Clinical trial NCT03629184
Conditions: Influenza
Sponsor: Hoffmann-La Roche
Start date: 2018-11-20; Completion date: 2019-04-03
Enrollment: 173 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study will evaluate the safety, pharmacokinetics, and efficacy of baloxavir marboxil compared with oseltamivir in a single influenza episode in otherwise healthy pediatric participants (i.e., 1 to \<12 years of age) with influenza-like symptoms.

Detailed description:

Arms: arm 1: Participants will receive a single oral dose of baloxavir marboxil on Day 1 (based on body weight). Oseltamivir matching placebo will also be administered orally twice daily (BID) for 5 days. arm 2: Participants will receive oseltamivir orally BID for 5 days (based on body weight). Baloxavir marboxil matching placebo will also be administered orally on Day 1
Interventions: intervention 1: Baloxavir Marboxil intervention 2: Oseltamivir
Intervention descriptions: intervention 1: Baloxavir marboxil will be administered as oral suspension in a single dose on Day 1.

Oseltamivir matching placebo will also be administered as oral suspension twice daily (BID) for 5 days. intervention 2: Oseltamivir will be administered as oral suspension BID for 5 days. Participants receiving oseltamivir will also receive baloxavir marboxil matching placebo as oral suspension, single dose on Day 1.

Protocol documents:
Prot_000.pdf: 
 
Official Title: 
 
A MULTICENTER, RANDOMIZED, DOUBLE-BLIND, ACTIVE 
(OSELTAMIVIR)-CONTROLLED STUDY TO ASSESS THE SAFETY, 
PHARMACOKINETICS, AND EFFICACY OF BALOXAVIR 
MARBOXIL IN OTHERWISE HEALTHY PEDIATRIC PATIENTS 1 
TO < 12 YEARS OF AGE WITH INFLUENZA-LIKE SYMPTOMS 
NCT Number: NCT03629184 
Document Date: Protocol Version 1: 29-June-2018 
 
 


FINAL PROTOCOL APPROVAL
CONFIDENTIAL
This clinical study is being sponsored globally by F. Hoffmann-La Roche Ltd of Basel, 
Switzerland. However, it may be implemented in individual countries by Roche’s local affiliates, 
including Genentech, Inc. in the United States.  The information contained in this document, especially 
any unpublished data, is the property of F. Hoffmann-La Roche Ltd (or under its control) and therefore 
is provided to you in confidence as an investigator, potential investigator, or consultant, for review by 
you, your staff, and an applicable Ethics Committee or Institutional Review Board.  It is understood that 
this information will not be disclosed to others without written authorization from Roche except to the 
extent necessary to obtain informed consent from persons to whom the drug may be administered.
Baloxavir Marboxil—F. Hoffmann-La Roche Ltd
Protocol CP40563, Version 1
PROTOCOL
TITLE:
A MULTICENTER, RANDOMIZED, DOUBLE-BLIND,
ACTIVE (OSELTAMIVIR)-CONTROLLED STUDY TO 
ASSESS THE SAFETY, PHARMACOKINETICS, AND 
EFFICACY OF BALOXAVIR MARBOXIL IN OTHERWISE 
HEALTHY PEDIATRIC PATIENTS 1 TO 12 YEARS OF 
AGE WITH INFLUENZA-LIKE SYMPTOMS
PROTOCOL NUMBER:
CP40563
VERSION NUMBER:
1
IND NUMBER:
126653
EudraCT NUMBER:
2018-002169-21
TEST PRODUCT:
Baloxavir marboxil (RO7191686)
MEDICAL MONITOR:
, M.D.
SPONSOR:
F. Hoffmann-La Roche Ltd
DATE FINAL:
See electronic date stamp below.
 
29-Jun-2018 09:04:04
Title
Approver's Name
Company Signatory
Date and Time (UTC)


Baloxavir Marboxil—F. Hoffmann-La Roche Ltd
2/Protocol CP40563, Version 1
TABLE OF CONTENTS
PROTOCOL ACCEPTANCE FORM .................................................................... 7
PROTOCOL SYNOPSIS ...................................................................................... 8
1.
BACKGROUND .......................................................................................... 14
1.1
Background on Influenza....................................................... 14
1.2
Background on Baloxavir Marboxil ........................................ 15
1.2.1
Phase II Proof-of-Concept and Dose-Finding 
Study (Study 1518T0821)...................................................... 15
1.2.2
Phase III Double-Blind Study in Otherwise 
Healthy Patients (Study 1601T0831)..................................... 16
1.2.3
Phase III Open-Label Study in Otherwise Healthy 
Pediatric Patients (Study 1618T0822) ................................... 17
1.3
Study Rationale and Benefit-Risk Assessment...................... 18
2.
OBJECTIVES AND ENDPOINTS ............................................................... 19
3.
STUDY DESIGN......................................................................................... 21
3.1
Description of the Study......................................................... 21
3.2
End of Study and Length of Study......................................... 22
3.3
Rationale for Study Design.................................................... 23
3.3.1
Rationale for Baloxavir Marboxil Dose and 
Schedule................................................................................ 23
3.3.2
Rationale for Patient Population ............................................ 23
3.3.3
Rationale for Control Group................................................... 24
4.
MATERIALS AND METHODS .................................................................... 24
4.1
Patients.................................................................................. 24
4.1.1
Inclusion Criteria.................................................................... 24
4.1.2
Exclusion Criteria................................................................... 25
4.2
Method of Treatment Assignment and Blinding..................... 25
4.2.1
Blinding Methods................................................................... 25
4.2.2
Unblinding Methods............................................................... 26
4.3
Study Treatment and Other Treatments Relevant 
to the Study Design ............................................................... 27
4.3.1
Study Treatment Formulation, Packaging, and 
Handling ................................................................................ 27


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4.3.1.1
Baloxavir Marboxil ................................................................. 27
4.3.1.2
Oseltamivir............................................................................. 27
4.3.2
Study Treatment Dosage, Administration, and 
Compliance............................................................................ 27
4.3.2.1
Baloxavir Marboxil and Placebo ............................................ 27
4.3.2.2
Oseltamivir and Placebo........................................................ 28
4.3.3
Rescue Medication................................................................ 28
4.3.4
Investigational Medicinal Product Accountability ................... 28
4.3.5
Continued Access to Baloxavir Marboxil and 
Oseltamivir............................................................................. 29
4.4
Concomitant Therapy ............................................................ 29
4.4.1
Permitted Therapy................................................................. 29
4.4.2
Cautionary Therapy ............................................................... 29
4.4.2.1
Herbal Therapies................................................................... 29
4.4.3
Prohibited Therapy ................................................................ 29
4.5
Study Assessments ............................................................... 30
4.5.1
Informed Consent Forms and Screening Log........................ 30
4.5.2
Medical History, Concomitant Medication, and 
Demographic Data................................................................. 30
4.5.3
Physical Examinations........................................................... 30
4.5.4
Vital Signs.............................................................................. 31
4.5.5
Laboratory and Other Biological Samples ............................. 31
4.5.6
Patient-Reported Outcomes .................................................. 32
4.6
Treatment, Patient, Study, and Site 
Discontinuation...................................................................... 32
4.6.1
Study Treatment Discontinuation........................................... 32
4.6.2
Patient Discontinuation from Study........................................ 33
4.6.3
Study Discontinuation............................................................ 33
4.6.4
Site Discontinuation............................................................... 33
5.
ASSESSMENT OF SAFETY....................................................................... 34
5.1
Safety Plan ............................................................................ 34
5.1.1
Internal Monitoring Committee............................................... 34
5.1.2
Management of Patients Who Experience 
Adverse Events ..................................................................... 34


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5.2
Safety Parameters and Definitions ........................................ 34
5.2.1
Adverse Events ..................................................................... 35
5.2.2
Serious Adverse Events (Immediately Reportable 
to the Sponsor)...................................................................... 35
5.2.3
Adverse Events of Special Interest (Immediately 
Reportable to the Sponsor).................................................... 36
5.3
Methods and Timing for Capturing and 
Assessing Safety Parameters................................................ 36
5.3.1
Adverse Event Reporting Period ........................................... 36
5.3.2
Eliciting Adverse Event Information....................................... 37
5.3.3
Assessment of Severity of Adverse Events ........................... 37
5.3.4
Assessment of Causality of Adverse Events ......................... 38
5.3.5
Procedures for Recording Adverse Events............................ 39
5.3.5.1
Diagnosis versus Signs and Symptoms................................. 39
5.3.5.2
Adverse Events That Are Secondary to Other 
Events.................................................................................... 40
5.3.5.3
Persistent or Recurrent Adverse Events................................ 40
5.3.5.4
Abnormal Laboratory Values ................................................. 40
5.3.5.5
Abnormal Vital Sign Values ................................................... 41
5.3.5.6
Abnormal Liver Function Tests.............................................. 42
5.3.5.7
Deaths ................................................................................... 42
5.3.5.8
Preexisting Medical Conditions.............................................. 42
5.3.5.9
Lack of Efficacy or Worsening of Influenza............................ 43
5.3.5.10
Hospitalization or Prolonged Hospitalization.......................... 43
5.4
Immediate Reporting Requirements from 
Investigator to Sponsor.......................................................... 43
5.4.1
Emergency Medical Contacts................................................ 44
5.4.2
Reporting Requirements for Serious Adverse 
Events and Adverse Events of Special Interest..................... 44
5.4.2.1
Events That Occur prior to Study Drug Initiation.................... 44
5.4.2.2
Events That Occur after Study Drug Initiation........................ 44
5.4.3
Reporting Requirements for Cases of Overdose, 
Medication Error, Drug Abuse, or Drug Misuse ..................... 45
5.5
Follow-Up of Patients after Adverse Events .......................... 47
5.5.1
Investigator Follow-Up........................................................... 47


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5/Protocol CP40563, Version 1
5.5.2
Sponsor Follow-Up ................................................................ 47
5.6
Adverse Events That Occur after the Adverse 
Event Reporting Period.......................................................... 48
5.7
Expedited Reporting to Health Authorities, 
Investigators, Institutional Review Boards, and 
Ethics Committees................................................................. 48
6.
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN....................... 48
6.1
Analysis Populations ............................................................. 49
6.1.1
Randomized Population......................................................... 49
6.1.2
Per Protocol Population......................................................... 49
6.1.3
Intent-to-Treat Patient Population.......................................... 49
6.1.4
Intent-to-Treat Influenza-Infected Patient 
Population.............................................................................. 49
6.1.5
Pharmacokinetic Evaluable Population ................................. 49
6.1.6
Safety Population .................................................................. 50
6.2
Determination of Sample Size ............................................... 50
6.3
Summaries of Conduct of Study............................................ 50
6.4
Summaries of Demographic and Baseline 
Characteristics....................................................................... 50
6.5
Safety Analyses..................................................................... 51
6.6
Pharmacokinetic Analyses..................................................... 51
6.7
Efficacy Analyses .................................................................. 52
6.8
Interim Analyses .................................................................... 52
7.
DATA COLLECTION AND MANAGEMENT ............................................... 52
7.1
Data Quality Assurance......................................................... 52
7.2
Electronic Case Report Forms............................................... 53
7.3
Electronic Patient-Reported Outcome Data........................... 53
7.4
Source Data Documentation.................................................. 54
7.5
Use of Computerized Systems .............................................. 54
7.6
Retention of Records............................................................. 55
8.
ETHICAL CONSIDERATIONS.................................................................... 55
8.1
Compliance with Laws and Regulations ................................ 55
8.2
Informed Consent.................................................................. 55
8.3
Institutional Review Board or Ethics Committee.................... 56


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6/Protocol CP40563, Version 1
8.4
Confidentiality........................................................................ 57
8.5
Financial Disclosure .............................................................. 58
9.
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION ..................................................................................... 58
9.1
Study Documentation ............................................................ 58
9.2
Protocol Deviations................................................................ 58
9.3
Site Inspections ..................................................................... 58
9.4
Administrative Structure......................................................... 58
9.5
Dissemination of Data and Protection of Trade 
Secrets .................................................................................. 59
9.6
Protocol Amendments ........................................................... 60
10. REFERENCES ........................................................................................... 61
LIST OF TABLES
Table 1
Objectives and Corresponding Endpoints................................... 19
Table 2
Adverse Event Severity Grading Scale for Events Not 
Specifically Listed in NCI CTCAE ............................................... 38
Table 3
Causal Attribution Guidance ....................................................... 39
Table 4
Probability of Adverse Events by Incidence Rates...................... 50
LIST OF FIGURES
Figure 1
Study Schema............................................................................. 22
LIST OF APPENDICES
Appendix 1
Schedule of Activities.................................................................. 62
Appendix 2
Schedule of Pharmacokinetic Samples....................................... 65
Appendix 3
Canadian Acute Respiratory Illness and Flu Scale 
(CARIFS) Questionnaire ............................................................. 66


Baloxavir Marboxil—F. Hoffmann-La Roche Ltd
7/Protocol CP40563, Version 1
PROTOCOL ACCEPTANCE FORM
TITLE:
A MULTICENTER, RANDOMIZED, DOUBLE-BLIND,
ACTIVE (OSELTAMIVIR)-CONTROLLED STUDY TO 
ASSESS THE SAFETY, PHARMACOKINETICS,
AND EFFICACY OF BALOXAVIR MARBOXIL IN 
OTHERWISE HEALTHY PEDIATRIC PATIENTS 
1 TO 12 YEARS OF AGE WITH INFLUENZA-LIKE 
SYMPTOMS
PROTOCOL NUMBER:
CP40563
VERSION NUMBER:
1
IND NUMBER:
126653
EudraCT NUMBER:
2018-002169-21
TEST PRODUCT:
Baloxavir marboxil (RO7191686)
MEDICAL MONITOR:
, M.D.
SPONSOR:
F. Hoffmann-La Roche Ltd
I agree to conduct the study in accordance with the current protocol.
Principal Investigator’s Name  (print)
Principal Investigator’s Signature
Date
Please retain the signed original of this form for your study files.  Please return a copy of 
the signed form as instructed by the CRO.


Baloxavir Marboxil—F. Hoffmann-La Roche Ltd
8/Protocol CP40563, Version 1
PROTOCOL SYNOPSIS
TITLE:
A MULTICENTER, RANDOMIZED, DOUBLE-BLIND, ACTIVE 
(OSELTAMIVIR)-CONTROLLED STUDY TO ASSESS THE 
SAFETY, PHARMACOKINETICS, AND EFFICACY OF BALOXAVIR 
MARBOXIL IN OTHERWISE HEALTHY PEDIATRIC PATIENTS
1 TO 12 YEARS OF AGE WITH INFLUENZA-LIKE SYMPTOMS
PROTOCOL NUMBER:
CP40563
VERSION NUMBER:
1
IND NUMBER:
126653
EudraCT NUMBER:
2018-002169-21
TEST PRODUCT:
Baloxavir marboxil (RO7191686)
PHASE:
III
INDICATION:
Influenza
SPONSOR:
F. Hoffmann-La Roche Ltd
Objectives and Endpoints
This study will evaluate the safety, pharmacokinetics, and efficacy of baloxavir marboxil
compared with oseltamivir in a single influenza episode in otherwise healthy pediatric patients
(i.e., 1 to 12 years of age) with influenza-like symptoms.  Specific objectives and 
corresponding endpoints for the study are outlined below.
Safety (Primary) Objective
Corresponding Endpoints
To compare the safety of a single 
dose of baloxavir marboxil with 5 days 
of oseltamivir administered twice daily
Incidence, severity, and timing of adverse events, 
serious adverse events, vital sign measurements,
and clinical laboratory test results
Pharmacokinetic Objective
Corresponding Endpoints
To evaluate the PK of baloxavir 
marboxil after single-dose 
administration
Plasma concentrations of baloxavir marboxil 
(pro-drug) and S-033447 (active metabolite) will be 
summarized by time (C24 and C72) and body weight
Population PK model derived parameters 
(e.g., AUCinf, Cmax, Tmax, t1/2) (modelling report)
Efficacy (Secondary) Objectives
Key Corresponding Secondary Endpoint
To evaluate the clinical efficacy of 
baloxavir marboxil compared with 
oseltamivir
Time to alleviation of influenza signs and symptoms, 
defined as the length of time taken from the start of 
treatment to the point at which all of the following 
criteria are met and remain so for at least 
21.5 hours:

A score of 0 (no problem) or 1 (minor problem) 
for cough and nasal symptoms (items 14 and 
15 of the CARIFS) 

A “yes” response to the following question on 
the CARIFS: “Since the last assessment has 


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9/Protocol CP40563, Version 1
the subject been able to return to day 
care/school, or resume his or her normal daily 
activity in the same way as performed prior to 
developing the flu?”

First return to afebrile state (tympanic 
temperature 37.2°C)
Efficacy (Secondary) Objectives
Corresponding Endpoints
To evaluate the clinical efficacy of 
baloxavir marboxil compared with 
oseltamivir 
Duration of fever (time to return to afebrile state 
[tympanic temperature 37.2C] and remaining so for 
at least 21.5 hours)
Duration of symptoms (alleviation of all symptoms as 
defined by a score of 0 [no problem] or 1 [minor 
problem] and remaining so for at least 21.5 hours, for 
all 18 symptoms specified in the CARIFS 
questionnaire)
Time to return to normal health and activity
Frequency of influenza-related complications (death, 
hospitalization, radiologically confirmed pneumonia, 
bronchitis, sinusitis, otitis media, 
encephalitis/encephalopathy, febrile seizures, 
myositis)
Proportion of patients requiring antibiotics 
Secondary Virology Objective
Corresponding Endpoints
To evaluate the virological activity of 
baloxavir marboxil compared with 
oseltamivir
Time to cessation of viral shedding by virus titer and 
by RT-PCR 
Change from baseline in influenza virus titer and in 
the amount of virus RNA (RT-PCR) at each time point
Proportion of patients with positive influenza virus titer 
and proportion of patients positive by RT-PCR at each 
time point
Area under the curve in virus titer and in the amount 
of virus RNA (RT-PCR)
Exploratory Objectives
Corresponding Endpoints
To evaluate the polymorphic and 
treatment-emergent amino acid 
substitutions in the PA, PB1, and PB2
genes and drug susceptibility in patients 
with evaluable virus
Polymorphic and treatment-emergent amino acid 
substitutions in the PA, PB1, and PB2 genes
Drug susceptibility in patients with evaluable virus
To evaluate extended PK parameters of 
baloxavir marboxil after single-dose 
administration
Non-compartmental PK parameters (intensive PK)
AUCinfarea under the concentrationtime curve from Time 0 to infinity; C24plasma 
concentration 24 hours postdose (acceptable time window:  20 to 28 hours); C72plasma 
concentration 72 hours postdose; CARIFSCanadian Acute Respiratory Illness and Flu Scale;
Cmaxmaximum plasma concentration; PApolymerase acidic protein; PKpharmacokinetic; 
RT-PCRreverse transcriptase-polymerase chain reaction; t1/2half-life; Tmaxtime to maximum 
plasma concentration.


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Study Design
Description of Study
This is a multicenter, randomized, double-blind, active-controlled (i.e., oseltamivir) study to 
assess the safety, pharmacokinetics, and efficacy of baloxavir marboxil compared with 
oseltamivir in pediatric patients 1 to 12 years of age with influenza-like symptoms.  
The approved dose for oseltamivir in pediatric patients 1 to 12 years of age is twice daily (BID)
for 5 days, based on body weight.  Baloxavir marboxil will be given as a single-dose, based on
body weight at screening.  Either drug, along with the corresponding placebo of its comparator 
in this trial, will be started at the time of randomization.
Patients will be screened and randomized on Day 1 and assigned in a 2:1 ratio to receive a 
single oral dose of baloxavir marboxil based on body weight (2 mg/kg for patients weighing 
20 kg or 40 mg for patients weighing 20 kg) or oseltamivir (dose based on body weight) for 
5 days. Re-screening of patients who fail to meet the inclusion and exclusion criteria will not be 
permitted for the same illness episode.
The study consists of two periods:  a 5-day treatment period (mandatory visits on Days 1, 2, 
and 4) and a 24-day safety follow-up period (mandatory visits on Days 6, 10, and 29).  
Therefore, the total study duration for each patient will be 29 days.
During the 5-day treatment period, each patient randomized to baloxavir marboxil will receive 
the oseltamivir matching placebo BID for 5 days, and those patients randomized to oseltamivir 
will receive one dose of baloxavir marboxil matching placebo on Day 1.
The following assessments will be conducted at clinic visits:  physical examination, vital signs, 
adverse events, concomitant therapies, clinical laboratory tests, and nasal/throat swabs.  
Throughout the treatment and safety follow-up periods, the parents/caregivers will maintain a
patient diary for each patient in order to record body temperatures (tympanic assessment),
influenza symptoms, and acetaminophen use.  Temperatures will be recorded four times daily 
(morning, noon, evening, and bedtime) on Days 1 to 3; BID (morning and evening) on Days 4 to 
9; and once daily on Days 10 to 15.  Influenza symptoms will be recorded BID (morning and 
evening) on Days 1 to 9 and once daily on Days 10 to 15.
This study will be conducted at sites in the United States and globally.  
To facilitate early and close monitoring of safety parameters over time, an Internal Monitoring 
Committee (IMC) will review aggregate safety data on an ongoing basis as defined in the IMC 
charter. If there is any concern noted in the safety parameters, the Sponsor may suspend or 
discontinue a treatment arm or the entire study, as appropriate.
Number of Patients
This study is designed to enroll approximately 120 otherwise healthy male and female pediatric 
patients with influenza-like symptoms presenting within 48 hours of symptom onset.
Patients will be recruited in parallel to the following two cohorts:

5 to 12 years of age (minimum 40 patients)

1 to 5 years of age (minimum 20 patients)
Target Population
Inclusion Criteria
Patients must meet the following criteria for study entry:

Written informed consent/assent for study participation obtained from patient’s parents or 
legal guardian, with assent as appropriate by the patient, depending on the patient’s level of 
understanding

Aged 1 to 12 years at randomization (Day 1)

Parent/guardian willing and able to comply with study requirements, in the investigator’s 
judgment

Patient able to comply with study requirements, depending on the patient’s level of 
understanding

Patient with a diagnosis of influenza virus infection confirmed by the presence of all of the 
following:


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
Fever 38C (tympanic temperature) at screening

At least one respiratory symptom (either cough or nasal congestion) 

The time interval between the onset of symptoms and screening is 48 hours (the onset of 
symptoms is defined as the time when body temperature first exceeded 37.5C if known, or 
the time when the first symptom was noticed by patient, parent or caregiver)
Exclusion Criteria
Patients who meet any of the following criteria will be excluded from study entry:

Severe symptoms of influenza virus infection requiring inpatient treatment

Concurrent infections requiring systemic antiviral therapy at screening

Require, in the opinion of the investigator, any of the prohibited medication during the study

Previous treatment with peramivir, laninamivir, oseltamivir, zanamivir, or amantadine within 
2 weeks prior to screening

Immunization with a live/attenuated influenza vaccine in the 2 weeks prior to randomization

Concomitant treatment with steroids or other immuno-suppressant therapy

Known HIV infection or other immunosuppressive disorder

Uncontrolled renal, vascular, neurologic, or metabolic disease (e.g., diabetes, thyroid 
disorders, adrenal disease), hepatitis, cirrhosis, or pulmonary disease or patients with 
known chronic renal failure

Active cancer at any site

History of organ transplantation

Known allergy to either study drug (i.e., baloxavir marboxil and oseltamivir) or to 
acetaminophen

Females who have commenced menarche (i.e., child-bearing potential)

Participation in a clinical trial within 4 weeks or 5 half-lives of exposure to an investigational 
drug prior to screening, whichever is longer
End of Study
The end of this study is defined as the date when the last patient, last visit (LPLV) occurs or the 
date at which the last data point required for statistical analysis or safety follow-up is received 
from the last patient, whichever occurs later.  The end of the study is expected to occur 29 days 
after the last patient has been enrolled.
Length of Study
The total length of the study, from screening of the first patient to the end of the study, is 
expected to be approximately 9 months. Given the seasonal variability of incidence and 
severity of influenza, the total length of the study may be extended to complete enrollment.
In addition, the Sponsor may decide to terminate the study at any time.
Investigational Medicinal Products
Test Product (Investigational Drug)
The investigational medicinal product (IMP) for this study is baloxavir marboxil.  Each treatment 
will be administered in combination with the matching placebo for the alternate treatment.
Comparator
Oseltamivir will be administered as an active control.  Each treatment will be administered in 
combination with the matching placebo for the alternate treatment.
Non-Investigational Medicinal Products
Not applicable.
Statistical Methods
Primary Analysis
The safety analysis population will be used for all analyses. 


