Conditions: Influenza
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 4138
Healthy volunteers: no

Brief summary:
Otherwise healthy index patients (IP) are randomized to either baloxavir marboxil or placebo if their influenza symptoms onset was within 48 hours of screening. Their households are enrolled within 24 hours of randomization if at least 1 household contacts (HHC) have not received influenza vaccine within 6 months of screening and if all HHC screen negative for influenza infection. The main endpoints are assessed based on multiple respiratory swabs, obtained from both IP and HHC up to 9 (+/-1) days post IP randomization, and through the assessment of symptoms.

Detailed description:

Arms:
arm 1: Participants who are IPs will receive a single oral dose of baloxavir marboxil. HHCs of the IPs will not receive study medication. arm 2: Participants who are IPs will receive a single oral dose of placebo. HHCs of the IPs will not receive study medication.

Interventions: intervention 1: Baloxavir Marboxil intervention 2: Placebo
Intervention descriptions: intervention 1: IPs less than 12 years old will receive either 2 mg/kg (if weight less than 20 kg) or 40 mg (if weight more than or equal to 20 kg) of Baloxavir Marboxil as oral suspension. IPs more than or equal to 12 years old will receive either 40 mg (if weight less than 80 kg) or 80 mg (if weight more than or equal to 80 kg) of Baloxavir Marboxil as tablets. HHCs of IPs will not receive study medication. intervention 2: IPs less than 12 years old will receive placebo oral suspension and those above 12 years will receive placebo tablets. HHCs of IPs will not receive study medication.

Protocol document:
Prot_000.pdf: 
PROTOCOL AMENDMENT APPROVAL
CONFIDENTIAL
This clinical study is being sponsored globally by F. Hoffmann-La Roche Ltd of Basel, 
Switzerland. However, it may be implemented in individual countries by Roche’s local affiliates, 
including Genentech, Inc. in the United States.  The information contained in this document, especially 
any unpublished data, is the property of F. Hoffmann-La Roche Ltd (or under its control) and therefore 
is provided to you in confidence as an investigator, potential investigator, or consultant, for review by 
you, your staff, and an applicable Ethics Committee or Institutional Review Board.  It is understood that 
this information will not be disclosed to others without written authorization from Roche except to the 
extent necessary to obtain informed consent from persons to whom the drug may be administered.
Baloxavir Marboxil—F. Hoffmann-La Roche Ltd
Protocol MV40618, Version 4
PROTOCOL
TITLE:
A PHASE IIIb, MULTICENTER, RANDOMIZED, 
DOUBLE-BLIND, PLACEBO-CONTROLLED, 
CLINICAL EFFICACY STUDY OF BALOXAVIR 
MARBOXIL FOR THE REDUCTION OF DIRECT 
TRANSMISSION OF INFLUENZA FROM 
OTHERWISE HEALTHY PATIENTS TO 
HOUSEHOLD CONTACTS
PROTOCOL NUMBER:
MV40618
VERSION NUMBER:
4
EUDRACT NUMBER:
2018-004056-37
IND NUMBER:
126653
NCT NUMBER:
NCT03969212
TEST PRODUCT:
Baloxavir marboxil (RO7191686) 
MEDICAL MONITOR:
 B.M., B.Ch.
SPONSOR:
F. Hoffmann-La Roche Ltd
APPROVAL DATE:
See electronic date stamp below.
 
Company Signatory
Approver's Name
Title
Date and Time (UTC)
29-Mar-2022 17:24:41


Baloxavir Marboxil—F. Hoffmann-La Roche Ltd
2/Protocol MV40618, Version 4
PROTOCOL HISTORY
Protocol
Version
Date Final
4
See electronic date stamp on title page.
3
10 August 2020
2
11 June 2019
1
14 March 2019


Baloxavir Marboxil—F. Hoffmann-La Roche Ltd
3/Protocol MV40618, Version 4
PROTOCOL AMENDMENT, VERSION 4:
RATIONALE
Protocol MV40618 has been amended to reduce the requirement from 2 or more 
household contacts (HHCs) to 1 or more HHCs to participate in the entire duration of the 
study (referred to herein as "full study" HHCs) and who have not received the influenza 
vaccine within 6 months prior to screening. In addition, index patients (IPs) who are 
12 years old who have received the oral suspension will be asked to answer a 
questionnaire regarding the palatability and acceptability of the study drug.
Changes to the protocol along with a rationale for each change are summarized below:

The name of the Medical Monitor has been changed (title page and Protocol 
Amendment Acceptance Form).

The background on clinical experience with baloxavir marboxil (BXM) has been 
updated to align with the recent data in Baloxavir Marboxil Investigator’s Brochure, 
Version 9 (Sections 1.2.2, 1.2.2.1, 1.2.2.4, and 1.2.2.5). Results of a new pediatric 
study (1813T0835) and a study (CP40617) in adult patients who are hospitalized 
with severe influenza have been added.

The description and background information on the cobasLiatsystem and assay 
tubes have been updated to remove reference to the use of the single assay cobas
Influenza A/B nucleic acid test as this is no longer in production. Sites will only be 
provided with the combination assay, cobas severe acute respiratory syndrome 
coronavirus 2 (SARS-CoV-2) & Influenza A/B nucleic acid test for use on the cobas 
Liat System (cobas SARS-CoV-2 & Influenza A/B test) (Sections 1.3, 3.4.6.1, 4.1.1, 
and 4.5.5.2). The description of the test has been revised to align with the most 
recent literature (Section 1.3). As a result, Table 1 has been removed and 
subsequent tables have been re-numbered.

For completeness, the benefitrisk assessment has been revised to include an 
assessment of SARS-CoV-2 infection (Section 1.4.2).

The secondary efficacy objective has been clarified to indicate the transmission of 
influenza A/B as virological or symptomatic to align with wording in the secondary 
efficacy endpoints (Section 2.1.2).

It has been clarified that HHCs bearing an amino acid substitution of isoleucine for 
another amino acid at position 38 (I38X) or other identified substitution in the
polymerase acidic (PA) protein require a matched PA substitution with their IP
(Section 2.1.3.1).

The assessment of infectious viral titer assays has been expanded and will be 
conducted on samples collected from IPs on Days 0, 3, 5, and 9, and not on Day 0 
only (Sections 2.1.3.1, 3.4.6.3, and 4.5.5.3). Such titer samples will be used to 
maximize the chance of identifying a relationship between viral titer load in IPs and 
the ability of BXM to prevent transmission to HHCs. No additional samples are 
required from IPs for this additional testing.


Baloxavir Marboxil—F. Hoffmann-La Roche Ltd
4/Protocol MV40618, Version 4

Clarification has been made that the EQ-5D-5L questionnaire and Work Productivity 
and Activity Impairment Questionnaire plus Classroom Impairment Questions are to 
be completed by IPs aged 12 years old because the questionnaires are not age 
appropriate for IPs 12 years old (Sections 2.3.1, 3.1, and 4.5.7, and Appendix 1a).

A palatability and acceptability endpoint has been added to address a request from 
the European Medicines Agency's Paediatric Committee to assess the acceptability 
of the BXM granules for the oral suspension for the treatment of pediatric patients 
(Section 2.4).
As a result, the following changes have also been made:
–
A description of the questionnaire has been added (Sections 3.1 and 4.5.8).
–
The questionnaire has been added at the screening study site visit in the 
schedule of activities for IPs 12 years of age (Appendix 1a).
–
An appendix describing the questionnaire has been added (Appendix 5).

The number of sites has been updated in the description of the study to reflect the 
current number of sites participating in the study (Sections 3.1 and 9.5).

The reduction in the required number of eligible unvaccinated HHCs per household 
from 2 or more HHCs to 1 or more HHCs has been incorporated to broaden 
potential households that may be eligible for enrollment (Sections 3.1, 3.3, 3.4.2, 
4.1.1, and 4.5.9). The change allows households with two occupants or those 
households from regions where the number of influenza vaccinations may have 
increased during the coronavirus disease 2019 (COVID-19) pandemic to participate 
in the study.

The total length of the study has been extended from 2.5 years to 3.5 years. Sites 
recruited fewer patients than expected due to a combination of weak 20202021 
and 20212022 influenza seasons at many sites and the impact of the COVID-19 
pandemic (Section 3.2).

Additional treatment-emergent amino acid substitutions in the polymerase acidic 
protein that have been associated with reduced susceptibility to BXM for 
influenza A/H1N1 have been added to align with recent data (Section 3.4.6.4).

The COVID-19 statistic has been removed as it does not reflect the impact of 
COVID-19 in 2022 following vaccination programs and the approval of targeted 
therapeutic agents (Section 3.4.6.7).

Favipiravir has been added as an exclusion criterion for IPs and HHCs and as a 
prohibited therapy for IPs and HHCs (Sections 4.1.1, 4.1.2, 4.4.1, and 4.4.2).

The potential risk factor "m" of the exclusion criterion 2 for IPs has been revised to 
align with the updated definition of "People at Higher Risk of Flu Complications"
provided by the Centers for Disease Control and Prevention (Section 4.1.2).

The regional stratification has been revised and replaced southern hemisphere with
"rest of world" as several new countries, including Mexico and India, are 
participating in the trial and do not strictly fit into the original three regions for 
stratification (United States or Europe, Asia, and southern hemisphere). An 


Baloxavir Marboxil—F. Hoffmann-La Roche Ltd
5/Protocol MV40618, Version 4
adjustment has also been made to the stratification for household size to account for 
the reduction in the required number of eligible unvaccinated HHCs per household
(Section 4.2).

The responsibilities of the investigator and the role of the Medical Monitor during 
study conduct have been clarified (Section 4.2).

Language has been added to indicate that sites can confirm that appropriate 
temperature conditions have been maintained during investigational medicinal 
product transit either by time monitoring (shipment arrival date and time) or 
temperature monitoring (Section 4.3.4).

Examples have been provided to help determine if a traditional Chinese medicine or 
other herbal remedies should be prohibited for IPs and HHCs (Sections 4.4.1 and 
4.4.2).

The description of the local analysis of respiratory samples has been updated as the 
single assay cobas Influenza A/B nucleic acid test is no longer in production and the 
preferred system for local influenza analysis for respiratory samples will be the 
cobas SARS-CoV-2 & Influenza A/B test. As both influenza and SARS-CoV-2 
results are being generated, sites are expected to supply both results, including 
when SARS-CoV-2 testing is not mandated by the protocol (Section 4.5.5.2).

Sequencing to evaluate reduced-susceptibility substitutions, additional genome 
sequencing (selected sites only), and phenotypic resistance assays for selected 
samples for central laboratory analysis have been added for IPs on the Day 3 visit to 
ensure all incidences of reduced susceptibility substitutions and related phenotypic 
resistance are identified (Section 4.5.5.3, Table 3).

HHCs will measure their temperature daily at bedtime and any time they feel 
feverish. It has been clarified that on the Day 9 (end of study) visit, body 
temperature must be measured during the visit either at the study site or at home as 
it would not be possible to take the bedtime measurement as HHCs would likely 
complete the Day 9 (end of study) visit earlier in the day (Section 4.5.6 and 
Appendix 1b).

Guidance has been added to clarify that adverse events associated with a special 
situation that also qualify as adverse events of special interest should be reported 
within 24 hours (Section 5.3.5.10).

Language has been added to indicate that the Informed Consent Form will instruct 
female patients to inform the investigator if they become pregnant (Section 5.4.3.1).

Language regarding investigator reporting of pregnancies has been clarified 
(Section 5.4.3.2).

Depending on the exact timing of the group-sequential interim analysis, it has been 
clarified that other acceptable boundaries may be preferable for efficiency reasons 
(Section 6.9.2).

A new section has been added to describe the implementation of a system to 
manage the quality of the study (Section 9.3).


Baloxavir Marboxil—F. Hoffmann-La Roche Ltd
6/Protocol MV40618, Version 4

Language has been modified to clarify that Roche's global policy on data sharing 
does not have requirements that must be met before study results can be made 
available (Section 9.6).

The name of a Roche policy on data sharing has been corrected (Section 9.6).

References have been revised based on changes made to the body of the protocol 
(Section 10).
Additional minor changes have been made to improve clarity and consistency
throughout the protocol. Substantive new information appears in italics. The Synopsis
and appendices have been updated accordingly.


Baloxavir Marboxil—F. Hoffmann-La Roche Ltd
7/Protocol MV40618, Version 4
TABLE OF CONTENTS
PROTOCOL AMENDMENT ACCEPTANCE FORM .......................................... 14
PROTOCOL SYNOPSIS .................................................................................... 15
1.
BACKGROUND ............................................................................ 26
1.1
Background on Influenza Virus Infection ................................. 26
1.2
Background on Baloxavir Marboxil .......................................... 26
1.2.1
Previous Non-Clinical Studies.................................................. 26
1.2.1.1
Toxicology and Safety Pharmacology...................................... 27
1.2.2
Previous Clinical Experience ................................................... 28
1.2.2.1
Completed Phase 3 Studies in Otherwise Healthy 
Influenza Patients .................................................................... 28
1.2.2.2
Completed Phase 3 Study in High-Risk Influenza Patients ..... 32
1.2.2.3
Completed Phase 3 Post-Exposure Prophylaxis Study ........... 32
1.2.2.4
Completed Phase 3 Study in Hospitalized Patients with 
Severe Influenza (Aged 12 Years Old) ................................. 33
1.2.2.5
Pharmacokinetics .................................................................... 34
1.2.3
Postmarketing Safety Data ...................................................... 35
1.3
Background on the cobasSARS-CoV-2 & Influenza A/B 
Nucleic Acid Test for Use on the cobas LiatSystem.............. 36
1.4
Study Rationale and BenefitRisk Assessment....................... 37
1.4.1
Study Rationale ....................................................................... 37
1.4.2
BenefitRisk Assessment ........................................................ 38
2.
OBJECTIVES AND ENDPOINTS ................................................. 40
2.1
Efficacy Objectives .................................................................. 40
2.1.1
Primary Efficacy Objective....................................................... 40
2.1.1.1
Primary Efficacy Endpoint........................................................ 40
2.1.2
Secondary Efficacy Objective .................................................. 40
2.1.2.1
Secondary Efficacy Endpoints ................................................. 40
2.1.3
Other Efficacy Objective .......................................................... 41
2.1.3.1
Other Efficacy Endpoints ......................................................... 41
2.2
Safety Objective....................................................................... 42
2.2.1
Safety Endpoints...................................................................... 42
2.3
Health Status Utility Objective.................................................. 42


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2.3.1
Health Status Utility Endpoints................................................. 42
2.4
Additional Objective................................................................ 43
3.
STUDY DESIGN ........................................................................... 43
3.1
Description of the Study........................................................... 43
3.2
End of Study and Length of Study ........................................... 45
3.3
Study Schema ......................................................................... 45
3.4
Rationale for Study Design ...................................................... 47
3.4.1
Rationale for Baloxavir Marboxil Dose and Schedule.............. 47
3.4.2
Rationale for Patient Population and Analysis Groups ............ 47
3.4.3
Rationale for Study Duration.................................................... 48
3.4.4
Rationale for Selection of Symptoms Assessed in 
Household Contacts and the Definition of Clinical Influenza.... 49
3.4.5
Rationale for Control Group..................................................... 50
3.4.6
Rationale for Virology Assessments ........................................ 51
3.4.6.1
Diagnosis of Influenza A/B Infection ........................................ 51
3.4.6.2
Viral Type and Subtype Assessment....................................... 51
3.4.6.3
Viral Titer Assessment............................................................. 52
3.4.6.4
Analysis of Viruses with Reduced Susceptibility to 
Baloxavir Marboxil ................................................................... 52
3.4.6.5
Viral Genome Sequencing....................................................... 52
3.4.6.6
Other Viral Parameters ............................................................ 53
3.4.6.7
Diagnosis of SARS-CoV-2 Infection ........................................ 53
4.
MATERIALS AND METHODS ...................................................... 54
4.1
Index Patients and Household Contacts.................................. 54
4.1.1
Inclusion Criteria...................................................................... 54
4.1.2
Exclusion Criteria..................................................................... 56
4.2
Method of Treatment Assignment and Blinding ....................... 59
4.3
Study Treatment and Other Treatments Relevant to the 
Study Design ........................................................................... 60
4.3.1
Study Treatment Formulation, Packaging, and Handling......... 60
4.3.1.1
Baloxavir Marboxil and Placebo............................................... 60
4.3.2
Study Treatment Dosage, Administration, and Compliance .... 60
4.3.2.1
Baloxavir Marboxil and Placebo............................................... 60


