A Multicenter, Single-Arm, Open-Label Study to Assess the Safety, Pharmacokinetics, and Efficacy of Baloxavir Marboxil in Otherwise Healthy Pediatric Patients From Birth to < 1 Year With Influenza-Like Symptoms
Phase: PHASE3
Conditions: Influenza
Sponsor: Hoffmann-La Roche

 
Official Title: A Multicenter, Single-Arm, Open-Label Study to Assess the Safety, 
Pharmacokinetics, and Efficacy of Baloxavir Marboxil in Otherwise 
Healthy Pediatric Patients From Birth To <1 Year With Influenza-Like 
Symptoms 
NCT Number: NCT03653364 
Document Date: Protocol Version 6: 27-April-2022 
 
 
 

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any unpublished data, is the property of F. Hoffmann-La Roche Ltd (or under its control) and therefore 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 CP40559, Version 6 
PROTOCOL 
TITLE: 
A MULTICENTER, SINGLE-ARM, OPEN-LABEL 
STUDY TO ASSESS THE SAFETY, 
PHARMACOKINETICS, AND EFFICACY OF 
BALOXAVIR MARBOXIL IN OTHERWISE HEALTHY 
PEDIATRIC PATIENTS FROM BIRTH TO  1 YEAR 
WITH INFLUENZA-LIKE SYMPTOMS 
PROTOCOL NUMBER: CP40559 
VERSION NUMBER: 
6 
IND NUMBER: 
126653 
EUDRACT NUMBER: 
2018-002154-70 
NCT NUMBER 
NCT03653364 
TEST PRODUCT: 
Baloxavir marboxil (RO7191686) 
MEDICAL MONITOR: 
M.D. 
SPONSOR: 
F. Hoffmann-La Roche Ltd
APPROVAL: 
See electronic signature and date stamp on the final
page of the document

PROTOCOL HISTORY 
Protocol 
Associated Country-Specific Protocol 
Version 
Date Final 
Country 
Version 
Date Final 
6 
See electronic date 
stamp on the final 
page of this 
document 
 
 
 
4 
1 June 2020 
Thailand 
5 
8 Jun 2021 
2 
25 May 2019 
South Africa 
3 
7 May 2020 
1 
2 July 2018 
 
 
 
 

 
PROTOCOL AMENDMENT VERSION 6 
RATIONALE 
Protocol CP40559 has been amended to remove the requirement for fever at screening 
and to reflect a reduction in the minimum number of patients required in Cohort III.  
Changes to the protocol, along with a rationale for each change, are summarized below: 
 
Background on influenza has been updated to include additional symptoms in adults 
and children (Section 1.1). 
 
Background on baloxavir marboxil has been updated to indicate the completion of 
two pediatric studies and to include the approval date for baloxavir marboxil in 
European Union (Section 1.2). 
 
A rapid antigen test has been added as an option to detect severe acute respiratory 
syndrome coronavirus 2 (SARS-CoV-2) infection at prescreening to facilitate 
enrollment of eligible patients at sites where rapid testing is available (Section 3.1, 
Section 4.1, Section 4.1.1, and Section 4.5.1). 
 
The minimum number of patients recruited into cohort III has been reduced to 3 
patients as this was judged to be sufficient to assess PK in this age group. 
(Section 3.1). 
 
A palatability assessment has been added to list of assessments to be conducted at 
clinic visits because it was previously omitted (Section 1.3). 
 
The requirement for fever at screening has been removed. Given the requirement 
for rapid antigen testing for influenza at screening, this change will allow enrollment 
of patients who have symptomatic influenza with a fever of  38 °C at screening 
(Section 4.1.1). 
 
The window for pre-screening testing for influenza and SARS-CoV-2 has been 
increased from 24 hours to 48 hours. This change will facilitate enrollment of 
patients at sites where rapid testing is unavailable (Section 4.1.1 and Appendix 1). 
 
Clarification has been added to allow influenza and SARS-CoV-2  test results 
undertaken as standard of care (and within 48 hours of study screening) to be used 
for eligibility assessment, without the need to retest (Section 4.1.1, 4.5.1 and 
Appendix 1) 
 
Negative SARS-CoV-2 results from either a polymerase chain reaction or rapid 
antigen test can now be used to confirm study eligibility (Section 4.1.1 and 
Appendix 1). 
 
Clarification has been added that a patient hospitalized for observation, monitoring 
or precautionary supportive care may be acceptable for enrollment in the study, 
provided they fulfill all other eligibility criteria (Section 4.1.1). 
 
Clarification has been added that parents/caregivers will measure the patient 
temperature as indicated in the schedule of activities and record the temperature 
measurement in the patient eDiary (Section 4.5.4). 

 
Clarification has been added that tympanic temperature measurements taken by 
parents/caregivers and recorded in the patient eDiary will be used to evaluate the 
safety endpoints (Section 6.5)  
 
The text has been amended to clarify that optional interim analyses may be 
conducted if appropriate.  
Additional minor changes were made to improve clarity and consistency.  Substantive 
new information appears in italics.  This amendment represents cumulative changes to 
the original protocol. 

 
Baloxavir Marboxil—F. Hoffmann-La Roche Ltd 
5/Protocol CP40559, Version 6 
TABLE OF CONTENTS 
PROTOCOL AMENDMENT ACCEPTANCE FORM .......................................... 10 
PROTOCOL SYNOPSIS .................................................................................... 11 
1. 
BACKGROUND ............................................................................ 18 
1.1 
Background on Influenza ......................................................... 18 
1.2 
Background on Baloxavir Marboxil .......................................... 19 
1.2.1 
Post-Marketing Safety Data ..................................................... 19 
1.2.2 
Phase II Proof-of-Concept and Dose-Finding Study 
(Study 1518T0821) .................................................................. 20 
1.2.3 
Phase III Double-Blind Study in Otherwise Healthy 
Patients (Study 1601T0831) .................................................... 20 
1.2.4 
Phase III, Open-Label Study in Otherwise Healthy 
Pediatric Patients (Study 1618T0822) ..................................... 22 
1.3 
Study Rationale and BenefitRisk Assessment ....................... 23 
2. 
OBJECTIVES AND ENDPOINTS ................................................. 23 
3. 
STUDY DESIGN ........................................................................... 26 
3.1 
Description of the Study ........................................................... 26 
3.2 
End of Study and Length of Study ........................................... 27 
3.3 
Rationale for Study Design ...................................................... 27 
3.3.1 
Rationale for Baloxavir Marboxil Dose and Schedule .............. 27 
3.3.2 
Rationale for Patient Population and Study Design ................. 28 
4. 
MATERIALS AND METHODS ...................................................... 29 
4.1 
Patients .................................................................................... 29 
4.1.1 
Inclusion Criteria ...................................................................... 29 
4.1.2 
Exclusion Criteria ..................................................................... 29 
4.2 
Method of Treatment Assignment ............................................ 30 
4.3 
Study Treatment and Other Treatments Relevant to the 
Study Design ........................................................................... 31 
4.3.1 
Study Treatment Formulation, Packaging, and Handling ......... 31 
4.3.2 
Study Treatment Dosage, Administration, and Compliance .... 31 
4.3.2.1 
Baloxavir Marboxil ................................................................... 31 