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All verbatim adverse event terms will be mapped to MedDRA thesaurus terms, and adverse 
event severity will be graded according to National Cancer Institute Common Terminology 
Criteria for Adverse Events, Version 5.0 (NCI CTCAE v5.0).
The safety of baloxavir marboxil will be evaluated from adverse events, vital sign measurements,
and clinical laboratory tests.  Safety parameters will be summarized or listed for the safety 
population.
Determination of Sample Size  
No formal sample-size calculations have been performed.  Approximately 120 pediatric patients 
(80 patients in the baloxavir marboxil treatment group and 40 patients in the oseltamivir 
treatment group) will be enrolled.
Interim Analyses
An interim pharmacokinetic (PK) analysis is planned in this study. The PK samples, up to and 
including Visit 4/5 of first 12 patients dosed, will be batched for an early shipment.  This will
enable a timely review of the systemic plasma concentrations, in particular the concentration at 
24 hours and 72 hours post dosing.  This is in order to verify, in a timely manner, that exposures 
at the proposed dose are in reasonable agreement with the corresponding values seen in adults. 
The estimated turnaround time between last sample collected and data review is estimated to 
be approximately 2 to 3 weeks and recruitment will continue during this time. Data review of 
blinded PK samples (dummy ID) will be performed by members of the Sponsor study team.
No other interim analyses are planned in this study.  However, given there is no formal 
statistical hypothesis testing in this study, the Sponsor may choose to conduct up to two interim 
analyses.  The decision to conduct an optional interim analysis and the timing of the analysis 
will be documented in the Sponsor’s trial master file prior to the conduct of the interim analysis.  
The interim analysis would be performed and interpreted by members of the Sponsor study 
team and appropriate senior management personnel.  Access to treatment assignment 
information would follow the Sponsor’s standard procedures.


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviation
Definition
AUC
area under the concentration–time curve
AUCinf
area under the concentration–time curve from Time 0 to infinity
BID
twice daily
C24
plasma concentration 24 hours postdose (acceptable time window:  20 to 28 hours)
C72
plasma concentration 72 hours postdose 
Cmax
maximum plasma concentration
CARIFS
Canadian Acute Respiratory Illness and Flu Scale
CTCAE
Common Terminology Criteria for Adverse Events
EC
Ethics Committee
eCRF
electronic Case Report Form
EDC
electronic data capture
E.U.
European Union
FDA
Food and Drug Administration
HA
hemagglutinin complex
HIPAA
Health Insurance Portability and Accountability Act
ICH
International Council for Harmonisation
IMC
Internal Monitoring Committee
IMP
investigational medicinal product
IND
Investigational New Drug (Application)
IRB
Institutional Review Board
ITT
intent-to-treat
ITTi
intent-to-treat influenza-infected
IxRS
interactive voice or web-based response system
LPLV
last patient, last visit
M2
matrix-2
NA
neuraminidase
NCI
National Cancer Institute
NCI CTCAE
National Cancer Institute Common Terminology Criteria for Adverse Events
NONMEM
non-linear mixed-effects model
PCR
polymerase chain reaction
PK
pharmacokinetic
PKEP
pharmacokinetic-evaluable patient
PRO
non-patient-reported outcome
QTc
corrected QT interval
RT-PCR
reverse transcriptase-polymerase chain reaction
TCID50
50% tissue culture infectious dose
ULN
upper limit of normal


Baloxavir Marboxil—F. Hoffmann-La Roche Ltd
14/Protocol CP40563, Version 1
1.
BACKGROUND
1.1
BACKGROUND ON INFLUENZA
Influenza is an acute respiratory infectious disease caused by a virus of the 
orthomyxovirus family. Two forms are known to infect humans, influenza A and B. 
These viruses cause an acute febrile infection of the respiratory tract after an incubation 
period of 1 to 4 days, characterized by the sudden onset of fever, cough, fatigue, 
headache, and myalgia. Annual influenza epidemics are thought to result in between 
3 to 5 million cases of severe illness, and between 250,000 and 500,000 deaths every 
year around the world (WHO 2018).
Although the condition is usually self-limiting in healthy adults, it can be associated with 
substantial morbidity and occasional mortality in children, the elderly, and the 
immunocompromised (Paules and Subbarao 2017). Children play a central role in the 
dissemination of influenza in the community by virtue of their relative serosusceptibility 
and consequently higher illness attack rates. In addition to the acute illness, young 
children are at particular risk of secondary bacterial infections. Children develop more 
severe disease compared with adults, with higher hospitalization rates particularly in 
children aged 5 years (Rotrosen and Neuzil 2017). 
The influenza viruses have a segmented, negative-sense, single-stranded, 
lipid-encapsulated RNA genome; they range between 80 and 100 nm in size. Subtypes 
are defined according to glycoproteins present in the viral lipid coat. The hemagglutinin 
complex (HA) is the major surface protein of the virus. The neuraminidase (NA) proteins 
are the second major surface proteins in the virion and play a role in enhancing virus 
penetration of the mucus layer around the target cell and in release of virus from the cell 
surface. The matrix-2 (M2) protein triggers the disintegration of the virion during virus
entry into the cell and may also be involved in protecting the HA prior to assembly of 
new virus particles.
The following anti-influenza virus drugs are currently available in different countries:  the 
M2 ion-channel inhibitors (i.e., amantadine and rimantadine) (CDC 2011), the 
RNA-polymerase inhibitor favipiravir, and the NA inhibitors (i.e., oseltamivir, zanamivir, 
peramivir, and laninamivir).  Many cases of seasonal influenza infection are resistant to 
amantadine and rimantadine, hence their use in clinical practice is limited.  NA inhibitors 
are the mainstay of treatment for influenza infections, but their oral formulations need to 
be administered for 5 days, potentially resulting in poor patient compliance and 
convenience.  In addition, inhalation formulations can only be used in patients who are 
able to inhale the drug.  These factors contribute to an unmet medical need for anti-viral 
influenza drugs that can be easily administered and dosed within a single day.
Influenza viruses are known to mutate during the course of replication and can mutate 
into a strain resistant to existing anti-viral influenza drugs, or a strain to which most 
people are not immune. The latter may result in a pandemic. To protect against these 


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situations, the development of new anti-viral influenza drugs with novel mechanisms of 
action are warranted.
1.2
BACKGROUND ON BALOXAVIR MARBOXIL 
Baloxavir marboxil is a compound discovered by Shionogi & Co., Ltd. that exerts antiviral 
effects against influenza.  Baloxavir marboxil (also referred to as S-033188, Shionogi 
Compound Identification Number) is a pro-drug that is converted to an active form 
(S-033447) in the blood, liver, and small intestine through a metabolic process called 
hydrolysis.
Baloxavir marboxil acts on cap-dependent endonuclease, an enzyme specific to 
influenza viruses, and inhibits viral cap-snatching, thereby suppressing the growth of 
influenza viruses.
Detailed profiles of baloxavir marboxil and its active form, S-033447, derived from 
non-clinical and Phase I studies are provided in the Baloxavir Marboxil Investigator’s 
Brochure.  To date, one Phase II study and two Phase III studies (one in adults and one 
in pediatric patients) have been completed and are summarized below.  A further 
Phase III study in adults and adolescents (aged 12 years) with influenza at high risk of 
influenza complications is currently in progress and is not further discussed in this 
protocol.
1.2.1
Phase II Proof-of-Concept and Dose-Finding Study 
(Study 1518T0821)
In this Phase II study, the efficacy and safety of baloxavir marboxil in patients with 
influenza virus infection were investigated.  A single dose of 10, 20, or 40 mg baloxavir 
marboxil or placebo was administered to a total of 400 patients with influenza virus 
infection (100 patients per dose group).
The median times to alleviation of influenza symptoms in the 10-mg, 20-mg, and 40-mg
group were 54.2, 51.0, and 49.5 hours, respectively, compared with 77.7 hours in the 
placebo group. Of the secondary endpoints, the median times to resolution of fever in 
the 10-mg, 20-mg, and 40-mg groups were 33.4, 31.6, and 28.9 hours, respectively, 
compared with 45.3 hours in the placebo group. 
All of the baloxavir marboxil groups showed a significantly greater reduction compared 
with the placebo group in the proportion of patients with positive influenza virus titer, 
change in influenza virus titer, and change in amount of influenza virus on Days 2 and 3 
using the predefined secondary analysis methods.
No deaths or serious adverse events were reported in any of the groups. Adverse 
events were reported in 27 of 100 patients (34 events) in the 10-mg group, 23 of 
100 patients (29 events) in the 20-mg group, and 26 of 100 patients (29 events) in the 
40-mg group compared with 29 of 100 patients (40 events) in the placebo group. Most 


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adverse events were mild. No statistically significant difference was found in the 
incidence between any of the three dose groups and the placebo group.
1.2.2
Phase III Double-Blind Study in Otherwise Healthy Patients 
(Study 1601T0831)
In this Phase III, double-blind study in otherwise healthy adults and adolescents 
12 to 64 years of age with influenza, the efficacy and safety of baloxavir marboxil were
investigated. The dose studied was 40 mg for patients weighing 80 kg and 80 mg for 
patients weighing 80 kg.
Patients in the 20 to 64 years of age stratum received a single dose of 40 or 80 mg 
baloxavir marboxil (based on the patient’s body weight), repeated dose of 75 mg 
oseltamivir twice daily (BID) for 5 days, or placebo.  In addition, patients in the 12 to 
19 years of age stratum received a single dose of 40 mg or 80 mg baloxavir marboxil 
(based on the patient’s body weight) or placebo. A total of 1,432 patients received the 
study drug: 610 in the baloxavir marboxil group, 309 in the placebo group, and 513 in 
the oseltamivir group.
The median time to alleviation of symptoms was 53.7 hours in the baloxavir marboxil 
group compared with 80.2 hours in the placebo group. The difference in the median 
time was 26.5 hours between the baloxavir marboxil group and the placebo group. 
The baloxavir marboxil group showed a significantly greater reduction in the time to 
alleviation of symptoms compared with the placebo group (two-sided p-value 0.0001). 
In the adult stratum of patients, the median time to alleviation of symptoms was 
53.5 hours in the baloxavir marboxil group compared with 53.8 hours in the oseltamivir 
group; no significant difference was found.
Of the secondary endpoints, significant decreases in both virus titer and the amount of 
virus RNA were found in the baloxavir marboxil group compared with the placebo group.  
The virus titer in the baloxavir marboxil group was reduced rapidly, and the mean virus 
titer on Day 2 was less than−3 log10 (50% tissue culture infectious dose [TCID50/mL]) of 
that in the placebo group.  The mean change from baseline in the influenza virus titer 
was significantly greater in the baloxavir marboxil group than in the placebo group from 
Days 2 through 5.
The median time to cessation of viral shedding determined by virus titer was 24 hours in 
the baloxavir marboxil group compared with 96 hours in the placebo group.  The 
difference in the time to cessation of virus shedding was 72 hours between the groups
(p0.0001).  A significant difference in the median time to cessation of viral shedding of 
48 hours (p0.0001) was found also in comparison between the baloxavir marboxil 
(24 hours) group and the oseltamivir group (72 hours).  In addition, baloxavir marboxil 
rapidly and significantly reduced the proportion of patients with positive influenza virus 
titer from Days 2 through 5 compared with that in the placebo group.  Also, when 


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compared with the oseltamivir group, the proportion of patients with positive influenza 
virus titer decreased significantly in the baloxavir marboxil group.
Beneficial effects of baloxavir marboxil on fever were also demonstrated. The proportion 
of patients who had fever was reduced more rapidly in the baloxavir marboxil group than 
in the placebo group following the study drug administration. The median time to 
resolution of fever was shortened by 17.5 hours in the baloxavir marboxil group 
compared with the placebo group.
No deaths were reported in any groups. Two serious adverse events (viral meningitis 
and incarcerated inguinal hernia) were reported in 2 of 610 patients (0.3%) in the 
baloxavir marboxil group. The events resolved and were considered not related to study 
drug. Nine adverse events leading to withdrawal of study drug were reported: 3 events 
in 2 of 610 patients (0.3%) in the baloxavir marboxil group, 4 events in 1 of 309 patients 
(0.3%) in the placebo group, and 2 events in 2 of 513 patients (0.4%) in the oseltamivir 
group. 
All of the adverse events leading to withdrawal of study drug in the baloxavir marboxil 
group were considered not related to the study drug. Adverse events were reported in 
126 of 610 patients (20.7%, 172 events) in the baloxavir marboxil group, 76 of 
309 patients (24.6%, 118 events) in the placebo group, and 127 of 513 patients (24.8%, 
179 events) in the oseltamivir group. No statistically significant difference was found in 
the incidence between the baloxavir marboxil group and the placebo group (the Fisher’s 
exact test, two-sided p-value0.1781) or between the baloxavir marboxil group and the 
oseltamivir group (p0.1146).
Except for bronchitis in the placebo group, there were no common adverse events 
(incidence 5%) in any of the treatment groups. The relatively common adverse events 
(incidence 2%) in any of the groups were bronchitis, sinusitis, diarrhea, and nausea; 
however, each incidence of the adverse event in the baloxavir marboxil group was lower 
than or equal to that in the placebo group. In all three groups, the majority of the 
adverse events was categorized as Grade 1 or 2 and resolved.
1.2.3
Phase III Open-Label Study in Otherwise Healthy Pediatric 
Patients (Study 1618T0822)
In this Phase III, open-label study in otherwise healthy pediatric patients, the efficacy of 
a single dose of baloxavir marboxil in patients aged 6 months to 12 years was
investigated.  This study was conducted in Japan.  A total of 107 patients were enrolled:  
2, 31, 66, and 8 patients received a single 5-, 10-, 20-, and 40-mg dose of baloxavir 
marboxil, respectively. The doses administered in this study were 5, 10, 20, and 40 mg 
for patients who weighed 5 to 10 kg, 10 to 20 kg, 20 to 40 kg, and 40 kg, 
respectively.


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The median time to alleviation of influenza illness (time to alleviation of cough, nasal 
discharge/nasal congestion, and fever) was 44.6 hours. Of the secondary endpoints, the 
median time to resolution of fever was 21.4 hours. In the virological endpoints, the mean 
change from baseline in the virus titer was 4.20 log10 (TCID50/mL) and the mean change 
from baseline in the amount of viral RNA was 1.75 log10 (virus particles/mL) on Day 2.
No deaths, serious adverse events, or discontinuations due to adverse events were 
reported in the study. Adverse events were reported in 37 of 107 patients 
(34.6%, 49 events). All adverse events were classified as Grade 1 or 2. Most of the 
adverse events resolved except for 3 adverse events in 3 patients: 1 event each of 
dental caries, dry skin, and ligament sprain (these were judged by the investigator to not
require further follow-up).
Adverse events occurring at an incidence of at least 5% was vomiting in 8 patients 
(7.5%, 8 events). All the cases of vomiting were classified as Grade 1, resolved, and 
considered not related to the study drug.
Baloxavir marboxil was considered generally safe when administered to pediatric 
patients with influenza at a single oral dose between 5 mg and 40 mg based on the 
patient’s body weight.
1.3
STUDY RATIONALE AND BENEFIT-RISK ASSESSMENT
Influenza virus infection predisposes to secondary bacterial infection, which may 
progress in severity leading to poor prognosis, particularly in children. Other serious 
complications can also develop, including cardiac and neurological complications.
Although NA inhibitors, such as oseltamivir, zanamivir, and peramivir, can be used for 
the treatment of pediatric patients at present, more convenient and potent anti-influenza 
virus drugs without restriction of use are needed for the following reasons: 1) zanamivir 
is not licensed for treatment of influenza in very young children due to the difficulty with 
inhalation in this group (5 or 7 years of age, depending on country), 2) peramivir needs 
to be intravenously administered, and 3) oseltamivir requires BID dosing orally for 5 days.
The efficacy of currently marketed antivirals against preventing complications in pediatric 
patients has not been demonstrated. Baloxavir marboxil appears to have greater 
antiviral efficacy compared with currently available antivirals, offering the potential to 
treat influenza in the pediatric population more effectively.
A new antiviral drug against influenza is needed with a novel mode of action to 
overcome potential resistance to existing antivirals or offer a different resistance profile.
The results of the clinical studies outlined above have proven the efficacy and safety of 
baloxavir marboxil in the treatment of influenza virus infections for adult and adolescent
patients. Although limited clinical data is available in children (one open-label Phase III


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study in children in Japan), an active-controlled study of children is justified to confirm 
the safety, pharmacokinetics, and efficacy of baloxavir marboxil in the pediatric 
population.
2.
OBJECTIVES AND ENDPOINTS
This study will evaluate the safety, pharmacokinetics, and efficacy of baloxavir marboxil
compared with oseltamivir in a single influenza episode in otherwise healthy pediatric 
patients (i.e., 1 to 12 years of age) with influenza-like symptoms.  Specific objectives 
and corresponding endpoints for the study are outlined in Table 1.
Table 1
Objectives and Corresponding Endpoints
Safety (Primary) Objective
Corresponding Endpoint
To compare the safety of a single 
dose of baloxavir marboxil with 5 days 
of oseltamivir administered twice daily
Incidence, severity, and timing of adverse events, 
serious adverse events, vital sign measurements,
and clinical laboratory test results
Pharmacokinetic Objective
Corresponding Endpoints
To evaluate the PK of baloxavir 
marboxil after single-dose 
administration
Plasma concentrations of baloxavir marboxil 
(pro-drug) and S-033447 (active metabolite) will be 
summarized by time (C24 and C72) and body weight
Population PK model derived parameters 
(e.g., AUCinf, Cmax, Tmax, t1/2) (modelling report)
Efficacy (Secondary) Objectives
Key Corresponding Secondary Endpoint
To evaluate the clinical efficacy of 
baloxavir marboxil compared with 
oseltamivir
Time to alleviation of influenza signs and symptoms, 
defined as the length of time taken from the start of 
treatment to the point at which all of the following 
criteria are met and remain so for at least 21.5 hours:

A score of 0 (no problem) or 1 (minor problem) 
for cough and nasal symptoms (items 14 and 15 
of the CARIFS) 

A “yes” response to the following question on the 
CARIFS: “Since the last assessment has the 
subject been able to return to day care/school, or 
resume his or her normal daily activity in the 
same way as performed prior to developing the 
flu?”

First return to afebrile state (tympanic 
temperature 37.2°C)


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Table 1
Objectives and Corresponding Endpoints (cont.)
Efficacy (Secondary) Objectives
Corresponding Endpoints
To evaluate the clinical efficacy of 
baloxavir marboxil compared with 
oseltamivir 
Duration of fever (time to return to afebrile state 
[tympanic temperature 37.2C] and remaining so for 
at least 21.5 hours)
Duration of symptoms (alleviation of all symptoms as 
defined by a score of 0 [no problem] or 1 [minor 
problem] and remaining so for at least 21.5 hours, for 
all 18 symptoms specified in the CARIFS 
questionnaire)
Time to return to normal health and activity
Frequency of influenza-related complications (death, 
hospitalization, radiologically confirmed pneumonia, 
bronchitis, sinusitis, otitis media, 
encephalitis/encephalopathy, febrile seizures, 
myositis)
Proportion of patients requiring antibiotics 
Secondary Virology Objective
Corresponding Endpoints
To evaluate the virological activity of 
baloxavir marboxil compared with 
oseltamivir
Time to cessation of viral shedding by virus titer and 
by RT-PCR 
Change from baseline in influenza virus titer and in 
the amount of virus RNA (RT-PCR) at each time point
Proportion of patients with positive influenza virus titer 
and proportion of patients positive by RT-PCR at each 
time point
Area under the curve in virus titer and in the amount 
of virus RNA (RT-PCR)
Exploratory Objectives
Corresponding Endpoints
To evaluate the polymorphic and 
treatment-emergent amino acid 
substitutions in the PA, PB1, and PB2
genes and drug susceptibility in patients 
with evaluable virus
Polymorphic and treatment-emergent amino acid 
substitutions in the PA, PB1, and PB2 genes
Drug susceptibility in patients with evaluable virus
To evaluate extended PK parameters of 
baloxavir marboxil after single-dose 
administration
Non-compartmental PK parameters (intensive PK)
AUCinfarea under the concentrationtime curve from Time 0 to infinity; C24plasma 
concentration 24 hours postdose (acceptable time window:  20 to 28 hours); C72plasma 
concentration 72 hours postdose; CARIFSCanadian Acute Respiratory Illness and Flu Scale;
Cmaxmaximum plasma concentration; PApolymerase acidic protein; PKpharmacokinetic; 
RT-PCRreverse transcriptase-polymerase chain reaction; t1/2half-life; Tmaxtime to maximum 
plasma concentration.