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4.3.3
Additional Medication............................................................... 61
4.3.4
Investigational Medicinal Product Accountability ..................... 61
4.3.5
Continued Access to Baloxavir Marboxil.................................. 61
4.4
Concomitant Therapy .............................................................. 62
4.4.1
Permitted and Prohibited Therapy for the Index Patient .......... 62
4.4.2
Permitted and Prohibited Therapy for the Full Study HHCs..... 62
4.4.3
Cautionary Therapy and Foods for Index Patients................... 63
4.5
Study Assessments ................................................................. 63
4.5.1
Informed Consent Forms and Screening Log .......................... 64
4.5.2
Medical History, Concomitant Medication, and 
Demographic Data................................................................... 64
4.5.3
Physical Examinations............................................................. 65
4.5.4
Vital Signs................................................................................ 65
4.5.5
Laboratory and Other Biological Samples ............................... 65
4.5.5.1
Respiratory Samples ............................................................... 65
4.5.5.2
Local Analysis of Respiratory Samples.................................... 66
4.5.5.3
Central Laboratory Analyses.................................................... 67
4.5.5.4
Other Laboratory Samples....................................................... 69
4.5.5.5
Sample Procedures and Storage............................................. 70
4.5.6
Household Contact Symptoms and Temperature.................... 70
4.5.7
Patient-Reported Outcomes .................................................... 71
4.5.8
Palatability and Acceptability ................................................. 71
4.5.9
Household Contact Screening (including Late-Arrival 
HHCs)...................................................................................... 71
4.6
Treatment, Patient, Study, and Site Discontinuation................ 72
4.6.1
Study Treatment Discontinuation............................................. 72
4.6.2
Subject Discontinuation from Study......................................... 72
4.6.3
Study Discontinuation.............................................................. 73
4.6.4
Site Discontinuation................................................................. 74
5.
ASSESSMENT OF SAFETY......................................................... 74
5.1
Safety Plan .............................................................................. 74
5.1.1
Risks Associated with Baloxavir Marboxil................................ 74
5.1.2
Management of Study Participants Who Experience 
Adverse Events........................................................................ 75


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5.1.2.1
Dose Modifications .................................................................. 75
5.1.2.2
Treatment Interruption ............................................................. 75
5.2
Safety Parameters and Definitions .......................................... 75
5.2.1
Adverse Events........................................................................ 75
5.2.2
Serious Adverse Events (Immediately Reportable to the 
Sponsor) .................................................................................. 76
5.2.3
Adverse Events of Special Interest (Immediately 
Reportable to the Sponsor)...................................................... 76
5.3
Methods and Timing for Capturing and Assessing 
Safety Parameters................................................................... 77
5.3.1
Adverse Event Reporting Period.............................................. 77
5.3.2
Eliciting Adverse Event Information ......................................... 78
5.3.3
Assessment of Severity of Adverse Events ............................. 78
5.3.4
Assessment of Causality of Adverse Events............................ 78
5.3.5
Procedures for Recording Adverse Events.............................. 79
5.3.5.1
Infusion-Related or Injection Reactions ................................... 79
5.3.5.2
Diagnosis versus Signs and Symptoms................................... 80
5.3.5.3
Adverse Events That Are Secondary to Other Events............. 80
5.3.5.4
Persistent or Recurrent Adverse Events.................................. 80
5.3.5.5
Abnormal Liver Function Tests ................................................ 81
5.3.5.6
Deaths ..................................................................................... 81
5.3.5.7
Preexisting Medical Conditions................................................ 82
5.3.5.8
Lack of Efficacy or Worsening of Influenza Virus Infection ...... 82
5.3.5.9
Hospitalization or Prolonged Hospitalization............................ 82
5.3.5.10
Cases of Accidental Overdose or Medication Error ................. 83
5.3.5.11
Patient-Reported Outcome Data.............................................. 84
5.4
Immediate Reporting Requirements from Investigator to 
Sponsor ................................................................................... 84
5.4.1
Emergency Medical Contacts .................................................. 84
5.4.2
Reporting Requirements for Serious Adverse Events and 
Adverse Events of Special Interest.......................................... 85
5.4.2.1
Events That Occur prior to Study Drug Initiation...................... 85
5.4.2.2
Events That Occur after Study Drug Initiation (Index 
Patients Only) .......................................................................... 85
5.4.3
Reporting Requirements for Pregnancies................................ 85


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5.4.3.1
Pregnancies in Female Index Patients .................................... 85
5.4.3.2
Pregnancies in Female Partners of Male Index Patients ......... 86
5.4.3.3
Abortions.................................................................................. 86
5.4.3.4
Congenital Anomalies/Birth Defects ........................................ 87
5.4.4
Reporting Requirements for Medical Device Complaints......... 87
5.5
Follow-Up of Patients after Adverse Events............................. 87
5.5.1
Investigator Follow-Up ............................................................. 87
5.5.2
Sponsor Follow-Up .................................................................. 87
5.6
Adverse Events That Occur after the Adverse Event 
Reporting Period...................................................................... 87
5.7
Expedited Reporting to Health Authorities, Investigators, 
Institutional Review Boards, and Ethics Committees............... 88
6.
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN......... 88
6.1
Determination of Sample Size ................................................. 89
6.2
Summaries of Conduct of Study .............................................. 89
6.3
Summaries of Demographic and Baseline Characteristics ...... 89
6.4
Efficacy Analyses..................................................................... 89
6.4.1
Primary Efficacy Endpoint........................................................ 89
6.4.2
Secondary Efficacy Endpoints ................................................. 90
6.4.3
Other Efficacy Endpoints ......................................................... 91
6.5
Safety Analyses....................................................................... 91
6.6
Pharmacokinetic Analyses....................................................... 91
6.7
Immunogenicity Analyses ........................................................ 91
6.8
Analysis of Subgroups............................................................. 91
6.9
Interim Analyses ...................................................................... 92
6.9.1
Planned Interim Analyses ........................................................ 92
6.9.2
Optional Interim Analyses........................................................ 92
7.
DATA COLLECTION AND MANAGEMENT ................................. 93
7.1
Data Quality Assurance ........................................................... 93
7.2
Electronic Case Report Forms................................................. 93
7.3
Source Data Documentation.................................................... 94
7.4
Use of Computerized Systems ................................................ 94
7.5
Retention of Records............................................................... 94


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8.
ETHICAL CONSIDERATIONS...................................................... 95
8.1
Compliance with Laws and Regulations .................................. 95
8.2
Informed Consent .................................................................... 95
8.3
Institutional Review Board or Ethics Committee ...................... 96
8.4
Confidentiality .......................................................................... 97
8.5
Financial Disclosure................................................................. 97
9.
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION ....................................................................... 98
9.1
Study Documentation .............................................................. 98
9.2
Protocol Deviations.................................................................. 98
9.3
Management of Study Quality ................................................ 98
9.4
Site Inspections ....................................................................... 98
9.5
Administrative Structure........................................................... 98
9.6
Dissemination of Data and Protection of Trade Secrets .......... 99
9.7
Protocol Amendments ........................................................... 100
10.
REFERENCES............................................................................ 101
LIST OF TABLES
Table 1
Study Drug Administration and Dose for Index Patients 
12 Years Old............................................................................ 60
Table 2
Study Drug Administration and Dose for Index Patients 
12 Years Old............................................................................ 61
Table 3
Central Laboratory Assessments on Respiratory Samples 
Obtained From Index Patients and Household Contacts on 
the Visits Indicated...................................................................... 69
Table 4
Adverse Event Severity Grading Scale for Events Not 
Specifically Listed in NCI CTCAE ............................................... 78
Table 5
Causal Attribution Guidance ....................................................... 79
Table 6
Confirmatory Hierarchical Order for Secondary Efficacy 
Endpoints.................................................................................... 90
LIST OF FIGURES
Figure 1
Study Schema............................................................................. 46


Baloxavir Marboxil—F. Hoffmann-La Roche Ltd
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LIST OF APPENDICES
Appendix 1a
Schedule of Activities for the Index Patient............................... 106
Appendix 1b
Schedule of Activities for Each Household Contact .................. 108
Appendix 2
Symptoms Assessed in the Full Study Household Contacts..... 110
Appendix 3
EQ-5D-5L to Measure Quality of Life........................................ 113
Appendix 4
Work Productivity and Activity Impairment Questionnaire  
plus Classroom Impairment Questions: SHP, Version 2 
(WPAICIQ:SHP, V2) ............................................................... 115
Appendix 5
Palatability and Acceptability Questionnaire of Study Drug 
(Index Patients Aged 5 Years Old to 12 Years Old).............. 118


Baloxavir Marboxil—F. Hoffmann-La Roche Ltd
14/Protocol MV40618, Version 4
PROTOCOL AMENDMENT ACCEPTANCE FORM
TITLE:
A PHASE IIIb, MULTICENTER, RANDOMIZED, 
DOUBLE-BLIND, PLACEBO-CONTROLLED, 
CLINICAL EFFICACY STUDY OF BALOXAVIR 
MARBOXIL FOR THE REDUCTION OF DIRECT 
TRANSMISSION OF INFLUENZA FROM 
OTHERWISE HEALTHY PATIENTS TO 
HOUSEHOLD CONTACTS
PROTOCOL NUMBER:
MV40618
VERSION NUMBER:
4
EUDRACT NUMBER:
2018-004056-37
IND NUMBER:
126653
NCT NUMBER:
NCT03969212
TEST PRODUCT:
Baloxavir marboxil (RO7191686)
MEDICAL MONITOR:
 B.M., B.Ch.
SPONSOR:
F. Hoffmann-La Roche Ltd
I agree to conduct the study in accordance with the current protocol.
Principal Investigator's Name (print)
Principal Investigator's Signature
Date
Please retain the signed original of this form for your study files. Please return a copy 
as instructed by your local study monitor.


Baloxavir Marboxil—F. Hoffmann-La Roche Ltd
15/Protocol MV40618, Version 4
PROTOCOL SYNOPSIS
TITLE:
A PHASE IIIb, MULTICENTER, RANDOMIZED, DOUBLE-BLIND,
PLACEBO-CONTROLLED, CLINICAL EFFICACY STUDY OF 
BALOXAVIR MARBOXIL FOR THE REDUCTION OF DIRECT 
TRANSMISSION OF INFLUENZA FROM OTHERWISE HEALTHY 
PATIENTS TO HOUSEHOLD CONTACTS
PROTOCOL NUMBER:
MV40618
VERSION NUMBER:
4
EUDRACT NUMBER:
2018-004056-37
IND NUMBER:
126653
NCT NUMBER:
NCT03969212
TEST PRODUCT:
Baloxavir marboxil (RO7191686)
PHASE:
Phase IIIb
INDICATION:
Influenza
SPONSOR:
F. Hoffmann-La Roche Ltd
OBJECTIVES AND ENDPOINTS
This study will evaluate the efficacy of a single, oral dose of baloxavir marboxil (BXM) compared 
with placebo for the reduction of the direct transmission rate of influenza A/B from otherwise 
healthy (OwH) index patients (IPs) to household contacts (HHCs). Specific objectives and 
corresponding endpoints for the study are outlined below.
Objectives and their associated Endpoints
Primary Efficacy Objective: To evaluate the efficacy of a single, oral dose of BXM compared 
with placebo to prevent secondary within-household transmission of influenza A/B.
Primary Efficacy Endpoint

Virological transmission by Day 5: Proportion of HHCs who become PCR () [confirmed 
at central laboratory] for influenza by Day 5 visit, with virus subtype consistent with IP.
Secondary Efficacy Objective: To evaluate the efficacy of a single, oral dose of BXM 
compared with placebo to prevent virological or symptomatic transmission of influenza A/B and 
effects beyond secondary within-household transmission.
Secondary Efficacy Endpoints

Symptomatic transmission by Day 5: Proportion of HHCs who become PCR () 
[confirmed at central laboratory] for influenza by Day 5 visit, with virus subtype consistent 
with IP, AND:

For HHC aged 12 years:

Temperature 38.0C* and one respiratory symptom, OR

One respiratory symptom and one general systemic symptom (with or 
without fever).

For HHC aged 2 to 12 years:

Temperature 38.0C* AND signs or symptoms of an upper respiratory tract 
infection.


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
Symptoms must be either new, or have worsened versus baseline in HHC with 
baseline symptoms due to a preexisting comorbidity.

* Temperature obtained from tympanic thermometers provided to households 
(or exceptionally from other thermometers/locations in case of tympanic 
thermometer failure for any reason).

Virological transmission at the household level by Day 5: Proportion of households with 
at least one HHC who meets the primary endpoint.

Symptomatic transmission at the household level by Day 5: Proportion of households 
with at least one HHC who meets the “Symptomatic transmission by Day 5” endpoint.

Virological transmission by Day 9: Proportion of HHCs who become PCR () (confirmed 
at central laboratory) for influenza by Day 9 visit, with virus subtype consistent with IP, 
including:

(1) all HHC meeting primary endpoint, AND

(2) all HHC cases detected after Day 5 visit meeting the following criteria:

Included HHC case is in a household where another HHC has already met 
the primary endpoint, OR

Included HHC case is PCR () [confirmed at central laboratory] for influenza 
bearing an amino acid substitution of isoleucine for another amino acid at 
position 38 (I38X) in the polymerase acidic (PA) protein (PA/I38X 
substitution) (or other identified substitutions).

Symptomatic transmission by Day 9: Proportion of HHCs who meet the “Virological 
transmission by Day 9” endpoint AND are symptomatic per the definition for symptoms in the 
“Symptomatic transmission by Day 5” endpoint.

Any virological infection by Day 9: Proportion of HHCs who become PCR () for influenza 
(confirmed at central laboratory) by Day 9.

Any virological infection at the household level by Day 9: Proportion of households with 
at least one HHC who meets the “Any virological infection by Day 9” endpoint.

Any symptomatic infection by Day 9: Proportion of HHCs who meet the “Any virological 
infection by Day 9” endpoint AND are symptomatic per the definition for symptoms in the 
“Symptomatic transmission by Day 5” endpoint.

Any symptomatic infection at the household level by Day 9: Proportion of households 
with at least one HHC who meets the “Any symptomatic infection by Day 9” endpoint.
Other Efficacy Objective: To further evaluate the efficacy of a single, oral dose of BXM 
compared with placebo to prevent transmission of influenza A/B.
Other Efficacy Endpoints

The effect of IP baseline viral titer on the rate of direct transmission of influenza A or 
influenza B to HHCs.

BXM arm only: Proportion of IPs who are PCR () [confirmed at central laboratory] for 
influenza bearing a PA/I38X substitution (or other identified substitution) post randomization.

BXM arm only: Proportion of HHCs who become PCR () [confirmed at central laboratory] 
for influenza bearing a PA/I38X substitution (or other identified substitution) with matched 
PA substitution with their IP by Day 9 visit.

BXM arm only: Proportion of symptomatic cases among HHCs who become PCR () 
[confirmed at central laboratory] for influenza bearing a PA/I38X substitution (or other 
identified substitution) with matched PA substitution with their IP by Day 9 visit (utilizing 
same symptoms definition as used for secondary symptomatic transmission endpoint).