 
Baloxavir Marboxil—F. Hoffmann-La Roche Ltd 
6/Protocol CP40559, Version 6 
4.3.2.2 
Overdose or Incorrect Administration ...................................... 31 
4.3.3 
Rescue Medication .................................................................. 31 
4.3.4 
Investigational Medicinal Product Accountability ..................... 31 
4.3.5 
Continued Access to Baloxavir Marboxil .................................. 32 
4.4 
Concomitant Therapy .............................................................. 32 
4.4.1 
Permitted Therapy ................................................................... 32 
4.4.2 
Cautionary Therapy ................................................................. 32 
4.4.2.1 
Herbal Therapies ..................................................................... 32 
4.4.2.2 
Polyvalent CationContaining Products ................................... 32 
4.4.3 
Prohibited Therapy .................................................................. 33 
4.5 
Study Assessments ................................................................. 33 
4.5.1 
Informed Consent Forms and Screening Log .......................... 33 
4.5.2 
Medical History, Concomitant Medication, and 
Demographic Data ................................................................... 33 
4.5.3 
Physical Examinations ............................................................. 34 
4.5.4 
Vital Signs ................................................................................ 34 
4.5.5 
Laboratory and Other Biological Samples ............................... 34 
4.5.6 
Patient-Reported and Investigator-Reported Outcomes .......... 35 
4.6 
Treatment, Patient, Study, and Site Discontinuation ................ 36 
4.6.1 
Study Treatment Discontinuation ............................................. 36 
4.6.2 
Patient Discontinuation from Study .......................................... 36 
4.6.3 
Study Discontinuation .............................................................. 37 
4.6.4 
Site Discontinuation ................................................................. 37 
5. 
ASSESSMENT OF SAFETY ......................................................... 37 
5.1 
Safety Plan .............................................................................. 37 
5.1.1 
Internal Monitoring Committee ................................................. 38 
5.1.2 
Management of Patients Who Experience Adverse Events ..... 38 
5.2 
Safety Parameters and Definitions .......................................... 38 
5.2.1 
Adverse Events ........................................................................ 38 
5.2.2 
Serious Adverse Events (Immediately Reportable to the 
Sponsor) .................................................................................. 39 
5.2.3 
Adverse Events of Special Interest (Immediately 
Reportable to the Sponsor) ...................................................... 39 

 
Baloxavir Marboxil—F. Hoffmann-La Roche Ltd 
7/Protocol CP40559, Version 6 
5.3 
Methods and Timing for Capturing and Assessing 
Safety Parameters ................................................................... 40 
5.3.1 
Adverse Event Reporting Period .............................................. 40 
5.3.2 
Eliciting Adverse Event Information ......................................... 40 
5.3.3 
Assessment of Severity of Adverse Events ............................. 41 
5.3.4 
Assessment of Causality of Adverse Events............................ 41 
5.3.5 
Procedures for Recording Adverse Events .............................. 42 
5.3.5.1 
Diagnosis versus Signs and Symptoms ................................... 42 
5.3.5.2 
Adverse Events That Are Secondary to Other Events ............. 43 
5.3.5.3 
Persistent or Recurrent Adverse Events .................................. 43 
5.3.5.4 
Abnormal Laboratory Values ................................................... 43 
5.3.5.5 
Abnormal Vital Sign Values ..................................................... 44 
5.3.5.6 
Abnormal Liver Function Tests ................................................ 45 
5.3.5.7 
Deaths ..................................................................................... 45 
5.3.5.8 
Preexisting Medical Conditions ................................................ 45 
5.3.5.9 
Lack of Efficacy or Worsening of Influenza .............................. 46 
5.3.5.10 
Hospitalization or Prolonged Hospitalization ............................ 46 
5.3.5.11 
Reporting Requirements for Cases of Accidental Overdose 
or Medication Error .................................................................. 46 
5.4 
Immediate Reporting Requirements from Investigator to 
Sponsor ................................................................................... 47 
5.4.1 
Emergency Medical Contacts .................................................. 48 
5.4.2 
Reporting Requirements for Serious Adverse Events and 
Adverse Events of Special Interest .......................................... 48 
5.4.2.1 
Events That Occur prior to Study Drug Initiation ...................... 48 
5.4.2.2 
Events That Occur after Study Drug Initiation .......................... 49 
5.5 
Follow-Up of Patients after Adverse Events............................. 49 
5.5.1 
Investigator Follow-Up ............................................................. 49 
5.5.2 
Sponsor Follow-Up .................................................................. 49 
5.6 
Adverse Events That Occur after the Adverse Event 
Reporting Period ...................................................................... 49 
5.7 
Expedited Reporting to Health Authorities, Investigators, 
Institutional Review Boards, and Ethics Committees ............... 50 
6. 
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN ......... 50 

 
Baloxavir Marboxil—F. Hoffmann-La Roche Ltd 
8/Protocol CP40559, Version 6 
6.1 
Analysis Populations ................................................................ 50 
6.1.1 
Randomized Population ........................................................... 50 
6.1.2 
Per Protocol Population ........................................................... 51 
6.1.3 
Intent-to-Treat Patient Population ............................................ 51 
6.1.4 
Intent-to-Treat Influenza-Infected Patient Population ............... 51 
6.1.5 
Pharmacokinetic Evaluable Population .................................... 51 
6.1.6 
Safety Population ..................................................................... 51 
6.2 
Determination of Sample Size ................................................. 51 
6.3 
Summaries of Conduct of Study .............................................. 52 
6.4 
Summaries of Demographic and Baseline Characteristics ...... 52 
6.5 
Safety Analyses ....................................................................... 52 
6.6 
Pharmacokinetic Analyses ....................................................... 52 
6.7 
Efficacy Analyses ..................................................................... 53 
6.8 
Interim Analyses ...................................................................... 53 
7. 
DATA COLLECTION AND MANAGEMENT ................................. 54 
7.1 
Data Quality Assurance ........................................................... 54 
7.2 
Electronic Case Report Forms ................................................. 54 
7.3 
Electronic Patient-Reported Outcome Data ............................. 55 
7.4 
Source Data Documentation .................................................... 55 
7.5 
Use of Computerized Systems ................................................ 56 
7.6 
Retention of Records ............................................................... 56 
8. 
ETHICAL CONSIDERATIONS ...................................................... 56 
8.1 
Compliance with Laws and Regulations .................................. 56 
8.2 
Informed Consent .................................................................... 57 
8.3 
Institutional Review Board or Ethics Committee ...................... 58 
8.4 
Confidentiality .......................................................................... 58 
8.5 
Financial Disclosure ................................................................. 59 
9. 
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION ....................................................................... 59 
9.1 
Study Documentation .............................................................. 59 
9.2 
Protocol Deviations .................................................................. 59 
9.3 
Site Inspections ....................................................................... 60 