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3.
STUDY DESIGN
3.1
DESCRIPTION OF THE STUDY
This is a multicenter, randomized, double-blind, active-controlled (i.e., oseltamivir) study 
to assess the safety, pharmacokinetics, and efficacy of baloxavir marboxil compared 
with oseltamivir in pediatric patients 1 to 12 years of age with influenza-like symptoms.  
This study is designed to enroll approximately 120 otherwise healthy male and female 
pediatric patients with influenza-like symptoms presenting within 48 hours of symptom 
onset.
Patients will be recruited in parallel to the following two cohorts:

5 to 12 years of age (minimum 40 patients)

1 to 5 years of age (minimum 20 patients)
Baloxavir marboxil will be given as a single-dose, based on body weight at screening.  
The approved dose for oseltamivir in pediatric patients 1 to 12 years of age is BID for 
5 days, based on body weight (see Section 4.3.2.2).  Either drug, along with the 
corresponding placebo of its comparator in this trial, will be started at the time of 
randomization.
Patients will be screened and randomized on Day 1 and assigned in a 2:1 ratio to 
receive a single oral dose of baloxavir marboxil based on body weight (2 mg/kg for 
patients weighing 20 kg or 40 mg for patients weighing 20 kg) or oseltamivir (dose 
based on body weight) for 5 days. Re-screening of patients who fail to meet the 
inclusion and exclusion criteria will not be permitted for the same illness episode, as the 
time from symptom onset to treatment window is limited to 48 hours.
The study consists of two periods:  a 5-day treatment period (mandatory visits on Days 1, 
2, and 4) and a 24-day safety follow-up period (mandatory visits on Days 6, 10, and 29).  
Therefore, the total study duration for each patient will be 29 days.
During the 5-day treatment period, each patient randomized to baloxavir marboxil will 
receive the oseltamivir matching placebo BID for 5 days, and those patients randomized 
to oseltamivir will receive one dose of baloxavir marboxil matching placebo on Day 1.
The following assessments will be conducted at clinic visits:  physical examination, vital 
signs, adverse events, concomitant therapies, clinical laboratory tests, and nasal/throat 
swabs.  Please see Appendix 1 for details concerning the timing of these assessments.  
In addition, pharmacokinetic (PK) samples will be collected at the timepoints indicated in 
Appendix 2.
Throughout the treatment and safety follow-up periods, the parents/caregivers will 
maintain a patient diary for each patient in order to record body temperatures (tympanic 
assessment), influenza symptoms, and acetaminophen use.  Temperatures will be 


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recorded four times daily (morning, noon, evening, and bedtime) on Days 1 to 3; 
BID (morning and evening) on Days 4 to 9; and once daily on Days 10 to 15.  Influenza 
symptoms will be recorded BID (morning and evening) on Days 1 to 9 and once daily on 
Days 10 to 15.
Figure 1 presents an overview of the study design.  
Figure 1
Study Schema
Baloxavir baloxavir marboxil; BID twice daily.
Note:  The baloxavir marboxil dose will be based on the body weight of the child (2 mg/kg for 
patients weighing 20 kg or 40 mg for patients weighing 20 kg).  Oseltamivir will be 
administered per the Tamiflu® local prescribing information (see Section 4.3.2.2).
This study will be conducted at sites in the United States and globally. 
To facilitate early and close monitoring of safety parameters over time, an Internal 
Monitoring Committee (IMC) will review aggregate safety data on an ongoing basis as 
defined in the IMC charter.  If there is any concern noted in the safety parameters, the 
Sponsor may suspend or discontinue a treatment arm or the entire study, as 
appropriate.
A schedule of activities is provided in Appendix 1.
3.2
END OF STUDY AND LENGTH OF STUDY
The end of this study is defined as the date when the last patient, last visit (LPLV) occurs 
or the date at which the last data point required for statistical analysis or safety follow-up 
is received from the last patient, whichever occurs later.  The end of the study is 
expected to occur 29 days after the last patient has been enrolled.
The total length of the study, from screening of the first patient to the end of the study, is 
expected to be approximately 9 months. Given the seasonal variability of incidence and 
severity of influenza, the total length of the study may be extended to complete 
enrollment.
In addition, the Sponsor may decide to terminate the study at any time.


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3.3
RATIONALE FOR STUDY DESIGN
3.3.1
Rationale for Baloxavir Marboxil Dose and Schedule
The safety and efficacy of baloxavir marboxil in adult and pediatric patients with 
influenza virus infection have been demonstrated in previous studies using baloxavir 
marboxil 10-mg and 20-mg tablets.
In this study, baloxavir marboxil will be administered as granules for suspension. 
Bioequivalence of the suspension and the 20-mg tablet (which was tested in clinical 
studies) was confirmed in a previous study.  
Proposed pediatric doses in this study were determined according to the modeling and
simulation of S-033447 pharmacokinetics in a pediatric population. Population PK 
analysis had been performed in pediatric populations by using PK data obtained in the 
Phase III study involving pediatric patients in Japan (1618T0822) to develop a 
population PK model for pediatrics.
Simulation of Caucasian pediatric drug exposure was performed for 1,000 patients 
(26,000 patients in total) for every 5-kg body weight for 10- to 60-kg pediatric patients, 
and various dosing regimens were evaluated with respect to their ability to match adult 
drug exposure in terms of area under the plasma concentrationtime curve (AUC), 
maximum plasma concentration (Cmax), plasma concentration 24 hours after dosing (C24;
acceptable time window:  20 to 28 hours), and 72 hours after dosing (C72).  The optimal 
dose and body weight cutoff for flat dosing were based on a comparison of the simulated 
drug exposures with those obtained in the Phase III study (1601T0831) for patients 
receiving 40 mg baloxavir marboxil (body weight 80 kg) and patients receiving 80 mg 
baloxavir marboxil (body weight 80 kg), those obtained in the pediatric Phase III study 
(1618T0822), and those obtained in the Phase I thorough corrected QT interval (QTc)
study (1527T0816) for patients receiving 80 mg baloxavir marboxil. Simulations showed 
that optimal exposure matching to adults in terms of both total (AUC) and sustained (C72) 
drug exposure was achieved with 2 mg/kg in children weighing less than 20 kg and flat
dosing of 40 mg in children weighing 20 kg.
In this study, baloxavir marboxil will be administered based to the body weight recorded 
at screening (i.e., 2 mg/kg for patients weighing 20 kg or 40 mg for patients weighing 
20 kg) to obtain similar exposure of S-033447 to that resulting from the administration 
of 40 mg or 80 mg baloxavir marboxil (based on body weight) to adults in Phase III and 
Japanese pediatric Phase III studies.  For information on the formulation and handling of 
baloxavir marboxil, see the pharmacy manual.
3.3.2
Rationale for Patient Population
The safety and efficacy of baloxavir marboxil has been investigated in adult and 
adolescent populations in the United States and Japan.  Two open-label studies have
also been conducted in children in Japan. Given the burden of influenza in young 


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children, particularly 5 years of age, this study in children in the United States and 
globally is justified to confirm the safety and pharmacokinetics of baloxavir marboxil in 
this population.
3.3.3
Rationale for Control Group
It may not be considered ethical to withhold active treatment from children with 
influenza-like symptoms given the potential severity of the disease, so a placebo control 
group has not been included. Oseltamivir is a well-established and well-characterized 
antiviral agent effective against influenza and is currently the standard of care for 
influenza.
While the main objectives for this study are to assess the safety and pharmacokinetics of 
baloxavir marboxil, efficacy data will be collected as a secondary endpoint. Use of 
oseltamivir in this study will allow a descriptive evaluation of secondary efficacy and 
virological endpoints, as well as comparison of adverse events.
The dose of oseltamivir to be used in this study is the approved dose for children in the 
treatment of influenza, which is based on body weight. The standard duration of 
treatment in healthy children is 5 days of BID dosing, which will be assessed in this 
study. To maintain the double-blind nature of the study, matching placebo for both 
baloxavir marboxil and oseltamivir will be administered.
4.
MATERIALS AND METHODS
4.1
PATIENTS
Approximately 120 pediatric patients with influenza-like symptoms are planned for 
enrollment in this study.
4.1.1
Inclusion Criteria
Patients must meet the following criteria for study entry:

Written informed consent/assent for study participation obtained from patient’s 
parents or legal guardian, with assent as appropriate by the patient, depending on 
the patient’s level of understanding

Aged 1 to 12 years at randomization (Day 1)

Parent/guardian willing and able to comply with study requirements, in the 
investigator’s judgment

Patient able to comply with study requirements, depending on the patient’s level of 
understanding

Patient with a diagnosis of influenza virus infection confirmed by the presence of all 
of the following:

Fever 38C (tympanic temperature) at screening

At least one respiratory symptom (either cough or nasal congestion) 


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
The time interval between the onset of symptoms and screening is 48 hours (the 
onset of symptoms is defined as the time when body temperature first exceeded
37.5C if known, or the time when the first symptom was noticed by patient, parent,
or caregiver)
4.1.2
Exclusion Criteria
Patients who meet any of the following criteria will be excluded from study entry:

Severe symptoms of influenza virus infection requiring inpatient treatment

Concurrent infections requiring systemic antiviral therapy at screening

Require, in the opinion of the investigator, any of the prohibited medication during 
the study

Previous treatment with peramivir, laninamivir, oseltamivir, zanamivir, or amantadine 
within 2 weeks prior to screening

Immunization with a live/attenuated influenza vaccine in the 2 weeks prior to 
randomization

Concomitant treatment with steroids or other immuno-suppressant therapy

Known HIV infection or other immunosuppressive disorder

Uncontrolled renal, vascular, neurologic, or metabolic disease (e.g., diabetes, 
thyroid disorders, adrenal disease), hepatitis, cirrhosis, or pulmonary disease or
patients with known chronic renal failure

Active cancer at any site

History of organ transplantation

Known allergy to either study drug (i.e., baloxavir marboxil and oseltamivir) or to 
acetaminophen

Females who have commenced menarche (i.e., child-bearing potential)

Participation in a clinical trial within 4 weeks or five half-lives of exposure to an 
investigational drug prior to screening, whichever is longer
4.2
METHOD OF TREATMENT ASSIGNMENT AND BLINDING 
4.2.1
Blinding Methods
After written informed consent and assent, where applicable, have been obtained, all 
patients will receive a screening number, which will be assigned by an interactive voice
or web-based response system (IxRS). Following completion of the screening period 
and after all patient eligibility requirements are confirmed, patients will be assigned a 
patient number (a different number from the screening number) on Day 1 and will 
undergo randomization in a 2:1 ratio. All patients will receive one of two active 
treatments: a single oral dose of baloxavir marboxil based on body weight (2 mg/kg for 
patients weighing 20 kg or 40 mg for patients weighing 20 kg) or oseltamivir (dose 
based on body weight) for 5 days. Both groups will receive matching placebo for the 


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alternate treatment.  A permuted block randomization method will be used to obtain an 
approximate 2:1 ratio of baloxavir marboxil to oseltamivir.
Study site personnel and patients will be blinded to treatment assignment during the 
study.  The Sponsor and its agents will also be blinded to treatment assignment, with the 
exception of individuals who require access to patient treatment assignments to fulfill
their job roles during a clinical trial. These roles include the unblinding group 
responsible, clinical supply chain managers, sample handling staff, operational assay 
group personnel, IxRS service provider, and IMC members if applicable.
While PK samples must be collected from patients assigned to the comparator arm to 
maintain the blinding of treatment assignment, PK assay results for these patients are 
generally not needed for the safe conduct or proper interpretation of this study.  
Laboratories responsible for performing study drug PK assays will be unblinded to 
patients' treatment assignments to identify appropriate samples to be analyzed.  PK 
samples from patients assigned to the comparator arm will not be analyzed for study 
drug PK concentration except by request (e.g., to evaluate a possible error in dosing).
4.2.2
Unblinding Methods
If unblinding is necessary for a medical emergency (e.g., in the case of a serious 
adverse event for which patient management might be affected by knowledge of 
treatment assignment), the investigator will be able to break the treatment code by 
contacting the IxRS.  The investigator is not required to contact the Medical Monitor prior 
to breaking the treatment code; however, the treatment code should not be broken 
except in emergency situations.
If the investigator wishes to know the identity of the study drug for any reason other than 
a medical emergency, he or she should contact the Medical Monitor directly.  The 
investigator should document and provide an explanation for any non-emergency 
unblinding.  The investigator will be able to break the treatment code by contacting the 
IxRS.
As per health authority reporting requirements, the Sponsor's Drug Safety representative
will break the treatment code for all serious, unexpected suspected adverse reactions 
(see Section 5.7) that are considered by the investigator or Sponsor to be related to 
study drug.  The patient may continue to receive treatment, and the investigator, patient, 
and Sponsor personnel, with the exception of the Drug Safety representative and 
personnel who must have access to patient treatment assignments to fulfill their roles 
(as defined above), will remain blinded to treatment assignment.


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4.3
STUDY TREATMENT AND OTHER TREATMENTS RELEVANT 
TO THE STUDY DESIGN
The investigational medicinal product (IMP) for this study is baloxavir marboxil.  
Oseltamivir (also an IMP) will be administered as an active control.  Each treatment will 
be administered in combination with the matching placebo for the alternate treatment.
4.3.1
Study Treatment Formulation, Packaging, and Handling
4.3.1.1
Baloxavir Marboxil 
Baloxavir marboxil will be supplied by the Sponsor as white to light yellow granules for 
oral suspension in 50-mL glass bottles.  For information on the formulation and handling 
of baloxavir marboxil, see the pharmacy manual.
Placebo for baloxavir marboxil will be supplied as white to light yellow granules for oral 
suspension in 50-mL glass bottles that match the active study drug.
4.3.1.2
Oseltamivir
Oseltamivir will be supplied by the Sponsor as powder for oral suspension in 
100-mL glass bottles with child-resistant caps.  For information on the formulation and 
handling of oseltamivir, see the pharmacy manual and the local prescribing information 
for oseltamivir.
Placebo for oseltamivir will be supplied as powder for oral suspension in 100-mL glass 
bottles with child-resistant caps that match the active study drug.
4.3.2
Study Treatment Dosage, Administration, and Compliance
The treatment regimens are summarized in Section 3.1.
Any dose modification should be noted on the Study Drug Administration electronic 
Case Report Form (eCRF).  Cases of overdose, medication error, drug abuse, or drug 
misuse, along with any associated adverse events, should be reported as described in 
Section 5.4.3.
Guidelines for treatment interruption or discontinuation for patients who experience 
adverse events are provided in Section 5.1.2.
4.3.2.1
Baloxavir Marboxil and Placebo 
Baloxavir marboxil is provided as granules for oral suspension; it will be administered 
orally as a single dose on Day 1, only. The granules for oral suspension will be 
reconstituted with water to provide a fixed dose based on the body weight of the child
(2 mg/kg for patients weighing 20 kg, or 40 mg for patients weighing 20 kg).
The baloxavir marboxil matching placebo is provided as granules for oral suspension 
and will be administered orally on Day 1 only.


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4.3.2.2
Oseltamivir and Placebo
Oseltamivir will be administered orally BID (morning and evening) for 5 days.  The 
powder for suspension will be reconstituted with water, to provide a fixed dose based on
the body weight of the child.
Weight-adjusted dosing regimen for children aged 1 to 12 years, for 5 days:

15 kg:
30 mg BID

16 kg to 23 kg: 45 mg BID

24 kg to 40 kg: 60 mg BID

41 kg:
75 mg BID
The oseltamivir matching placebo powder is an oral suspension and will be administered 
orally BID (morning and evening) for 5 days.
Oseltamivir, or matching placebo, will be given orally 12 hours apart. If the first dose is 
taken after 4 pm (16:00 hours) on Day 1, the next dose will be taken in the morning of 
Day 2. For these patients, the 10th dose will be taken on the morning of Day 6. If the 
first dose is taken prior to 4 pm (16:00 hours) on Day 1, the next dose should be taken in 
the evening of the same day (i.e., prior to midnight on the same calendar day with a 
minimum of 7 hours between doses). For these patients, the 10th dose will be taken in 
the evening of Day 5.
4.3.3
Rescue Medication
If influenza symptoms, such as fever and headache, are so severe, in the opinion of the 
patient/caregiver, that the patient needs rescue therapy between Day 1 and Day 29, the 
use of acetaminophen at a dose appropriate to the age and weight of the child will be 
permitted only for the relief of fever or pain. If acetaminophen is used, the 
patient/parent/caregiver will record the use in the patient diary, and the investigator will 
record the date, time, and dose at the next visit. Acetaminophen will not be provided by 
the Sponsor.
4.3.4
Investigational Medicinal Product Accountability
All IMPs required for completion of this study (baloxavir marboxil and oseltamivir, with 
matching placebo formulations) will be provided by the Sponsor where required by local 
health authority regulations.  The study site will acknowledge receipt of IMPs supplied by 
the Sponsor, using the IxRS to confirm the shipment condition and content.  Any 
damaged shipments will be replaced.
The IMPs will either be disposed of at the study site according to the study site’s 
institutional standard operating procedure or be returned to the Sponsor (if supplied by 
the Sponsor) with the appropriate documentation.  The site’s method of destroying 
Sponsor-supplied IMPs must be agreed to by the Sponsor.  The site must obtain written 


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authorization from the Sponsor before any Sponsor-supplied IMP is destroyed, and IMP 
destruction must be documented on the appropriate form.
Accurate records of all IMPs received at, dispensed from, returned to, and disposed of by 
the study site should be recorded on the Drug Inventory Log.
4.3.5
Continued Access to Baloxavir Marboxil and Oseltamivir 
Currently, the Sponsor does not have any plans to provide the Roche IMPs (baloxavir 
marboxil or oseltamivir) or any other study treatments or interventions to patients who 
have completed the study.  The Sponsor may evaluate whether to continue providing 
baloxavir marboxil in accordance with the Roche Global Policy on Continued Access to 
Investigational Medicinal Product, available at the following website:
http://www.roche.com/policy_continued_access_to_investigational_medicines.pdf
4.4
CONCOMITANT THERAPY
Concomitant therapy consists of any medication (e.g., prescription drugs, 
over-the-counter drugs, vaccines, herbal or homeopathic remedies, nutritional 
supplements) used by a patient in addition to protocol-mandated treatment from 2 weeks
prior to the initiation of study drug to the study completion/discontinuation visit.  All such 
medications should be reported to the investigator and recorded on the Concomitant 
Medications eCRF.
4.4.1
Permitted Therapy 
Acetaminophen is permitted between Day 1 and Day 29 for severe influenza symptoms 
at a dose appropriate to the weight and age of the child. See Section 4.3.3 for further 
details.
4.4.2
Cautionary Therapy
4.4.2.1
Herbal Therapies
Concomitant use of herbal therapies during this study is not recommended because their 
pharmacokinetics, safety profiles, and potential drugdrug interactions are generally 
unknown.  
4.4.3
Prohibited Therapy
The use of the following drugs and over-the-counter drugs with equivalent efficacy are
prohibited from Day 1, after administration of study drug, until study completion or early 
termination:

Systemic antiviral drugs

Antipyretics/analgesics except acetaminophen

Corticosteroids in injection, oral, or inhalation formulation

Immunosuppressants


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4.5
STUDY ASSESSMENTS 
The schedule of activities to be performed during the study is provided in Appendix 1.  
All activities should be performed and documented for each patient.  
Patients will be closely monitored for safety throughout the study.  
4.5.1
Informed Consent Forms and Screening Log
Written informed consent for participation in the study must be obtained from the child’s 
parent/caregiver or legal guardian before performing any study-related procedures
(including screening evaluations).  The written assent form should also be signed and 
dated by those children who are considered to have a sufficient level of understanding.
Informed Consent Forms (and Assent Forms where appropriate) for enrolled patients 
and for patients who are not subsequently enrolled will be maintained at the study site.
All screening evaluations must be completed and reviewed to confirm that patients meet 
all eligibility criteria before enrollment.  The investigator will maintain a screening log to 
record details of all patients screened and to confirm eligibility or record reasons for 
screening failure, as applicable.
4.5.2
Medical History, Concomitant Medication, and Demographic 
Data
Medical history, including clinically significant diseases, surgeries, cancer history 
(including prior cancer therapies and procedures), and reproductive status in females will 
be recorded at baseline.  In addition, all medications (e.g., prescription drugs, 
over-the-counter drugs, vaccines, herbal or homeopathic remedies, nutritional 
supplements) used by the patient within 2 weeks prior to initiation of study treatment will 
be recorded.  At the time of each follow-up physical examination, an interval medical 
history should be obtained and any changes in medications and allergies should be 
recorded.
Demographic data will include age, sex, and parent/caregiver- or self-reported 
race/ethnicity.
Influenza vaccination history for the 12 months before screening will be recorded, 
including the type of vaccine (e.g., live, inactivated) and date administered, if known.
4.5.3
Physical Examinations
A complete physical examination, performed at screening and other specified visits, 
should include an evaluation of the head, eyes, ears, nose, and throat, and the 
cardiovascular, dermatologic, musculoskeletal, respiratory, gastrointestinal, 
genitourinary, and neurologic systems.  Any abnormality identified at baseline should be 
recorded on the General Medical History and Baseline Conditions eCRF.


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Limited, symptom-directed physical examinations should be performed at specified 
post-baseline visits and as clinically indicated.  Changes from baseline abnormalities 
should be recorded in patient notes.  New or worsened clinically significant abnormalities 
should be recorded as adverse events on the Adverse Event eCRF.
Limited, symptom-directed physical examinations may be performed by a mobile nursing
professional.
4.5.4
Vital Signs
Vital signs should include measurements of respiratory rate, pulse rate, and systolic and 
diastolic blood pressure while the patient is in a seated position, as well as tympanic
temperature.
4.5.5
Laboratory and Other Biological Samples
Samples for the following laboratory tests will be sent to one or several central 
laboratories for analysis:

Hematology:  WBC count, RBC count, hemoglobin, hematocrit, platelet count, 
differential count (neutrophils, eosinophils, basophils, monocytes, lymphocytes, 
other cells)

Chemistry panel (serum or plasma):  sodium, potassium, chloride, bicarbonate, BUN 
or urea, creatinine, total protein, albumin, total and direct bilirubin, alkaline 
phosphatase, ALT, AST

Plasma samples for PK analysis
Consent for optional supplementary PK sampling (intensive schedule) will be 
obtained at the time of study entry (see Appendix 2).

Nasal/nasopharyngeal swabs for virology tests (i.e., reverse 
transcriptase-polymerase chain reaction [RT-PCR], TCID50, genotyping)
For sampling procedures, storage conditions, and shipment instructions, see the 
laboratory manual.
Biological samples will be destroyed when the final Clinical Study Report has been 
completed, with the following exception:

Plasma samples collected for PK analysis may be needed for PK assay 
development and validation; therefore, these samples will be destroyed no later than 
5 years after the final Clinical Study Report has been completed.
When a patient withdraws from the study, samples collected prior to the date of 
withdrawal may still be analyzed, unless the patient specifically requests that the 
samples be destroyed or local laws require destruction of the samples.  However, if 
samples have been tested prior to withdrawal, results from those tests will remain as 
part of the overall research data.