Proportion of HHC who become PCR () [confirmed at central laboratory] for influenza by 
Day 9 visit, with virus subtype consistent with IP.

Measurement of viral titer by PCR and TCID50 in IPs over the Day 0, 3, 5, and 9 visits.

Subgroup analysis: endpoints requiring a subtype match will be assessed with a match 
based on sequencing in a subset of households (sequencing will be performed for samples 
from selected sites and countries based on feasibility, including availability of adequate 
number of IP sequences for specific community).


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Safety Objective: To evaluate the safety and tolerability of a single, oral dose of BXM compared 
with placebo.
Safety Endpoints

IP only: The incidence, severity, and timing of adverse events, and serious adverse events.
Health Status Utility Objective: To evaluate IPs treated with BXM compared with those 
receiving placebo.
Health Status Utility Endpoints

IP 12 years old only: Change from baseline in health-related quality of life according to 
EQ-5D-5L questionnaire at Day 3 and Day 9 visits.

IP 12 years old only: Work Productivity and Activity Impairment Questionnaire plus 
Classroom Impairment Questions: SHP, Version 2 (WPAICIQ:SHP, V2) to measure lost 
work or school days assessed at Day 9 visit.
Additional Objective: To describe the palatability and acceptability of BXM oral suspension 
in IPs 12 years old
Additional Endpoint

Proportion of IPs reporting each palatability and acceptability response
STUDY DESIGN
DESCRIPTION OF THE STUDY
This is a randomized, double-blind, multicenter, parallel-group, placebo-controlled study 
designed to evaluate the clinical efficacy of BXM for the reduction of direct transmission of 
influenza A/B from OwH IPs to their HHCs. For this household study, IPs with influenza will be 
randomized to receive BXM or placebo, and their HHCs will be repeatedly tested for influenza 
virus and assessed for influenza symptoms during the next 9 days. The total number of new 
HHC infections (symptomatic and asymptomatic) and total number of new HHC infections 
associated with symptoms will be key measures used to evaluate the “virological transmission” 
and “symptomatic transmission” endpoints.
Approximately 1,130 IPs with influenza and approximately 2,030 evaluable HHCs will participate 
in the study.
Index Patient: Screening and Randomization
Eligible IPs must be aged from 5 to 64 years old, have influenza symptom onset within 
48 hours, test positive for influenza A/B, and be OwH (i.e., not at high risk for complications of 
influenza). Screening assessments informing IP eligibility include physical examination, vital 
signs, height and weight, medical history and concomitant therapies, urine pregnancy testing, 
and respiratory sampling for influenza testing.
With regard to the household, IPs should be determined at screening to live with 1 or 
more HHCs who have not received an influenza vaccine in the past 6 months (“unvaccinated 
HHCs”), are likely to fulfill all HHC eligibility criteria, and are expected to participate in the “full 
study” (i.e., participate in all study assessments).
IPs who meet the eligibility criteria will be randomized in a 1:1 ratio to receive a single dose of 
either BXM or placebo within 2 hours of randomization. The dose and formulation of BXM is 
based on weight and age.
Index Patient: Post-Randomization
Respiratory samples and AEs will be collected. IPs who are 12 years old will also complete 
questionnaires describing their health status and absence from work or school. IPs who are 
12 years old will be asked to complete a questionnaire on the palatability and acceptability of 
the study drug oral suspension.
Household Contacts: Screening and Enrollment
All HHCs present in the home must have their screening visit start within 24 hours of IP 
randomization. If any HHC tests positive for influenza A/B, then all HHCs fail screening. If 1 or 
more unvaccinated HHCs meet all HHC eligibility criteria and agree to participate in the full 
study, it is allowable for additional HHCs to not participate beyond the screening visit (even if 


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they meet all HHC eligibility criteria). There is no maximum number of vaccinated and 
unvaccinated HHCs that can participate in the full study. 
HHCs who agree to participate in the full study (“full study HHCs”) must meet the full study 
criteria (HHC inclusion criteria 7 to 14), including that they must reside in the household for 7 of 
the 9 study days, and must not have any influenza symptoms at screening (mild symptoms 
determined by the investigator to be due to a preexisting condition are allowed).
Screening assessments informing HHC eligibility include influenza symptoms, medical history, 
concomitant medications, and respiratory sampling for influenza testing.
Full Study Household Contacts: Post-Screening
Only full study HHCs participate in visits and assessments post-screening. Full study HHCs are 
monitored for new or worsening influenza symptoms, and will also maintain a daily temperature 
diary. HHCs will be instructed to telephone the site if they develop influenza symptoms or fever 
so that a scheduled or unscheduled visit occurring within 24 hours can be arranged. Respiratory 
samples, adverse events due to study procedures, and concomitant medications will be 
collected.
Study Visits
The IP screening visit must occur at the study site. All other visits for IPs and HHCs may be 
conducted at home or at the study site. Home visits may be performed by home nurses or by 
site staff (if local practices are in place). All assessments except respiratory swab collection may 
be conducted remotely (e.g., via telephone or computer).
SARS-CoV-2 Testing
Given overlapping influenza and coronavirus disease 2019 symptoms, severe acute respiratory 
syndrome coronavirus 2 (SARS-CoV-2) testing will be conducted at screening and as needed 
during study conduct. If any subject (IP or HHC) tests positive for SARS-CoV-2, then all 
subjects in the household should be discontinued.
Independent Data Monitoring Committee
An external independent Data Monitoring Committee (iDMC) will evaluate safety according to 
policies and procedures detailed in an iDMC Charter.
NUMBER OF PATIENTS
The proposed sample size for this study is 2,030 evaluable HHCs. Assuming a 15% drop-out for 
inclusion of HHCs into the primary analysis population, an average of 2.5 HHCs per IP and a 
15% exclusion rate on the household level, this equates to an approximate number of IPs of 
1,130.
Target Population
Inclusion Criteria
Inclusion Criteria: Index Patients
Each IP must meet the following criteria for study entry:
1.
Signed Informed Consent Form (ICF). In the case of minors, a parent or authorized adult 
will be required to sign the ICF on behalf of the patient. The informed consent/assent of 
voluntary participation should be obtained in accordance with local requirements.
2.
Age 5 and 64 years at time of signing ICF.
3.
Able to comply with the study protocol per investigator judgment.
4.
Diagnosed with acute influenza infection by investigator.
5.
PCR () or RIDT () for influenza A/B based on cobasSARS-CoV-2 & Influenza A/B test
or other point-of-care/local laboratory results.
6.
PCR () or antigen test () for SARS-CoV-2 based on cobas SARS-CoV-2 & Influenza 
A/B test or other point-of-care/local laboratory result.
7.
Presence of (a) fever (38.0C per tympanic or rectal thermometer; 37.5C per axillary, 
oral or forehead/temporal thermometer) or (b) any influenza symptoms (cough, sore throat, 
nasal congestion, headache, feverishness or chills, muscle or joint pain, fatigue).
8.
The time interval between the onset of fever or influenza symptoms and the pre-dose 
examinations is 48 hours or less.


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9.
IP lives in a household where:
a. No HHC is known to have been diagnosed with influenza or SARS-CoV-2 infection
by a healthcare professional in the past 4 weeks.
b. All HHCs are expected to meet the key HHC inclusion criteria (criteria 1, 2, 3, 4, 5, 
and 6).
c. 1 or more HHCs are expected to participate in the full study who have not received
the influenza vaccine within 6 months prior to screening.
10. For women of childbearing potential: agreement to remain abstinent (refrain from 
heterosexual intercourse) or use contraceptive measures as defined below:
Women must remain abstinent or use contraceptive methods with a failure rate of 1% 
per year during the treatment period and for 21 days after the final dose of study 
treatment.
A woman is considered to be of childbearing potential if she is postmenarcheal, has 
not reached a postmenopausal state (12 continuous months of amenorrhea with no 
identified cause other than menopause), and is not permanently infertile due to surgery 
(i.e., removal of ovaries, fallopian tubes, and/or uterus) or another cause as 
determined by the investigator (e.g., Müllerian agenesis).
Examples of contraceptive methods with a failure rate of 1% per year include bilateral 
tubal ligation, male sterilization, hormonal contraceptives that inhibit ovulation, 
hormone-releasing intrauterine devices, and copper intrauterine devices.
Hormonal contraceptive methods must be supplemented by a barrier method.
The reliability of sexual abstinence should be evaluated in relation to the duration of 
the clinical trial and the preferred and usual lifestyle of the patient. Periodic abstinence 
(e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal 
are not acceptable methods of contraception. If required per local guidelines or 
regulations, locally recognized acceptable methods of contraception and information 
about the reliability of abstinence will be described in the local Informed Consent Form.
Inclusion Criteria: All Household Contacts 
Each HHC living in the home at any time during the study must meet criteria 1‒6 below. The 
screening visit should start within 24 hours after IP randomization unless the HHC is a 
late-arrival HHC.
1.
Signed ICF. In the case of minors, a parent or authorized adult will be required to sign the 
ICF on behalf of the HHC. The informed consent/assent of voluntary participation should be 
obtained in accordance with local requirements. All late-arrival HHCs must be willing to be 
consented for screening as soon as possible after their arrival.
2.
PCR () or RIDT () based on cobas SARS-CoV-2 & Influenza A/B test or other local 
point-of-care/local laboratory result. 
3.
PCR () or antigen test () for SARS-CoV-2 based on cobas SARS-CoV-2 & Influenza 
A/B test or other POC/local laboratory result.
4.
HHC lives with no HHC who will be present in the home at any time during the study and 
who meets any HHC exclusion criteria.
5.
HHC lives with no HHC (except late-arrival HHCs) who does not meet HHC inclusion 
criteria 16.
6.
HHC lives in a household where 1 or more HHCs meet all of the following:
a. Start screening within 24 hours after IP randomization.
b. Have NOT received the influenza vaccine within 6 months prior to screening.
c. Fulfill full study HHC inclusion criteria 7‒14.
Inclusion Criteria: Full Study Household Contacts
Each HHC intended for full study must meet the following additional criteria:
7.
Agree to participate in the full study (i.e., participate in all assessments after screening). 
8.
Able to comply with the study protocol per investigator judgment. 


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9.
No influenza symptoms within 7 days prior to screening. Alternatively, mild symptoms 
(at worst) are permissible if determined by the investigator to be due to a preexisting 
condition (e.g., mild nasal congestion due to seasonal allergies).
a. Symptoms for HHC 12 years old: cough, sore throat, nasal congestion, headache, 
feverishness or chills, muscle or joint pain, fatigue. 
b. Symptoms for HHC 2 to 12 years old: cough, nasal congestion or rhinorrhea.
10. Temperature 38.0C (tympanic).
11. Will reside in the IP’s house for at least 7 of the next 9 days and will be present for 
scheduled study visits.
12. Willing and able to measure and record temperature, or have another household member 
perform the task on his or her behalf. Furthermore, a responsible adult will assume 
responsibility to oversee or perform this task on behalf of minors.
13. In the 6 months prior to screening:
a. Has not been diagnosed with influenza by a healthcare professional
b. Has not received BXM, peramivir, laninamivir, oseltamivir, zanamivir, rimantadine, 
umifenovir, amantadine, or favipiravir
14. Does not have a moderate or worse active infections OR infections requiring systemic 
(e.g., oral or intravenous) or otherwise internally administered (e.g., inhaled, intrathecal) 
antibiotic/antiviral/antifungal therapy, (topical therapies for mild external infections allowed).
Exclusion Criteria
Exclusion Criteria: Index Patients
An IP meeting any of the following criteria will be excluded from the study:
1.
IP with severe influenza virus infection requiring inpatient treatment.
2.
IP judged by the investigator to be at high risk for complications of influenza, after 
consideration of the following* or other potential risk factors:
a.
Women who are pregnant or within 2 weeks post-partum;
b.
Chronic respiratory diseases including chronic obstructive pulmonary disease, 
current asthma, and cystic fibrosis;
c.
Neurological and neurodevelopmental disorders including disorders of the brain, 
spinal cord, peripheral nerve, and muscle (e.g., cerebral palsy, epilepsy [seizure 
disorders], stroke, intellectual disability, moderate to severe developmental delay, 
muscular dystrophy, or spinal cord injury);
d.
Heart disease (such as congenital heart disease, congestive heart failure, or 
coronary artery disease);
e.
Blood disorders (such as sickle cell disease);
f.
Endocrine disorders (such as diabetes mellitus);
g.
Kidney disorders;
h.
Liver disorders;
i.
Metabolic disorders (such as inherited metabolic disorder and mitochondrial 
disorders);
j.
Compromised immune system due to disease (such as people with HIV or AIDS, or 
some cancers such as leukemia) or medications (such as those receiving 
chemotherapy or radiation treatment for cancer, or persons with chronic conditions 
requiring chronic corticosteroids or other drugs that suppress the immune system);
k.
Morbid obesity (body mass index [BMI] 40);
l.
People younger than 19 years of age on long-term aspirin- or salicylate-containing 
medications;
m. People from certain racial and ethnic minority groups are at increased risk for 
hospitalization with influenza, including non-Hispanic Black persons, Hispanic 
or Latino persons, and American Indian or Alaska Native persons. The investigator 
should consider the overall risk of the individual.;


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n.
People who live in nursing homes and other long-term care facilities.
* Adapted from the definition of “People at Higher Risk of Flu Complications” provided by 
the Centers for Disease Control and Prevention
3.
IP is 12 years old and unable to swallow tablets (not applicable to IPs 5 to 12 year olds 
who will receive oral suspension).
4.
Women who are breastfeeding or have a positive pregnancy test in the pre-dose 
examinations. Female patients with documentation of at least one of the following items are 
exempt from pregnancy testing:
a.
Postmenopausal women (defined as cessation of regular menstrual periods for 
12 continuous months).
b.
Women who are surgically sterile by hysterectomy, bilateral oophorectomy, or tubal 
ligation.
c.
Females 12 years old and pre-menarcheal.
5.
IP with concurrent (non-influenza) infections requiring systemic antimicrobial and/or antiviral 
therapy at the pre-dose examinations.
6.
IP who has received BXM, peramivir, laninamivir, oseltamivir, zanamivir, rimantadine, 
umifenovir, amantadine, or favipiravir within 30 days prior to screening.
7.
IP who has received an investigational monoclonal antibody for a viral disease in the last 
year.
8.
IP who has received an investigational therapy within 30 days or 5 drug-elimination 
half-lives, whichever is longer, prior to screening.
9.
IP lives with an HHC who, based on available information, is:
a.
Pregnant or within 2 weeks post-partum.
b.
Immunocompromised (including patients receiving immunosuppressant therapy, or 
those with cancer or HIV infection).
c.
2 years old.
d.
Unwilling to sign informed consent.
e.
Diagnosed with influenza or SARS-CoV-2 infection by a healthcare professional in 
the past 4 weeks.
f.
Previously included in the study.
g.
Plan to arrive home from after 24 hours post IP randomization to Day 9 and 
(late-arrival HHC defined in Section 4.5.9 of the protocol) is not willing to be 
consented as soon as possible upon arrival.
10. Known hypersensitivity to BXM or the drug product excipients.
11. Any other contraindication for treatment with BXM as deemed by the treating physician or 
Principal Investigator.
12. IP previously included in the study.
Exclusion Criteria: All Household Contacts
An HHC (living in the home at any time during the study) meeting any of the following criteria 
will be excluded from study entry:
1.
Pregnant or within 2 weeks post-partum at screening.
2.
Immunocompromised (including patients receiving immunosuppressant therapy, or those 
with cancer or HIV infection).
3.
2 years old.
4.
Received an investigational therapy within 30 days or 5 drug-elimination half-lives, 
whichever is longer, prior to screening. 
5.
Diagnosed with influenza or SARS-CoV-2 infection by a healthcare professional in the past 
4 weeks. 
6.
HHC previously included in the study.