 
Baloxavir Marboxil—F. Hoffmann-La Roche Ltd 
9/Protocol CP40559, Version 6 
9.4 
Administrative Structure ........................................................... 60 
9.5 
Dissemination of Data and Protection of Trade Secrets .......... 60 
9.6 
Protocol Amendments ............................................................. 61 
10. 
REFERENCES.............................................................................. 62 
 
LIST OF TABLES 
Table 1 
Objectives and Corresponding Endpoints ................................... 24 
Table 2 
Adverse Event Severity Grading Scale for Events Not 
Specifically Listed in NCI CTCAE Toxicity Grading Scale ........... 41 
Table 3 
Causal Attribution Guidance ....................................................... 42 
 
LIST OF FIGURES 
Figure 1 
Study Schema ............................................................................. 27 
 
LIST OF APPENDICES 
Appendix 1 
Schedule of Activities .................................................................. 63 
Appendix 2 
Schedule of Pharmacokinetic Samples ....................................... 66 
Appendix 3 
Canadian Acute Respiratory Illness and Flu Scale (CARIFS) 
Questionnaire .............................................................................. 67 
Appendix 4 
Palatability Assessment .............................................................. 68 

 
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Principal Investigator¶s Name print) 
 
 
 
 
 
Principal Investigator¶s 6ignature 
 
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 C5O. 
 

 
Baloxavir Marboxil—F. Hoffmann-La Roche Ltd 
11/Protocol CP40559, Version 6 
PROTOCOL SYNOPSIS 
TITLE: 
A MULTICENTER, SINGLE-ARM, OPEN-LABEL STUDY TO 
ASSESS THE SAFETY, PHARMACOKINETICS, AND EFFICACY OF 
BALOXAVIR MARBOXIL IN OTHERWISE HEALTHY PEDIATRIC 
PATIENTS FROM BIRTH TO  1 YEAR WITH INFLUENZA-LIKE 
SYMPTOMS 
PROTOCOL NUMBER: 
CP40559 
VERSION NUMBER: 
6 
IND NUMBER: 
126653 
EUDRACT NUMBER: 
2018-002154-70 
TEST PRODUCT: 
Baloxavir marboxil (RO7191686) 
PHASE: 
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 in 
otherwise healthy patients from birth to < 1 year of age with influenza-like symptoms.  Specific 
objectives and corresponding endpoints for the study are outlined below. 
Safety (Primary) Objective 
Corresponding Endpoint 
 To evaluate the safety of a 
single dose of baloxavir 
marboxil 
 Incidence, severity, and timing of adverse events, serious 
adverse events, vital sign measurements, and clinical 
laboratory tests 
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 cohort 
 Population PK model derived PK parameters (e.g., AUCinf, 
Cmax, Tmax, t1/2 (modelling report) 
Efficacy (Secondary) Objectives 
Key Corresponding (Secondary) Endpoint 
 To evaluate the efficacy of 
baloxavir marboxil 
 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 
remaining 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)

 
Baloxavir Marboxil—F. Hoffmann-La Roche Ltd 
12/Protocol CP40559, Version 6 
Efficacy (Secondary) Objectives 
(cont.) 
Corresponding Endpoint (cont.) 
 To evaluate the efficacy of 
baloxavir marboxil  
 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  
 Time to cessation of viral shedding by virus titer and by 
reverse transcription-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) 
Exploratory Efficacy Objective 
Corresponding Endpoints 
 To evaluate the polymorphic and 
treatment-emergent amino acid 
substitutions 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 
Exploratory Palatability 
Objective 
Corresponding Endpoints 
 To evaluate the palatability of the 
oral suspension in the pediatric 
population  
 Proportion of patients within each response category for 
Question 1 of the palatability assessment 
 Proportion of patients with issues with the administration of the 
full dose 
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, single-arm, open-label study to assess the safety, pharmacokinetics, and 
efficacy of baloxavir marboxil in otherwise healthy pediatric patients from birth to  1 year with 
influenza-like symptoms. 

 
Baloxavir Marboxil—F. Hoffmann-La Roche Ltd 
13/Protocol CP40559, Version 6 
Potential patients will be prescreened using an influen]a test rapid influen]a diagnostic test 
>5ID7@ or polymerase chain reaction >PC5@) and a coronavirus disease 2019 COVID19) test 
approved rapid antigen test [RAT] or PCR).  7his is to ensure that patients with a high 
probability of having influen]a infection are enrolled and to minimi]e the likelihood of enrolling a 
COVID19 patient in the study.  Patients will be screened on Day 1 and assigned to one of three 
cohorts, based upon their age, to receive a single oral dose of baloxavir marboxil based on 
body weight and age.  5escreening of patients who fail to meet the inclusion and exclusion 
criteria will not be permitted, as the time from symptom onset to treatment window is limited to 
96 hours. 
7he study consists of two periods:  a 1day treatment period screening and study drug 
administration on Day 1) and a 28day safety followup period mandatory visits on Days 2, 4, 6, 
10, and 29).  7herefore, the total study duration for each patient will be 29 days. 
7he following assessments will be conducted at clinic visits:  physical examination, vital signs, 
adverse events, concomitant therapies, clinical laboratory tests, nasal/throat swabs and 
palatability assessment.   
7hroughout 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), 
influen]a symptoms, and acetaminophen use.  7emperatures will be recorded four times daily 
morning, noon, evening, and bedtime) on Days 1 to 3 twice daily morning and evening) on 
Days 4 to 9 and once daily on Days 10 to 15.  Influen]a symptoms will be recorded twice daily 
morning and evening) on Days 1 to 9 and once daily on Days 10 to 15. 
7his study will be conducted at sites in the 8nited 6tates and globally.   
7o facilitate early and close monitoring of safety parameters over time, an Internal 0onitoring 
Committee I0C) will review aggregate safety data on an ongoing basis as defined in the I0C 
charter.  If there is any concern noted in the safety parameters, the 6ponsor may suspend or 
discontinue the entire study, as appropriate. 
18MB(R 2F PA7,(176 
7his study is designed to enroll approximately 30 otherwise healthy male and female pediatric 
patients with influen]alike symptoms. Patients will be recruited in parallel to the following three 
cohorts: 
 
&ohort ,:   3 months to  12 months old minimum 8 patients) 
 
&ohort ,,:   4 weeks to  3 months old minimum 4 patients) 
 
&ohort ,,,:  birth to  4 weeks old minimum 3 patients) 
7AR*(7 P2P8LA7,21 
Inclusion Criteria 
Patients must meet the following criteria for study entry: 
 
:ritten informed consent for study participation obtained from patient¶s parents or legal 
guardian 
 
Age from birth to  1 year at screening  
 
Parent/guardian willing and able to comply with study reTuirements, in the investigator¶s 
Mudgment  
 
Patients with a diagnosis of influen]a virus infection confirmed by the presence of all of the 
following: 
– 
In the investigator’s judgement there is a clinical suspicion of influenza 
– 
At least one respiratory symptom either cough or cory]a) 
– 
Positive prescreening influen]a test 5ID7 or PC5) performed within 48 hours of screening 
Results from local testing as part of standard of care are acceptable if samples are 
collected within 48 hours of screening and recorded in the patients’ medical records. 
 
