month
The extent to which the subject’s health problems impacted the 
parent’s/caregiver’s health per Month. The answer to Questionnaire 
section E question 4.
Inability of the parent/caregiver to care 
for other family members due to the
subject’s health per Month
The inability of the parent/caregiver to care for other family members 
due to the subject’s health per Month. The answer to Questionnaire 
section E question 5. The result will be either “Yes” or “No”.
Subject’s health limited the parent’s/
caregiver’s time spent with other family 
members each Month
The extent to which the subject’s health limited the parent’s/caregiver’s 
time spent with other family members each Month.


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The answer to Questionnaire section E question 6. The result will be 
categorical as listed in the Questionnaire.
Percentage of days other family 
members missed from work due to the 
subject’s health problems per Month
The percentage of days each Month that other family members missed 
from work due to the subject’s health problems.
Derived base on the Questionnaire section E question 7. 
Calculated as the number of days as recorded in question 7 divided by 
the number of days since the last study visit/telephone call.
For subjects currently not in paid employment, the value will be 100% 
for parents/caregivers who were not employed due to the child's health 
problem and missing if this was not due the child's health problem.
Clinical diagnosis of eczema within the 
first 2 years after the RSV infection
Clinical diagnosis of eczema within the first 2 years after the RSV 
infection, as diagnosed by a physician and reported by the 
parent/caregiver. The result will be either “Yes” or “No”.
Derived based on the answer to Questionnaire section C until the 
Month 24 analysis visit.
Clinical diagnosis of allergic rhinitis 
within the first 2 years after the RSV 
infection
Clinical diagnosis of allergic rhinitis within the first 2 years after the 
RSV infection, as diagnosed by a physician and reported by the 
parent/caregiver. The result will be either “Yes” or “No”.
Derived based on the answer to Questionnaire section D until the 
Month 24 analysis visit.
5.3.2.
Analysis Methods
Descriptive statistics and frequency tabulations will be used to present the parameters of long-
term impact of RSV and its treatment with lumicitabine or placebo by previous treatment group
at each analysis visit. For parameters that have continuous results (where the result is based on a 
scale from 0 to 10) descriptive statistics will be used, for the parameters with categorical results 
frequency tabulation will be used. The results will be presented graphically over time (mean for 
continuous parameters, stacked bar charts for categorical parameters).
Clinical diagnosis of eczema and allergic rhinitis within the first 2 years after the RSV infection 
per treatment group will be presented together with the 95% (2-sided) Wilson confidence 
intervals.
Listings will be provided for the parameters of long-term impact of RSV and its treatment with 
lumicitabine or placebo for each subject. Listings will also be provided for the clinical diagnosis 
of eczema and allergic rhinitis within the first 2 years after the RSV infection for each subject.


Lumicitabine  (JNJ-64041575, ALS-008176)
Statistical Analysis Plan 64041575RSV2002
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6.
SAFETY
6.1.
Reportable Adverse Events
6.1.1.
Definitions
A reportable AE was defined in the protocol as a respiratory illness AE and/or an AE considered 
at least possibly related to study drug that was administered in study 64041575RSV2004
(lumicitabine or placebo), or a serious AE (SAE).
Information on eczema and allergic rhinitis was also asked to be collected in the questionnaire and 
has been collected as AEs. These will also be presented as reportable AEs. AEs that were reported 
but do not seem to fit the definition will be reported as other.
Reportable AEs will be categorized as:

respiratory illness AE

eczema

allergic rhinitis

other
The verbatim terms used in the eCRF by investigators to identify adverse events will be coded 
using the Medical Dictionary for Regulatory Activities (MedDRA). Events are looked at on the 
level of their preferred term.
6.1.2.
Analysis Methods
A summary by treatment and overall of number of subjects with at least one event will be provided 
for the following reportable adverse events:
-
any reportable adverse events, 
-
respiratory illness,
-
eczema,
-
allergic rhinitis,
-
other,
-
serious adverse events, 
-
reportable adverse events by toxicity grade, 
-
reportable AEs at least possibly related to study medication administered in study 
64041575RSV2004, 
-
serious reportable adverse events that were at least possibly related to study medication
administered in study 64041575RSV2004. 
Tabulations will be reported by treatment and overall by category for the number of events 
experienced by a subject. A tabulation by system organ class and preferred term will be generated.


Lumicitabine  (JNJ-64041575, ALS-008176)
Statistical Analysis Plan 64041575RSV2002
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Approved, Date: 11 May 2020
Listings will be provided for at least the following categories: all reportable AEs, serious AEs, 
reportable AEs leading to death, grade 3-4 reportable AEs, complications related to the RSV 
experienced during study 64041575RSV2004 (sorted by type of complication).
7.
MEDICAL RESOURCE UTILIZATION 
7.1.
Definition
The following parameter will be considered:
Table 4: Calculations and Conversion Formulae (Medical Resource Utilization)
Measurement
Formula
Medical encounters: number 
of medical visits
The number of medical encounters due to respiratory conditions for each visit,
derived from the eCRF overall and by type of medical encounter (as recorded).
Counted as the number of unique medical encounters per subjects based on the 
unique combinations of the medical encounter start date and type of medical 
encounter.
Medical encounters: number 
of emergency room visits
The number of emergency room visits due to respiratory conditions for each visit, 
derived from the eCRF when type of medical encounter equals to emergency room.
Medical encounters: number 
of hospitalizations
The number of hospitalizations due to respiratory conditions for each visit, derived 
from the eCRF when type of medical encounter equals to hospital inpatient 
department, intensive care unit or Hospice/Palliative Care Unit.
7.2.
Analysis Methods
Frequency tabulation will be used to summarize the number of medical encounters by categories 
and type of medical encounters per month by previous treatment group. A listing will be provided 
for the medical encounter records of each subject.


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Approved, Date: 11 May 2020
REFERENCES
1.
Clinical Trial Protocol 64041575RSV2004, “A Phase 2, Randomized, Double-blind, Placebo-controlled Study 
to Evaluate the Antiviral Activity, Clinical Outcomes, Safety, Tolerability, and Pharmacokinetics of Orally 
Administered Lumicitabine (JNJ-64041575) Regimens in Hospitalized Infants and Children Aged 28 Days to 
36 Months Infected with Respiratory Syncytial Virus”.
2.
Clinical Trial Protocol 64041575RSV2002, “A Long-term Follow-up of Study 64041575RSV2004 to Evaluate 
the Impact of Lumicitabine (JNJ-64041575) on the Incidence of Asthma and/or Wheezing in Infants and
Children with a History of Respiratory Syncytial Virus Infection”.