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7.
HHC who plans to arrive home after 24 hours post IP randomization to Day 9 and is not 
willing to be consented as soon as possible upon arrival.
END OF STUDY
The end of this study is defined as the date when the last patient, last visit occurs. The end of 
the study for all patients (except IPs 12 years old) is expected to occur 9 days after the last IP 
is enrolled. For IPs 12 years old, the last visit will be Day 21.
LENGTH OF STUDY
The expected study duration for both IPs and full study HHCs is 9 days, and study duration for 
IPs 12 years old is 21 days. The total length of the study, from screening of the first patient to 
the end of the study, is expected to be approximately 3.5 years.
INVESTIGATIONAL MEDICINAL PRODUCTS
BALOXAVIR MARBOXIL AND PLACEBO
IPs will receive the initial and only dose of study drug (BXM or matching placebo) to be taken in 
tablet or oral suspension form at the study center within 2 hours of randomization. IPs will be 
dosed according to age and body weight as listed below.
STUDY DRUG ADMINISTRATION AND DOSE FOR INDEX PATIENTS 12 YEARS OLD
Weight
Dose, Formulation
20 kg 
2 mg/kg, oral suspension
20 kg 
40 mg, oral suspension
STUDY DRUG ADMINISTRATION AND DOSE FOR INDEX PATIENTS 12 YEARS OLD
Weight
Dose, Formulation
80 kg
40 mg, (two 20 mg tablets)
80 kg 
80 mg, (four 20 mg tablets)
NON-INVESTIGATIONAL MEDICINAL PRODUCTS
During the study, influenza antiviral drugs are among the prohibited concomitant medications for 
IPs and full study HHCs. Symptomatic therapies without antiviral properties are permitted for all 
subjects. Antivirals are only permitted for full study HHCs as soon as they are diagnosed with 
influenza A/B, and their further treatment will be determined by the investigator according to 
local standards. The study sponsor will not provide treatment beyond the investigational 
medicinal products.
STATISTICAL METHODS
PRIMARY ANALYSIS
The primary efficacy analysis population will consist of all unvaccinated full study HHCs in 
households where all HHCs were confirmed at screening to be PCR negative and the IP was 
confirmed at screening to be PCR positive for influenza A/B. Supportive analyses including all 
full study HHCs of all randomized IPs will be performed. Treatment groups will be defined based 
on the arm to which the respective IP was randomized.
The primary analysis will compare the transmission rate for the primary endpoint between the 
two arms and express the effect by an adjusted odds ratio. The comparison will be based on a 
model providing population-averaged estimates using a generalized estimating equations 
approach and accounting for the stratification factors used at randomization. The primary test 
for the treatment effect will be two-sided and the significance level will be 5%. For this analysis, 
missing values will not be imputed. The Statistical Analysis Plan will specify sensitivity analyses 
performed with different imputation methods and alternative definitions of the analysis 
population.
A hierarchical testing strategy will be used for secondary endpoints.


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DETERMINATION OF SAMPLE SIZE
A transmission rate in the placebo arm of approximately 20% is assumed based on data from
the literature, including work by Welliver et al. (2001). For a 30% relative risk reduction with 
BXM, which is considered clinically meaningful, the transmission rate in the active treatment 
group is expected to be 14%. Under these assumptions and for a two-sided test for binary 
proportions at the 5% significance level, the power for the between-arm comparison based on 
the primary endpoint will be approximately 90%. For the secondary “Symptomatic 
transmission endpoint” (symptomatic influenza) the power will be 80% for an assumed 65%
proportion of symptomatic cases among infected HHCs, and not considering the hierarchical 
testing procedure.
INTERIM ANALYSES
There are no planned interim efficacy analyses for this study. Safety interim analyses will be 
performed regularly by an iDMC. Efficacy data will only be provided if requested by the iDMC. 
Further details on the function and logistics (e.g., frequency of the meetings) of the iDMC will be 
provided in the iDMC Charter.
To adapt to information that may emerge during the course of this study, the Sponsor may 
choose to conduct one or more interim efficacy analyses. Possible goals of these interim 
analyses include assessing the futility of study continuation or reassessing the sample size in 
case the overall transmission rates (calculated in a blinded manner) are smaller than 
anticipated. If recruitment projections indicate that a large proportion of the currently planned 
sample can be recruited by the end of the 2020/2021 or subsequent Northern hemisphere 
influenza seasons (e.g., 70%), the Sponsor will determine whether to perform an interim 
analysis with stopping rules based on efficacy endpoints in accordance to a group-sequential 
design. 


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviation
Definition
AE
adverse event
AUC0-inf
area under the concentrationtime curve from time 0 
extrapolated to infinity
BID
twice daily
BMI
body mass index
BXM
baloxavir marboxil
C24
concentration 24 hours post dose
C72
concentration 72 hours post dose
CDC
Center for Disease Control and Prevention
CEN
cap-dependent endonuclease 
CLIA
Clinical Laboratory Improvement Amendments
COVID-19
coronavirus disease 2019
CRO
contract research organization
CT
threshold cycle
CTCAE
Common Terminology Criteria for Adverse Events
eCRF
electronic Case Report Form
EDC
electronic data capture
EC
Ethics Committee
EUA
Emergency Use Authorization
FDA
Food and Drug Administration
HHC
household contact
HIPAA
Health Insurance Portability and Accountability Act
I38X
substitution of isoleucine for another amino acid at 
position 38 (of the polymerase acidic protein)
ICF
Informed Consent Form
ICH
International Council for Harmonisation
iDMC
independent Data Monitoring Committee
IMP
investigational medicinal product
IND
Investigational New Drug
IP
index patient
IRB
Institutional Review Board
ITTI
intent-to-treat-influenza-infected
IxRS
interactive voice or web-based response system


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Abbreviation
Definition
MDCK
Madin-Darby Canine Kidney
NAI
neuraminidase inhibitor
NCI
National Cancer Institute
NPA
negative percent agreement
OwH
otherwise healthy
PA
polymerase acidic (protein)
PB1/2
polymerase basic (protein) 1/2
PCR
polymerase chain reaction
PK
pharmacokinetic
POC
point of care
PPA
positive percent agreement
PRO
patient-reported outcome
RIDT
Rapid Influenza Diagnostic Test
RSV
respiratory syncytial virus
RT-PCR
reverse transcription polymerase chain reaction
SAE
serious adverse event
SAP
Statistical Analysis Plan
SARS-CoV-2
severe acute respiratory syndrome coronavirus 2
SOC
standard of care
t1/2
half-life
TCID50
50% tissue culture infectious dose
TTAS
time to alleviation of symptoms
TTCVS
time to cessation of viral shedding
TTIIS
time to improvement of influenza symptoms
ULN
upper limit of normal
WPAICIQ
Work Productivity and Activity Impairment 
Questionnaire plus Classroom Impairment Questions


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1.
BACKGROUND
1.1
BACKGROUND ON INFLUENZA VIRUS INFECTION
Influenza virus infection is an acute respiratory infectious disease caused by the 
influenza viruses and is spread mainly by droplet infection. Following an incubation 
period of 1–4 days, clinical symptoms such as sudden onset of fever, chills, headache 
and myalgia occur. Within 24 hours from the onset, body temperature reaches 38C to 
40C (Wright et al. 2007; Monto et al. 2000). Other symptoms include cough (often 
highly frequent and persistent), sore throat and nasal congestion (Pringle 2014). Based 
on these symptoms, influenza virus infection tends to be a severe illness and should be 
discriminated from the common cold. There are four types of influenza viruses, A, B, C, 
and D; A and B viruses show a seasonal spread of infection.
Anti-influenza virus drugs have been approved (with geographic variability): M2 channel 
inhibitors - amantadine hydrochloride and rimantadine hydrochloride; NA inhibitors -
oseltamivir phosphate, zanamivir hydrate, peramivir hydrate and laninamivir octanoate 
hydrate; RNA polymerase inhibitor - favipiravir. The U.S. Centers for Disease Control 
and Prevention (CDC) advised that use of current M2 channel inhibitors (amantadine 
hydrochloride and rimantadine hydrochloride) be restricted for the treatment of influenza 
virus infection (CDC 2006). Use of amantadine hydrochloride is also restricted in Japan 
and rimantadine hydrochloride has not been approved in Japan.
1.2
BACKGROUND ON BALOXAVIR MARBOXIL
Baloxavir marboxil (BXM; S-033188/RO7191686) is an anti-influenza virus drug with a 
novel mechanism of action. It was discovered and is being developed by Shionogi & Co., 
Ltd. and F. Hoffman-La Roche, Ltd. BXM is a prodrug that is metabolized to an active 
form (S-033447) through hydrolysis. The active form selectively inhibits cap-dependent 
endonuclease (CEN) activity necessary for replication of influenza viruses (Omoto et al.
2018). A broad spectrum of activity against seasonal influenza viruses and on alleviating 
effects of influenza symptoms were shown in nonclinical efficacy studies and clinical 
studies in patients with influenza, including the Phase 2 proof of concept and 
dose-finding study, the Phase 3 double-blind study in otherwise healthy (OwH) patients 
(Hayden et al. 2018), and the Phase 3 open-label study in OwH pediatric patients
(Baker et al. 2020). Clinical studies also showed that with a single oral administration, 
BXM led to more rapid reduction of influenza viruses than oseltamivir phosphate. Due to 
its novel mechanism of action, BXM is anticipated to be effective against influenza virus 
strains resistant to currently marketed drugs.
1.2.1
Previous Non-Clinical Studies
In in vivo nonclinical studies, S-033447 inhibited transcription of influenza virus by 
selective inhibition of CEN activity. The 50% inhibitory concentration values of S-033447 
against CEN activity for influenza A and B viruses ranged from 1.4 to 3.1 nmol/L and 
from 4.5 to 8.9 nmol/L, respectively; determined by using Madin-Darby Canine Kidney 


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(MDCK) cells infected with influenza A virus. The 90% effective concentration values of 
S-033447 against replication of influenza A and B viruses in MDCK cells ranged from 
0.46 to 0.98 nmol/L and from 2.21 to 6.48 nmol/L, respectively. S-033447 exhibited more 
potent inhibition on virus replication compared with anti-influenza virus drugs such as the 
active form of oseltamivir phosphate. In vivo studies with S-033447 using 
mouse-adapted influenza A and B viruses (A/Osaka/129/2009, A/Hong Kong/8/68, 
B/Hong Kong/5/72) found that the EC50 values of S-033447 for A/Osaka/129/2009, 
A/Hong Kong/8/86, and B/Hong Kong/5/72 were 0.75, 0.58, and 8.37 nmol/L, 
respectively, indicating that the susceptibility to S-033447 of the mouse-adapted viruses 
was comparable to that of the parent viruses. In mouse models infected with influenza A, 
B or NA inhibitor-resistant virus with NA/H274Y, BXM showed inhibitory effects on viral 
titers in the lung 24 hours after twice daily (BID) oral administration for 1 day and these 
results reflected the in vitro antiviral effects. A dose of 5 mg/kg BID BXM for 1 day, 
5 days post-infection, exhibited significantly lower viral titers in the lung than oseltamivir 
phosphate at the clinically equivalent dose (5 mg/kg BID). In the mouse model infected 
with influenza A virus, BXM given orally 5 days post-infection, at 0.5 mg/kg BID for 
1 day, exhibited significantly lower viral titers in the lung over 3 days after one BID 
administration compared with oseltamivir phosphate at the clinically equivalent dose 
given for 3 days.
In ferrets infected with influenza A(H1N1)pdm09 virus, BXM treatment (4injections, 
4 mg/mL/kg total, subcutaneously) at 24 or 48 hours post-infection significantly reduced 
the duration of viral shedding and reduced viral transmission to co-housed 
treatment-naive ferrets (direct transmission) by 75% and 50%, respectively, compared 
with both oseltamivir and placebo (Study 1102424).
In ferrets infected with a recombinant influenza A(H1N1)2009 virus, BXM treatment 
(4injections, 4 mg/mL/kg total, subcutaneously) at 24 hours post-infection led to 
decreased viral shedding and reduced the transmission to treatment-naive ferrets in 
adjacent cages (indirect transmission) by 66% compared with both oseltamivir and 
placebo (Study 1100893).
1.2.1.1
Toxicology and Safety Pharmacology
No single-dose toxicity study of BXM has been conducted. Acute toxicity was evaluated 
in a 2-week repeated oral toxicity study of BXM in rats (up to 2,000 mg/kg/day), a 
2-week repeated oral toxicity study of BXM in monkeys (up to 200 mg/kg/day), and a 
safety pharmacology study of BXM for cardiovascular system in monkeys (up to 
400 mg/kg/day). There were no deaths or acute toxicity symptoms in these studies.
In an oral fertility and early development study of BXM (0 [control], 20, 200, and 
1,000 mg/kg/day) in rats, there were no test substance-related deaths throughout the 
study period. There were no adverse effects of BXM on any parameter in parent 
animals. No effects of BXM were observed in embryos. In an oral embryo-fetal 
development study of BXM (0 [control], 20, 200, and 1000 mg/kg/day) in rats, no death 


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occurred in any animals. Slight decreases in body weight gain and food consumption 
were observed in the 200-mg/kg/day or higher dosing groups. These changes were not 
considered to be adverse since they were slight and temporary. There were no adverse 
effects on fetal viability, intrauterine growth, or external, visceral and skeletal 
morphologies of live fetuses. In an oral embryo-fetal development study of BXM
(0 [control], 30, 100, and 1000 mg/kg/day) in rabbits, 2/19 dams in the 1,000-mg/kg/day 
group aborted their litters. No death was observed in any dams. Maternal toxicities such 
as decreases in food consumption and body weight gain were observed in the 
1,000-mg/kg/day group. There were no adverse effects on fetal viability and intrauterine 
growth. The incidence of cervical rib was high in the 1,000-mg/kg/day group, and the 
finding was considered to be fetal toxicity but not teratogenicity. There were no adverse 
effects on external, placental or visceral morphologies of live fetuses up to 
1,000 mg/kg/day.
1.2.2
Previous Clinical Experience
To date, BXM has been investigated in twelve Phase 1 studies, one Phase 2 study, and 
eight Phase 3 studies as part of its global development program. A total of 2944 subjects 
have been exposed to at least one dose of BXM in the completed studies. The 
completed Phase 3 studies are summarized below; please see the Baloxavir Marboxil 
Investigator’s Brochure for details regarding all completed and ongoing studies.
1.2.2.1
Completed Phase 3 Studies in Otherwise Healthy Influenza 
Patients
Study 1601T0831 (Adults and Adolescents)
Study 1601T0831 (CAPSTONE-1; Hayden et al. 2018) was a double-blind, randomized 
study that compared single dose BXM (40 mg for patients 80 kg; 80 mg for patients 
80 kg) versus placebo in adolescent and adult patients aged 1264 years old with 
influenza-like illness in Japan and the United States. The study also compared single 
dose BXM (with same weight-based dosing) versus repeated dose oseltamivir (75 mg 
BID for 5 days) in adult patients aged 2064 years old. A total of 1,432 patients received 
study drug (610 in the BXM group, 309 in the placebo group, and 513 in the oseltamivir 
group). Of these, 456, 231, and 377 patients, respectively, were included in the 
intent-to-treat-influenza-infected (ITTI) population for the efficacy analyses.
Efficacy: The median time to alleviation of symptoms (TTAS) was significantly shorter in 
the BXM group (53.7 hours) compared with the placebo group (80.2 hours; delta 
26.5 hours; two-sided p0.0001). In adults, the median TTAS was 53.5 hours in the 
BXM group compared with 53.8 hours in the oseltamivir group (difference not statistically 
significant). Of the secondary endpoints, significant decreases in virus titer and the 
amount of virus RNA were found in the BXM group compared with the placebo group. 
Rapid reduction in virus titer and amount of viral RNA results in a significantly shortened 
time to cessation of viral shedding (TTCVS), which is analogous to a shortened 
infectivity period. The median TTCVS determined by virus titer was 24 hours in the BXM 
group compared with 96 hours in the placebo group—a significant difference of 