Patients with a negative prescreening COVID19 test RAT or PC5) performed within 48 
hours of screening 

 
Baloxavir Marboxil—F. Hoffmann-La Roche Ltd 
14/Protocol CP40559, Version 6 
Results from local testing as part of standard of care are acceptable if samples are 
collected within 48 hours of screening and recorded in the patients’ medical records. 
 
7he time interval between the onset of symptoms and screening is  96 hours the onset of 
symptoms is defined as the time when body temperature first exceeded 3.5C if known, or 
the time when the first symptom was noticed by the parent or caregiver) 
(xclusion Criteria 
Patients who meet any of the following criteria will be excluded from study entry: 
 
+ospitali]ed for complications of influen]a or significant comorbidities  
Patients hospitalized for observation, monitoring or precautionary supportive care 
may still be acceptable for enrollment provided all eligibility criteria are met.  
 
Concurrent infections reTuiring systemic antiviral therapy at screening 
 
5eTuire, in the opinion of the investigator, any of the prohibited medication during the study 
 
Preterm neonates born at  3 weeks gestation)   
 
:eigh  2.5 kg at screening 
Only children  4.5 kg will be eligible to take part in countries that have volume limits 
for blood draws set at 1 of the total blood volume maximum over 24hour period) 
and 3 of the total blood volume maximum over 30day period).  
 
Previous treatment with peramivir, laninamivir, oseltamivir, ]anamivir, or amantadine within 
2 weeks prior to screening 
 
Immuni]ation with a live/attenuated influen]a vaccine during the 2 weeks prior to screening 
 
Concomitant treatment with steroids or other immunosuppressant therapy 
 
.nown +IV infection or other immunosuppressive disorder 
 
8ncontrolled 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 
 
+istory of organ transplant  
 
.nown hypersensitivity to study drug i.e., baloxavir marboxil) or the drug product excipients 
 
.nown hypersensitivity to acetaminophen 
 
Participation in a clinical trial with an investigational drug within 4 weeks or five halflives of 
exposure to an investigational drug prior to screening, whichever is longer 
(1' 2F 678'< 
7he end of this study is defined as the date when the last patient, last visit /P/V) occurs or the 
date at which the last data point reTuired for statistical analysis or safety followup is received 
from the last patient, whichever occurs later.  7he end of the study is expected to occur 29 days 
after the last patient has been enrolled. 
L(1*7H 2F 678'< 
7he total length of the study, from screening of the first patient to the end of the study, is 
expected to be approximately 9 months.  *iven the seasonal variability of incidence and 
severity of influen]a, the total length of the study may be extended to complete enrollment. 
In addition, the 6ponsor may decide to terminate the study at any time. 
,19(67,*A7,21AL M(',&,1AL PR2'8&76 
7(67 PR2'8&7 ,19(67,*A7,21AL 'R8* 
7he investigational medicinal product I0P) for this study is baloxavir marboxil. 
121-,19(67,*A7,21AL M(',&,1AL PR2'8&76 
Not applicable. 

 
Baloxavir Marboxil—F. Hoffmann-La Roche Ltd 
15/Protocol CP40559, Version 6 
67A7,67,&AL M(7H2'6 
PR,MAR< A1AL<6,6 
7he safety evaluable population will be used for all analyses. 
All verbatim adverse event terms will be mapped to 0edD5A thesaurus terms, and adverse 
event severity will be graded according to National Cancer Institute Common 7erminology 
Criteria of Adverse (vents, Version 5.0 NCI C7CA( v5.0). 
7he safety of baloxavir marboxil will be evaluated from adverse events, vital sign 
measurements, and clinical laboratory tests.  6afety parameters will be summari]ed or listed for 
the safety population. 
'(7(RM,1A7,21 2F 6AMPL( 6,=( 
No formal samplesi]e calculations have been performed.  Approximately 30 pediatric patients 
will be enrolled in order to estimate the pharmacokinetic P.) parameters and maturation factor 
which is incorporated in the population P. model with a probability of  90. 
,17(R,M A1AL<6(6 
An interim P. analysis is planned for this study.  7he P. samples, up to and including those 
collected at Visit 4/5 of first 6 patients dosed, will be batched for an early shipment.  7his will 
enable a timely review of the systemic plasma concentrations, in particular the concentrations at 
24 hours and 2 hours after dosing.  7his 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.  7he 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 will be performed by members of the 6ponsor study team.   
No other interim analyses are planned in this study.  +owever, given there is no formal 
statistical hypothesis testing in this study, the 6ponsor may choose to conduct optional interim 
analyses as appropriate.  7he decision to conduct an optional interim analysis and the timing of 
the analysis will be documented in the 6ponsor¶s trial master file prior to the conduct of the 
interim analysis.  7he interim analysis will be performed and interpreted by members of the 
6ponsor study team and appropriate senior management personnel. 
 

 
Baloxavir Marboxil—F. Hoffmann-La Roche Ltd 
16/Protocol CP40559, Version 6 
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 
CL/F 
apparent clearance 
COVID-19 
coronavirus disease 2019 
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 
OwH 
otherwise healthy 
PCR 
polymerase chain reaction 
PK 
pharmacokinetic 
PKEP 
pharmacokinetic-evaluable patient 

 
Baloxavir Marboxil—F. Hoffmann-La Roche Ltd 
17/Protocol CP40559, Version 6 
 
Abbreviation 
Definition 
PRO 
patient-reported outcome 
QTc 
corrected QT interval 
RAT 
rapid antigen test 
RIDT 
rapid influenza diagnostic test 
RT-PCR 
reverse transcription-polymerase chain reaction 
TCID50 
50% tissue culture infectious dose 
Vc/F 
apparent volume of distribution for the central compartment 
ULN 
upper limit of normal 

 
Baloxavir Marboxil—F. Hoffmann-La Roche Ltd 
18/Protocol CP40559, Version 6 
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.  Some may experience vomiting and diarrhea, although this is 
more common in children than adults, and others may be infected with influenza and 
have respiratory symptoms in the absence of fever (CDC 2011).  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 the 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 the 
assembly of new virus particles. 
The following anti-influenza virus drugs are currently available in various countries:  the 
M2 ion-channel inhibitors (i.e., amantadine and rimantadine) (CDC 2011), a 
RNA-polymerase inhibitor (i.e., 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. 