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Data arising from sample analysis will be subject to the confidentiality standards 
described in Section 8.4.
4.5.6
Patient-Reported Outcomes
The Canadian Acute Respiratory Illness and Flu Scale (CARIFS) will be used to 
document the treatment benefit of baloxavir marboxil.
CARIFS is a reliable parental questionnaire and is composed of 18 questions, each with 
a 4-point Likert response. The questionnaire covers three domains: symptoms 
(e.g., cough), function (e.g., play), and parental impact (e.g., clinginess).  The CARIFS is 
calculated as the sum of the items and measures duration of illness.  Data handling 
conventions will be defined and described in the statistical analysis plan.
The questionnaire will be completed in its entirety by the parent or caregiver at specified 
timepoints during the study (see Appendix 1). To ensure instrument validity and that 
data standards meet health authority requirements, the questionnaire will be 
administered before the parent/caregiver or patient receives any information on disease 
status, prior to the performance of nonpatient-reported outcome (PRO) assessments, 
and prior to the administration of study treatment, unless otherwise specified.
Parent/caregivers will use an electronic device to capture PRO data.  The electronic 
device and/or instructions for completing the questionnaires electronically will be 
provided by site staff.  The data will be transmitted to a centralized database maintained 
by the electronic device vendor.  The data will be available for access by appropriate 
study personnel.
4.6
TREATMENT, PATIENT, STUDY, AND SITE DISCONTINUATION
4.6.1
Study Treatment Discontinuation
Patients must permanently discontinue study treatment if they experience any of the 
following:

Any medical condition that the investigator or Sponsor determines may jeopardize 
the patient’s safety if he or she continues to receive study treatment

Investigator or Sponsor determination that treatment discontinuation is in the best 
interest of the patient
The primary reason for study treatment discontinuation should be documented on the 
appropriate eCRF.  Patients who discontinue study treatment prematurely will not be 
replaced.
Patients will return to the clinic for a treatment completion or treatment discontinuation 
visit on Day 29 (3 days) (see Appendix 1 for additional details).


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4.6.2
Patient Discontinuation from Study
Patients have the right to voluntarily withdraw from the study (or be withdrawn by their 
parents or caregivers) at any time for any reason. In addition, the investigator has the 
right to withdraw a patient from the study at any time.  Reasons for withdrawal from the 
study may include, but are not limited to, the following:

Patient withdrawal of assent (or withdrawal of consent by their parents or caregivers) 
at any time

Study termination or site closure

Patient or patient’s parent/caregiver non-compliance, defined as failure to comply 
with protocol requirements as determined by the investigator or Sponsor
Every effort should be made to obtain information on each patient who withdraws or is 
withdrawn by the parent/caregiver from the study.  The primary reason for withdrawal 
from the study should be documented on the appropriate eCRF. If a patient or the 
patient’s parent/caregiver requests that the patient be withdrawn from the study, this 
request must be documented in the source documents and signed by the investigator. 
Patients who withdraw or are withdrawn from the study will not be replaced.
4.6.3
Study Discontinuation
The Sponsor has the right to terminate this study at any time.  Reasons for terminating 
the study may include, but are not limited to, the following:

The incidence or severity of adverse events in this or other studies indicates a 
potential health hazard to patients

Patient enrollment is unsatisfactory
The Sponsor will notify the investigator if the Sponsor decides to discontinue the study.  
4.6.4
Site Discontinuation
The Sponsor has the right to close a site at any time.  Reasons for closing a site may 
include, but are not limited to, the following:

Excessively slow recruitment

Poor protocol adherence

Inaccurate or incomplete data recording

Non-compliance with the International Council for Harmonisation (ICH) guideline for 
Good Clinical Practice

No study activity (i.e., all patients have completed the study and all obligations have 
been fulfilled)


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5.
ASSESSMENT OF SAFETY
5.1
SAFETY PLAN
The safety plan for patients in this study is based on clinical experience with baloxavir 
marboxil in completed and ongoing studies.  There are no anticipated important safety 
risks for baloxavir marboxil.  Please refer to the Baloxavir Marboxil Investigator's 
Brochure for a complete summary of safety information.
Several measures will be taken to ensure the safety of patients participating in this study.  
Eligibility criteria have been designed to exclude patients potentially at higher risk for 
serious influenza and toxicities.  Patients will undergo safety monitoring during the study, 
including assessment of the nature, frequency, and severity of adverse events.  
In addition, guidelines for managing adverse events, including criteria for dosage 
modification and treatment interruption or discontinuation, are provided below.
5.1.1
Internal Monitoring Committee
An IMC will review the clinical study data at regular intervals as defined in the IMC 
charter.  Should a safety concern be identified, a treatment arm or the entire study may 
be suspended or discontinued, as appropriate.
5.1.2
Management of Patients Who Experience Adverse Events
Baloxavir marboxil is administered as a single-dose treatment, so no dose modification
or treatment discontinuation is possible. However, the study medication can still be 
suspended or the patients can be discontinued if adverse events are considered to be 
related to the study medication (baloxavir marboxil or oseltamivir) in patients who 
experience toxicity considered to be related to oseltamivir.  
5.2
SAFETY PARAMETERS AND DEFINITIONS
Safety assessments will consist of monitoring and recording adverse events, including 
serious adverse events and adverse events of special interest, performing 
protocol-specified safety laboratory assessments, measuring protocol-specified vital 
signs, and conducting other protocol-specified tests that are deemed critical to the safety 
evaluation of the study.
Certain types of events require immediate reporting to the Sponsor, as outlined in 
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5.2.1
Adverse Events
According to the ICH guideline for Good Clinical Practice, an adverse event is any 
untoward medical occurrence in a clinical investigation patient administered a 
pharmaceutical product, regardless of causal attribution.  An adverse event can 
therefore be any of the following:

Any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of a medicinal product, 
whether or not considered related to the medicinal product

Any new disease or exacerbation of an existing disease (a worsening in the 
character, frequency, or severity of a known condition) (see Section 5.3.5.8 and 
Section 5.3.5.9 for more information)

Recurrence of an intermittent medical condition (e.g., headache) not present at 
baseline

Any deterioration in a laboratory value or other clinical test (e.g., ECG, X-ray) that is 
associated with symptoms or leads to a change in study treatment or concomitant 
treatment or discontinuation from study drug

Adverse events that are related to a protocol-mandated intervention, including those 
that occur prior to assignment of study treatment (e.g., screening invasive 
procedures such as biopsies)
5.2.2
Serious Adverse Events (Immediately Reportable to the 
Sponsor)
A serious adverse event is any adverse event that meets any of the following criteria:

Is fatal (i.e., the adverse event actually causes or leads to death)

Is life threatening (i.e., the adverse event, in the view of the investigator, places the 
patient at immediate risk of death)
This does not include any adverse event that, had it occurred in a more severe 
form or was allowed to continue, might have caused death.

Requires or prolongs inpatient hospitalization (see Section 5.3.5.10)

Results in persistent or significant disability/incapacity (i.e., the adverse event 
results in substantial disruption of the patient’s ability to conduct normal life 
functions)

Is a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to 
study drug

Is a significant medical event in the investigator's judgment (e.g., may jeopardize the 
patient or may require medical/surgical intervention to prevent one of the outcomes 
listed above)
The terms "severe" and "serious" are not synonymous.  Severity refers to the intensity of 
an adverse event (e.g., rated as mild, moderate, or severe, or according to National 
Cancer Institute Common Terminology Criteria for Adverse Events [NCI CTCAE]; see 


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Section 5.3.3); the event itself may be of relatively minor medical significance (such as 
severe headache without any further findings).
Severity and seriousness need to be independently assessed for each adverse event 
recorded on the eCRF.
Serious adverse events are required to be reported by the investigator to the Sponsor 
immediately (i.e., no more than 24 hours after learning of the event; see Section 5.4.2 for 
reporting instructions).
5.2.3
Adverse Events of Special Interest (Immediately Reportable to 
the Sponsor)
Adverse events of special interest are required to be reported by the investigator to the 
Sponsor immediately (i.e., no more than 24 hours after learning of the event; see 
Section 5.4.2, for reporting instructions).  Adverse events of special interest for this study 
are as follows:

Cases of potential drug-induced liver injury that include an elevated ALT or AST in 
combination with either an elevated bilirubin or clinical jaundice, as defined by Hy's 
law (see Section 5.3.5.6)

Suspected transmission of an infectious agent by the study drug, as defined as 
follows:
Any organism, virus, or infectious particle (e.g., prion protein transmitting 
transmissible spongiform encephalopathy), pathogenic or non-pathogenic, is 
considered an infectious agent.  A transmission of an infectious agent may be 
suspected from clinical symptoms or laboratory findings that indicate an 
infection in a patient exposed to a medicinal product.  This term applies only
when a contamination of the study drug is suspected.
5.3
METHODS AND TIMING FOR CAPTURING AND ASSESSING 
SAFETY PARAMETERS
The investigator is responsible for ensuring that all adverse events (see Section 5.2.1 for 
definition) are recorded on the Adverse Event eCRF and reported to the Sponsor in 
accordance with instructions provided in this section and in Section 5.4, Section 5.5, and 
Section 5.6.
For each adverse event recorded on the Adverse Event eCRF, the investigator will make 
an assessment of seriousness (see Section 5.2.2 for seriousness criteria), severity (see 
Section 5.3.3), and causality (see Section 5.3.4).  
5.3.1
Adverse Event Reporting Period
Investigators will seek information on adverse events at each patient contact.  All 
adverse events, whether reported by the parent/caregiver or patient or noted by study 
personnel, will be recorded in the patient’s medical record and on the Adverse Event 
eCRF.


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After informed consent has been obtained but prior to initiation of study drug, only 
serious adverse events caused by a protocol-mandated intervention (e.g., invasive 
procedures such as biopsies, discontinuation of medications) should be reported 
(see Section 5.4.2 for instructions for reporting serious adverse events).
After initiation of study drug, all adverse events will be reported until 28 days after the 
last dose of study drug.
Instructions for reporting adverse events that occur after the adverse event reporting 
period are provided in Section 5.6.
5.3.2
Eliciting Adverse Event Information
A consistent methodology of non-directive questioning should be adopted for eliciting 
adverse event information at all patient evaluation timepoints.  Examples of non-directive 
questions include the following:
"How have you felt since your last clinic visit?"
"Have you had any new or changed health problems since you were last here?"
5.3.3
Assessment of Severity of Adverse Events
The adverse event severity grading scale for the NCI CTCAE (v5.0) will be used for 
assessing adverse event severity.  Table 2 will be used for assessing severity for 
adverse events that are not specifically listed in the NCI CTCAE.


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Table 2
Adverse Event Severity Grading Scale for Events Not Specifically 
Listed in NCI CTCAE Toxicity Grading Scale
Grade
Severity
1
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
or intervention not indicated
2
Moderate; minimal, local, or non-invasive intervention indicated; or limiting 
age-appropriate instrumental activities of daily living a
3
Severe or medically significant, but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; or 
limiting self-care activities of daily living b, c
4
Life-threatening consequences or urgent intervention indicated d
5
Death related to adverse event d
NCI CTCAENational Cancer Institute Common Terminology Criteria for Adverse Events.
Note:  Based on the most recent version of NCI CTCAE (v5.0), which can be found at:  
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm
a Instrumental activities of daily living refer to preparing meals, shopping for groceries or 
clothes, using the telephone, managing money, etc.
b Examples of self-care activities of daily living include bathing, dressing and undressing, 
feeding oneself, using the toilet, and taking medications, as performed by patients who are 
not bedridden.
c If an event is assessed as a "significant medical event," it must be reported as a serious
adverse event (see Section 5.4.2 for reporting instructions), per the definition of serious 
adverse event in Section 5.2.2.
d Grade 4 and 5 events must be reported as serious adverse events (see Section 5.4.2 for 
reporting instructions), per the definition of serious adverse event in Section 5.2.2.
5.3.4
Assessment of Causality of Adverse Events
Investigators should use their knowledge of the patient, the circumstances surrounding 
the event, and an evaluation of any potential alternative causes to determine whether an 
adverse event is considered to be related to the study drug, indicating "yes" or "no"
accordingly.  The following guidance should be taken into consideration (see also 
Table 3):

Temporal relationship of event onset to the initiation of study drug

Course of the event, with special consideration of the effects of dose reduction, 
discontinuation of study drug, or reintroduction of study drug (as applicable)

Known association of the event with the study drug or with similar treatments

Known association of the event with the disease under study

Presence of risk factors in the patient or use of concomitant medications known to 
increase the occurrence of the event

Presence of non-treatment-related factors that are known to be associated with the 
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Table 3
Causal Attribution Guidance
Is the adverse event suspected to be caused by the study drug on the basis of facts, evidence, 
science-based rationales, and clinical judgment?
YES
There is a plausible temporal relationship between the onset of the adverse event and 
administration of the study drug, and the adverse event cannot be readily explained by 
the patient's clinical state, intercurrent illness, or concomitant therapies; and/or the 
adverse event follows a known pattern of response to the study drug; and/or the 
adverse event abates or resolves upon discontinuation of the study drug or dose 
reduction and, if applicable, reappears upon re-challenge.
NO
An adverse event will be considered related, unless it fulfills the criteria specified below.  
Evidence exists that the adverse event has an etiology other than the study drug 
(e.g., preexisting medical condition, underlying disease, intercurrent illness, 
or concomitant medication); and/or the adverse event has no plausible temporal 
relationship to administration of the study drug (e.g., cancer diagnosed 2 days after 
first dose of study drug).
For patients receiving combination therapy, causality will be assessed individually for 
each protocol-mandated therapy.
5.3.5
Procedures for Recording Adverse Events
Investigators should use correct medical terminology/concepts when recording adverse 
events on the Adverse Event eCRF.  Avoid colloquialisms and abbreviations.
Only one adverse event term should be recorded in the event field on the Adverse Event 
eCRF.
5.3.5.1
Diagnosis versus Signs and Symptoms
A diagnosis (if known) should be recorded on the Adverse Event eCRF rather than 
individual signs and symptoms (e.g., record only liver failure or hepatitis rather than 
jaundice, asterixis, and elevated transaminases).  However, if a constellation of signs 
and/or symptoms cannot be medically characterized as a single diagnosis or syndrome 
at the time of reporting, each individual event should be recorded on the Adverse Event 
eCRF.  If a diagnosis is subsequently established, all previously reported adverse events 
based on signs and symptoms should be nullified and replaced by one adverse event 
report based on the single diagnosis, with a starting date that corresponds to the starting 
date of the first symptom of the eventual diagnosis.


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5.3.5.2
Adverse Events That Are Secondary to Other Events
In general, adverse events that are secondary to other events (e.g., cascade events or 
clinical sequelae) should be identified by their primary cause, with the exception of 
severe or serious secondary events.  A medically significant secondary adverse event 
that is separated in time from the initiating event should be recorded as an independent 
event on the Adverse Event eCRF.  For example:

If vomiting results in mild dehydration with no additional treatment in a healthy adult, 
only vomiting should be reported on the eCRF.

If vomiting results in severe dehydration, both events should be reported separately 
on the eCRF.

If a severe gastrointestinal hemorrhage leads to renal failure, both events should be 
reported separately on the eCRF.

If dizziness leads to a fall and consequent fracture, all three events should be 
reported separately on the eCRF.

If neutropenia is accompanied by an infection, both events should be reported 
separately on the eCRF.
All adverse events should be recorded separately on the Adverse Event eCRF if it is 
unclear as to whether the events are associated.
5.3.5.3
Persistent or Recurrent Adverse Events
A persistent adverse event is one that extends continuously, without resolution, between 
patient evaluation timepoints.  Such events should only be recorded once on the 
Adverse Event eCRF.  The initial severity (intensity or grade) of the event will be 
recorded at the time the event is first reported.  If a persistent adverse event becomes 
more severe, the most extreme severity should also be recorded on the Adverse Event 
eCRF.  If the event becomes serious, it should be reported to the Sponsor immediately 
(i.e., no more than 24 hours after learning that the event became serious; see 
Section 5.4.2 for reporting instructions).  The Adverse Event eCRF should be updated 
by changing the event from "non-serious" to "serious," providing the date that the event 
became serious, and completing all data fields related to serious adverse events.
A recurrent adverse event is one that resolves between patient evaluation timepoints 
and subsequently recurs.  Each recurrence of an adverse event should be recorded as a 
separate event on the Adverse Event eCRF.
5.3.5.4
Abnormal Laboratory Values
Not every laboratory abnormality qualifies as an adverse event.  A laboratory test result 
must be reported as an adverse event if it meets any of the following criteria:

Is accompanied by clinical symptoms

Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation)


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
Results in a medical intervention (e.g., potassium supplementation for hypokalemia) 
or a change in concomitant therapy

Is clinically significant in the investigator’s judgment 
It is the investigator’s responsibility to review all laboratory findings.  Medical and 
scientific judgment should be exercised in deciding whether an isolated laboratory 
abnormality should be classified as an adverse event.
If a clinically significant laboratory abnormality is a sign of a disease or syndrome 
(e.g., ALP and bilirubin 5upper limit of normal [ULN] associated with cholestasis), only 
the diagnosis (i.e., cholestasis) should be recorded on the Adverse Event eCRF.
If a clinically significant laboratory abnormality is not a sign of a disease or syndrome, 
the abnormality itself should be recorded on the Adverse Event eCRF, along with a 
descriptor indicating whether the test result is above or below the normal range 
(e.g., "elevated potassium," as opposed to "abnormal potassium").  If the laboratory 
abnormality can be characterized by a precise clinical term per standard definitions, the 
clinical term should be recorded as the adverse event.  For example, an elevated serum 
potassium level of 7.0 mEq/L should be recorded as "hyperkalemia."
Observations of the same clinically significant laboratory abnormality from visit to visit 
should only be recorded once on the Adverse Event eCRF (see Section 5.3.5.3 for 
details on recording persistent adverse events).
5.3.5.5
Abnormal Vital Sign Values
Not every vital sign abnormality qualifies as an adverse event.  A vital sign result must
be reported as an adverse event if it meets any of the following criteria:

Is accompanied by clinical symptoms

Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation)

Results in a medical intervention or a change in concomitant therapy

Is clinically significant in the investigator’s judgment 
It is the investigator’s responsibility to review all vital sign findings.  Medical and scientific 
judgment should be exercised in deciding whether an isolated vital sign abnormality 
should be classified as an adverse event.
If a clinically significant vital sign abnormality is a sign of a disease or syndrome 
(e.g., high blood pressure), only the diagnosis (i.e., hypertension) should be recorded on 
the Adverse Event eCRF.
Observations of the same clinically significant vital sign abnormality from visit to visit 
should only be recorded once on the Adverse Event eCRF (see Section 5.3.5.3 for 
details on recording persistent adverse events).


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5.3.5.6
Abnormal Liver Function Tests
The finding of an elevated ALT or AST (3ULN) in combination with either an elevated 
total bilirubin (2ULN) or clinical jaundice in the absence of cholestasis or other 
causes of hyperbilirubinemia is considered to be an indicator of severe liver injury (as 
defined by Hy's law).  Therefore, investigators must report as an adverse event the 
occurrence of either of the following:

Treatment-emergent ALT or AST 3ULN in combination with total bilirubin 
2ULN

Treatment-emergent ALT or AST 3ULN in combination with clinical jaundice
The most appropriate diagnosis or (if a diagnosis cannot be established) the abnormal 
laboratory values should be recorded on the Adverse Event eCRF (see Section 5.3.5.1) 
and reported to the Sponsor immediately (i.e., no more than 24 hours after learning of 
the event), either as a serious adverse event or an adverse event of special interest (see 
Section 5.4.2).
5.3.5.7
Deaths
All deaths that occur during the protocol-specified adverse event reporting period (see 
Section 5.3.1), regardless of relationship to study drug, must be recorded on the 
Adverse Event eCRF and immediately reported to the Sponsor (see Section 5.4.2).  This 
includes death attributed to progression of influenza.
Death should be considered an outcome and not a distinct event.  The event or condition 
that caused or contributed to the fatal outcome should be recorded as the single medical 
concept on the Adverse Event eCRF.  Generally, only one such event should be 
reported.  If the cause of death is unknown and cannot be ascertained at the time of 
reporting, "unexplained death" should be recorded on the Adverse Event eCRF.  If the 
cause of death later becomes available (e.g., after autopsy), "unexplained death" should 
be replaced by the established cause of death.  The term "sudden death" should not be 
used unless combined with the presumed cause of death (e.g., "sudden cardiac death").
If the death is attributed to progression of influenza, “influenza progression" should be 
recorded on the Adverse Event eCRF.  
Deaths that occur after the adverse event reporting period should be reported as 
described in Section 5.6.
The IMC will monitor the frequency of deaths from all causes.
5.3.5.8
Preexisting Medical Conditions
A preexisting medical condition is one that is present at the screening visit for this study.  
Such conditions should be recorded on the General Medical History and Baseline 
Conditions eCRF.


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A preexisting medical condition should be recorded as an adverse event only if the 
frequency, severity, or character of the condition worsens during the study.  When 
recording such events on the Adverse Event eCRF, it is important to convey the concept 
that the preexisting condition has changed by including applicable descriptors 
(e.g., "more frequent headaches").
5.3.5.9
Lack of Efficacy or Worsening of Influenza
Medical occurrences or symptoms of deterioration that are anticipated as part of 
influenza, such as fluctuation in symptoms, should only be recorded as an adverse event 
if judged by the investigator to have unexpectedly worsened in severity or frequency or 
changed in nature at any time during the study.  When recording an unanticipated 
worsening of influenza on the Adverse Event eCRF, it is important to convey the concept 
that the condition has changed by including applicable descriptors (e.g., "accelerated 
worsening of influenza").
5.3.5.10
Hospitalization or Prolonged Hospitalization
Any adverse event that results in hospitalization (i.e., inpatient admission to a hospital)
or prolonged hospitalization should be documented and reported as a serious adverse 
event (per the definition of serious adverse event in Section 5.2.2), except as 
outlined below.  
An event that leads to hospitalization under the following circumstances should not be 
reported as an adverse event or a serious adverse event:

Hospitalization for respite care

Hospitalization for a preexisting condition, provided that all of the following criteria 
are met:

The hospitalization was planned prior to the study or was scheduled during the 
study when elective surgery became necessary because of the expected normal 
progression of the disease

The patient has not experienced an adverse event
5.4
IMMEDIATE REPORTING REQUIREMENTS FROM 
INVESTIGATOR TO SPONSOR
Certain events require immediate reporting to allow the Sponsor to take appropriate 
measures to address potential new risks in a clinical trial.  The investigator must report 
such events to the Sponsor immediately; under no circumstances should reporting take 
place more than 24 hours after the investigator learns of the event.  The following is a list 
of events that the investigator must report to the Sponsor within 24 hours after learning 
of the event, regardless of relationship to study drug:

Serious adverse events (defined in Section 5.2.2; see Section 5.4.2 for details on 
reporting requirements)

Adverse events of special interest (defined in Section 5.2.3; see Section 5.4.2 for 
details on reporting requirements)


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
Overdoses, medication errors, drug abuse, or drug misuse (see Section 5.4.3 for 
details on reporting requirements)
The investigator must report new significant follow-up information for these events to the 
Sponsor immediately (i.e., no more than 24 hours after becoming aware of the 
information).  New significant information includes the following:

New signs or symptoms or a change in the diagnosis

Significant new diagnostic test results

Change in causality based on new information

Change in the event’s outcome, including recovery

Additional narrative information on the clinical course of the event
Investigators must also comply with local requirements for reporting serious adverse 
events to the local health authority and Institutional Review Board/Ethics Committee 
(IRB/EC).
5.4.1
Emergency Medical Contacts
Medical Monitor Contact Information for All Sites
Medical Monitor/Roche Medical Responsible:
, M.D. (Primary)
Telephone No.:
To ensure the safety of study patients, an Emergency Medical Call Center Help Desk will 
access the Roche Medical Emergency List, escalate emergency medical calls, provide 
medical translation service (if necessary), connect the investigator with a Roche Medical 
Responsible (listed above and/or on the Roche Medical Emergency List), and track all 
calls.  The Emergency Medical Call Center Help Desk will be available 24 hours per day, 
7 days per week.  Toll-free numbers for the Help Desk, as well as Medical Monitor and 
Medical Responsible contact information, will be distributed to all investigators. 
5.4.2
Reporting Requirements for Serious Adverse Events and 
Adverse Events of Special Interest
5.4.2.1
Events That Occur prior to Study Drug Initiation
After informed consent has been obtained but prior to initiation of study drug, only 
serious adverse events caused by a protocol-mandated intervention should be reported.  
The paper Clinical Trial Serious Adverse Event/Adverse Event of Special Interest 
Reporting Form provided to investigators should be completed and submitted to the 
Sponsor or its designee immediately (i.e., no more than 24 hours after learning of the 
event), either by faxing or by scanning and emailing the form using the fax number or 
email address provided to investigators.
5.4.2.2
Events That Occur after Study Drug Initiation
After initiation of study drug, serious adverse events and adverse events of special 
interest will be reported until 28 days after the last dose of study drug.  Investigators 


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should record all case details that can be gathered immediately (i.e., within 24 hours 
after learning of the event) on the Adverse Event eCRF and submit the report via the 
electronic data capture (EDC) system.  A report will be generated and sent to Roche 
Safety Risk Management by the EDC system.
In the event that the EDC system is unavailable, the paper Clinical Trial Serious Adverse 
Event/Adverse Event of Special Interest Reporting Form provided to investigators should 
be completed and submitted to the Sponsor or its designee immediately (i.e., no more 
than 24 hours after learning of the event), either by faxing or by scanning and emailing 
the form using the fax number or email address provided to investigators.  Once the 
EDC system is available, all information will need to be entered and submitted via the 
EDC system.  
Instructions for reporting serious adverse events that occur 28 daysafter the last dose 
of study treatment are provided in Section 5.6.
5.4.3
Reporting Requirements for Cases of Overdose, Medication 
Error, Drug Abuse, or Drug Misuse
Overdose (accidental or intentional), medication error, drug abuse, and drug misuse 
(hereafter collectively referred to as "special situations") are defined as follows:

Accidental overdose:  accidental administration of a drug in a quantity that is higher 
than the assigned dose

Intentional overdose:  intentional administration of a drug in a quantity that is higher 
than the assigned dose}

Medication error:  accidental deviation in the administration of a drug 
In some cases, a medication error may be intercepted prior to administration of 
the drug.