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72 hours. A significant difference was also found between the BXM group and the 
oseltamivir group. BXM 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. In addition, when compared to the oseltamivir group, the proportion of patients 
with positive influenza virus titer decreased significantly in the BXM group. Beneficial 
effects on fever were also shown with BXM, with significantly fewer patients reporting 
fever compared with the placebo group. The median time to the resolution of fever was 
shorter for patients who received BXM than with placebo (24.5 hours vs. 42.0 hours,
respectively; p0.001) and a significant improvement was found in the proportion of 
patients reporting a normal temperature in the BXM group compared with the placebo 
group.
Safety: No deaths were reported in all the three groups (BXM, oseltamivir, and placebo). 
Two serious adverse events (SAEs) (1 each of meningitis viral and incarcerated inguinal 
hernia) were reported in 2 of 610 (0.3%) patients in the BXM group. The events resolved 
and were considered not related to the study drug. Nine adverse events (AEs) that led to 
withdrawal of study drug were reported: 3 AEs in 2 of 610 (0.3%) patients in the BXM
group, 4 AEs in 1 of 309 (0.3%) patients in the placebo group, and 2 AEs in 2 of 
513 (0.4%) patients in the oseltamivir group. All AEs that led to withdrawal of study drug 
in the BXM group were considered not related to the study drug. AEs were reported in 
126 of 610 patients (20.7%) in the BXM group, 76 of 309 patients (24.6%) in the placebo 
group, and 127 of 513 patients (24.8%) in the oseltamivir group. No statistically 
significant difference was found in the incidence between the BXM group and the 
placebo group (the Fisher’s exact test, two-sided p0.1781) or between the BXM group 
and the oseltamivir group (p0.1146). Treatment-related AEs were reported in 27 of 
610 patients (4.4%) in the BXM group, 12 of 309 patients (3.9%) in the placebo group, 
and 43 of 513 patients (8.4%) in the oseltamivir group. No statistically significant 
difference was found in the incidence between the BXM group and the placebo group 
(the Fisher’s exact test, two-sided p0.8627). However, the incidence was significantly 
lower in the BXM group than in the oseltamivir group (the Fisher’s exact test, two-sided 
p0.0088). Except for bronchitis in the placebo group, there were no common AEs 
(incidence, 5%) among any of the treatment groups. Relatively common AEs 
(incidence, 2%) in any of the groups were bronchitis, sinusitis, diarrhea, and nausea; 
however, for each AE, the incidence in the BXM group was lower than or equal to that in 
the placebo group. In all the three groups, the majority of the AEs were categorized as 
Grade 1 or 2 and resolved.
Study CP40563 (Children Aged 1 to 12 Years Old)
Study CP40563 (MINISTONE-2; Baker et al. 2020) was a multicenter, randomized, 
double-blind, active (oseltamivir)-controlled study in non-Asian OwH pediatric patients 
aged from 1 to 12 years old with influenza-like symptoms. Patients received either a 
single dose of BXM (granules for oral suspension [2 mg/mL]) based on body weight 
(20 kg [2 mg/kg] and 20 kg [40 mg]) or oseltamivir (body weight-adjusted dosing 


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ranging from 30 mg to 75 mg twice a day) for 5 days with a 24-day safety follow-up 
period after treatment. The total study duration for each patient was 29 days. A total of 
176 patients were randomized, and of these 173 patients received the study drug (115 in 
the BXM group and 58 in the oseltamivir group). Of these, 81 patients in the BXM group 
and 43 patients in the oseltamivir group were included in the ITTI population for the 
efficacy analyses.
Efficacy: Overall, the efficacy analysis results were comparable between the two 
treatment groups including time to influenza signs and symptoms, fever, duration of 
symptoms, complications, and the proportion of patients requiring antibiotics. The 
median TTCVS as determined by virus titer was 24.2 hours in the BXM group compared 
with 75.8 hours in the oseltamivir group.
Safety: The overall incidence of AEs was similar between the BXM (46.1%) and 
oseltamivir group (53.4%). No SAEs or deaths were reported. The incidence of AEs 
related to study drug was 2.6% (3 of 115 patients) in the BXM group and 8.6% 
(5 of 58 patients) in the oseltamivir group. The most commonly reported AEs were 
vomiting, diarrhea, and otitis media in either treatment group. All AEs were Grade 12 in 
severity in both treatment groups, with the exception of 3 Grade 3 AEs, one in the BXM 
group (abdominal pain on Day 8) and two in the oseltamivir group (both undiagnosed 
preexisting condition of severe vitamin D deficiency on Day 1). The vast majority of AEs 
(95.1%) were resolving by study end, with the exception of 6 AEs that had not resolved 
by study end (Day 29). No clinically meaningful changes from baseline were observed 
for any laboratory parameters in this study, and no clinically meaningful differences were 
observed between treatment groups for vital signs.
Study 1618T0822 (Children Aged from 6 Months to 12 Years Old in Japan)
Study 1618T0822 (Hirotsu et al. 2019) was an open-label study that investigated a 
single dose of BXM (tablet formulation) in OwH patients aged 6 months11 years old in 
Japan. Dosages studied were 5, 10, 20, and 40 mg for patients weighing from 5 to 
10 kg, from 10 to 20 kg, from 20 to 40 kg and 40 kg, respectively. A total of 
108 pediatric patients were enrolled, of whom 107 received study drug, and of whom 
104 were included in the ITTI population for efficacy analyses.
Efficacy: The median time to alleviation of influenza illness (i.e., alleviation of cough, 
nasal discharge/nasal congestion and fever, the primary endpoint) was 44.6 hours. The 
median time to resolution of fever (a secondary endpoint) was 21.4 hours. For selected 
virological endpoints, the mean change from baseline in the virus titer was −4.20 log10
(50% tissue culture infectious dose [TCID50]/mL) and the mean change from baseline 
in the amount of viral RNA was −1.75 log10 (virus particles/mL) on Day 2.
Safety: No deaths, SAEs, or discontinuations due to AEs were reported in the study. 
AEs were reported in 37 of 107 patients (34.6%). Treatment-related AEs were reported 
in 4 of 107 patients (3.7%). All AEs were classified as Grade 1 or 2. Most of the AEs 


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resolved except for 3 AEs in 3 patients: 1 event each of dental caries, dry skin, and 
ligament sprain; all 3 events were judged by the investigator as not requiring further 
follow-up. AEs occurring at an incidence of at least 5% were vomiting in 8 patients 
(7.5%). All cases of vomiting were classified as Grade 1, resolved, and considered not 
related to the study drug.
Study 1705T0833 (Children Aged 12 Years Old and Weighing 20 kg in 
Japan)
Study 1705T0833 (Yokoyama et al. 2020) was an open-label, multicenter, non-controlled 
study investigating BXM 2% granules in OwH patients aged 12 years old and whose 
body weight was 20 kg in Japan. Patients received a single oral dose of BXM 
(2% granules) on Day 1 within 48 hours of the onset of influenza symptoms based on 
body weight at screening. All 33 pediatric patients enrolled received BXM (1 mg/kg for 
12 children weighing 10 kg, 10 mg for 21 children weighing from 10 to 20 kg), 
completed the study, and were included in the ITTI population for efficacy.
Efficacy: The median time to alleviation of influenza illness was 45.3 hours. The median 
time to resolution of fever (a secondary endpoint) was 34.0 hours. The median TTCVS 
evaluated by virus titer was 48.0 hours, and the median TTCVS evaluated by reverse 
transcription polymerase chain reaction (RT-PCR) was 240.0 hours.
Safety: No deaths, SAEs, or discontinuations due to AEs were reported in the study. 
AEs were reported in 18 of 33 patients (54.5%). Most common AEs reported were 
vomiting, diarrhea, and pharyngitis. Treatment-related AEs (as assessed by the 
investigator) were reported in 1 of 33 patients (3.0%, 1 event of platelet count 
increased). All AEs were classified as Grade 1 or 2. All AEs were resolved or were 
resolving at the end of the study.
Study 1813T0835 (Children Aged 12 Years Old and Weighing 20 kg in 
Japan)
Study 1813T0835 (Sonoyama et al. 2021) was an open-label, multicenter, 
non-controlled study investigating BXM 2% granules in OwH patients aged 12 years 
old and whose body weight was 20 kg in Japan. Patients received a single oral dose of 
BXM on Day 1 within 48 hours of the onset of influenza symptoms based on age and 
body weight at screening (1 mg/kg: 10 kg and 3 months old, 2 mg/kg: 10 kg and 
3 months old, 20 mg: 10 to 20 kg). A total of 45 pediatric patients were enrolled (0 
were 3 months and 10 kg, 9 were 10 kg and 36 were 10 to 20 kg). Of the 45 
patients, 43 pediatric patients were included in the ITTI population.
Efficacy: The median time to alleviation of influenza illness was 37.8 hours. The median 
time to resolution of fever (a secondary endpoint) was 22.0 hours. The mean change 
from baseline in the virus titer was −4.40 log10 (TCID50/mL) and the mean change 
from baseline in the amount of viral RNA was −1.28 log10 (virus particles/mL) on 
Day 2.


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Safety: No deaths, SAEs, or discontinuations due to AEs were reported in the study. 
AEs were reported in 24 of 45 patients (53.3%). Most common AEs reported were 
nasopharyngitis and diarrhea. Treatment-related AEs were reported in 3 of 45 patients 
(6.7%; 3 events of diarrhea). All AEs were classified as Grade 1 or 2 in severity. All 
AEs were resolved or were resolving at the end of the study.
1.2.2.2
Completed Phase 3 Study in High-Risk Influenza Patients
Study 11602T0832 (Adults and Adolescents)
Study 11602T0832 (CAPSTONE-2; Ison et al. 2020) was a double-blind, randomized 
study that compared a single oral dose of BXM (40 mg for patients 80 kg; 80 mg for 
patients 80 kg) with placebo or 75 mg of oseltamivir BID for 5 days in patients with 
influenza-like illness who were 12 years old and at high risk of complications from 
influenza. The study was conducted in 17 countries and territories. Overall, a total of 
730, 729, and 725 patients were randomized to receive BXM, placebo, and oseltamivir,
respectively, and of these, 388, 386, and 389 patients, respectively, were included in the 
ITTI population for the efficacy analyses.
Efficacy: The time to improvement of influenza symptoms (TTIIS) was significantly 
shorter in patients treated with BXM than placebo (median 73.2 vs. 102.3 hours, 
p0.0001) and numerically shorter than oseltamivir (81.0 hours, p0.8347). TTIIS in 
patients with A/H3N2 virus treated with BXM was shorter than those treated with placebo 
(median: 75.4 vs. 100.4 hours; p0.0141). TTIIS in patients with influenza B treated with 
BXM was also significantly shorter (74.6 hours) than those treated with either placebo 
(100.6 hours; p0.0138) or oseltamivir (101.6 hours; p0.0251). Median TTCVS in 
BXM-treated patients was 48 hours, which was significantly less than the 96 hours seen 
with both placebo and oseltamivir. Systemic antibiotic use and influenza-related 
complications were significantly fewer in the BXM versus the placebo group (3.4% vs.
7.5%, p0.0112; and 2.8% vs. 10.4%, p0.0001; respectively).
Safety: The incidence of any AE (25.1%–29.7%) or any SAE (0.7%–1.2%) did not differ 
significantly between the groups treated with a single oral dose of BXM, placebo, or 
oseltamivir.
1.2.2.3
Completed Phase 3 Post-Exposure Prophylaxis Study
Study 1719T0834 (Adults and Children Aged 1 Years Old)
Study 1719T0834 (BLOCKSTONE; Ikematsu et al. 2020) was a randomized, 
double-blind, multicenter, parallel-group, placebo-controlled, comparative post-exposure 
prophylaxis study that evaluated a single dose of BXM in the prevention of influenza 
virus infection in Japanese subjects (adults and children 1 years old) who were 
household members of influenza-infected index patients (IPs). Eligible subjects were 
randomly assigned with the stochastic minimization method in a 1:1 ratio to receive BXM 
or placebo. BXM was administered based on the subjects’ age and body weight (adults 
and adolescents: 40 mg for patients 80 kg; 80 mg for patients 80 kg and pediatrics: 
10 kg [1 mg/kg], from 10 to 20 kg [10 mg], from 20 to 40 kg [20 mg], 


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40 kg [40 mg]). Study drug was orally administered at the study site on Day 1. Subjects 
visited the study site a maximum of 5 times during the 15-day period for 11 days of 
efficacy evaluations and 15 days of safety evaluations. A total of 752 household 
participants underwent randomization, 749 of whom constituted the modified intention-
to-treat population for efficacy analyses.
Efficacy: The proportion of subjects who were infected with influenza virus (RT-PCR 
positive) and presented with fever and at least one respiratory symptom from Day 1 to 
Day 10 (primary efficacy endpoint) in the modified intent-to-treat population was 
significantly lower in the BXM group (7 of 374 subjects; 1.9%) compared with the 
placebo group (51 of 375 subjects; 13.6%); the adjusted risk ratio was 0.14 [95% CI: 
0.06, 0.30], p0.0001).
Safety: One SAE (psychotic disorder in the placebo group) was reported in a patient who 
had a medical history of acute psychosis. The event was the only AE that lead to 
withdrawal from the study. The event was considered related to the study drug. 
No deaths were reported. The incidences of AEs and treatment-related AEs were similar 
between the treatment groups. All AEs were Grade 1 or 2 in severity except for 
1 (0.3%) patient with Grade 3 psychotic disorder in the placebo group. The majority of 
AEs resolved or were resolving at the end of the study. No clinically relevant differences 
were found in the changes from baseline in laboratory values between the treatment 
groups. 
1.2.2.4
Completed Phase 3 Study in Hospitalized Patients with 
Severe Influenza (Aged 12 Years Old)
Study CP40617 (FLAGSTONE; Kumar et al. 2022) was a Phase 3, randomized, 
double-blind, placebo-controlled, multicenter study to assess the efficacy, safety, and 
pharmacokinetics of BXM in combination with a standard-of-care (SOC) 
neuraminidase inhibitor (NAI) (i.e., oseltamivir, zanamivir, or peramivir) compared 
with a matching placebo in combination with a SOC NAI in hospitalized adult and 
adolescent patients (aged 12 years old) with severe influenza. BXM was administered 
as a body weightbased dose (40 mg for patients weighing 40 to 80 kg, 80 mg for 
patients weighing 80 kg) on Days 1 and 4 and on Day 7 if clinical improvement had 
not occurred on Day 5 per protocol-defined criteria. Treatment with a SOC NAI was 
administered to patients in accordance with local clinical practice. A total of 366 
patients were randomized to receive BXM plus SOC NAI or matching placebo plus 
SOC NAI. Of the 366 patients, 322 patients constituted the modified intent-to-treat
infected population.
Efficacy: There was no statistically significant difference in the time to clinical 
improvement observed between the BXM plus SOC NAI and placebo plus SOC NAI 
treatment groups (the primary efficacy endpoint). The median time to clinical 
improvement was 97.5 hours (95% CI: 75.9 to 117.2 hours) in the BXM group 
compared with 100.2 hours (95% CI: 75.9 to 144.4 hours) in the control group, with a 