 
Baloxavir Marboxil—F. Hoffmann-La Roche Ltd 
19/Protocol CP40559, Version 6 
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 into a strain to which most 
people are not immune.  The latter may result in a pandemic.  To protect against these 
situations, the development of an anti-viral influenza drug with a novel mechanism of 
action is 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 prodrug 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, two Phase III studies in adults and adolescents 
(one in otherwise healthy [OwH] individuals and one in patients at high risk of 
complications), and two Phase III Japanese studies in otherwise healthy pediatric patients 
have been completed.  Two additional Phase III pediatric studies have been completed, 
Study T0835 in Japan, which examined higher doses of baloxavir than earlier studies in 
the Japanese pediatric population, and Study CP40563, which investigated baloxavir 
marboxil in otherwise healthy pediatric patients 1 to  12 years of age with influenza in 
the global setting.  
Baloxavir marboxil was first approved in Japan for the treatment of influenza A or B virus 
infection in OwH patients on 26 February 2018, including pediatric patients weighing 
 10 kg.  In the United States (on 24 October 2018) and European Union (7 January 
2021), baloxavir marboxil was approved for the treatment of acute uncomplicated 
influenza in patients  12 years of age who have been symptomatic for no more than 
48 hours.  Regulatory filings in other global regions are completed, ongoing, or planned 
to gain market authorization for the use of baloxavir for the treatment of influenza. 
1.2.1 
Post-Marketing Safety Data 
Hypersensitivity reactions have been observed in the post-marketing setting which 
include reports of anaphylaxis/anaphylactic reactions and less severe forms of 
hypersensitivity reactions including angioedema and urticaria.  Refer to Section 6 of the 
Baloxavir Marboxil Investigator’s Brochure for further details on post-marketing safety 
information. 

 
Baloxavir Marboxil—F. Hoffmann-La Roche Ltd 
20/Protocol CP40559, Version 6 
1.2.2 
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 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 
groups 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 
adverse events were mild.  No statistically significant difference was found in the 
incidence between any of the three dose groups and the placebo group. 
1.2.3 
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 of 
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 

 
Baloxavir Marboxil—F. Hoffmann-La Roche Ltd 
21/Protocol CP40559, Version 6 
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 
group (24 hours) 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 
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 

 
Baloxavir Marboxil—F. Hoffmann-La Roche Ltd 
22/Protocol CP40559, Version 6 
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. 
1.2.4 
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 patents 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. 
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. 

 
Baloxavir Marboxil—F. Hoffmann-La Roche Ltd 
23/Protocol CP40559, Version 6 
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 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, especially in children 
aged  1 year of age (one open-label Phase III study in children in Japan), a further 
study of children within this age group 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 
in otherwise healthy patients from birth to  1 year of age with influenza-like symptoms.  
Specific objectives and corresponding endpoints for the study are outlined in Table 1. 

 
Baloxavir Marboxil—F. Hoffmann-La Roche Ltd 
24/Protocol CP40559, Version 6 
Table 1 
Objectives and Corresponding Endpoints 
Safety (Primary) Objective 
Corresponding Endpoint 
 To evaluate the safety of a 
single dose of baloxavir 
marboxil 
 Incidence, severity, and timing of adverse events, serious 
adverse events, vital sign measurements, and clinical 
laboratory tests 
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 cohort 
 Population PK model derived PK parameters (e.g., AUCinf, 
Cmax, Tmax, t1/2 (modelling report) 
Efficacy (Secondary) Objective 
Key Corresponding (Secondary) Endpoint 
 To evaluate the efficacy of 
baloxavir marboxil 
 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 
remaining 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) 

 
Baloxavir Marboxil—F. Hoffmann-La Roche Ltd 
25/Protocol CP40559, Version 6 
Table 1 
Objectives and Corresponding Endpoints (cont.)  
Efficacy (Secondary) Objective 
Corresponding Endpoints 
 To evaluate the efficacy of 
baloxavir marboxil  
 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  
 Time to cessation of viral shedding by virus titer and by 
reverse transcription-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) 
Exploratory Efficacy Objective 
Corresponding Endpoints 
 To evaluate the polymorphic and 
treatment-emergent amino acid 
substitutions 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 
Exploratory Palatability 
Objective 
Corresponding Endpoints 
 To evaluate the palatability of the 
oral suspension in the pediatric 
population 
 Proportion of patients within each response category for 
Question 1 of the palatability assessment 
 Proportion of patients with issues with the administration of 
the full dose 
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. 
 

 
Baloxavir Marboxil—F. Hoffmann-La Roche Ltd 
26/Protocol CP40559, Version 6 
3. 
STUDY DESIGN 
3.1 
DESCRIPTION OF THE STUDY 
This is a multicenter, single-arm, open-label study to assess the safety, 
pharmacokinetics, and efficacy of baloxavir marboxil in otherwise healthy pediatric 
patients from birth to  1 year with influenza-like symptoms. 
This study is designed to enroll approximately 30 otherwise healthy male and female 
pediatric patients with influenza symptoms presenting within 96 hours of symptom onset. 
Potential patients will be prescreened using an influenza test (Rapid Influenza 
Diagnostic Test [RIDT] or Polymerase Chain Reaction [PCR]) and a COVID-19 test 
(Rapid Antigen Test [RAT] or PCR).  This is to ensure that patients with a high 
probability of having influenza infection are enrolled and to minimize the likelihood of 
enrolling a patient with COVID-19 in the study.  Patients will be screened on Day 1 and 
assigned to receive a single oral dose of baloxavir marboxil according to body weight 
and age, as defined below.  
Patients will be recruited in parallel to the following three cohorts: 
 
Cohort I:   3 months to  12 months old (minimum 8 patients):  2 mg/kg 
 
Cohort II:   4 weeks to  3 months old (minimum 4 patients):  1 mg/kg 
 
Cohort III:  birth to  4 weeks old (minimum 3 patients):  1 mg/kg 
 
Patients will be screened on Day 1 and assigned to one of these three cohorts based 
upon their age (see Figure 1).  Re-screening of patients who fail to meet the inclusion 
and exclusion criteria will not be permitted, as the time from symptom onset to treatment 
window is limited to 96 hours. 
The study consists of two periods:  a 1-day treatment period (screening and study drug 
administration on Day 1) and a 28-day safety follow-up period (mandatory visits on 
Days 2, 4, 6, 10, and 29).  Therefore, the total study duration for each patient will be 
29 days. 
The following assessments will be conducted at clinic visits:  physical examination, vital 
signs, adverse events, concomitant therapies, clinical laboratory tests, nasal/throat 
swabs and palatability assessment.  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 recorded four times daily 