Drug abuse:  intentional excessive use of a drug that may lead to addiction or 
dependence, physical harm, and/or psychological harm

Drug misuse:  intentional deviation in the administration of a drug that does not 
qualify as drug abuse
In cases where drug is to be self administered by the patient, drug misuse could 
involve the drug being administered to someone other than the patient.


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Special situations are not in themselves adverse events, but may result in adverse 
events.  Each adverse event associated with a special situation should be recorded 
separately on the Adverse Event eCRF.  If the associated adverse event fulfills 
seriousness criteria, the event should be reported to the Sponsor immediately 
(i.e., no more than 24 hours after learning of the event; see Section 5.4.2).  For baloxavir 
marboxil and oseltamivir, adverse events associated with special situations should be 
recorded as described below for each situation:

Accidental overdose:  Enter the adverse event term.  Check the "Accidental 
overdose" and "Medication error" boxes.

Intentional overdose:  Enter the adverse event term.  Check the "Intentional 
overdose" box.  If drug abuse is suspected, check the "Drug abuse" box.  If drug 
abuse is not suspected, check the "Drug misuse" box.

Medication error that does not qualify as an overdose:  Enter the adverse event term.  
Check the "Medication error" box.

Medication error that qualifies as an overdose:  Enter the adverse event term.  
Check the "Accidental overdose" and "Medication error" boxes.

Drug abuse that does not qualify as an overdose:  Enter the adverse event term.  
Check the "Drug abuse" box.

Drug abuse that qualifies as an overdose:  Enter the adverse event term.  Check the 
"Intentional overdose" and "Drug abuse" boxes.

Drug misuse that does not qualify as an overdose:  Enter the adverse event term.  
Check the "Drug misuse" box.

Drug misuse that qualifies as an overdose:  Enter the adverse event term.  Check 
the "Intentional overdose" and "Drug misuse" boxes.
In addition, all special situations associated with baloxavir marboxil and oseltamivir, 
regardless of whether they result in an adverse event, should be recorded on the 
Adverse Event eCRF and reported to the Sponsor immediately (i.e., no more than 
24 hours after learning of the event).  Special situations should be recorded as described 
below:

Accidental overdose:  Enter the drug name and "accidental overdose" as the event 
term.  Check the "Accidental overdose" and "Medication error" boxes.

Intentional overdose:  Enter the drug name and "intentional overdose" as the event 
term.  Check the "Intentional overdose" box.  If drug abuse is suspected, check the 
"Drug abuse" box.  If drug abuse is not suspected, check the "Drug misuse" box.

Medication error that does not qualify as an overdose:  Enter the name of the drug 
administered and a description of the error (e.g., wrong dose administered, wrong 
dosing schedule, incorrect route of administration, wrong drug, expired drug 
administered) as the event term.  Check the "Medication error" box.


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
Medication error that qualifies as an overdose:  Enter the drug name and "accidental 
overdose" as the event term.  Check the "Accidental overdose" and "Medication 
error" boxes.  Enter a description of the error in the additional case details.

Intercepted medication error:  Enter the drug name and "intercepted medication 
error" as the event term.  Check the "Medication error" box.  Enter a description of 
the error in the additional case details.

Drug abuse that does not qualify as an overdose:  Enter the drug name and "drug 
abuse" as the event term.  Check the "Drug abuse" box.

Drug abuse that qualifies as an overdose:  Enter the drug name and "intentional 
overdose" as the event term.  Check the "Intentional overdose" and "Drug abuse" 
boxes.

Drug misuse that does not qualify as an overdose:  Enter the drug name and "drug 
misuse" as the event term.  Check the "Drug misuse" box.

Drug misuse that qualifies as an overdose:  Enter the drug name and "intentional 
overdose" as the event term.  Check the "Intentional overdose" and "Drug misuse" 
boxes.

Drug administered to someone other than the patient:  Enter the drug name and 
"patient supplied drug to third party" as the event term.  Check the "Drug misuse" 
box.
As an example, an accidental overdose that resulted in a headache would require the 
completion of two Adverse Event eCRF pages, one to report the accidental overdose 
and one to report the headache.  The "Accidental overdose" and "Medication error"
boxes would need to be checked on both eCRF pages.
5.5
FOLLOW-UP OF PATIENTS AFTER ADVERSE EVENTS
5.5.1
Investigator Follow-Up
The investigator should follow each adverse event until the event has resolved to baseline 
grade or better, the event is assessed as stable by the investigator, the patient is lost to 
follow-up, or the patient withdraws consent.  Every effort should be made to follow all 
serious adverse events considered to be related to study drug or trial-related procedures 
until a final outcome can be reported.
During the study period, resolution of adverse events (with dates) should be documented 
on the Adverse Event eCRF and in the patient’s medical record to facilitate source data 
verification.
5.5.2
Sponsor Follow-Up
For serious adverse events and adverse events of special interest, the Sponsor or a 
designee may follow up by telephone, fax, email, and/or a monitoring visit to obtain 
additional case details and outcome information (e.g., from hospital discharge 
summaries, consultant reports, autopsy reports) in order to perform an independent 
medical assessment of the reported case.


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5.6
ADVERSE EVENTS THAT OCCUR AFTER THE ADVERSE 
EVENT REPORTING PERIOD
The Sponsor should be notified if the investigator becomes aware of any serious 
adverse event that occurs after the end of the adverse event reporting period (defined as 
28 days after the last dose of study drug), if the event is believed to be related to prior 
study drug treatment.  These events should be reported through use of the Adverse 
Event eCRF.  However, if the EDC system is not available, the investigator should report 
these events directly to the Sponsor or its designee, either by faxing or by scanning and 
emailing the paper Clinical Trial Serious Adverse Event/Adverse Event of Special 
Interest Reporting Form using the fax number or email address provided to investigators.
5.7
EXPEDITED REPORTING TO HEALTH AUTHORITIES, 
INVESTIGATORS, INSTITUTIONAL REVIEW BOARDS, AND 
ETHICS COMMITTEES
The Sponsor will promptly evaluate all serious adverse events and adverse events of 
special interest against cumulative product experience to identify and expeditiously 
communicate possible new safety findings to investigators, IRBs, ECs, and applicable 
health authorities based on applicable legislation.
To determine reporting requirements for single adverse event cases, the Sponsor will 
assess the expectedness of these events using the following reference documents:

Baloxavir Marboxil Investigator's Brochure

Tamiflu® local prescribing information
The Sponsor will compare the severity of each event and the cumulative event 
frequency reported for the study with the severity and frequency reported in the 
applicable reference document.
Reporting requirements will also be based on the investigator's assessment of causality 
and seriousness, with allowance for upgrading by the Sponsor as needed.
An IMC will monitor the incidence of the above-listed anticipated events during the study.  
An aggregate report of any clinically relevant imbalances that do not favor the test 
product will be submitted to health authorities in countries where the study is being 
conducted, within adverse event/serious adverse event reporting timelines upon the 
Sponsor being informed by the IMC.
6.
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN
The primary objective of this study is to compare the safety of a single dose of baloxavir 
marboxil with 5 days of oseltamivir administered twice daily in pediatric patients 
1 to12 years of age with influenza-like symptoms. The statistical analyses of safety,
pharmacokinetics, and efficacy will be descriptive.


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Full details of all planned tables, listings, graphs, and descriptive analyses will be 
provided in a Statistical Analysis Plan, which will be finalized prior to the end of the study.
6.1
ANALYSIS POPULATIONS
The main analysis populations are defined below.
6.1.1
Randomized Population
Not applicable.
6.1.2
Per Protocol Population
Not applicable.
6.1.3
Intent-to-Treat Patient Population
The intent-to-treat (ITT) population comprises all patients who received at least one dose 
of treatment regardless of whether they have any follow-up assessments. Patients will 
be grouped on the basis of randomized treatment. If there is any doubt whether a 
patient was treated, that patient will be assumed to have been treated for the purpose of 
analysis.
6.1.4
Intent-to-Treat Influenza-Infected Patient Population
The intent-to-treat influenza-infected (ITTi) population is a subset of ITT patients who 
have had a laboratory confirmation of influenza infection (polymerase chain reaction 
[PCR] result) from any swab sample collected at baseline or during the study. The ITTi 
population is the primary efficacy population, unless specified otherwise. Patients will be 
grouped based on randomized treatment.
Decisions on patient exclusion from the ITTi population will be made prior to database 
closure. Excluded patients will be documented, together with the reason for exclusion.
6.1.5
Pharmacokinetic Evaluable Population
The pharmacokinetic-evaluable patient (PKEP) population comprises all patients in the 
ITT population who have at least one post-dose drug concentration measurement at a 
scheduled visit timepoint. Patients may be excluded from the PKEP population if they 
significantly violate the inclusion or exclusion criteria or deviate significantly from the
protocol, or if data are unavailable or incomplete (which may influence the PK analysis).
Decisions on patient exclusion from the PKEP population will be made prior to database 
closure by the clinical pharmacologist. Excluded patients will be documented, together 
with the reason for exclusion.


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6.1.6
Safety Population
The safety-evaluable patient population should be the same as the ITT population, (i.e.,
patients who have received any portion of a single dose) regardless of whether or not 
they had any follow-up visits. However for the safety population, patients will be 
classified according to treatment actually received.
6.2
DETERMINATION OF SAMPLE SIZE
No formal sample-size calculations have been performed.  Approximately 120 pediatric 
patients (80 patients in the baloxavir marboxil treatment group and 40 patients in the 
oseltamivir treatment group) will be enrolled.
To detect adverse events with a 3% incidence for at least 1 patient with a probability of 
90%, the study will require 80 patients exposed to baloxavir marboxil.  The given 
sample size provides a probability of at least 1 patient experiencing an adverse event 
with a true incidence rate of from 1% to 5% as shown in Table 4
Table 4
Probability of Adverse Events by Incidence Rates
True incidence rate of an AE
1%
2%
3%
4%
5%
Probability of at least one patient experiencing an AE
55.2%
80.1%
91.3%
96.2%
98.3%
AE adverse event.
The number of patients in the ITTi population will be monitored on an ongoing basis in 
order to ensure that an adequate number of influenza-infected patients are recruited.
Additional patients may be recruited if the ITTi population is considerably smaller than 
expected.
6.3
SUMMARIES OF CONDUCT OF STUDY
The number of patients who enroll, discontinue, or complete the study will be 
summarized by treatment arm.  Reasons for premature study withdrawal will be listed 
and summarized by treatment arm.  Enrollment and major protocol deviations will be 
listed and evaluated for their potential effects on the interpretation of study results.
6.4
SUMMARIES OF DEMOGRAPHIC AND BASELINE 
CHARACTERISTICS
Demographic and baseline characteristics (including age, sex, race/ethnicity, and
vaccination status) will be summarized using means, standard deviations, medians, and 
ranges for continuous variables and proportions for categorical variables, as appropriate.  
Summaries will be presented overall and by treatment group.


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6.5
SAFETY ANALYSES
The safety analysis population will be used for all analyses. 
All verbatim adverse event terms will be mapped to MedDRA thesaurus terms, and 
adverse event severity will be graded according to NCI CTCAE v5.0.
The safety of baloxavir marboxil will be evaluated from adverse events, vital sign 
measurements, and clinical laboratory tests.  Safety parameters will be summarized or 
listed for the safety population.
6.6
PHARMACOKINETIC ANALYSES
The PKEP population (see Section 6.1.5) will be used for all analyses. 
For patients with blood samples collected, individual plasma baloxavir marboxil and 
S-033447 concentrations will be tabulated by patient and by timepoint. Individual and 
mean (if appropriate) plasma baloxavir marboxil and S-033447 concentrations versus 
time data will be plotted by defined body-weight groups (e.g., 510 kg, 1015 kg, etc.).
For patients undergoing intensive PK assessments (Appendix 2), individual PK
parameters of baloxavir marboxil and S-033447 (AUC, Cmax, time to maximum plasma 
concentration, and terminal half-life) may be calculated using model-independent 
methods, as applicable. Parameters will be listed and summarized (mean, standard 
deviation, coefficient of variation, median, minimum, and maximum) by defined 
body-weight group. The C24 and C72 of S-033447 will be listed and summarized (mean, 
standard deviation, coefficient of variation, median, minimum, and maximum) by defined 
body-weight group.
In addition, non-linear mixed-effects model (NONMEM, Version 7.3 or higher) will be 
used to analyze the PK data. The population typical PK parameters (e.g., apparent 
clearance, apparent volume of distribution for the central compartment) and their 
covariates will be estimated.  Individual PK metrics, such as area under the 
concentration–time curve from Time 0 to infinity (AUCinf), C24, C72, and Cmax, will be also 
calculated using post hoc Bayesian estimation for each patient, and plotted against 
significant covariates identified (e.g., body weight, age).  The derived individual values 
will be plotted against body weight and age. PK parameters will be tabulated and 
summarized (i.e., by mean, standard deviation, coefficient of variation, median, and 
minimum and maximum) by age group. PK exposure and response (e.g., virus titers) 
relationships will be explored. Population PK results may be reported in a dedicated 
modelling and simulation report.
Additional PK analyses will be conducted as appropriate.
Pediatric exposure matching to adults will use C24 (observed, as well as Bayesian 
post hoc) as a primary PK parameter.  Key secondary PK metrics, such as C72 and 


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AUCinf (derived as Bayesian post hoc), will assess whether exposure is sustained 
similarly as in adults, and to explore whether or not viral rebound, if any, may be 
associated with lower C72 values.  For completeness, Cmax will be calculated as 
secondary PK parameter. 
6.7
EFFICACY ANALYSES
The statistical analyses of efficacy endpoints will be descriptive. The ITTi population will 
be used for all analyses, with the ITT population also described for the primary analysis.
The data will be summarized using means, standard deviations, medians, and ranges for 
continuous variables and proportions for categorical variables, as appropriate.  
Time-to-event endpoints and duration endpoints will be summarized using Kaplan-Meier 
plots and summaries of the median survival time.  Summaries will be presented by 
treatment group.
Full details of all planned tables, listings, graphs, and descriptive analyses will be 
provided in a Statistical Analysis Plan, which will be finalized prior to unblinding.
6.8
INTERIM ANALYSES
An interim PK analysis is planned in this study. PK samples, up to and including those 
collected at Visit 4/5 of first 12 patients dosed, will be batched for an early shipment.  
This will enable a timely review of the systemic plasma concentrations, in particular the 
concentration at 24 hours and 72 hours after dosing (C24 and C72, respectively ) 
(Appendix 1 and Appendix 2).  This is in order to verify, in a timely manner, that 
exposures at the proposed doses are in reasonable agreement with the corresponding 
values seen in adults. The estimated turnaround time between last sample collected 
and data review is estimated to be approximately 2 to 3 weeks, and recruitment will 
continue during this time. Data review of blinded PK samples (dummy ID) will be 
performed by members of the Sponsor study team.
No other interim analyses are planned in this study. However, given there is no formal 
statistical hypothesis testing in this study, the Sponsor may choose to conduct up to two 
interim analyses.  The decision to conduct an optional interim analysis and the timing of 
the analysis will be documented in the Sponsor’s trial master file prior to the conduct of 
the interim analysis.  The interim analysis will be performed and interpreted by members 
of the Sponsor study team and appropriate senior management personnel.  Access to 
treatment assignment information would follow the Sponsor’s standard procedures.
7.
DATA COLLECTION AND MANAGEMENT
7.1
DATA QUALITY ASSURANCE
The Sponsor will be responsible for data management of this study, including quality 
checking of the data.  Data entered manually will be collected via EDC through use of 
eCRFs.  Sites will be responsible for data entry into the EDC system.  In the event of 


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discrepant data, the Sponsor will request data clarification from the sites, which the sites 
will resolve electronically in the EDC system.
The Sponsor will produce an EDC Study Specification document that describes the 
quality checking to be performed on the data.  Central laboratory data will be sent 
directly to the Sponsor, using the Sponsor’s standard procedures to handle and process 
the electronic transfer of these data.
eCRFs and correction documentation will be maintained in the EDC system’s audit trail.  
System backups for data stored by the Sponsor and records retention for the study data 
will be consistent with the Sponsor’s standard procedures.
PRO data will primarily be collected through the use of an electronic device provided by 
a vendor (see Section 7.3 for details).  In exceptional circumstances, PRO data might be 
collected on paper questionnaires. In the event PROs are completed on paper, the 
questionnaires will be maintained by the patient and delivered to the site at the next 
regularly scheduled visit.
7.2
ELECTRONIC CASE REPORT FORMS
eCRFs are to be completed through use of a Sponsor-designated EDC system.  Sites 
will receive training and have access to a manual for appropriate eCRF completion.  
eCRFs will be submitted electronically to the Sponsor and should be handled in 
accordance with instructions from the Sponsor.
All eCRFs should be completed by designated, trained site staff.  eCRFs should be 
reviewed and electronically signed and dated by the investigator or a designee.
At the end of the study, the investigator will receive patient data for his or her site in a 
readable format on a compact disc that must be kept with the study records.  
Acknowledgement of receipt of the compact disc is required.
7.3
ELECTRONIC PATIENT-REPORTED OUTCOME DATA
An electronic device will be used to capture PRO data.  The device is designed for entry 
of data in a way that is attributable, secure, and accurate, in compliance with U.S. Food 
and Drug Administration (FDA) regulations for electronic records (21 CFR Part 11).  The 
data will be transmitted to a centralized database maintained by the electronic device 
vendor.
The electronic data will be available for view access only, via a secure web server 
maintained by the electronic PRO vendor.  Only identified and trained users may view 
the data, and their actions will become part of the audit trail.  The Sponsor will have view 
access only.  System backups for data stored by the Sponsor and records retention for 
the study data will be consistent with the Sponsor’s standard procedures.


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Once the study is complete, the data, audit trail, and trial and system documentation will 
be archived.  The investigator will receive patient data for the site in both human- and 
machine-readable formats on an archival-quality compact disc that must be kept with the 
study records as source data.  Acknowledgement of receipt of the compact disc is 
required.  In addition, the Sponsor will receive all data in a machine-readable format on a 
compact disc.
7.4
SOURCE DATA DOCUMENTATION
Study monitors will perform ongoing source data verification and review to confirm that 
critical protocol data (i.e., source data) entered into the eCRFs by authorized site 
personnel are accurate, complete, and verifiable from source documents. 
Source documents (paper or electronic) are those in which patient data are recorded 
and documented for the first time.  They include, but are not limited to, hospital records, 
clinical and office charts, laboratory notes, memoranda, PROs, evaluation checklists, 
pharmacy dispensing records, recorded data from automated instruments, copies of 
transcriptions that are certified after verification as being accurate and complete, 
microfiche, photographic negatives, microfilm or magnetic media, X-rays, patient files, 
and records kept at pharmacies, laboratories, and medico-technical departments
involved in a clinical trial.
Before study initiation, the types of source documents that are to be generated will be 
clearly defined in the Trial Monitoring Plan.  This includes any protocol data to be 
entered directly into the eCRFs (i.e., no prior written or electronic record of the data) and 
considered source data.
Source documents that are required to verify the validity and completeness of data 
entered into the eCRFs must not be obliterated or destroyed and must be retained per 
the policy for retention of records described in Section 7.6.
To facilitate source data verification and review, the investigators and institutions must 
provide the Sponsor direct access to applicable source documents and reports for 
trial-related monitoring, Sponsor audits, and IRB/EC review.  The study site must also 
allow inspection by applicable health authorities.
7.5
USE OF COMPUTERIZED SYSTEMS
When clinical observations are entered directly into a study site’s computerized medical 
record system (i.e., in lieu of original hardcopy records), the electronic record can serve 
as the source document if the system has been validated in accordance with health 
authority requirements pertaining to computerized systems used in clinical research.  An 
acceptable computerized data collection system allows preservation of the original entry 
of data.  If original data are modified, the system should maintain a viewable audit trail 
that shows the original data as well as the reason for the change, name of the person 
making the change, and date of the change.