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median difference of −2.7 hours (95% CI: −53.4 to 25.9 hours). The results of the key 
secondary and other secondary efficacy endpoints were consistent with the results of the 
primary endpoint, although the results generally showed numerical improvements in 
favor of the BXM plus SOC NAI group.
Safety: Study CP40617 was the first study evaluating the efficacy and safety of repeat 
dosing with BXM and it was also the first study of BXM used in combination with an 
NAI. The incidence of AEs and SAEs were similar between the two treatment groups 
and neither repeat dosing nor use in combination with NAI identified any new safety 
signal. Overall, BXM was well tolerated in combination with a NAI with no change in 
safety profile observed.
1.2.2.5
Pharmacokinetics
Baloxavir (S-033447) pharmacokinetic (PK) results are provided below for OwH patients 
and post-exposure prophylaxis subjects enrolled in the studies described in 
Sections 1.2.2.1 and 1.2.2.3. Please see the Baloxavir Marboxil Investigator’s Brochure 
for further details (or results from other studies). 
Results for OwH Patients and Post-Exposure Prophylaxis Subjects Aged 
12 Years Old
Study 1601T0831 (CAPSTONE-1; Hayden et al. 2018): The geometric mean 
concentration 24 hours post dose (C24) of S-033447 was similar between the patients 
weighing 40 to 80 kg and those weighing 80 kg, and between the patients 12 to 
19 years old and 20 to 64 years old. The geometric mean C24 was 34% and 39% lower 
in Caucasians and others than that in Asians, respectively. The geometric mean C24 was 
slightly lower (7.2% to 10.8%) in the fed condition (dosing 2 hours before or 2 hours 
after food intake) compared with the fasted condition (dosing 4 hours before and 
4 hours after food intake). The geometric mean C24 in the intermediate fed state 
(dosing between 2 to 4 hours before or between 2 to 4 hours after food intake) was 
similar to that in the fasted state.
Study 1719T0834 (BLOCKSTONE; Ikematsu et al. 2020): Baloxavir concentration 
values in subjects aged 12 years old were comparable with those observed in 
Study 1601T0831.
Results for OwH Patients and Post-Exposure Prophylaxis Subjects Aged 
12 Years Old
The pharmacokinetics of baloxavir was investigated in non-Asian pediatric patients 
(1 to 12 years old; Study CP40563) and in Japanese pediatric patients 
(Studies 1618T0822, 1705T0833, 1719T0834, and 1813T0835).
Study CP40563 (MINISTONE-2; Baker et al. 2020): Similar plasma C24 (derived from the 
population PK model) was observed at 2 mg/kg (55.7 ng/mL, 28.1 CV%) and 40 mg 
(53.2 ng/mL, 22.4 CV%). Overall, the Bayesian estimates of the PK parameters from the 
pediatric patients in Study CP40563 were comparable with PK parameters in non-Asian 


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adult and adolescent patients from the OwH and high-risk studies (1601T0831 and
1602T0832). The mean area under the concentrationtime curve from time 0 
extrapolated to infinity (AUC0-inf) in pediatric patients was between the mean AUC0-inf
values observed with the 40 mg and 80 mg dose in adults/adolescents. The mean 
maximum concentration and C24 in pediatric patients were similar to the mean of the 
80 mg dose group, and the mean concentration 72 hours post dose (C72) matched the 
40 mg dose group in adults, indicating an apparent shorter half-life (t1/2) in patients 
12 years old relative to adults and adolescents.
Study 1618T0822 (Hirotsu et al. 2019): The C24 values of patients treated with BXM 
ranged between 11.2146 ng/mL, with a trend toward lower C24 with decreasing 
bodyweight. All values were within the range of the overall mean C24 (55.1 ng/mL 
[0.322209 ng/mL]) observed in Study 1601T0831.
Study 1705T0833 (Yokoyama et al, 2020): The C24 values were comparable with those 
observed in Study 1618T0822.
Study 1813T0835 (Sonoyama et al. 2021): The observed C24 (as Geometric Mean [CV% 
Geometric Mean]) for all patients of 90.2 ng/mL (43.5%) was 1.7 times higher than in 
Study 1705T0833 (52.7 ng/mL [51.5%]), in accordance with the dose differences 
between the two studies. The mean (range) of the estimated plasma C72 was 31.2 ng/mL 
(13.564.9 ng/mL), which was similar to the estimated C72 for adults following a single 
oral dose of 40 mg or 80 mg of BXM in Study 1601T0831 
(23.9 ng/mL [4.4270.6 ng/mL]).
Study 1719T0834 (BLOCKSTONE; Ikematsu et al. 2020): Baloxavir concentration 
values were comparable with those observed in Studies 1618T0822 and 1705T0833.
As evidenced by a population PK model, both race and body weight influenced the PK of 
baloxavir. The effect of race (Asian/non-Asian) on baloxavir pharmacokinetics was 
similar across age groups. On an equal body weight basis, exposures were 
approximately 2-fold higher in Asians compared with non-Asians regardless of age 
(adult, adolescent, and pediatric patients). The impact of body weight was the same for 
both ethnic groups. Overall, an apparent shorter baloxavir t1/2 was observed in both the 
Japanese and non-Asian patients aged 12 years old relative to adults and adolescents. 
Consequently, because the t1/2 tends to be shorter in patients with lower bodyweight, the 
higher dose expressed in mg/kg body weight used in pediatrics in Study CP40563 
results in matching baloxavir exposures (e.g., AUC0-inf, C72) to those observed in adults 
(Study 1601T0831).
1.2.3
Postmarketing Safety Data
Hypersensitivity reactions have been observed in the postmarketing setting which 
include reports of anaphylaxis/anaphylactic reactions and less severe forms of 
hypersensitivity reactions including angioedema, and urticaria.


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Refer to Section 6 of the Baloxavir Marboxil Investigator's Brochure for current details 
relating to post marketing safety information.
1.3
BACKGROUND ON THE COBASSARS-COV-2 & 
INFLUENZA A/B NUCLEIC ACID TEST FOR USE ON THE 
COBAS LIATSYSTEM
The cobas severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) &
Influenza A/B nucleic acid test for use on the cobas Liat System (cobas SARS-CoV-2 & 
Influenza A/B test) is an automated multiplex real-time RT-PCR assay for the rapid 
in vitro qualitative detection and discrimination of SARS-CoV-2, influenza A virus, and 
influenza B virus RNA in nasopharyngeal and nasal swabs from individuals suspected of 
a respiratory viral infection. The cobas SARS-CoV-2 & Influenza A/B test is intended for 
use as an aid in the differential diagnosis of SARS-CoV-2, influenza A, and influenza B 
virus nucleic acids in clinical specimens and is not intended to detect influenza C 
virus. This test is CE-IVD marked and authorized for use at the point of care (POC) or 
in a clinical lab setting under the Food and Drug Administration (FDA) Emergency 
Use Authorization ([EUA] 201779).
This assay targets both the ORF1 a/b non-structural region and nucleocapsid protein 
gene that are unique to SARS-CoV-2, a well-conserved region of the matrix gene of 
influenza A, and the non-structural protein gene of influenza B. The cobas SARS-CoV-2 
& Influenza A/B test was developed by mainly replacing the respiratory syncytial virus 
(RSV) primers and probes with those required to detect the SARS-CoV-2 targets in the 
existing FDA-cleared cobas Influenza A/B & RSV assay (K153544). Previous studies of 
the cobas Influenza A/B & RSV assay remain relevant for the performance of 
influenza A/B targets in the cobas SARS-CoV-2 & Influenza A/B test (Gibson et al. 2017; 
Banerjee et al. 2018, 2019; Gosert et al. 2019; Schmidt et al. 2019; Vos et al. 2019). 
For influenza A/B targets, clinical performance of the assay was evaluated at 
12 CLIA-waived healthcare facilities using nasopharyngeal specimens prospectively 
collected from patients with signs and symptoms of respiratory infection in the 
United States during the 20132014 and 20142015 flu seasons (N1350). Additionally, 
retrospective nasopharyngeal specimens were obtained from two reference laboratories 
and tested at healthcare sites (N292). A total of 38 untrained operators representative 
of CLIA waived site intended operators participated in the study. Results for Influenza 
A/B were compared against the results from an FDA-cleared laboratory-based RT-PCR
test (ProFluTM, Prodesse, Waukesha, WI, USA).
For prospective specimens, the assay demonstrated positive percent agreement (PPA) 
of 98.3% and 95.2% for influenza A and influenza B, respectively; and negative percent 
agreement (NPA) of 96.0% and 99.4% for influenza A and influenza B, respectively. For 
retrospective specimens, the assay demonstrated PPA of 98.7% and 99.0% for 
influenza A and influenza B, respectively; and NPA of 99.1% and 99.5% for influenza A 
and influenza B, respectively. Overall, the cobas Liat System showed sensitivities of 


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98.4% and 97.9% for influenza A and influenza B, respectively, with specificities of 
96.5% and 99.4% for influenza A and influenza B, respectively, as determined from PPA 
and NPA with reference test results (cobas SARS-CoV-2 & Influenza A/B Package 
Insert).
The accuracy of the cobas SARS-CoV-2 & Influenza A/B test for the detection of 
SARS-CoV-2 was established using remnant clinical specimens collected from patients 
with a suspected respiratory infection. Testing of remnant clinical samples was 
performed with the cobas SARS-CoV-2 & Influenza A/B test and confirmed with a
highly sensitive FDA EUA-authorized RT-PCR SARS-CoV-2 assay, cobas SARS-CoV-2 
test for use on the cobas 6800/8800 systems (Poljak et al. 2020). Results of this clinical 
performance evaluation demonstrated 100% PPA and 100% NPA compared with the
comparator assay (cobas SARS-CoV-2 & Influenza A/B Package Insert). Clinical 
performance of the cobas SARS-CoV-2 & Influenza A/B test relative to the cobas 
SARS-CoV-2 test for use on the cobas 6800/8800 systems was also evaluated in a 
multisite study using fresh clinical specimens from symptomatic and asymptomatic 
patients, which yielded 100% PPA and 97.4% NPA for SARS-CoV-2 targets 
(Hansen et al. 2021).
Additionally, paired clinical nasopharyngeal and nasal swab specimens prospectively 
collected from patients with a suspected respiratory infection were tested with the 
cobas SARS-CoV-2 & Influenza A/B test and compared with another highly sensitive 
FDA EUA-authorized multiplexed RT-PCR EUA assay. For nasopharyngeal specimens, 
the cobas SARS-CoV-2 & Influenza A/B test demonstrated 95.2% PPA and 99.6% 
NPA for SARS-CoV-2 detection compared to the reference test. For nasal specimens 
(either healthcare provider-collected or self-collected swabs), cobas SARS-CoV-2 & 
Influenza A/B test demonstrated 96.4% PPA and 99.5% NPA for SARS-CoV-2 
detection compared to paired nasopharyngeal specimen results from the reference test 
(cobas SARS-CoV-2 & Influenza A/B Package Insert). Since EUA was granted in 
September 2020, independent studies have also evaluated the sensitivity and specificity 
of the cobas SARS-CoV-2 & Influenza A/B test and found its clinical performance 
equivalent to routine laboratory-based RT-PCR methods (Er et al. 2021; Jian et al. 
2021; Tsang et al. 2021).
These data demonstrate that the cobas SARS-CoV-2 & Influenza A/B test will provide 
accurate diagnosis of influenza A/B and SARS-CoV-2 infections.
1.4
STUDY RATIONALE AND BENEFITRISK ASSESSMENT
1.4.1
Study Rationale
Seasonal influenza is a major burden to global health. There are an estimated 
35 million cases of severe disease worldwide and approximately 290–650 thousand 
people die from influenza annually (Baxter 2016; WHO 2018a). Influenza also places 
significant demands on healthcare services each season, and impacts society through 


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lost workforce productivity (WHO 2018). Annual vaccination programs are the 
cornerstone of attempts to prevent influenza infections, but the effectiveness of these 
programs is variable due to both suboptimal uptake of vaccinations and mismatches 
between the vaccine and circulating influenza strains (CDC 2017). Consequently, the 
need for antiviral agents remains high.
Influenza A and B viruses are highly contagious (Vanderlinden and Naesens 2014). 
Most individuals with influenza infection are advised to stay at home until they have been 
afebrile for at least 24 hours, which puts other household members at risk of infection 
(CDC 2018a). Once one household member is infected with influenza, the risk of 
transmission to a household contact (HHC) can be up to 38%, with a delay between 
onset in the IP and infection of the HHC of around 3 days (Tsang et al. 2016). There is 
currently no agent for infected patients proven to reduce influenza transmission, and this 
is an important unmet medical need.
BXM is a first-in-class influenza antiviral that blocks RNA replication by inhibiting 
cap-dependent endonuclease activity (Omoto et al. 2018). BXM is administered by a 
convenient and unique one-dose, one-time regimen. In the Phase III 
(1601T0831/CAPSTONE-1) double-blind randomized study in OwH patients 
(Hayden et al. 2018), a single treatment of BXM (40 mg for patients 80 kg and 80 mg 
for patients 80 kg) significantly reduced the TTAS compared with placebo and also 
effectively reduced viral load, as shown by a significant reduction compared with 
placebo in:

The proportion of patients with positive influenza titer between Days 2 and 5

The proportion with positive influenza virus RNA determined by PCR on Day 5

The median TTCVS
Study MV40618 was therefore designed to assess if the ability of BXM to rapidly reduce 
viral load would translate into a reduction in onward transmission of influenza virus from 
infected individuals. The study will randomize patients with locally diagnosed 
influenza A/B infection to receive a single treatment with BXM (40 mg for patients 
80 kg and 80 mg for patients 80 kg) or matching placebo. The primary objective will 
be to assess the rate of onwards transmission to HHCs of the IPs who are PCR-negative 
(central laboratory confirmed) for influenza infection at baseline.
1.4.2
BenefitRisk Assessment
The HHCs of the IPs with confirmed influenza infection may benefit in this study if 
treatment of the IP with BXM prevents transmission of the influenza virus to their HHCs. 
The IPs may also directly benefit from a therapeutic effect of treatment with BXM
(see Section 1.2.2.1).
The risks posed to the IPs recruited to this study are believed to be minimal, as 
treatment with BXM has been shown to be well tolerated (see Sections 1.2.2.3 and 


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1.2.3). The numerous inclusion and exclusion criteria related to comorbidities associated 
with a high risk of influenza complications are designed to limit the IP study population to 
OwH individuals. These criteria will also limit the risk that IPs experience influenza 
complications. HHCs will not receive treatment with BXM. 
With overlapping clinical symptoms between influenza and coronavirus disease 2019 
(COVID-19), POC testing for the detection of influenza and SARS-CoV-2 infection is 
required for entry into the study to reduce the risk of enrolling IP and HHCs infected 
with SARS-CoV-2. During the study, IPs and HHCs will be tested for SARS-CoV-2 
infection and if any household member tests positive, the household will be discontinued
from the study given that self-quarantine remains as an advised or mandated 
requirement in many countries for the management of the COVID-19 pandemic. With 
the incorporation of the above measures, the benefitrisk profile of participants in this 
study is considered unchanged compared with study conduct pre-COVID-19 pandemic.
The protocol will permit enrollment of pediatric IPs aged 511 years old. Study CP40563 
provides the necessary safety and PK data to support the dose rationale described in 
Section 3.4.1. This dose schedule was shown to be well tolerated with comparable 
efficacy to oseltamivir (see Section 1.2.2.1). The risks posed for OwH IPs aged 
511 years old are believed to be minimal (no SAEs or deaths were reported in pediatric 
Studies CP40563, 1618T0822, and 1705T0833; see Section 1.2.2.3). Investigators must 
exclude IPs 511 years old judged to be at high risk for complications of influenza. 
In addition, IPs aged 5 years old will be excluded, given that this age range is 
considered to be at high risk of developing influenza-related complications 
(see Section 3.4.5).
No blood samples will be taken during the study, minimizing the risk of adverse events 
related to study procedures. The only invasive study-specific procedure that IPs and 
HHCs will undergo is a respiratory swab, which is generally considered to be a safe and 
routine medical procedure. The nasopharyngeal swab can be replaced with less invasive 
swabs such as midturbinate or nasal swabs as decided by the healthcare professional 
taking into account the tolerability of the procedure from the IP or HHC (e.g., for very 
young children). The location of the swab will be recorded each time.
It is possible that neither the HHCs nor the IPs will benefit in this study. However, HHCs
who participate in this study will benefit from free, convenient monitoring and early/rapid 
diagnosis. HHCs who develop influenza will be allowed to be treated according to the 
local SOC for influenza management by their physician.
The data generated in this study will also enable further development of BXM. 