 
Baloxavir Marboxil—F. Hoffmann-La Roche Ltd 
28/Protocol CP40559, Version 6 
In this study, baloxavir marboxil will be administered as granules for suspension.  
Bioequivalence of the suspension and the 20-mg tablet (which was previously tested in 
clinical studies) was confirmed in a separate bioequivalence 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 each age in months for  2-year old infants.  In addition, 
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), and plasma concentration at 24 hours after dosing (C24; 
acceptable time window:  20 to 28 hours), and 72 hours after dosing (C72).  The optimal 
dose selected was based on a comparison of the simulated drug exposure 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 infants of 3 months and older and 1 mg/kg in younger infants 
(4 weeks3 months) as well as for newborns (04 weeks). 
In this study, baloxavir marboxil will be administered according to the infant’s body 
weight and age recorded at screening (i.e., 2 mg/kg  3 months, 1 mg/kg  3 months) to 
obtain similar exposure of S-033447 to that resulting from the administration of 40 mg or 
80 mg baloxavir marboxil (based on the patient’s body weight) to adults in the 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 and Study Design 
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 
children, particularly  5 years of age, this study in children is justified to confirm the 
safety and pharmacokinetics of baloxavir marboxil in this population. 
Given the difficulties of recruiting very young children ( 1 year) into clinical trials and the 
challenge of repeated sample requirements (including blood draws for PK analysis and 
nasal swabs for virology assays), an open-label design was selected.  The rationale is 
that this study design enables a smaller sample size and also minimizes unnecessary 

 
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discomfort in those children who could otherwise be assigned to a placebo or 
activecontrol group in a doubleblind study. 
4. 
MA7(R,AL6 A1' M(7H2'6 
4. 
PA7,(176 
Approximately 30 pediatric patients with influen]alike symptoms are planned for 
enrollment in this study.  Potential patients will be prescreened using an influen]a test 
5ID7 or PC5) and a COVID19 test RAT or PC5). 7his is to ensure that patients with 
a high probability of having influen]a infection are enrolled and to minimi]e the likelihood 
of enrolling a patient with COVID19 in the study. 
4.. 
,nclXsion &riteria 
Patients must meet the following criteria for study entry: 
 
:ritten informed consent for study participation obtained from patient¶s parents or 
legal guardian 
 
Age from birth to  1 year at screening  
 
Parent/guardian willing and able to comply with study reTuirements, in the 
investigator¶s Mudgment  
 
Patients with a diagnosis of influen]a virus infection confirmed by the presence of 
all of the following: 
– 
 In the investigator’s judgement there is a clinical suspicion of influenza 
– 
At least one respiratory symptom either cough or cory]a)  
– 
Positive prescreening influen]a test 5ID7 or PC5) performed within 48 hours of 
screening 
Results from local testing as part of standard of care are acceptable if 
samples are collected within 48 hours of screening and recorded in the 
patients’ medical records. 
 
Patients with a negative prescreening COVID19 test RAT or PC5) within 48 
hours of screening 
Results from local testing as part of standard of care are acceptable if 
samples are collected within 48 hours of screening and recorded in the 
patients’ medical records.  
 
7he time interval between the onset of symptoms and screening is  96 hours the 
onset of symptoms is defined as the time when body temperature first exceeded 
3.5C if known, or the time when the first symptom was noticed by the parent or 
caregiver) 
4.. 
(xclXsion &riteria 
Patients who meet any of the following criteria will be excluded from study entry: 
 
+ospitali]ed for complications of influen]a or significant comorbidities  

 
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Patients hospitalized for observation, monitoring or precautionary 
supportive care may still be acceptable for enrollment provided all eligibility 
criteria are met.  
 
Concurrent infections requiring systemic antiviral therapy at screening 
 
Require, in the opinion of the investigator, any of the prohibited medication during 
the study 
 
Preterm neonates (born at  37 weeks gestation)   
 
Weigh  2.5 kg at screening 
Only children  4.5 kg will be eligible to take part in countries that have volume 
limits for blood draws set at 1% of the total blood volume (maximum over 
24-hour period) and 3% of the total blood volume (maximum over 30-day 
period).  
 
 
Previous treatment with peramivir, laninamivir, oseltamivir, zanamivir, or amantadine 
within 2 weeks prior to screening 
 
Immunization with a live/attenuated influenza vaccine during the 2 weeks prior to 
screening 
 
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 transplant  
 
Known hypersensitivity to study drug (i.e., baloxavir marboxil) or the drug product 
excipients 
 
Known hypersensitivity to acetaminophen 
 
Participation in a clinical trial within 4 weeks or 5 half-lives of exposure to an 
investigational drug prior to screening, whichever is longer 
 
4.2 
METHOD OF TREATMENT ASSIGNMENT 
Since this is an open-label study, the Sponsor and its agents, the study site personnel, 
and the patients’ parents/caregivers will be aware of the treatment administered in this 
study. 
All patients will receive the same open-label treatment with the dose determined by both 
body weight and age (see Section 3.3.1), thus a method for assigning treatment is not 
warranted. 

 
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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. 
4.3.1 
Study Treatment Formulation, Packaging, and Handling 
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. 
4.3.2 
Study Treatment Dosage, Administration, and Compliance 
The treatment regimens are summarized in Section 3.1. 
4.3.2.1 
Baloxavir Marboxil 
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 depending on both the body weight and 
age of the child (2 mg/kg  3 months, 1 mg/kg  3 months). 
4.3.2.2 
Overdose or Incorrect Administration 
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 5.3.5.11. 
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 body weight and age of the child will 
be permitted only for the relief of fever or pain.  If acetaminophen is used, the 
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 
The IMP required for completion of this study (baloxavir marboxil) will be provided by the 
Sponsor where required by local health authority regulations.  The study site will 
acknowledge receipt of the IMP supplied by the Sponsor, using the interactive voice or 
web-based response system (IxRS) to confirm the shipment condition and content.  Any 
damaged shipments will be replaced. 
The IMP 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 IMP 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 IMP 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  
Currently, the Sponsor does not have any plans to provide the Roche IMP (baloxavir 
marboxil) 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 web site: 
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 body 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.   
4.4.2.2 
Polyvalent CationContaining Products 
Polyvalent cationcontaining products may decrease plasma concentrations of 
baloxavir.  Thus, polyvalent cation-containing oral laxatives or oral antacids and oral 
supplements containing iron, zinc, selenium, calcium, or magnesium should not be taken 
with baloxavir marboxil.  