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7.6
RETENTION OF RECORDS
Records and documents pertaining to the conduct of this study and the distribution of 
IMP, including eCRFs, electronic or paper PRO data (if applicable), Informed Consent 
Forms/Assent Forms, laboratory test results, and medication inventory records, must be 
retained by the Principal Investigator for 15 years after completion or discontinuation of 
the study or for the length of time required by relevant national or local health authorities, 
whichever is longer.  After that period of time, the documents may be destroyed, subject 
to local regulations.  
No records may be disposed of without the written approval of the Sponsor.  Written 
notification should be provided to the Sponsor prior to transferring any records to 
another party or moving them to another location.
Roche will retain study data for 25 year after the final study results have been reported 
or for the length of time required by relevant national or local health authorities, 
whichever is longer.
8.
ETHICAL CONSIDERATIONS
8.1
COMPLIANCE WITH LAWS AND REGULATIONS
This study will be conducted in full conformance with the ICH E6 guideline for Good 
Clinical Practice and the principles of the Declaration of Helsinki, or the laws and 
regulations of the country in which the research is conducted, whichever affords the 
greater protection to the individual.  The study will comply with the requirements of the 
ICH E2A guideline (Clinical Safety Data Management:  Definitions and Standards for 
Expedited Reporting).  Studies conducted in the United States or under a U.S. 
Investigational New Drug (IND) Application will comply with U.S. FDA regulations and 
applicable local, state, and federal laws.  Studies conducted in the European Union (E.U.)
or European Economic Area will comply with the E.U. Clinical Trial Directive 
(2001/20/EC).
8.2
INFORMED CONSENT
The Sponsor’s sample Informed Consent Form (and ancillary sample Informed Consent 
Forms, such as a Child’s Informed Assent Form or Mobile Nursing Informed Consent 
Form, if applicable) will be provided to each site.  If applicable, it will be provided in a 
certified translation of the local language.  The Sponsor or its designee must review and 
approve any proposed deviations from the Sponsor's sample Informed Consent Forms 
or any alternate consent forms proposed by the site (collectively, the "Consent Forms") 
before IRB/EC submission.  The final IRB/ECapproved Consent Forms must be 
provided to the Sponsor for health authority submission purposes according to local 
requirements.
If applicable, the Informed Consent Form will contain separate sections for any optional 
procedures.  The investigator or authorized designee will explain to each 


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parent/caregiver the objectives, methods, and potential risks associated with each 
optional procedure.  Parents/caregivers will be told that they are free to refuse 
participation and may withdraw their consent at any time for any reason.  A separate, 
specific signature will be required to document a parent’s/caregiver’s agreement to 
participate in optional procedures.  Parents/caregivers who decline participation will not 
provide a separate signature.
The Consent Forms must be signed and dated by the parent/caregiver or the patient’s 
legally authorized representative before his or her participation in the study.  The case 
history or clinical records for each patient shall document the informed consent process 
and that written informed consent was obtained prior to participation in the study.
The Consent Forms should be revised whenever there are changes to study procedures 
or when new information becomes available that may affect the willingness of the patient 
to participate.  The final revised IRB/EC-approved Consent Forms must be provided to 
the Sponsor for health authority submission purposes.
Parents/caregivers must be re-consented to the most current version of the Consent 
Forms (or to a significant new information/findings addendum in accordance with 
applicable laws and IRB/EC policy) during participation in the study.  For any updated or 
revised Consent Forms, the case history or clinical records for each patient shall 
document the informed consent process and that written informed consent was obtained 
using the updated/revised Consent Forms for continued participation in the study.
A copy of each signed Consent Form must be provided to the parent/caregiver or the 
patient’s legally authorized representative.  All signed and dated Consent Forms must 
remain in each patient’s study file or in the site file and must be available for verification 
by study monitors at any time.
Each Consent Form may also include parent/caregiver authorization to allow use and 
disclosure of personal health information in compliance with the U.S. Health Insurance 
Portability and Accountability Act (HIPAA) of 1996.  If the site utilizes a separate 
Authorization Form for parent/caregiver authorization for use and disclosure of personal 
health information under the HIPAA regulations, the review, approval, and other 
processes outlined above apply except that IRB review and approval may not be 
required per study site policies.
8.3
INSTITUTIONAL REVIEW BOARD OR ETHICS COMMITTEE
This protocol, the Informed Consent Forms, any information to be given to the 
parent/caregiver, and relevant supporting information must be submitted to the IRB/EC 
by the Principal Investigator and reviewed and approved by the IRB/EC before the study 
is initiated.  In addition, any patient recruitment materials must be approved by the 
IRB/EC. 


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The Principal Investigator is responsible for providing written summaries of the status of 
the study to the IRB/EC annually or more frequently in accordance with the requirements, 
policies, and procedures established by the IRB/EC.  Investigators are also responsible 
for promptly informing the IRB/EC of any protocol amendments (see Section 9.6).
In addition to the requirements for reporting all adverse events to the Sponsor, 
investigators must comply with requirements for reporting serious adverse events to the 
local health authority and IRB/EC.  Investigators may receive written IND safety reports 
or other safety-related communications from the Sponsor.  Investigators are responsible 
for ensuring that such reports are reviewed and processed in accordance with health 
authority requirements and the policies and procedures established by their IRB/EC, and 
archived in the site’s study file. 
8.4
CONFIDENTIALITY
The Sponsor maintains confidentiality standards by coding each patient enrolled in the 
study through assignment of a unique patient identification number.  This means that 
patient names are not included in data sets that are transmitted to any Sponsor location.
Patient medical information obtained by this study is confidential and may be disclosed 
to third parties only as permitted by the Informed Consent Form (or separate 
authorization for use and disclosure of personal health information) signed by the 
parent/caregiver, unless permitted or required by law.
Medical information may be given to a patient’s personal physician or other appropriate 
medical personnel responsible for the patient’s welfare, for treatment purposes.
Given the complexity and exploratory nature of exploratory biomarker analyses, data 
derived from these analyses will generally not be provided to study investigators or 
parents/caregivers unless required by law.  The aggregate results of any conducted 
research will be available in accordance with the effective Roche policy on study data 
publication (see Section 9.5).
Data generated by this study must be available for inspection upon request by 
representatives of national and local health authorities, Sponsor monitors, 
representatives, and collaborators, and the IRB/EC for each study site, as appropriate.
Study data may be submitted to government or other health research databases or 
shared with researchers, government agencies, companies, or other groups that are not 
participating in this study.  These data may be combined with or linked to other data and 
used for research purposes, to advance science and public health, or for analysis, 
development, and commercialization of products to treat and diagnose disease.  In 
addition, redacted clinical study reports and other summary reports will be provided upon 
request.


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8.5
FINANCIAL DISCLOSURE
Investigators will provide the Sponsor with sufficient, accurate financial information in 
accordance with local regulations to allow the Sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate health authorities.  
Investigators are responsible for providing information on financial interests during the 
course of the study and for 1 year after completion of the study (see definition of end of 
study in Section 3.2).
9.
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION
9.1
STUDY DOCUMENTATION
The investigator must maintain adequate and accurate records to enable the conduct of 
the study to be fully documented, including, but not limited to, the protocol, protocol 
amendments, Informed Consent Forms, and documentation of IRB/EC and 
governmental approval.  In addition, at the end of the study, the investigator will receive 
the patient data, including an audit trail containing a complete record of all changes 
to data.
9.2
PROTOCOL DEVIATIONS
The investigator should document and explain any protocol deviations. The investigator 
should promptly report any deviations that might have an impact on patient safety and 
data integrity to the Sponsor and to the IRB/EC in accordance with established IRB/EC 
policies and procedures.  The Sponsor will review all protocol deviations and assess 
whether any represent a serious breach of Good Clinical Practice guidelines and require 
reporting to health authorities.  As per the Sponsor's standard operating procedures, 
prospective requests to deviate from the protocol, including requests to waive protocol 
eligibility criteria, are not allowed.
9.3
SITE INSPECTIONS
Site visits will be conducted by the Sponsor or an authorized representative for 
inspection of study data, patients' medical records, and eCRFs.  The investigator will 
permit national and local health authorities; Sponsor monitors, representatives, and 
collaborators; and the IRBs/ECs to inspect facilities and records relevant to this study.
9.4
ADMINISTRATIVE STRUCTURE
This trial will be sponsored and managed by F. Hoffmann-La Roche Ltd.  The Sponsor 
will provide clinical operations management, data management, and medical monitoring.
Approximately 75 sites, in the United States and globally, will participate to 
enroll approximately 120 patients.  Enrollment will occur through an IxRS.  
Central facilities will be used for certain study assessments throughout the study (e.g., 
specified laboratory tests and PK analyses), as specified in Section 4.5.  


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An IMC will be employed to monitor and evaluate patient safety throughout the study.  
9.5
DISSEMINATION OF DATA AND PROTECTION OF TRADE 
SECRETS
Regardless of the outcome of a trial, the Sponsor is dedicated to openly providing 
information on the trial to healthcare professionals and to the public, at scientific 
congresses, in clinical trial registries of the U.S. National Institutes of Health and the 
European Medicines Agency, and in peer-reviewed journals. The Sponsor will comply 
with all requirements for publication of study results.  Study data may be shared with 
others who are not participating in this study, and redacted clinical study reports and 
other summary reports will be provided upon request (see Section 8.4 for more details).  
For more information, refer to the Roche Global Policy on Sharing of Clinical Trials Data 
at the following website:
www.roche.com/roche_global_policy_on_sharing_of_clinical_study_information.pdf
The results of this study may be published or presented at scientific congresses.  For all 
clinical trials in patients involving an IMP for which a marketing authorization application 
has been filed or approved in any country, the Sponsor aims to submit a journal 
manuscript reporting primary clinical trial results within 6 months after the availability of 
the respective Clinical Study Report.  In addition, for all clinical trials in patients involving 
an IMP for which a marketing authorization application has been filed or approved in any 
country, the Sponsor aims to publish results from analyses of additional endpoints and 
exploratory data that are clinically meaningful and statistically sound.
The investigator must agree to submit all manuscripts or abstracts to the Sponsor prior 
to submission for publication or presentation.  This allows the Sponsor to protect 
proprietary information and to provide comments based on information from other 
studies that may not yet be available to the investigator.
In accordance with standard editorial and ethical practice, the Sponsor will generally 
support publication of multicenter trials only in their entirety and not as individual center 
data.  In this case, a coordinating investigator will be designated by mutual agreement.
Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements.  Any formal publication 
of the study in which contribution of Sponsor personnel exceeded that of conventional 
monitoring will be considered as a joint publication by the investigator and the 
appropriate Sponsor personnel.
Any inventions and resulting patents, improvements, and/or know-how originating from 
the use of data from this study will become and remain the exclusive and unburdened 
property of the Sponsor, except where agreed otherwise.


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9.6
PROTOCOL AMENDMENTS
Any protocol amendments will be prepared by the Sponsor.  Protocol amendments will 
be submitted to the IRB/EC and to regulatory authorities in accordance with local 
regulatory requirements.
Approval must be obtained from the IRB/EC and regulatory authorities (as locally 
required) before implementation of any changes, except for changes necessary to 
eliminate an immediate hazard to patients or changes that involve logistical or 
administrative aspects only (e.g., change in Medical Monitor or contact information).


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10.
REFERENCES
[CDC] Centers for Disease Control and Prevention. Antiviral agents for the treatment 
and chemoprophylaxis of influenza: recommendations of the Advisory Committee 
on Immunization Practices (ACIP) [resource on the Internet]. 2011. Available from: 
https://www.cdc.gov/mmwr/preview/mmwrhtml/rr6001a1.htm.
Paules C, Subbarao K. Influenza. Lancet 2017;390:697708.
Rotrosen ET, Neuzil KM. Influenza: a global perspective. Pediatr Clin North Am 
2017;64:91136.
WHO. WHO fact sheet 211: influenza (seasonal) [resource on the Internet]. 2018. 
Available from: http://www.who.int/mediacentre/factsheets/fs211/en/.


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Appendix 1
Schedule of Activities
Treatment Period
Follow-Up Period
Day(s)
D1
D2
D3
D4
D5
D6
D7-9
D10
D15
D29 or ET
Visits
V1 
Screening
V1 Post-dose
V2
OpV1 a
V3
V4
V5
OpV2 a
V6
Visit Window (days)
1
1
2
3
3
Written informed consent/assent
x
Inclusion/exclusion criteria
x
Demographics
x
Medical history b
x
Randomization
x
Study drug administration c
x
x
x
x
x
Patient diary: 
Body temperature measurement d
Four times daily
Twice daily
Once daily
Assessment of influenza symptoms e
Twice daily
Once daily
Physical examination
x f
x f
(x) f
x f
x
x
(x g)
x f
Vital signs measurement
x
x
(x)
x
x
x
(x g)
x h
Adverse event assessment
x
x
(x)
x
x
x
(x g)
x
Concomitant therapies assessment
x
x
(x)
x
x
x
(x g)
x
Interview for meal consumption
x
x
Clinical laboratory tests
x
x
(x g)
(x g)
Nasal/nasopharyngeal swabs 
(virology test) i
x
x
x
x
x
(x g)
(x g)


Appendix 1
Schedule of Activities (cont.)
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Treatment Period
Follow-Up Period
Day(s)
D1
D2
D3
D4
D5
D6
D7-9
D10
D15
D29 or ET
Visits
V1 
Screening
V1 Post-dose
V2
OpV1 a
V3
V4
V5
OpV2 a
V6
Sparse PK samples j
x
(x) j
(x) j
x j
Intensive PK samples k
x
x
x
x k
CARIFSCanadian Acute Respiratory Illness and Flu Scale; DDay; ET early termination; OpVoptional visit; PKpharmacokinetic; Vvisit.
a
OpV1 and OpV2 are optional visits to be performed at the discretion of the investigator or parent/caregiver, for example, to obtain intensive PK 
analyses, or in the event of persistent influenza symptoms.
b
Prior therapies will also be reviewed.
c
Oseltamivir and matching placebo will be given orally, 12 hours apart. If the first dose is taken after 4 pm (16:00 hours) on Day 1, the next 
dose will be taken in the morning of Day 2. For these patients, the 10th dose will be taken on the morning of study Day 6. If the first dose is 
taken prior to 4 pm (16:00 hours) on Day 1, the next dose should be taken in the evening of the same day (i.e., prior to midnight on the same 
calendar day with a minimum of 7 hours between doses). For these patients, the 10th dose will be taken in the evening of study Day 5.
d
The parent/caregiver will assess and record in the patient diary, body temperature (tympanic assessment) four times daily (morning, noon, 
evening, and bedtime) from Days 1 to 3; twice daily (morning and evening) on Days 4 to 9; once daily on Days 10 to 15.
e
The parent/caregiver will complete the CARIFS questionnaire twice daily (morning and evening) on Days 1 to 9 and then once daily on
Days 10 to 15.
f
Body weight and height will be measured on Days 1 and 29, only. Physical examinations on Days 2, 3, and 4 will be limited symptom-directed 
physical examinations and may be performed by a mobile nursing professional.
g
Conduct assessment if the investigator determines that influenza symptoms or viral shedding are persisting or at the investigator’s discretion.
h
Vital signs will be recorded if abnormal physical examination findings or adverse events are recorded since last visit or at investigator’s 
discretion on Day 29.
i
At least two nasal and/or nasopharyngeal swabs (one for each nostril) to be taken at each visit.


Appendix 1
Schedule of Activities (cont.)
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j
Sparse PK samples (all patients):  See Appendix 2 for collection timepoints for required and optional baloxavir marboxil and S-033447 
concentration samples. Patients will be assigned to have either the Day 2 or the Day 4 sample.  Only one sample from Days 6 to 10 is 
required and can be collected at either Visit 4 or Visit 5.
k
Intensive PK samples:  See Appendix 2 for collection timepoints for baloxavir marboxil and S-033447 concentration samples. Patients 
undergoing intensive PK assessments will account for 15%-30% of the total patient population and will be distributed approximately equally 
among age groups. Only one sample from Days 6 to 10 is required and can be collected at either Visit 4 or Visit 5.


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Appendix 2
Schedule of Pharmacokinetic Samples
Visit
Timepoint
Sample Type
Sparse PK Sampling (all patients) a
Visit 1 (Day 1)
One sample between 0.5 and 2 hours
post-dose
Drug PK (plasma)
Visit 2 (Day 2) b
24 hours post-dose
Drug PK (plasma)
Visit 3 (Day 4) b
72 hours post-dose 
Drug PK (plasma)
Visits 45 (Days 610)
Only one sample is to be collected during the 
follow-up period; this sample may be collected 
at follow-up Visit 4 or 5
Drug PK (plasma)
Intensive PK samples c
Visit 1 (Day 1)
One sample between 0.5 and 2 hours, one 
sample at 4 hours, and one sample at 6 hours
Drug PK (plasma)
Visit 2 (Day 2) b
24 hours post-dose
Drug PK (plasma)
Visit 3 (Day 4) b
72 hours post-dose 
Drug PK (plasma)
Visits 45 (Days 610)
Only one sample is to be collected during the 
follow-up period; this sample may be collected 
at follow-up Visit 4 or 5
Drug PK (plasma)
PKpharmacokinetic.
a Samples will be used for S-033447 determination in patients aged 2 years;
baloxavir marboxil and S-033447 determination in patients aged 2 years.
b Patients will be assigned to have either the Day 2 or the Day 4 sample.
c Patients undergoing intensive PK assessments are expected to account for 15%–30% of the 
total patient population and will be distributed approximately equally among age groups.
Samples will be used for baloxavir marboxil and S-033447 determination.


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Appendix 3
Canadian Acute Respiratory Illness and Flu Scale 
(CARIFS) Questionnaire
Item
No
Problem
Minor
Problem
Moderate
Problem
Major
Problem
Don’t 
Know/Not 
Applicable
1.
Poor appetite ........................................
2.
Not sleeping well
3.
Irritable, cranky, fussy..........................
4.
Feels unwell .........................................
5.
Low energy, tired .................................
6.
Not playing well...................................
7.
Crying more than usual........................
8.
Needing extra care ...............................
9.
Clinginess.............................................
10. Headache..............................................
11. Sore throat............................................
12. Muscle aches or pains ..........................
13. Fever ....................................................
14. Cough...................................................
15. Nasal congestion, runny nose...............
16. Vomiting..............................................
17. Not interested in what’s going on
18. Unable to get out of bed.......................
Since the last assessment has the subject been able to return to day care/school, or resume their 
normal daily activity in the same way as performed prior to developing the flu?
Yes
No
This form was filled out by:
Parent
Carer
Other
Note:  The term “Carer” in this questionnaire corresponds to the term “caregiver” used throughout 
the protocol.  

SAP_001.pdf: 
 
Official Title: 
 
A MULTICENTER, RANDOMIZED, DOUBLE-BLIND, ACTIVE 
(OSELTAMIVIR)-CONTROLLED STUDY TO ASSESS THE SAFETY, 
PHARMACOKINETICS, AND EFFICACY OF BALOXAVIR 
MARBOXIL IN OTHERWISE HEALTHY PEDIATRIC PATIENTS 1 
TO < 12 YEARS OF AGE WITH INFLUENZA-LIKE SYMPTOMS 
NCT Number: NCT03629184 
Document Date: SAP Version 2: 24-May-2019 
 
 


STATISTICAL ANALYSIS PLAN APPROVAL
CONFIDENTIAL
This is an F. Hoffmann-La Roche Ltd document that contains confidential information.  Nothing 
herein is to be disclosed without written consent from F. Hoffmann-La Roche Ltd.
Baloxavir Marboxil—F. Hoffmann-La Roche Ltd
Statistical Analysis Plan CP40563
STATISTICAL ANALYSIS PLAN
TITLE:
A MULTICENTER, RANDOMIZED, DOUBLE-BLIND, ACTIVE 
(OSELTAMIVIR)-CONTROLLED STUDY TO
ASSESS THE SAFETY, PHARMACOKINETICS, AND
EFFICACY OF BALOXAVIR MARBOXIL IN OTHERWISE
HEALTHY PEDIATRIC PATIENTS 1 TO 12 YEARS OF AGE 
WITH INFLUENZA-LIKE SYMPTOMS
PROTOCOL NUMBER:
CP40563
STUDY DRUG:
Baloxavir Marboxil
VERSION NUMBER:
2
IND NUMBER:
126653
EUDRACT NUMBER:
2018-002169-21
SPONSOR:
F. Hoffmann-La Roche Ltd
PLAN PREPARED BY:
, B.Sc.
DATE FINAL:
See electronic date stamp below
Name
Reason for Signing
Date and Time
(UTC)
24-May-2019 16:46:39
Company Signatory


Baloxavir Marboxil—F. Hoffmann-La Roche Ltd
2/Statistical Analysis Plan CP40563
STATISTICAL ANALYSIS PLAN AMENDMENT
RATIONALE
This Statistical Analysis Plan (SAP) has been amended to incorporate the following
changes:

Addition of Sparse Pharmacokinetic-Evaluable Population (Section 4.1.6) and 
Extensive Pharmacokinetic-Evaluable Population (Section 4.1.7).

Clarification of the baseline definition for Body Temperature (Section 4.5.5).

Addition of rule for imputation of CARIFS assessment time if the time was not 
recorded in the correct assessment time period (Section 4.6).

Clarification of censoring rule in time to event analysis (Section 4.6).

Clarification on handling rule for missing data in CARIFS assessments.

Further details on exploratory analysis endpoint Polymorphic and treatment-
emergent amino acid substitutions in the PA, PB1, and PB2 genes (Section 4.6.3)

Addition of subgroups analysis of some secondary endpoints, based on virus type 
and subtype (Section 4.6.4).

Additional minor changes have been made to improve clarity and consistency.