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2.
OBJECTIVES AND ENDPOINTS
This study will evaluate the efficacy of a single, oral dose of BXM compared with placebo 
for the reduction of the direct transmission rate of influenza A/B from OwH IPs to HHCs. 
Specific objectives and corresponding endpoints for the study are outlined below.
2.1
EFFICACY OBJECTIVES
2.1.1
Primary Efficacy Objective
The primary efficacy objective for this study is to evaluate the efficacy of a single, 
oral dose of BXM compared with placebo to prevent secondary within-household 
transmission of influenza A/B.
2.1.1.1
Primary Efficacy Endpoint

Virological transmission by Day 5: Proportion of HHCs who become PCR () 
[confirmed at central laboratory] for influenza by Day 5 visit, with virus subtype 
consistent with IP.
2.1.2
Secondary Efficacy Objective
The secondary efficacy objective for this study is to evaluate the efficacy of a single, oral 
dose of BXM compared with placebo to prevent virological or symptomatic transmission 
of influenza A/B and effects beyond secondary within-household transmission according 
to the measures below.
Secondary endpoints will be submitted to a confirmatory statistical analysis with control 
for multiplicity based on a hierarchical testing procedure in accordance with the order 
described in Section 6.4.2.
2.1.2.1
Secondary Efficacy Endpoints

Symptomatic transmission by Day 5: Proportion of HHCs who become PCR () 
[confirmed at central laboratory] for influenza by Day 5 visit, with virus subtype 
consistent with IP, AND: 
–
For HHC aged 12 years:
o
Temperature 38.0C* and one respiratory symptom, OR
o
One respiratory symptom and one general systemic symptom (with or 
without fever).
–
For HHC aged 2 to 12 years:
o
Temperature 38.0C* AND signs or symptoms of an upper respiratory 
tract infection. 
–
Symptoms must be either new, or have worsened versus baseline in HHC with 
baseline symptoms due to a preexisting comorbidity.
–
* Temperature obtained from tympanic thermometers provided to households 
(or exceptionally from other thermometers/locations in case of tympanic 
thermometer failure for any reason).


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
Virological transmission at the household level by Day 5: Proportion of 
households with at least one HHC who meets the primary endpoint.

Symptomatic transmission at the household level by Day 5: Proportion of 
households with at least one HHC who meets the “Symptomatic transmission by 
Day 5” endpoint.

Virological transmission by Day 9: Proportion of HHCs who become PCR () 
(confirmed at central laboratory) for influenza by Day 9 visit, with virus subtype 
consistent with IP, including:

(1) all HHC meeting primary endpoint, AND

(2) all HHC cases detected after Day 5 visit meeting the following criteria:
a) Included HHC case is in a household where another HHC has already met 
the primary endpoint, OR
b) Included HHC case is PCR () [confirmed at central laboratory] for influenza 
bearing an amino acid substitution of isoleucine for another amino acid at 
position 38 (I38X) in the polymerase acidic (PA) protein (PA/I38X 
substitution) (or other identified substitutions listed in Section 3.4.6.4).

Symptomatic transmission by Day 9: Proportion of HHCs who meet the 
“Virological transmission by Day 9” endpoint AND are symptomatic per the definition 
for symptoms in the “Symptomatic transmission by Day 5” endpoint.

Any virological infection by Day 9: Proportion of HHCs who become PCR () for 
influenza (confirmed at central laboratory) by Day 9.

Any virological infection at the household level by Day 9: Proportion of 
households with at least one HHC who meets the “Any virological infection by 
Day 9” endpoint.

Any symptomatic infection by Day 9: Proportion of HHCs who meet the “Any 
virological infection by Day 9” endpoint AND are symptomatic per the definition for 
symptoms in the “Symptomatic transmission by Day 5” endpoint.

Any symptomatic infection at the household level by Day 9: Proportion of 
households with at least one HHC who meets the “Any symptomatic infection by 
Day 9” endpoint.
2.1.3
Other Efficacy Objective
The other efficacy objective for this study is to further evaluate the efficacy of a single, 
oral dose of BXM compared with placebo to prevent transmission of influenza A/B
according to the measures below.
2.1.3.1
Other Efficacy Endpoints

The effect of IP baseline viral titer on the rate of direct transmission of influenza A or 
influenza B to HHCs.


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
BXM arm only: Proportion of IPs who are PCR () [confirmed at central laboratory]
for influenza bearing a PA/I38X substitution (or other identified substitution) post 
randomization.

BXM arm only: Proportion of HHCs who become PCR () [confirmed at central 
laboratory] for influenza bearing a PA/I38X substitution (or other identified 
substitution) with matched PA substitution with their IP by Day 9 visit.

BXM arm only: Proportion of symptomatic cases among HHCs who become 
PCR () [confirmed at central laboratory] for influenza bearing a PA/I38X 
substitution (or other identified substitution) with matched PA substitution with 
their IP by Day 9 visit (utilizing same symptoms definition as used for secondary 
symptomatic transmission endpoint).

Proportion of HHC who become PCR () [confirmed at central laboratory] for 
influenza by Day 9 visit, with virus subtype consistent with IP.

Measurement of viral titer by PCR and TCID50 in IPs over the Day 0, 3, 5, and 9 
visits.

Subgroup analysis: endpoints requiring a subtype match will be assessed with a 
match based on sequencing in a subset of households (sequencing will be 
performed for samples from selected sites and countries based on feasibility, 
including availability of adequate number of IP sequences for specific community).
2.2
SAFETY OBJECTIVE
The safety objective for this study is to evaluate the safety and tolerability of a single, 
oral dose of BXM compared with placebo according to the measures below.
2.2.1
Safety Endpoints

IP only: The incidence, severity, and timing of adverse events, and serious adverse 
events.
2.3
HEALTH STATUS UTILITY OBJECTIVE
The health status utility objective for this study is to evaluate IPs treated with BXM
compared with those receiving placebo according to the measures below.
2.3.1
Health Status Utility Endpoints

IP 12 years old only: Change from baseline in health-related quality of life 
according to EQ-5D-5L questionnaire (Appendix 3) at Day 3 and Day 9 visits.

IP 12 years old only: Work Productivity and Activity Impairment Questionnaire 
plus Classroom Impairment Questions: SHP, Version 2 (WPAICIQ:SHP, V2) to 
measure lost work or school days (Appendix 4) assessed at Day 9 visit.


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2.4
ADDITIONAL OBJECTIVE
An additional objective for this study is to describe the palatability and acceptability of 
BXM oral suspension in IPs 12 years old on the basis of the following endpoint:

Proportion of IPs reporting each palatability and acceptability response 
(Appendix 5)
3.
STUDY DESIGN
3.1
DESCRIPTION OF THE STUDY
This is a randomized, double-blind, multicenter, parallel-group, placebo-controlled study 
designed to evaluate the clinical efficacy of BXM for the reduction of direct transmission 
of influenza A/B from OwH IPs to their HHCs. For this household study, IPs with 
influenza will be randomized to receive BXM or placebo, and their HHCs will be 
repeatedly tested for influenza virus and assessed for influenza symptoms during the 
next 9 days. The total number of new HHC infections (symptomatic and asymptomatic) 
and total number of new HHC infections associated with symptoms will be key measures 
used to evaluate the “virological transmission” and “symptomatic transmission” 
endpoints (see Section 2).
Approximately 1,130 IPs with influenza and approximately 2,030 evaluable HHCs will 
participate (assuming an average of 2.5 HHCs per IP, a 15% exclusion rate at the 
household level, and a 15% drop-out rate) in the study. The total study duration for each 
household will be up to 9 (1) days (IPs aged 511 years old will have a safety follow-up 
visit at 21 [2] days). This study will be conducted at approximately 200 sites globally in 
the Northern and Southern hemispheres.
Index Patient: Screening and Randomization
Eligible IPs must be aged from 5 to 64 years old, have influenza symptom onset 
within 48 hours, test positive for influenza A/B, and be OwH (i.e., not at high risk for 
complications of influenza). Screening assessments informing IP eligibility include 
physical examination, vital signs, height and weight, medical history and concomitant 
therapies, urine pregnancy testing, and respiratory sampling for influenza testing 
(see Appendix 1a for details).
With regard to the household, IPs should be determined at screening to live with 1 or 
more HHCs who have not received an influenza vaccine in the past 6 months 
(“unvaccinated HHCs”), are likely to fulfill all HHC eligibility criteria, and are expected to 
participate in the “full study” (i.e., participate in all study assessments in Appendix 1b).
IPs who meet the eligibility criteria (see Section 4.1) will be randomized in a 1:1 ratio to 
receive a single dose of either BXM or placebo within 2 hours of randomization. The 
dose and formulation of BXM is based on weight and age (see Section 4.3.2).


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Index Patient: Post-Randomization
Respiratory samples and AEs will be collected. IPs who are 12 years old will also 
complete questionnaires describing their health status and absence from work or school 
(see Appendix 3 and Appendix 4). IPs who are 12 years old will be asked to complete a 
questionnaire on the palatability and acceptability of the study drug oral suspension 
(see Appendix 5). See Appendix 1a for details and timing of study assessments.
Household Contacts: Screening and Enrollment
All HHCs present in the home must have their screening visit start within 24 hours of IP 
randomization (see Section 4.5.9 for details). If any HHC tests positive for influenza A/B, 
then all HHCs fail screening. If 1 or more unvaccinated HHCs meet all HHC eligibility 
criteria and agree to participate in the full study, it is allowable for additional HHCs to not 
participate beyond the screening visit (even if they meet all HHC eligibility criteria). There 
is no maximum number of vaccinated and unvaccinated HHCs that can participate in the 
full study. 
HHCs who agree to participate in the full study (“full study HHCs”) must meet the full 
study criteria (HHC inclusion criteria 7 to 14; see Section 4.1.1), including that they must 
reside in the household for 7 of the 9 study days, and must not have any influenza 
symptoms at screening (mild symptoms determined by the investigator to be due to a 
preexisting condition are allowed).
Screening assessments informing HHC eligibility include influenza symptoms 
(see Appendix 2), medical history, concomitant medications, and respiratory sampling 
for influenza testing (see Appendix 1b for details).
Full Study Household Contacts: Post-Screening
Only full study HHCs participate in visits and assessments post-screening. Full study 
HHCs are monitored for new or worsening influenza symptoms (see Appendix 2), and 
will also maintain a daily temperature diary (see Section 4.5.6). HHCs will be instructed 
to telephone the site if they develop influenza symptoms or fever so that a scheduled or 
unscheduled visit occurring within 24 hours can be arranged (see Section 4.5.6). 
Respiratory samples, adverse events due to study procedures, and concomitant 
medications will be collected (see Appendix 1b for details).
Study Visits
The IP screening visit must occur at the study site. All other visits for IPs and HHCs may 
be conducted at home or at the study site. Home visits may be performed by home 
nurses or by site staff (if local practices are in place). All assessments except respiratory 
swab collection may be conducted remotely (e.g., via telephone or computer).
SARS-CoV-2 Testing
Given overlapping influenza and COVID-19 symptoms, SARS-CoV-2 testing will be 
conducted at screening and as needed during study conduct (see Section 4.5.5.2). If any 


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subject (IP or HHC) tests positive for SARS-CoV-2, then all subjects in the household 
should be discontinued (see Section 4.6.2).
Independent Data Monitoring Committee
An external independent Data Monitoring Committee (iDMC) will evaluate safety
according to policies and procedures detailed in an iDMC Charter.
3.2
END OF STUDY AND LENGTH OF STUDY
The end of this study is defined as the date when the last patient, last visit occurs. The 
end of the study for all patients (except IPs 12 years old) is expected to occur 9 days 
after the last IP is enrolled. For IPs 12 years old, the last visit will be Day 21.
The expected study duration for both IPs and full study HHCs is 9 days, and study 
duration for IPs 12 years old is 21 days.
The total length of the study, from screening of the first patient to the end of the study, is 
expected to be approximately 3.5 years.
In addition, the Sponsor may decide to terminate the study at any time.
3.3
STUDY SCHEMA
Figure 1 presents an overview of the study design. A schedule of activities for the IPs is 
provided in Appendix 1a and a schedule of activities for HHCs is provided in 
Appendix 1b.




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3.4
RATIONALE FOR STUDY DESIGN
3.4.1
Rationale for Baloxavir Marboxil Dose and Schedule
The doses and schedules selected for this study (see Section 4.3.2.1) have been 
demonstrated to be safe and effective in previous large randomized controlled studies in 
patients aged 12 years old and 12 years old.
Dose and Schedule for Patients 12 Years Old based on Study 1601T0831
Study 1601T0831 (CAPSTONE-1; Hayden et al. 2018) compared the effects of a single 
dose of BXM (40 mg for patients 80 kg and 80 mg for patients 80 kg administered as 
20 mg tablets) with placebo or oseltamivir in OwH patients with influenza aged from 12 
to 64 years of old. Study 1601T0831 demonstrated that a single 40 mg/80 mg dose on 
Day 1 was well tolerated and significantly reduced the TTAS (the primary efficacy 
endpoint; see Section 1.2.2 for further details). This dose and regimen were also 
effective at reducing viral load (see Section 1.4.1).
Dose and Schedule for Patients 5 to 12 Years Old based on 
Study CP40563
Study CP40563 (miniSTONE-2; Baker et al. 2020) compared the effects of a body 
weight-adjusted dose of BXM (20 kg [2 mg/kg] and 20 kg [40 mg] administered as an 
oral suspension) with oseltamivir administered twice daily on Days 15 in OwH patients 
with influenza aged from 1 to 12 years old. Study CP40563 demonstrated that both 
BXM and oseltamivir groups had a similar incidence of AEs and median TTAS of 
influenza. There were no deaths, SAEs, or hospitalizations reported (see Section 1.2.2). 
The antiviral activity of BXM was shown to be favorable compared with oseltamivir. This 
regimen enables BXM exposures in patients 12 years old that are similar to the 
exposures observed in Study 1601T0831.
3.4.2
Rationale for Patient Population and Analysis Groups
As described above, treatment with BXM has been shown to reduce viral load and 
symptoms in patients with influenza A/B. Therefore, this study was designed to see if 
this translated into a reduction in viral transmission. HHCs of patients with confirmed 
influenza A/B infection were selected to test this hypothesis, as these individuals will be 
in close contact with the infected individual. As stated in Section 1.4.1, the estimated risk 
of transmission from an IP to HHCs is up to 38% (Tsang et al. 2016).
The inclusion criteria limit IPs to those with symptom onset within 48 hours. This is 
because it is believed that BXM will be most effective at preventing viral transmission if 
given early in the course of infection. (This 48-hour period is also consistent with the 
labels approved to date for BXM in countries including the United States, Hong Kong, 
and Japan).
The study eligibility criteria allow for the inclusion of IPs who are minors. This is also 
consistent with the labels approved to date for BXM, which include approved for use in 
individuals aged 12 years old in some countries and any age in Japan 10 kg. As this 