 
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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 
 
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 
Potential patients will be prescreened using an influenza test (RIDT or PCR) and a 
COVID-19 test (RAT or PCR). This is to ensure that patients with a high probability of 
having influenza infection are enrolled and to minimize the likelihood of enrolling a 
patient with COVID-19 in the study.  A separate informed consent procedure will be 
implemented for this prescreening step.  If sites perform influenza (RIDT or PCR) 
and/or COVID-19 tests (RAT or PCR) as part of standard of care assessment, test 
results recorded in the patient medical record can be used for eligibility assessment, if 
samples were collected within 48 hours of screening. 
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). 
Informed Consent Forms 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, and cancer history 
(including prior cancer therapies and procedures), 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 

 
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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reported race/ethnicity. 
Influen]a 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.. 
Physical (xaminations 
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 *eneral 0edical +istory and %aseline Conditions eC5). 
/imited, 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 (vent eC5). 
/imited, symptomdirected physical examinations may be performed by a mobile nursing 
professional. 
4..4 
9ital 6iJns 
Vital signs will include measurements of respiratory rate, pulse rate, and systolic and 
diastolic blood pressure as well as tympanic temperature.   
Temperature will also be measured and recorded by parents/caregivers in patients 
eDiary (Section 4.5.6). 
4.. 
Laboratory and 2ther BioloJical 6amples  
6amples for the following laboratory tests will be sent to one or several central 
laboratories for analysis: 
 
+ematology:  :%C count, 5%C count, hemoglobin, hematocrit, platelet count, 
differential count neutrophils, eosinophils, basophils, monocytes, lymphocytes, 
other cells) 
 
Chemistry panel serum or plasma):  sodium, potassium, chloride, bicarbonate, %8N 
or urea, creatinine, total protein, albumin, total and direct bilirubin, alkaline 
phosphatase, A/7, A67 
 
Plasma samples for P. analysis 

 
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 
Nasopharyngeal swabs for virology tests (i.e., reverse transcriptase-polymerase 
chain reaction [RT-PCR], TCID50, viral phenotyping and genotyping) and for 
non-influenza respiratory pathogen coinfections panel (only at the screening visit) 
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.  
Data arising from sample analysis will be subject to the confidentiality standards 
described in Section 8.4. 
4.5.6 
Patient-Reported and Investigator-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 
time points during the study (see Appendix 1).  To ensure instrument validity and that 
data standards meet health authority requirements, the questionnaire will be 
self-administered before the parent or caregiver 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 (see 
Appendix 1). 
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. 

 
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In addition, a 4-question palatability assessment (performed by the investigator or 
delegate) will be used to determine the perceived acceptability of baloxavir marboxil for 
each patient and issues that occur with regard to dosing (see Appendix 4).  
Palatability plays a role in patient acceptability of a drug especially in the pediatric 
population and is likely to have a significant impact on a patient's adherence, especially 
when the medicinal product has to be given as multiple doses either daily or over a 
number of days.  This is largely determined by the characteristics of the medicinal 
product and the user, and compliance rates in children can range widely with factors 
attributed to formulation and palatability.  There will be no formal statistical analysis 
performed for this endpoint.   
Parent or Caregiver Reported Temperature 
The parents or caregivers will measure the patient’s temperature using tympanic 
thermometers provided. The temperature will be measured at specific time points 
during the study and will be recorded in the patient’s electronic diary (Appendix 1) 
The electronic device and/or instructions for recording the temperature 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). 
4.6.2 
Patient Discontinuation from Study 
Patients’ parents/caregivers have the right to voluntarily withdraw the patient from the 
study 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’s parent/caregiver withdrawal of consent 

 
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 
Study termination or site closure 
 
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 was withdrawn 
from the study by the parent/caregiver.  The primary reason for withdrawal from the 
study should be documented on the appropriate eCRF.  If a 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 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) 
 
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 

 
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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, 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.  
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 
Section 5.4. 
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) 
 

 
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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 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 
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) 

 
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 
Suspected transmission of an infectious agent by the study drug, as defined below 
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 noted by study personnel, 
will be recorded in the patient’s medical record and on the Adverse Event eCRF. 
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?"  
 

 
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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. 
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 

 
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 
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 
occurrence of the event 
 
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 
 
5.3.5.11 
Reporting Requirements for Cases of Accidental Overdose or 
Medication Error 
Accidental overdose and medication error (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 
 
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. 
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 

 
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separately on the Adverse Event eCRF.  If the associated adverse event fulfills 
seriousness criteria or qualifies as an adverse event of special interest, 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, 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. 
 
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. 
 
In addition, all special situations associated with baloxavir marboxil, regardless of 
whether they result in an adverse event, should be recorded on the Adverse Event 
eCRF as described below: 
 
Accidental overdose:  Enter the drug name and "accidental overdose" as the event 
term.  Check the "Accidental overdose" and "Medication error" boxes. 
 
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. 
 
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. 
 
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. 
 
5.4 
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 

 
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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) 
 
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/Ethic Committee 
(IRB/EC). 
5.4.1 
Emergency Medical Contacts 
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 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/Special Situations 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. 

 
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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 
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/Special Situations 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 days after the last dose 
of study treatment are provided in Section 5.6. 
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. 
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 

 
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these events directly to the Sponsor or its designee, either by faxing or by scanning and 
emailing the paper Clinical Trial Serious Adverse Event/Special Situations 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 document: 
 
Baloxavir Marboxil Investigator's Brochure  
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 evaluate the safety of baloxavir marboxil in 
pediatric patients from birth to  1 year with influenza-like symptoms.  Therefore, and as 
it is a single group study, there will be no formal statistical hypothesis testing.  The 
statistical analyses of safety, pharmacokinetics, and efficacy will be descriptive. 
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. 

 
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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.  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 (PCR result) from any swab 
sample collected at baseline or during the study.  The ITTi population is the primary 
efficacy population, unless specified otherwise.   
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 postdose 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. 
6.1.6 
Safety Population 
The safety-evaluable patient population will 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. 
6.2 
DETERMINATION OF SAMPLE SIZE 
No formal sample-size calculations have been performed. 
A total of approximately 30 pediatric patients will be enrolled in order to estimate the PK 
parameters and maturation factor which is incorporated in the population PK model with 
a probability of  90%. 
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.  

 
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Additional patients may be recruited if the ITTi population is considerably smaller than 
expected. 
The number of patients in the ITTi population entering the study with  48 hours since 
symptom onset will also be monitored.  Additional patients may be recruited if 
considerably fewer patients than expected enter the study with  48 hours since 
symptom onset. 
6.3 
SUMMARIES OF CONDUCT OF STUDY 
The number of patients who enroll, discontinue, or complete the study will be 
summarized.  Reasons for premature study withdrawal will be listed and summarized.  
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.  
6.5 
SAFETY ANALYSES 
The safety evaluable 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 (including parent/caregiver recorded temperature) 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 age group.   
As this study uses an optimized sparse PK regimen, individual PK parameters of 
baloxavir marboxil and S-033447 (AUC, Cmax, time to maximum concentration, and 
terminal half-life) will not be determined using model-independent methods.  However, 
individual drug concentrations determined plasma concentration 24 and 72 hours after 
dosing (C24 and C72, respectively) of S-033447 will be listed and summarized (mean, 

 
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standard deviation, coefficient of variation, median, minimum, and maximum) by age 
group. 
In addition, a 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 [CL/F], apparent volume of distribution for the central compartment [Vc/F]) 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 
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 
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 ITTi population will be used for efficacy analyses. 
The statistical analyses of efficacy endpoints will be descriptive:  Kaplan-Meier plots and 
summary statistics for time-to-event endpoints, proportions for categorical variables and 
means, standard deviations, medians, and ranges for continuous variables. 
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. 
6.8 
INTERIM ANALYSES 
An interim PK analysis is planned for this study.  PK samples, up to and including those 
collected at Visit 4/5 of first 6 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 

 
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and data review is estimated to be approximately 2 to 3 weeks, and recruitment will 
continue during this time.  Data review 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 optional 
interim analyses as appropriate.  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.   
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 
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 parent/caregiver 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. 