Baloxavir Marboxil—F. Hoffmann-La Roche Ltd
3/Statistical Analysis Plan CP40563
TABLE OF CONTENTS
STATISTICAL ANALYSIS PLAN AMENDMENT RATIONALE............................. 2
1.
BACKGROUND ............................................................................................ 5
2.
STUDY DESIGN........................................................................................... 5
2.1
Protocol Synopsis.................................................................... 5
2.2
Outcome Measures ................................................................. 5
2.2.1
Safety (Primary) Endpoints...................................................... 5
2.2.2
Pharmacokinetic Endpoints ..................................................... 5
2.2.3
Efficacy (Secondary) Endpoints............................................... 6
2.2.4
Virology (Secondary) Endpoints .............................................. 6
2.2.5
Exploratory Endpoints.............................................................. 6
2.3
Determination of Sample Size ................................................. 6
2.4
Analysis Timing ....................................................................... 7
3.
STUDY CONDUCT....................................................................................... 7
3.1
Randomization......................................................................... 7
3.2
Data Monitoring ....................................................................... 7
4.
STATISTICAL METHODS ............................................................................ 8
4.1
Analysis Populations ............................................................... 8
4.1.1
Randomized Population........................................................... 8
4.1.2
Per Protocol Population........................................................... 8
4.1.3
Intent-to-Treat Population........................................................ 8
4.1.4
Intent-to-Treat Influenza-Infected Population........................... 8
4.1.5
Pharmacokinetic-Evaluable Population ................................... 8
4.1.6
Sparse Pharmacokinetic-Evaluable Population....................... 9
4.1.7
Extensive Pharmacokinetic-Evaluable Population................... 9
4.1.8
Safety Population .................................................................... 9
4.2
Analysis of Study Conduct....................................................... 9
4.3
Analysis of Treatment Group Comparability ............................ 9
4.4
Visit Windows ........................................................................ 10
4.5
Safety Analyses..................................................................... 11
4.5.1
Adverse Events ..................................................................... 11


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4/Statistical Analysis Plan CP40563
4.5.2
Deaths ................................................................................... 12
4.5.3
Laboratory Data..................................................................... 12
4.5.4
Vital Signs.............................................................................. 13
4.5.5
Body Temperature................................................................. 13
4.5.6
Exposure of Study Medication............................................... 13
4.6
Efficacy Analysis.................................................................... 14
4.6.1
Efficacy Endpoints (Secondary Objectives)........................... 15
4.6.2
Virology (Secondary) Endpoints ............................................ 17
4.6.3
Exploratory Endpoints............................................................ 18
4.6.4
Subgroup Analyses ............................................................... 19
4.7
Pharmacokinetic and Pharmacodynamic 
Analyses................................................................................ 20
4.8
Missing Data.......................................................................... 21
4.9
Interim Analyses .................................................................... 21
5.
REFERENCES ........................................................................................... 22
LIST OF TABLES
Table 1
Probability of Adverse Events by Incidence Rates........................ 7
Table 2
Acceptable Time Windows for Parameters Other Than Data 
from the Patient Diary ................................................................. 10
Table 3
Pre-specified Abnormal Laboratory Criteria ................................ 13
LIST OF APPENDICES
Appendix 1
Protocol Synopsis ...................................................................... 23
Appendix 2
Schedule of Assessments.......................................................... 28
Appendix 3
Schedule of Pharmacokinetic Samples...................................... 29
Appendix 4
Canadian Acute Respiratory Illness and Flu Scale 
(CARIFS) Questionnaire ............................................................. 30


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5/Statistical Analysis Plan CP40563
1.
BACKGROUND
This Statistical Analysis Plan (SAP) provides details of the planned analyses and 
statistical methods for the clinical efficacy, clinical safety, pharmacokinetic (PK), and 
pharmacodynamic (PD) data for Study CP40563.
Baloxavir marboxil (also referred to as S-033188, Shionogi Compound Identification 
Number) is a pro-drug that is converted to an active form (baloxavir, S-033447) in the 
blood, liver, and small intestine through a metabolic process called hydrolysis.
Baloxavir marboxil acts on cap-dependent endonuclease, an enzyme specific to 
influenza viruses, and inhibits viral cap-snatching, thereby suppressing the replication of 
influenza viruses.
2.
STUDY DESIGN
This is a multicenter, randomized, double-blind, active-controlled (i.e., oseltamivir) study 
to assess the safety, PK, and efficacy of baloxavir marboxil compared with oseltamivir in 
pediatric patients 1 to12 years of age with influenza-like symptoms. This study is 
designed to enroll approximately 120 otherwise healthy male and female pediatric 
patients with influenza-like symptoms presenting within 48 hours of symptoms onset.
2.1
PROTOCOL SYNOPSIS
The Protocol Synopsis is in Appendix 1 and includes the study objectives, inclusion and
exclusion criteria, outcome measures, and statistical methods as stated in the Protocol.
2.2
OUTCOME MEASURES
All assessments and procedures are detailed in the Protocol.
2.2.1
Safety (Primary) Endpoints
Incidence, severity, and timing of:

Adverse events (AEs)

Serious adverse events (SAEs)

Vital sign measurements 

Clinical laboratory test results
2.2.2
Pharmacokinetic Endpoints

Plasma concentrations of baloxavir marboxil (pro-drug) and S-033447 (active 
metabolite) 

Population PK model derived parameters (e.g., AUCinf, Cmax, Tmax, t1/2) (modelling 
report)


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6/Statistical Analysis Plan CP40563
2.2.3
Efficacy (Secondary) Endpoints

Time to alleviation of influenza signs and symptoms, defined as the length of time 
taken from the start of treatment to the point at which all of the following criteria are 
met and remain so for at least 21.5 hours:
–
A score of 0 (no problem) or 1 (minor problem) for cough and nasal symptoms 
(items 14 and 15 of the Canadian Acute Respiratory Illness and Flu Scale (CARIFS) 
questionnaire (Appendix 4 )
–
A “yes” response to the following question on the CARIFS: “Since the last 
assessment has the subject been able to return to day care/school, or resume his or 
her normal daily activity in the same way as performed prior to developing the flu?”
–
First return to afebrile state (tympanic temperature37.2°C)

Duration of fever (time to return to afebrile state [tympanic temperature37.2°C] 
and remaining so for at least 21.5 hours)

Duration of symptoms (alleviation of all symptoms as defined by a score of 0 [no 
problem] or 1 [minor problem] and remaining so for at least 21.5 hours, for all 
18 symptoms specified in the CARIFS questionnaire)

Time to return to normal health and activity

Frequency of influenza-related complications (death, hospitalization, radiologically 
confirmed pneumonia, bronchitis, sinusitis, otitis media, febrile seizures, 
encephalitis/encephalopathy, myositis)

Proportion of patients requiring antibiotics
2.2.4
Virology (Secondary) Endpoints

Time to cessation of viral shedding by virus titer and by reverse 
transcriptase-polymerase chain reaction (RT-PCR)

Change from baseline in influenza virus titer and in the amount of virus RNA 
(RT-PCR) at each time point 

Proportion of patients with positive influenza virus titer and proportion of patients 
positive by RT-PCR at each time point

Area under the curve in virus titer and in the amount of virus RNA (RT-PCR)
2.2.5
Exploratory Endpoints

Polymorphic and treatment-emergent amino acid substitutions in the PA, PB1, and 
PB2 genes

Drug susceptibility in patients with evaluable virus

Non-compartmental PK parameters (intensive PK)
2.3
DETERMINATION OF SAMPLE SIZE
No formal sample-size calculations have been performed.  Approximately 120 pediatric 
patients (80 patients in the baloxavir marboxil treatment group and 40 patients in the 
oseltamivir treatment group) will be enrolled.


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7/Statistical Analysis Plan CP40563
To detect adverse events with a 3% incidence for at least 1 patient with a probability 
of 90%, the study will require 80 patients exposed to baloxavir marboxil.  The given 
sample size provides a probability of at least 1 patient experiencing an adverse event 
with a true incidence rate of from 1% to 5% as shown in Table 1.
Table 1
Probability of Adverse Events by Incidence Rates
True incidence rate of an AE
1%
2%
3%
4%
5
Probability of at least one 
patient experiencing an AE
55.2%
80.1%
91.3%
96.2%
98.3%
AEadverse event.
The number of patients in the intention to treat influenza infected (ITTi) population will be 
monitored on an ongoing basis in order to ensure that an adequate number of 
influenza-infected patients are recruited.  Additional patients may be recruited if the ITTi 
population is considerably smaller than expected.
2.4
ANALYSIS TIMING
The primary study analysis will occur when the last patient has either withdrawn or 
completed his or her Day 29 visit, and will be based on all available data for all patients 
up to and inclusive of their Day 29 assessment date, as well as safety follow-up data for 
patients that withdrew prior to Day 29.
3.
STUDY CONDUCT
3.1
RANDOMIZATION 
Following completion of the screening period and after all patient eligibility requirements 
are confirmed, patients will be assigned a patient number (a different number from the 
screening number) on Day 1 and will undergo randomization in a 2:1 ratio to baloxavir 
marboxil or oseltamivir respectively.  All patients will receive one of two active treatments: 
a single oral dose of baloxavir marboxil based on body weight (2 mg/kg for patients 
weighing20 kg or 40 mg for patients weighing20 kg) or oseltamivir (dose based on 
body weight) for 5 days.  Both groups will receive matching placebo for the alternate 
treatment.  A permuted block randomization method will be used to obtain an 
approximate 2:1 ratio of baloxavir marboxil to oseltamivir.
3.2
DATA MONITORING
To facilitate early and close monitoring of safety parameters over time, an Internal 
Monitoring Committee (IMC) will review aggregate safety data on an ongoing basis as 
defined in the IMC charter and according to the process defined in the 
Blinding/Unblinding Process document. If there is any concern noted in the safety 


Baloxavir Marboxil—F. Hoffmann-La Roche Ltd
8/Statistical Analysis Plan CP40563
parameters, the Sponsor may suspend or discontinue a treatment arm or the entire 
study, as appropriate.
4.
STATISTICAL METHODS
4.1
ANALYSIS POPULATIONS
Disposition summaries will be based on the Randomized Population. Analysis of safety 
data will be based on the safety population. The primary analysis population for efficacy 
will be the ITTi population.
4.1.1
Randomized Population
The randomized population will include all patients randomized in the study.
4.1.2
Per Protocol Population
Not applicable.
4.1.3
Intent-to-Treat Population
The intent-to-treat (ITT) population comprises all patients who received at least one dose 
of treatment regardless of whether they have any follow-up assessments. Patients will 
be grouped on the basis of randomized treatment. If there is any doubt whether a 
patient was treated, that patient will be assumed to have been treated for the purpose of 
analysis.
4.1.4
Intent-to-Treat Influenza-Infected Population
The ITTi population is a subset of ITT patients who have had a laboratory confirmation of 
influenza infection (polymerase chain reaction [PCR] result) from any swab sample 
collected at baseline or during the study. The ITTi population is the primary efficacy 
population, unless specified otherwise. Patients will be grouped based on randomized 
treatment.
Decisions on patient exclusion from the ITTi population will be made prior to database 
closure. Excluded patients will be documented, together with the reason for exclusion.
4.1.5
Pharmacokinetic-Evaluable Population
The pharmacokinetic-evaluable patient (PKEP) or PK population comprises all patients 
in the ITT population who have at least one post-dose drug concentration measurement 
at a scheduled visit timepoint. Patients may be excluded from the PKEP population if
they significantly violate the inclusion or exclusion criteria or deviate significantly from 
the protocol, or if data are unavailable or incomplete which may influence the PK 
analysis, such as the absence of properly documented date and time for the baloxavir 
marboxil administration and PK sample collection. 


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9/Statistical Analysis Plan CP40563
Decisions on exclusion from the PKEP population may be made prior to database 
closure by the clinical pharmacologist. Excluded patients will be documented, together 
with the reason for exclusion.
4.1.6
Sparse Pharmacokinetic-Evaluable Population
The sparse PKEP or sparse PK population comprises all patients in the PK population
who did not provided informed consent to intensive PK sampling.
4.1.7
Extensive Pharmacokinetic-Evaluable Population
The extensive PK population comprises all patients in the PK population who provided 
informed consent to intensive PK sampling.
4.1.8
Safety Population
The safety-evaluable patient population comprises all patients who received at least one 
dose of treatment regardless of whether they have any follow-up assessments. Patients 
will be classified according to treatment actually received.
4.2
ANALYSIS OF STUDY CONDUCT
The number of patients who enroll, discontinue, or complete the study will be 
summarized by treatment arm. Reasons for premature study withdrawal will be listed 
and summarized by treatment arm.  Major protocol deviations will be listed and 
evaluated for their potential effects on the interpretation of study results.
4.3
ANALYSIS OF TREATMENT GROUP COMPARABILITY
Demographic and baseline characteristics (including age, sex, race/ethnicity, height, 
weight, BMI and vaccination status) will be summarized using means, standard 
deviations, medians, and ranges for continuous variables and proportions for categorical 
variables, as appropriate. Summaries will be presented overall and by treatment 
received for the safety population.  If it is found that there is a large difference in the 
number of patients in the safety population compared to the ITTi population, additional 
summaries will be produced based on randomized treatment.
Medical history data, including surgery and procedures and baseline conditions, will be 
summarized descriptively by treatment group using the safety population. Descriptive 
summaries of any previous and concomitant treatment will be produced by treatment 
group.


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10/Statistical Analysis Plan CP40563
4.4
Visit Windows
Table 2
Acceptable Time Windows for Parameters Other Than Data from 
the Patient Diary
Time Point
(Scheduled Time Point)
Acceptable Time Window
Pre-dose at Visit 1 (Day 1)’
Before dosing on Day 1
Post-dose at Visit 1 (Day 1)’
Between 0.5 and 4 hours after dosing (on Day 1)
Visit 2 (Day 2)
Day 2
Optional Visit 1 (Day 3)
Day 3
Visit 3 (Day 4)
Day 4
Visit 4 (Day 6)
Between Day 5 and Day 7 as follows:
-if patient presents on Day 5 with no Day 4, and no Day 6 
this will be classed as Visit 4
-if patient presents on Day 5 with no Day 4, and Day 6 this 
will be classed as Visit 3. 
-if patient presents on Day 5 with Day 4 and no Day 6 this 
will be classed as Visit 4.
Visit 5 (Day 10)
Between Day 8 and Day 12
Optional Visit2 (Day 15)
Between Day 13 and Day 22
Visit 6 (Day 29)
On or after Day 23
Withdrawal
Date of withdrawal + 14 days
* if time is missing for data collected on Visit 1 where, per the schedule of activities, this data 
should be collected at ‘v1 screening’ or ‘v1 post-dose’ it is defined as ‘Pre-dose at Visit 1 (Day 1)’ 
or ‘Post-dose at Visit 1 (Day 1)’ respectively.
Measurements collected within the acceptable time window for each scheduled 
assessment time point, including data obtained at the time of withdrawal, will be used for 
the analyses of all endpoints at each assessment time point. For all patients with 
multiple values within a visit window, the value obtained closest to the target time point 
will be used. If two measurements collected with the same time deviation exist before 
and after the target time point, the measurement obtained before the target time point 
will be adopted for analysis. The assessment time point having no measurements within 
the corresponding acceptable time window will be considered as missing.
In the assessment of data from sources other than the patient diary, if there are multiple 
values which may be adopted for a scheduled assessment time point (even though the 
above rules have been strictly followed), the measurements at the time point entered in 
the Case Report Form (CRF) will be adopted.
For summaries of data not collected by visit, such as adverse events, medical history 
and concomitant medications, all data up to the last exposure date will be included.


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4.5
SAFETY ANALYSES
Safety Endpoints (Primary Objective)
The primary objective for this study is to compare the safety of a single dose of baloxavir 
marboxil with 5 days of oseltamivir administered twice daily.  The safety population will 
be used for all safety analyses.  Patients will be analyzed according to the treatment 
they actually received.
The safety of baloxavir marboxil will be evaluated for adverse events, vital signs 
measurements, and clinical laboratory tests.  Safety parameters will be summarized or 
listed for the safety population.
4.5.1
Adverse Events
AEs will be classified by system organ class (SOC) and preferred term using Medical 
Dictionary for Regulatory Activities (MedDRA) Version 22.0 and adverse event severity 
will be graded according to National Cancer Institute Common Terminology Criteria for 
Adverse Events (NCI CTCAE) v5.0 or the Adverse Event Severity Grading Scale for 
events not specifically listed in NCI CTCAE toxicity grading scale (Table 2 of the 
protocol) on the eCRF, AEs reported after the initial dose of the study drug will be used 
for safety analyses.
In summaries by SOC and preferred term (PT), AEs will be sorted by overall decreasing 
frequency within each SOC and PT. 
All Adverse Events
Only treatment-emergent AEs will be summarized. Treatment-emergent events are 
defined as those AEs with observed or imputed onset date on or after the start date of 
trial treatment.  Only where the most extreme intensity is greater than the initial intensity 
(or if most extreme intensity is not missing and initial intensity is missing) will events with 
an onset date prior to the start of study treatment be considered treatment-emergent. 
An AE with a completely missing start date will be assumed to be treatment-emergent 
unless the AE has a complete non-imputed end date that is prior to study Day 1.
Adverse events will be coded and tabulated by SOC and/or PT. In tabulations, PTs and 
their associated SOC will be presented in order of descending frequency summed 
across the treatment arms. Adverse events will also be tabulated by severity and 
relationship to the study drug as indicated by the investigator. Adverse events leading to 
withdrawal, AEs leading to death, and AEs leading to a dose modification or interruption 
will be summarized.


Baloxavir Marboxil—F. Hoffmann-La Roche Ltd
12/Statistical Analysis Plan CP40563
The following will also be summarized by treatment, and listings produced where 
required:

Serious AEs

AEs leading to withdrawal

AEs leading to death

AEs leading to a dose modification or interruption

Non-serious AEs occurring in≥5% of patients in at least one treatment group

Non-serious AEs occurring in≥1% of patients in at least one treatment group
Adverse Events of Special Interest
All adverse events of special interest (AESI) will be presented by treatment group. AESI 
include but are not limited to the following: 

Case of an elevated ALT or AST in combination with either an elevated bilirubin or 
clinical jaundice, as defined in protocol

Suspected transmission of an infectious agent by the study drug
4.5.2
Deaths
Details of any deaths will be presented in the form of an individual patient listing, as well 
as a frequency table by treatment.
4.5.3
Laboratory Data
For each of the hematological and biochemical test parameters, summary statistics of 
observed and change from baseline values at each time point will be presented by 
treatment group for each scheduled time point. For laboratory parameters, post-dose 
observations on Day 1 will be classed as baseline.
Each observed value will be classified into three categories: Normal (for values within 
the normal range), High (for values higher than normal) and Low (for values lower than 
normal). The frequency of each category will be summarized by treatment group for 
each scheduled time point. Additionally, a shift table will present the changes from 
baseline at each scheduled time point.
The number and proportion of patients who meet the pre-specified criteria shown in 
Table 3, will be presented by treatment group during the study.


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13/Statistical Analysis Plan CP40563
Table 3
Pre-specified Abnormal Laboratory Criteria
Term
Criteria
AST (U/L) or ALT (U/L) and Total bilirubin (mg/dL)
Meet all of the following criteria:

AST3ULN or ALT3ULN

Total bilirubin Value2ULN
at same timepoint
ULN upper limit of normal.
4.5.4
Vital Signs
For each of the vital signs (diastolic blood pressures, systolic blood pressures, 
respiratory rate and pulse rate), summary statistics of observation and the change from 
baseline will be presented by treatment group for each scheduled time point. 
Baseline is defined as the last assessment prior to treatment.
4.5.5
Body Temperature
Body temperature is collected in the patient diary 4 times daily for Day 1 3, twice daily 
for Day 4 9 and once daily thereafter.  Summary statistics of observation and the 
change from baseline in body temperature will be presented by treatment group for each 
recorded time point. 
Baseline is defined as the first recorded assessment after treatment on Day 1.
4.5.6
Exposure of Study Medication
The duration of treatment exposure will be summarized with descriptive statistics by 
treatment group for the safety population.
The duration of treatment exposure [days] in the oseltamivir group is defined as the 
dosing period during which a patient takes medication as follows:
{(final dose date) – (initial dose date)1}
For the baloxavir marboxil group, duration of exposure is defined as 1 day if actual 
baloxavir marboxil granules for oral suspension are dosed.
The treatment compliance rate will be summarized with descriptive statistics by the 
treatment group for the safety population. In addition, the frequency and percentage of 
patients with compliance 80% and80% will be presented.
The treatment compliance rate [%] in the oseltamivir group is defined as:
actual frequency of treatment exposure
expected frequency of treatment exposure ∗100


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For baloxavir marboxil group treatment compliance is defined as 100% if patients are 
dosed per protocol.
4.6
EFFICACY ANALYSIS
The statistical analyses of efficacy endpoints will be descriptive.  The ITTi population will 
be used for all analyses.  Additional analysis of efficacy analysis presenting the ITT 
population will not be completed.
The data will be summarized using means, standard deviations, medians, and ranges for 
continuous variables and proportions for categorical variables, as appropriate.  Time-to-
event endpoints and duration endpoints will be summarized using Kaplan-Meier plots 
and summaries of the median survival time.  Summaries will be presented by treatment 
group.
Efficacy endpoints are based on the CARIFS questionnaire data which is recorded by 
parent/ caregiver using handheld device. This assessment data should be recorded for 
the following time periods:
Period
Time
Morning
0.500-10.59
Noon
11.00-14.59
Evening
15.00-18.59
Bedtime
19.00-23.59
*data should not be recorded between 00.00 and 4.59.
In the case where the recorded time of an assessment is outside the period time window 
for that assessment, the end time of the period should be imputed as the assessment 
time.
In the case where the assessment time falls into the period between 00.00 and 4.59 
(due to technical error) the assessment date will be imputed to the date prior to recorded 
assessment date and the assessment time will be imputed to the end time of the period 
time window. 
The imputation method used in the derivation of time to alleviation of influenza signs and 
symptoms is described in Section 4.6.1. No further imputation methods will be used.
In all time to event analysis, patients who withdraw prior to event of interest will be 
censored at the last observation timepoint.


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4.6.1
Efficacy Endpoints (Secondary Objectives)
Time to alleviation of influenza signs and symptoms
Time to alleviation (TTAS) of influenza signs and symptoms in hours, will be summarized 
using descriptive statistics by treatment, as well as Kaplan-Meier plots.  It is defined as 
the length of time taken from the start of treatment to the point at which all of the 
following criteria are met and remain so for at least 21.5 hours:
–
A score of 0 (no problem) or 1 (minor problem) for cough and nasal symptoms 
(items 14 and 15 of the CARIFS questionnaire - see Appendix 4)
–
A “yes” response to the following question on the CARIFS: “Since the last 
assessment has the subject been able to return to day care/school, or resume his or 
her normal daily activity in the same way as performed prior to developing the flu?”
–
First return to afebrile state (tympanic temperature37.2°C).
If a score of 4 (“do not know” or “not applicable”) occurs at any assessment during the 
study for items 14 or 15, the assessment will not be included in the calculation of the 
alleviation of symptoms because the assessment was unobservable.
Patients with symptom scores1 for both items 14 and 15, as well as tympanic 
temperature37.2°C and a “yes” response to the question ‘Since the last assessment 
has the subject been able to return to day care/school, or resume his or her normal daily 
activity in the same way as performed prior to developing the flu?’ at baseline will have a 
TTAS of all symptoms set to missing.
Patients who do not experience alleviation of symptoms prior to completion or 
withdrawal from study will be censored at the last observation time point.
Baseline is defined as the first CARIFS assessment after start of treatment on Day 1. 
The number of patients with completed CARIFS as well as the number with missing 
CARIFS per assessment, will be presented by treatment.  Additionally, the number and 
percentage of those with ‘Don’t Know/ Not Applicable’ per Question per assessment will 
be presented by treatment.
Duration of fever
Duration of fever will be summarized using descriptive statistics by treatment, as well as 
Kaplan-Meier plots.  It is defined as the time to return to afebrile state [tympanic 
temperature37.2°C] and remaining so for at least 21.5 hours.
Patients who do not return to afebrile state will be censored at the last observation time 
point.


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Duration of symptoms
Duration of symptoms will be summarized using descriptive statistics by treatment, as 
well as Kaplan-Meier plots.  Duration of symptoms is defined as alleviation of all 
symptoms as defined by a score of 0 [no problem] or 1 [minor problem] and remaining 
so for at least 21.5 hours, for all 18 symptoms specified in the CARIFS questionnaire.
If a score of 4 (“do not know” or “not applicable”) occurs at any assessment during the 
study for any item, with the exception of items 10, 11 and 12 the assessment will not be 
included in the calculation of the alleviation of symptoms because the assessment was 
unobservable.
However, if a score of 4 occurs for items 10, 11 or 12, the assessment will be included, 
with a score of missing for these items.
In addition, duration of individual symptoms will be summarized using descriptive 
statistics by treatment, as supportive analysis. Patients who have an individual symptom 
score1 at baseline will have the duration of that symptom set to missing.
Time to return to normal health and activity
Time to return to normal health and activity will be summarized using descriptive 
statistics by treatment, as well as Kaplan-Meier plots.
‘Normal health and activity’ is identified by a ‘Yes’ response to the following question on 
the CARIFS: “Since the last assessment has the patient been able to return to day 
care/school, or resume his or her normal daily activity in the same way as performed 
prior to developing the flu?”
Patients who do not return to normal health and activity will be censored at the last 
observation time point.
Frequency of influenza-related complications
The number of influenza-related complications, as well as the number and percentage of 
patient with these complications, after treatment, will be presented by treatment.  
Influenza-related complications include death, hospitalization, radiologically-confirmed 
pneumonia, bronchitis, sinusitis, otitis media, encephalitis/encephalopathy, febrile 
seizures and myositis, as recorded on the AE pages of eCRF.
Proportion of patients requiring antibiotics
The number and percentage of patients requiring antibiotics for any reason will be 
presented by treatment group.