 
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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. 
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 on the eCRFs (i.e., no prior written or electronic record of the data) and 
considered source data. 

 
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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. 
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, 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 years after the Clinical Study Report has been 
completed 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 applicable 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 

 
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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) and applicable local, regional, and national laws. 
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 
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 
parent/caregiver 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. 

 
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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.  
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. 

 
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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. 
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 

 
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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 25 sites in the United States and globally will participate to enroll 
approximately 30 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 4.5.5.   
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, 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 (see Section 8.4 for more details), and 
redacted Clinical Study Reports and other summary reports will be made available upon 
request, provided the requirements of Roche's global policy on data sharing have been 
met.  For more information, refer to the Roche Global Policy on Sharing of Clinical Study 
Information at the following website: 
https://www.roche.com/innovation/process/clinical-trials/data-sharing/ 
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 

 
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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. 
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 
 
Prescreeninga 
Treatment 
Period 
Follow-Up Period 
Day(s) 
D1 
D1 
D2 
D3 
D4 
D5 
D6 
D7 
D8 
D9 
D10 
D15 
D29 
or ET 
Visits 
NA 
V1  
Screening 
V1  
Post-
dose 
V2 
OpV1 b 
V3 
V4 
V5 
OpV2 b 
V6 
Visit Window (days) 
-1 
 
1 
1 
2 
3 
3 
Prescreening influenza test 
xc 
 
 
 
 
 
 
 
 
 
 
 
 
 
Prescreening COVID-19 test 
xd 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed consents 
x 
x 
 
  
  
  
  
  
  
  
  
  
  
  
Inclusion/exclusion criteria 
 
x 
 
  
  
  
  
  
  
  
  
  
  
  
Demographics   
 
x 
 
  
  
  
  
  
  
  
  
  
  
  
Medical history e 
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
Study drug administration 
 
 
x 
  
  
  
  
  
  
  
  
  
  
  
Patient diary: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Body temperature 
measurement f 
 
 
Four times daily 
Twice daily 
Once daily 
  
Assessment of influenza 
symptoms g 
 
 
Twice daily 
Once daily 
  
Physical examination  
 
x h 
 
x h 
(x) h 
x h 
  
x h 
  
  
  
x h 
(x i) 
x h 
Vital signs measurement 
 
x 
 
x 
(x) 
x 
  
x 
  
  
  
x 
(x i) 
(x j) 
Adverse events assessment 
 
 
x 
x 
(x) 
x 
  
x 
  
  
  
x 
(x i) 
x 
Concomitant therapies 
assessment 
 
x 
 
x 
(x) 
x 
 
x 
 
 
 
x 
(x if) 
x 

 
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Appendix 1  
Schedule of Activities (cont.)  
 
Prescreening 
Treatment 
Period 
Follow-Up Period 
Day(s) 
 
D1 
D2 
D3 
D4 
D5 
D6 
D7 
D8 
D9 
D10 
D15 
D29 
or ET 
Visits 
NA 
V1  
Screening 
V1  
Post-
dose 
V2 
OpV1 a 
V3 
V4 
V5 
OpV2 b 
V6 
Visit Window (days) 
NA 
 
1 
1 
2 
3 
3 
Interview for meal 
consumption  
 
x 
x 
  
  
  
  
  
  
  
  
  
  
  
Clinical laboratory tests 
 
 
x 
 
  
  
  
x 
  
  
  
  
(x i) 
 
Nasopharyngeal swabs k 
 
x 
 
x 
  
x 
  
x 
  
  
  
x 
(x i) 
(x i) 
Pharmacokinetic samples l 
 
 
x 
(x) l 
 
(x) 
l 
 
x l 
 
Palatability assessment m 
 
 
x 
 
 
 
 
 
 
CARIFS  Canadian Acute Respiratory Illness and Flu Scale; COVID-19 = coronavirus disease 2019; D  Day; ET  early termination; NA  not 
applicable; OpV  optional visit; PK  pharmacokinetic; V  visit. 
a 
Pre-screening assessment is not required if the patient has a negative COVID-19 test result and positive influenza test performed as SOC 
within 48 hours of screening recorded in their medical records 
b 
OpV1 and OpV2 are optional visits to be performed at the discretion of the investigator or parent/caregiver, for example, in the event of 
persistent influenza symptoms. 
c 
Test is not required if the patient has a positive influenza test result performed as SOC within 48 hours of screening recorded in their 
medical records 
d 
Test is not required if the patient has negative COVID-19 test results performed as SOC within 48 hours of screening recorded in their 
medical records. 
e 
Prior therapies will also be reviewed. 
f 
The parent/caregiver will assess and record in the patient diary, body temperature (tympanic assessment) four times daily (morning, noon, 
evening, and bedtime) on Days 1 to 3; twice daily (morning and evening) on Days 4 to 9; once daily on Days 10 to 15. The first temperature 
recorded by the parent/caregiver will be measured post-dose. 

 
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Appendix 1  
Schedule of Activities (cont.) 
g 
The parent/caregiver will complete the CARIFS questionnaire twice (morning and evening) on Days 1 to 9 and then once daily on 
Days 10 to 15. The first CARIFS assessment will occur post-dose. 
h 
Perform if the investigator determines that influenza symptoms are persisting or at the investigator’s discretion. 
i 
Record vital sign measurements if abnormal physical examination, adverse events recorded since last visit, or at investigator’s discretion on 
Day 29. 
j 
At least two nasopharyngeal swabs (one for each nostril) will be taken at each visit.  
k 
PK samples (all patients):  See Appendix 2 for collection timepoints for 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 1 0 is required and can be collected at either 
Visit 4 or Visit 5. 
l 
The palatability assessment should be completed by the study investigator (or delegate) who administers baloxavir marboxil to  the patient. 

 
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Appendix 2  
Schedule of Pharmacokinetic Samples 
Visit 
Timepoint 
Sample Type 
Sparse PK Sampling 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) 
PK  pharmacokinetic. 
a Samples will be used for baloxavir marboxil and S-033447 determination. 
b Patients will be assigned to have either the Day 2 or the Day 4 sample. 
 

 
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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.   
 

 
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Appendix 4 Palatability Assessment 
Palatability Assessment 
1. 
On the basis of the reaction ⁄ facial expression of your patient, do you think that the 
medication has a: 
a) very pleasant taste 
b) slightly pleasant taste 
c) neutral taste or no reaction of patients to taste 
d) slightly unpleasant taste 
e) very unpleasant taste 
 
2. 
Did you have any problems administering the full dose to the patient? 
a) Yes 
b) No 
 
3. 
If you answered “yes” for Question 2, what is the main reason for this problem? 
 
 
4. 
Other comments or problems encountered administering the drug: 
 
 
 

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