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4.6.2
Virology (Secondary) Endpoints
Time to cessation of viral shedding by virus titer 
Time to cessation of viral shedding by virus titer is defined as the time, in hours, between 
the initiation of any study treatment and first time when the influenza virus titer is below 
the limit of detection.  Patients whose virus titers have not reached the limit by the last 
observation time point will be treated as censored at that time point.  One day is 
converted into 24 hours.
Patients with a positive virus titer on Day 1 will be included in this analysis.
This endpoint will be summarized using descriptive statistics by treatment, as well as 
Kaplan-Meier plots.
Time to cessation of viral shedding by RT-PCR
Time to cessation of viral shedding by RT-PCR, in hours, is defined as the time between 
the initiation of any study treatment and first time when the virus RNA by RT-PCR is 
below the limit of detection.  Patients whose virus RNA have not reached the limit by the 
last observation time point will be treated as censored at that time point.  For the patients 
with multiple virus types, this endpoint is defined as the time between the initiation of the 
study treatment and first time when the virus RNA by RT-PCR is below the limit of 
detection for all virus types.  One day is converted into 24 hours.
Patients with a positive virus RNA on Day 1 will be included in this analysis.
This endpoint will be summarized using descriptive statistics by treatment, as well as 
Kaplan-Meier plots.
Change from baseline in influenza virus titer at each time point 
Change from baseline in influenza virus titer (log10TCID50/ML) will be presented by 
treatment and is defined as the change from baseline in influenza virus titer on Days 2, 4, 
6, and 10. If influenza virus titer is less than the lower limit of quantification, the virus 
titer will be imputed as 0.749 (log10TCID50/mL).
Only patients with a positive virus titer on Day 1 will be included in this analysis.
Change from baseline in the amount of virus RNA (RT-PCR) at each time point 
Change from baseline in the amount of virus RNA (unit: log10 virus particles/mL) will be 
presented by treatment and is defined as the change from baseline in the amount of 
virus RNA on Days 2, 4, 6, and 10.
If the amount of virus RNA is less than the lower limit of quantification, the amount of 
virus RNA will be imputed as 2.18 for flu A and 2.93 for flu B (log10 virus particles/mL).  If 
a patient is infected with multiple virus types, the sum of those amounts of virus RNA will 
be used for analysis. 
Patients with a positive by RT-PCR on Day 1 will be included in this analysis. 


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Proportion of patients with positive influenza virus titer at each timepoint
Proportion of patients positive for influenza virus titer will be presented by treatment at 
each visit and is defined as the percentage of patients whose influenza virus titer is not 
less than the lower limit of quantification (0.75 log10TCID50/mL) or positive among those 
assessed for influenza virus titer on Days 2, 4, 6, and 10. 
Patients with a positive influenza virus titer on Day 1 will be included in this analysis.
Proportion of patients positive by RT-PCR at each time point 
Proportion of patients positive by RT-PCR will be presented by treatment at each visit is 
defined as the percentage of patients with detectable virus RNA (2.05 for flu A and 2.83 
for flu B log10 virus particles/mL) among those assessed by RT-PCR on Days 2, 4, 6, 
and 10.
Patients with a positive by RT-PCR on Day 1 will be included in this analysis.
Area under the curve in virus titer
Area under the curve (AUC) in virus titer will be presented by treatment group and will be
calculated using the trapezoidal method. AUC of change from time 0 (t0) to time K (tk) is 
given by the formula
?
( +  − !)(# −#)
 
$
%
where tk (hours) represents the date of the k h viral titer assessment (k = 0, ..., K) and yk
represents the log10 value of the kth viral titer assessment (TCID50/mL). 
24-hours of time will be converted into one day. Patients with a positive virus titer on 
Day 1 will be subjected to this analysis. The lower limit is defined as 0.75 log10
TCID50/mL for flu A and 0.75 log10 TCID50/mL for flu B (TCID50/mL). If a patient is 
infected with multiple virus types, the sum of those virus titers will be used for analysis.
Area under the curve in the amount of virus RNA (RT-PCR)
AUC in virus RNA (RT-PCR) will be presented by treatment group and is defined as 
AUC of change from baseline in the amount of virus RNA (RT-PCR) from Day 1 to
Day 10. AUC is calculated using the trapezoidal method similar to AUC in virus titer.
Patients with a positive RT-PCR result on Day 1 will be subjected to this analysis. The 
lower limit of quantification is defined as 2.18 for flu A and 2.93 for flu B (log10 virus 
particles/mL).  If a patient is infected with multiple virus types, the sum of those the 
amount of virus RNA will be used for analysis.
4.6.3
Exploratory Endpoints
Polymorphic and treatment-emergent amino acid substitutions in the PA, PB1, 
and PB2 genes
Sequencing of PB1 and PB2 will be done for:

baseline viruses with reduced susceptibility to baloxavir (fold-change in EC50 > 10 
for type A viruses and > 5 for type B viruses compared to reference virus in 
phenotypic assay).


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
viruses (baseline and last evaluable timepoint) without amino acid substitution in 
PA, but with reduced response to treatment or with virus rebound. 
These will be defined according to the following criteria below. If an amino acid 
substitution is detected, an additional intermediate timepoint sample will be 
sequenced.
Criteria
1) Subjects who exhibit 
viral titer rebound:
Viral titer at [(a certain time point) – (just before time point)] 
≥2 x SD value of viral titer of control virus in assay *
* 
 
 
 
2) Subjects who continue 
to shed virus at Day 
6 and beyond:
Viral titer (log10TCID50/mL) at Day 6 and beyond > 1.5
3) Subjects who do not 
show a reduction in 
virus titer:
Viral titer (log10TCID50/mL) at a certain time point: A > 1.5
Viral titer (log10TCID50/mL) at just before time point: B > 1.5
AND
Viral titer (log10TCID50/mL) at [(a certain time point: A) -
(just before time point: B)] >= 0
Drug susceptibility in patients with evaluable virus
Non-compartmental PK parameters (intensive PK)
Analysis methods for exploratory analysis will be described in a separate PK plan/report.
4.6.4
Subgroup Analyses
Subgroup analysis of the following secondary endpoints, based on virus type and 
subtype, will be conducted:

Time to alleviation of influenza signs and symptoms

Time to cessation of viral shedding by RT-PCR

Time to cessation of viral shedding by virus titer


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4.7
PHARMACOKINETIC AND PHARMACODYNAMIC ANALYSES
The PKEP population will be used for all analyses. 
For patients with blood samples collected, individual plasma baloxavir marboxil and 
S-033447 concentrations will be tabulated by patient and by timepoint.  Individual and 
mean (if appropriate) plasma baloxavir marboxil and S-033447 concentrations versus 
time data will be plotted by defined body-weight groups (e.g., 510 kg, 1015 kg, etc.).
The C24 and C72 of S-033447 will be listed and summarized (mean, standard deviation, 
coefficient of variation, median, minimum, and maximum) by defined body-weight group.
Additional PK analyses may be conducted as appropriate. For example, for patients 
undergoing intensive PK assessments (Appendix 3), individual PK parameters of 
baloxavir marboxil and S-033447 (AUC, Cmax, time to maximum plasma concentration, 
and terminal half-life) may be calculated using model-independent methods, as 
applicable (if sufficient data available for reliable AUC estimates).  Parameters will be 
listed and if deemed useful, summarized (mean, standard deviation, coefficient of 
variation, median, minimum, and maximum) by defined body-weight group.  
In addition, non-linear mixed-effects model (NONMEM, Version 7.3 or higher) will be 
used to analyze the PK data.  The population typical PK parameters (e.g., apparent 
clearance, apparent volume of distribution for the central compartment) and their 
covariates will be estimated.  Individual PK metrics, such as area under the 
concentration-time curve from Time 0 to infinity (AUCinf), C24, C72, and Cmax, will be also 
calculated using post hoc Bayesian estimation for each patient, and plotted against 
significant covariates identified (e.g., body weight, age).  The derived individual values 
will be plotted against body weight and age.  PK parameters will be tabulated and 
summarized (i.e., by mean, standard deviation, coefficient of variation, median, and 
minimum and maximum) by age group.  PK exposure and response (e.g., virus titers) 
relationships will be explored.  Details related to the Population PK analyses and 
downstream PK exposure-response analyses will be provided in a dedicated modelling 
and simulation plan, and results obtained in dedicated M&S reports.
Pediatric exposure matching to adults will use C24 (observed, as well as Bayesian post 
hoc) as a primary PK parameter.  Key secondary PK metrics, such as C72 and AUCinf
(derived as Bayesian post hoc), will assess whether exposure is sustained similarly as in 
adults, and to explore whether or not viral rebound, if any, may be associated with lower 
C72 values.  For completeness, Cmax will be calculated as secondary PK parameter.
Assessment of pediatric exposure and comparison to adults will use all PK data (sparse 
and intensive PK). Results may be described within the population PK report or in a 
dedicated extrapolation report.  


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4.8
MISSING DATA
In safety analyses, all deaths are included, from all sources, regardless of completeness 
of death date; patients who died with only a partial death date available will be included.  
Partial dates for AEs, concomitant medications, laboratory assessments, and medical 
history will be imputed following a conservative approach.
In efficacy analyses, a death is considered an event if and only if a complete death date 
is available; patients who died with only a partial death date available will be censored.
4.9
INTERIM ANALYSES
An interim PK analysis is planned in this study. The PK samples, up to and including 
Visit 4/5 of first 12 patients dosed, will be batched for an early shipment. This will enable 
a timely review of the systemic plasma concentrations, in particular the concentration at 
24 hours and 72 hours post dosing. This is in order to verify, in a timely manner, that 
exposures at the proposed dose are in reasonable agreement with the corresponding 
values seen in adults.
The estimated turnaround time between last sample collected and data review is 
estimated to be approximately 2 to 3 weeks and recruitment will continue during this 
time. Data review of blinded PK samples (dummy ID) will be performed by members of 
the Sponsor study team.
No other interim analyses are planned in this study.


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5.
REFERENCES
Not applicable


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Appendix 1
Protocol Synopsis
TITLE:
A MULTICENTER, RANDOMIZED, DOUBLE-BLIND, ACTIVE 
(OSELTAMIVIR)-CONTROLLED STUDY TO ASSESS THE 
SAFETY, PHARMACOKINETICS, AND EFFICACY OF BALOXAVIR 
MARBOXIL IN OTHERWISE HEALTHY PEDIATRIC PATIENTS
1 TO 12 YEARS OF AGE WITH INFLUENZA-LIKE SYMPTOMS
PROTOCOL NUMBER:
CP40563
VERSION NUMBER:
1
IND NUMBER:
126653
EudraCT NUMBER:
2018-002169-21
TEST PRODUCT:
Baloxavir marboxil (RO7191686)
PHASE:
III
INDICATION:
Influenza
SPONSOR:
F. Hoffmann-La Roche Ltd
Objectives and Endpoints
This study will evaluate the safety, pharmacokinetics, and efficacy of baloxavir marboxil
compared with oseltamivir in a single influenza episode in otherwise healthy pediatric patients
(i.e., 1 to 12 years of age) with influenza-like symptoms.  Specific objectives and 
corresponding endpoints for the study are outlined below.
Safety (Primary) Objective
Corresponding Endpoints
To compare the safety of a single 
dose of baloxavir marboxil with 5 days 
of oseltamivir administered twice daily
Incidence, severity, and timing of adverse events, 
serious adverse events, vital sign measurements,
and clinical laboratory test results
Pharmacokinetic Objective
Corresponding Endpoints
To evaluate the PK of baloxavir 
marboxil after single-dose 
administration
Plasma concentrations of baloxavir marboxil 
(pro-drug) and S-033447 (active metabolite) will be 
summarized by time (C24 and C72) and body weight
Population PK model derived parameters 
(e.g., AUCinf, Cmax, Tmax, t1/2) (modelling report)
Efficacy (Secondary) Objectives
Key Corresponding Secondary Endpoint
To evaluate the clinical efficacy of 
baloxavir marboxil compared with 
oseltamivir
Time to alleviation of influenza signs and symptoms, 
defined as the length of time taken from the start of 
treatment to the point at which all of the following 
criteria are met and remain so for at least 
21.5 hours:

A score of 0 (no problem) or 1 (minor problem) 
for cough and nasal symptoms (items 14 and 
15 of the CARIFS) 


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
A “yes” response to the following question on 
the CARIFS: “Since the last assessment has 
the subject been able to return to day 
care/school, or resume his or her normal daily 
activity in the same way as performed prior to 
developing the flu?”

First return to afebrile state (tympanic 
temperature 37.2°C)
Efficacy (Secondary) Objectives
Corresponding Endpoints
To evaluate the clinical efficacy of 
baloxavir marboxil compared with 
oseltamivir 
Duration of fever (time to return to afebrile state 
[tympanic temperature 37.2C] and remaining so for 
at least 21.5 hours)
Duration of symptoms (alleviation of all symptoms as 
defined by a score of 0 [no problem] or 1 [minor 
problem] and remaining so for at least 21.5 hours, for 
all 18 symptoms specified in the CARIFS 
questionnaire)
Time to return to normal health and activity
Frequency of influenza-related complications (death, 
hospitalization, radiologically confirmed pneumonia, 
bronchitis, sinusitis, otitis media, 
encephalitis/encephalopathy, febrile seizures, 
myositis)
Proportion of patients requiring antibiotics 
Secondary Virology Objective
Corresponding Endpoints
To evaluate the virological activity of 
baloxavir marboxil compared with 
oseltamivir
Time to cessation of viral shedding by virus titer and 
by RT-PCR 
Change from baseline in influenza virus titer and in 
the amount of virus RNA (RT-PCR) at each time point
Proportion of patients with positive influenza virus titer 
and proportion of patients positive by RT-PCR at each 
time point
Area under the curve in virus titer and in the amount 
of virus RNA (RT-PCR)


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Exploratory Objectives
Corresponding Endpoints
To evaluate the polymorphic and 
treatment-emergent amino acid 
substitutions in the PA, PB1, and PB2
genes and drug susceptibility in patients 
with evaluable virus
Polymorphic and treatment-emergent amino acid 
substitutions in the PA, PB1, and PB2 genes
Drug susceptibility in patients with evaluable virus
To evaluate extended PK parameters of 
baloxavir marboxil after single-dose 
administration
Non-compartmental PK parameters (intensive PK)
AUCinfarea under the concentrationtime curve from Time 0 to infinity; C24plasma 
concentration 24 hours postdose (acceptable time window:  20 to 28 hours); C72plasma 
concentration 72 hours postdose; CARIFSCanadian Acute Respiratory Illness and Flu Scale;
Cmaxmaximum plasma concentration; PApolymerase acidic protein; PKpharmacokinetic; 
RT-PCRreverse transcriptase-polymerase chain reaction; t1/2half-life; Tmaxtime to maximum 
plasma concentration.
Study Design
Description of Study
This is a multicenter, randomized, double-blind, active-controlled (i.e., oseltamivir) study to 
assess the safety, pharmacokinetics, and efficacy of baloxavir marboxil compared with 
oseltamivir in pediatric patients 1 to 12 years of age with influenza-like symptoms.  
The approved dose for oseltamivir in pediatric patients 1 to 12 years of age is twice daily (BID) 
for 5 days, based on body weight.  Baloxavir marboxil will be given as a single-dose, based on
body weight at screening.  Either drug, along with the corresponding placebo of its comparator 
in this trial, will be started at the time of randomization.
Patients will be screened and randomized on Day 1 and assigned in a 2:1 ratio to receive a 
single oral dose of baloxavir marboxil based on body weight (2 mg/kg for patients weighing 
20 kg or 40 mg for patients weighing 20 kg) or oseltamivir (dose based on body weight) for 
5 days. Re-screening of patients who fail to meet the inclusion and exclusion criteria will not be 
permitted for the same illness episode.
The study consists of two periods:  a 5-day treatment period (mandatory visits on Days 1, 2, 
and 4) and a 24-day safety follow-up period (mandatory visits on Days 6, 10, and 29).  
Therefore, the total study duration for each patient will be 29 days.
During the 5-day treatment period, each patient randomized to baloxavir marboxil will receive 
the oseltamivir matching placebo BID for 5 days, and those patients randomized to oseltamivir 
will receive one dose of baloxavir marboxil matching placebo on Day 1.
The following assessments will be conducted at clinic visits:  physical examination, vital signs, 
adverse events, concomitant therapies, clinical laboratory tests, and nasal/throat swabs.  
Throughout the treatment and safety follow-up periods, the parents/caregivers will maintain a
patient diary for each patient in order to record body temperatures (tympanic assessment), 
influenza symptoms, and acetaminophen use.  Temperatures will be recorded four times daily 
(morning, noon, evening, and bedtime) on Days 1 to 3; BID (morning and evening) on Days 4 to 
9; and once daily on Days 10 to 15.  Influenza symptoms will be recorded BID (morning and 
evening) on Days 1 to 9 and once daily on Days 10 to 15.
This study will be conducted at sites in the United States and globally.  
To facilitate early and close monitoring of safety parameters over time, an Internal Monitoring 
Committee (IMC) will review aggregate safety data on an ongoing basis as defined in the IMC 
charter. If there is any concern noted in the safety parameters, the Sponsor may suspend or 
discontinue a treatment arm or the entire study, as appropriate.


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Number of Patients
This study is designed to enroll approximately 120 otherwise healthy male and female pediatric 
patients with influenza-like symptoms presenting within 48 hours of symptom onset.
Patients will be recruited in parallel to the following two cohorts:

5 to 12 years of age (minimum 40 patients)

1 to 5 years of age (minimum 20 patients)
Target Population
Inclusion Criteria
Patients must meet the following criteria for study entry:

Written informed consent/assent for study participation obtained from patient’s parents or 
legal guardian, with assent as appropriate by the patient, depending on the patient’s level of 
understanding

Aged 1 to 12 years at randomization (Day 1)

Parent/guardian willing and able to comply with study requirements, in the investigator’s 
judgment

Patient able to comply with study requirements, depending on the patient’s level of 
understanding

Patient with a diagnosis of influenza virus infection confirmed by the presence of all of the 
following:

Fever 38C (tympanic temperature) at screening

At least one respiratory symptom (either cough or nasal congestion) 

The time interval between the onset of symptoms and screening is 48 hours (the onset of 
symptoms is defined as the time when body temperature first exceeded 37.5C if known, or 
the time when the first symptom was noticed by patient, parent or caregiver)
Exclusion Criteria
Patients who meet any of the following criteria will be excluded from study entry:

Severe symptoms of influenza virus infection requiring inpatient treatment

Concurrent infections requiring systemic antiviral therapy at screening

Require, in the opinion of the investigator, any of the prohibited medication during the study

Previous treatment with peramivir, laninamivir, oseltamivir, zanamivir, or amantadine within 
2 weeks prior to screening

Immunization with a live/attenuated influenza vaccine in the 2 weeks prior to randomization

Concomitant treatment with steroids or other immuno-suppressant therapy

Known HIV infection or other immunosuppressive disorder

Uncontrolled renal, vascular, neurologic, or metabolic disease (e.g., diabetes, thyroid 
disorders, adrenal disease), hepatitis, cirrhosis, or pulmonary disease or patients with 
known chronic renal failure

Active cancer at any site

History of organ transplantation

Known allergy to either study drug (i.e., baloxavir marboxil and oseltamivir) or to 
acetaminophen

Females who have commenced menarche (i.e., child-bearing potential)

Participation in a clinical trial within 4 weeks or 5 half-lives of exposure to an investigational 
drug prior to screening, whichever is longer


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End of Study
The end of this study is defined as the date when the last patient, last visit (LPLV) occurs or the 
date at which the last data point required for statistical analysis or safety follow-up is received 
from the last patient, whichever occurs later.  The end of the study is expected to occur 29 days 
after the last patient has been enrolled.
Length of Study
The total length of the study, from screening of the first patient to the end of the study, is 
expected to be approximately 9 months. Given the seasonal variability of incidence and 
severity of influenza, the total length of the study may be extended to complete enrollment.
In addition, the Sponsor may decide to terminate the study at any time.
Investigational Medicinal Products
Test Product (Investigational Drug)
The investigational medicinal product (IMP) for this study is baloxavir marboxil.  Each treatment 
will be administered in combination with the matching placebo for the alternate treatment.
Comparator
Oseltamivir will be administered as an active control.  Each treatment will be administered in 
combination with the matching placebo for the alternate treatment.
Non-Investigational Medicinal Products
Not applicable.
Statistical Methods
Primary Analysis
The safety population will be used for all analyses. 
All verbatim adverse event terms will be mapped to MedDRA thesaurus terms, and adverse 
event severity will be graded according to National Cancer Institute Common Terminology 
Criteria for Adverse Events, Version 5.0 (NCI CTCAE v5.0).
The safety of baloxavir marboxil will be evaluated from adverse events, vital sign measurements,
and clinical laboratory tests.  Safety parameters will be summarized or listed for the safety 
population.
Determination of Sample Size  
No formal sample-size calculations have been performed.  Approximately 120 pediatric patients 
(80 patients in the baloxavir marboxil treatment group and 40 patients in the oseltamivir 
treatment group) will be enrolled.
Interim Analyses
An interim pharmacokinetic (PK) analysis is planned in this study. The PK samples, up to and 
including Visit 4/5 of first 12 patients dosed, will be batched for an early shipment.  This will
enable a timely review of the systemic plasma concentrations, in particular the concentration at 
24 hours and 72 hours post dosing.  This is in order to verify, in a timely manner, that exposures 
at the proposed dose are in reasonable agreement with the corresponding values seen in adults. 
The estimated turnaround time between last sample collected and data review is estimated to 
be approximately 2 to 3 weeks and recruitment will continue during this time. Data review of 
blinded PK samples (dummy ID) will be performed by members of the Sponsor study team.
No other interim analyses are planned in this study.  However, given there is no formal 
statistical hypothesis testing in this study, the Sponsor may choose to conduct up to two interim 
analyses.  The decision to conduct an optional interim analysis and the timing of the analysis 
will be documented in the Sponsor’s trial master file prior to the conduct of the interim analysis.  
The interim analysis would be performed and interpreted by members of the Sponsor study 
team and appropriate senior management personnel.  Access to treatment assignment 
information would follow the Sponsor’s standard procedures.


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Appendix 2
Schedule of Assessments
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
    
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Appendix 3
Schedule of Pharmacokinetic Samples
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
  
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
  
  
 
 
 
 
 
 
  
 
 
 
 
 
   
 
 
 
   
 
  
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Appendix 4
Canadian Acute Respiratory Illness and Flu Scale 
(CARIFS) Questionnaire