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is a household study, and intended to reflect a real-world population, child HHCs aged 
2 years old are also included. Children have an important role in the transmission of 
influenza and have higher attack rates than adults (Longini et al. 1982).
The primary efficacy analysis population will consist of all unvaccinated full study HHCs
of the randomized IPs. HHCs vaccinated against the current season’s influenza are
expected to be protected from influenza transmission. However, to enhance the 
feasibility of the trial, and to reflect how BXM would be used for the prevention of 
influenza within households in the real-world setting, the protocol allows enrollment of 
vaccinated HHCs, as long as there is a minimum of one otherwise eligible 
non-vaccinated HHC. 
Similarly, HHCs who will not be present in the IP's home during the majority of the study 
due to travel commitments may be less likely to become infected than those present 
throughout the study period. Again, to enhance the study feasibility, the protocol allows 
enrollment of households with an unlimited number of HHCs who are not present for the 
minimum 7- of the 9-day study period, as long as there is at least one otherwise eligible 
non-travelling (and non-vaccinated) HHC.
3.4.3
Rationale for Study Duration
The focus of the study is to assess the effect of BXM on reduction of transmission. It is 
expected that by Day 5 most secondary transmission will have occurred, since at 
randomization (patients are randomized within 48 hours of onset of symptoms) IPs will 
be at or near their peak viral shedding, which subsequently decreases rapidly due to 
natural course of influenza in OwH patients.
Furthermore, by Day 9, many tertiary transmissions will have occurred, since HHCs
infected via secondary infection by Day 5 will achieve maximal viral shedding at least a 
few days before Day 9.
Finally, transmissions of virus with reduced susceptibility will have occurred by Day 9, 
based on maximum viral shedding of I38X mutants observed at approximately 4 days 
post BXM administration in previous studies.
Extension of the time window beyond Day 9 may increase the risk of externally acquired 
infections being counted in the assessment of the endpoints.
The 9-day study duration for IPs and full study HHCs was also designed with feasibility 
in mind. A short study duration will limit the burden on study participants. Furthermore, it 
would be difficult to ensure that study participants will be available for repeat visits over 
an extended period due to school and work obligations.
IPs aged 5 to 12 years old will have their study duration extended to facilitate a safety 
follow-up visit on Day 21. This last visit corresponds to at least five half-lives for 


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baloxavir, and safety data generated in this study will complement safety data generated 
in other pediatric studies.
3.4.4
Rationale for Selection of Symptoms Assessed in Household 
Contacts and the Definition of Clinical Influenza
The secondary “Symptomatic transmission endpoint” (see Section 2.1.2.1) is designed 
to measure the clinical burden resulting from transmission of influenza, i.e. measure the 
number of cases of symptomatic influenza.
Separate definitions for symptomatic influenza are applied to HHC 12 years versus 
12 years old. Both definitions assess constitutional and respiratory signs and 
symptoms which characterize uncomplicated influenza, namely fever, myalgia, 
headache, malaise, nonproductive cough, sore throat, and rhinitis (Fiore et al. 2008).
Key elements of both definitions have precedence in previous trials, including the 
Fluzonevaccine trials (FluzoneQuadrivalent Prescribing Information) and previous 
BXM studies (Hayden et al. 2018).
For HHCs 12 years old, the following defines symptomatic influenza:

PCR(confirmed at central laboratory), AND one of the following:
–
Temperature 38.0C AND one respiratory symptom (cough, sore throat, nasal 
congestion), OR
–
One respiratory symptom (cough, sore throat, nasal congestion) AND one 
general systemic symptom (headache, feverishness or chills, muscle or joint 
pain, fatigue) (with or without fever)
For HHCs 2 to 12 years old, the symptom assessment will be conducted by the 
responsible adult, and therefore a simplified list of objectively observable yet very 
frequently occurring signs and symptoms will be used. The following defines 
symptomatic influenza for this age range:

PCR(confirmed at central laboratory), AND

Temperature 38.0C AND signs or symptoms of an upper respiratory tract 
infection (cough, nasal congestion or rhinorrhea).
The study may enroll some HHCs who may have comorbidities with symptoms 
overlapping with influenza-like symptoms (e.g., respiratory allergies, autoimmune or 
musculoskeletal conditions). In order to strike a compromise between encouraging real 
world representation while simultaneously ensuring an adequately evaluable symptoms 
endpoint, HHCs with influenza-like symptoms at baseline will be allowed into the study 
IF their influenza-like symptoms are no worse than “mild” (per contact’s assessment) 
and considered by the investigator to be due to their underlying condition and not 
indicative of influenza. HHCs with fever 38.0°C or PCR/Rapid Influenza Diagnostic 
Test (RIDT)will not be enrolled. For HHCs with baseline symptoms, their influenza will 


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be considered to be symptomatic if the HHCs consider their baseline symptoms to have 
worsened (versus baseline), in addition to meeting the other symptom definition criteria.
An HHC will be determined to have ‘symptomatic influenza’ (i.e., the secondary 
“Symptomatic transmission endpoint” will be met) even if symptom onset occurs after the 
sample collection yielding influenza virus (the Day 5 visit or an unscheduled visit before 
the Day 5 visit). Therefore, symptoms will continue to be assessed throughout the study.
HHCs will measure their own temperatures at bedtime and whenever they feel feverish 
(or have their temperature measured by a responsible adult) (see Section 4.5.6). To 
promote consistency, households will be provided with tympanic thermometers, however 
other anatomical sites may be measured (axillary, oral, forehead/temporal, rectal 
temperatures) on an exceptional basis (in case of tympanic thermometer breakage, etc.) 
and the anatomical site will be documented by the contact.
To further promote consistency and capture of symptoms, study healthcare providers will 
query HHCs about new or worsening influenza-like symptoms at all screening, Day 5, 
Day 9, and unscheduled visits (see Appendix 2), and HHCs will be instructed to contact 
the site/study nurse at any time in case of not feeling well.
A note regarding fever: The presence of fever is not always required to meet the 
endpoint for HHCs 12 and older. Although fever is included in commonly accepted case 
definitions for influenza-like illness (CDC 2018b; WHO 2018b), fever is not always 
present in patients with confirmed influenza. In a retrospective, pooled analysis involving 
eight Phase II and Phase III clinical trials, 32% of 2,470 patients with 
laboratory-confirmed influenza did not have fever (37.8°C) (Monto et al. 2000). 
Furthermore, fever may present less commonly in the elderly compared with younger 
adults (Norman 2000).
3.4.5
Rationale for Control Group
This is a placebo-controlled study. Placebo was selected for the control group, as 
opposed to oseltamivir (Tamiflu), because oseltamivir is not a SOC treatment for 
preventing influenza virus transmission. The effect of oseltamivir on transmission from 
an IP to an HHC has not been studied in an adequately powered placebo-controlled 
randomized trial. Comparison with placebo will enable analysis of the true effect of BXM
on preventing influenza virus transmission.
Given that IPs randomized to the control group will receive placebo as the only treatment 
for influenza, this study is restricted to OwH patients (i.e., patients who are not at 
increased risk for complications of influenza). The U.S. Centers for Disease Control and 
World Health Organization provide guidance that IPs aged 5 and 64 years old are at 
high risk. Furthermore, certain medical conditions (e.g., emphysema or asthma) 
regardless of age predispose a person as high risk. Therefore, only patients aged from 


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5 to 64 years old and judged by the investigator not to be at high risk for 
complications will be eligible.
3.4.6
Rationale for Virology Assessments
All virology assessments in this study will be based on respiratory swabs.
3.4.6.1
Diagnosis of Influenza A/B Infection
This study will preferentially use the cobas SARS-CoV-2 & Influenza A/B test at study 
visits to provide information on influenza A/B infection for the enrollment of IPs and 
HHCs. This system has high sensitivity and specificity for detecting influenza A/B
infections (see Section 1.3). The use of this POC system will facilitate the timely 
diagnosis of influenza infection and enrollment of IPs, and the rule-out of infection in 
HHCs at screening.
This cobas Liat System will also be used for POC assessment of influenza A/B infection 
for HHCs throughout the study.
If PCR-based POC testing using the cobas SARS-CoV-2 & Influenza A/B test is not 
available at the study site, other POC tests or local laboratory results can be used 
instead (see Section 4.5.5.2).
All respiratory samples will also be analyzed in the central laboratory 
(see Section 4.5.5.3). Central laboratory PCR will be used to determine whether HHCs
meet the eligibility criteria for purposes of the primary analysis population (all HHCs
within a household were PCR-negative for influenza at screening), and to determine if 
primary and secondary efficacy endpoints have been met (HHCs become PCR-positive 
for influenza).
3.4.6.2
Viral Type and Subtype Assessment
Respiratory samples collected from IPs on Day 0 and HHCs who become PCR positive
(confirmed at central laboratory) for influenza during the study will be analyzed in a 
central laboratory. Only HHCs with an influenza type (A or B) and influenza A subtype 
(H1N1 and H3N2) subtype that is consistent with that of the IP (i.e., consistent with 
within-household transmission) will be considered for the primary efficacy endpoint and 
secondary efficacy endpoints as indicated in Section 2.1.
Viral genome sequencing will not be used to confirm infection origin in HHCs
(i.e., consistency with the IP) for the purpose of the primary and secondary endpoints. 
This is because sequencing and subsequent phylogenetic analysis cannot reliably 
determine infection origin at study sites with low IP numbers (see Section 3.4.6.5).
Several studies indicate that levels of co-incident transmission (i.e., transmission of 
infection originating outside the household) are likely low. One study estimated that 97% 
of secondary cases were acquired within the household (Tsang et al. 2015). In another 


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study, sequence analysis of 52 epidemiologically linked putative household transmission 
events (symptom onset within a 7-day window) showed that 47 (91%) were likely to be 
true household transmission pairs and five were suspicious for co-incident community 
acquired infection (McCrone et al. 2018).
Based on this low level of co-incident community-acquired infection, and the limitations 
of the sequencing approach, all infections in households will be assumed to be due to 
within-household transmission as long as the virus subtype is consistent with the IP.
3.4.6.3
Viral Titer Assessment
Respiratory samples collected from IPs at the timepoints indicated in Appendix 1a will 
also be used to measure influenza viral titer to determine if viral titer impacts on the 
ability of BXM to prevent transmission of influenza from OwH patients to HHCs (other 
efficacy endpoint).
To maximize the chances of identifying a relationship between viral titer in the IP and the 
ability of BXM to prevent transmission to HHCs, viral titer will be assessed using two 
techniques: quantitative PCR (using CT [threshold cycle] values on Days 0, 3, 5, and 9) 
and infectivity (using the TCID50 on Days 0, 3, 5, and 9).
3.4.6.4
Analysis of Viruses with Reduced Susceptibility to Baloxavir 
Marboxil
Amino acid substitutions in the polymerase acidic (PA) protein have been linked with 
reduced susceptibility to BXM (Omoto et al. 2018). In particular, the isoleucine to 
threonine substitution at position 38 (I38T substitution). Treatment-emergent amino acid 
substitutions in the PA protein that have been associated with reduced susceptibility to 
BXM to date include:

Influenza A/H1N1: E23K/R, I38F/N/S/T

Influenza A/H3N2: E23G/K, A37T, I38M/T, E199G

Influenza B: I38T
Viral RNA sequencing of samples collected from patients treated with BXM will be 
conducted to identify treatment-emergent amino acid substitutions to evaluate whether 
the efficacy of BXM for preventing viral transmission is affected by the viral genotype 
(selected secondary and other endpoints).
Samples from IPs who experience a rebound in viral titers and/or show 
treatment-emergent amino acid substitutions in PA identified by sequencing analysis will 
be assayed for phenotypic reduced susceptibility (as per Table 3).
3.4.6.5
Viral Genome Sequencing
Whole genome next-generation sequencing will be conducted on respiratory samples 
from HHCs and IPs at a central laboratory from selected sites. This will be done as a 
supportive analysis in a subset of study subjects to assess the accuracy of using viral 


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type/subtype assessment (see Section 3.4.6.2) to match IP to HHC transmission for the 
primary/secondary endpoints. The feasibility of this sequencing analysis will depend on 
sufficient samples being obtained. Sites will be selected on the basis that they can 
provide adequate numbers of IPs with unique sequences, or if sequences from 
databases for the same season are available for this community.
3.4.6.6
Other Viral Parameters
No blood-based assessments will be conducted in this study. The rationale for this is to 
reduce the burden on the study participants and to increase the feasibility of the study. 
Consequently, parameters such as the serum influenza antibody titer cannot be 
assessed in this study.
Serum antibody titer in patients treated with BXM has been studied previously. The 
CAPSTONE 1 study (Study 1601T0831; Hayden et al. 2018) measured serum influenza 
antibody titer on Day 1 and Day 22 in OwH adult and adolescent patients with 
uncomplicated influenza randomized to a single dose of BXM (40 mg for patients who 
weigh 80 kg and 80 mg for patients who weigh 80 kg), oseltamivir 75 mg twice daily 
for 5 days, or placebo (see Section 1.2.2.1). Apparent increases in serum influenza 
antibody titer were found on Day 22 in all three treatment groups, regardless of the 
infected virus type/subtype, with no statistically significant differences between groups.
3.4.6.7
Diagnosis of SARS-CoV-2 Infection
COVID-19 is an infectious disease caused by the coronavirus SARS-CoV-2. This virus 
and disease became known in December 2019 and has since become a global 
pandemic. Common symptoms are fever, dry cough, loss of taste or smell, and 
tiredness. Less common symptoms include aches and pains, nasal congestion, 
headache, conjunctivitis, sore throat, diarrhea, a rash on skin, or discoloration of fingers 
or toes. Some of these symptoms overlap with those for influenza.
Many communities worldwide recommend or require that people with suspected or 
confirmed SARS-CoV-2 infection self-isolate and only visit designated healthcare 
facilities. There is limited data concerning outcomes in patients with influenza and 
SARS-CoV-2 coinfection.
All IPs will be screened for SARS-CoV-2 infection. Those found to be infected will be 
excluded from the study.
All HHCs will also be screened for SARS-CoV-2 infection. If any HHC is found to be 
infected, no HHCs from the same household may be enrolled and the IP will be 
withdrawn from the study. Excluding households with SARS-CoV-2 infection will allow 
households to better comply with community requirements regarding isolation and avoid 
further unnecessary contact with healthcare providers and non-designated healthcare 
facilities (i.e., the study site).


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See Section 4.5.5.2 for SARS-CoV-2 testing post-enrollment.
4.
MATERIALS AND METHODS
4.1
INDEX PATIENTS AND HOUSEHOLD CONTACTS
The proposed sample size for this study is 2,030 evaluable HHCs. Assuming a 15% 
drop-out for inclusion of HHCs into the primary analysis population, an average of 
2.5 HHCs per IP and a 15% exclusion rate on the household level, this equates to an 
approximate number of IPs of 1,130.
4.1.1
Inclusion Criteria
Inclusion Criteria: Index Patients
Each IP must meet the following criteria for study entry:
1. Signed Informed Consent Form (ICF). In the case of minors, a parent or authorized 
adult will be required to sign the ICF on behalf of the patient. The informed 
consent/assent of voluntary participation should be obtained in accordance with local 
requirements.
2. Age 5 and 64 years at time of signing ICF.
3. Able to comply with the study protocol per investigator judgment.
4. Diagnosed with acute influenza infection by investigator.
5. PCR () or RIDT () for influenza A/B based on cobas SARS-CoV-2 & Influenza A/B 
test or other point-of-care/local laboratory results.
6. PCR () or antigen test () for SARS-CoV-2 based on cobas SARS-CoV-2 &
Influenza A/B test or other point-of-care/local laboratory result.
7. Presence of (a) fever (38.0C per tympanic or rectal thermometer; 37.5C per 
axillary, oral or forehead/temporal thermometer) or (b) any influenza symptoms 
(cough, sore throat, nasal congestion, headache, feverishness or chills, muscle or 
joint pain, fatigue).
8. The time interval between the onset of fever or influenza symptoms and the pre-dose 
examinations is 48 hours or less.
9. IP lives in a household where:
a) No HHC is known to have been diagnosed with influenza or SARS-CoV-2 
infection by a healthcare professional in the past 4 weeks.
b) All HHCs are expected to meet the key HHC inclusion criteria (criteria 1, 2, 3, 
4, 5, and 6).
c) 1 or more HHCs are expected to participate in the full study who have not 
received the influenza vaccine within 6 months prior to screening.


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10. For women of childbearing potential: agreement to remain abstinent (refrain from 
heterosexual intercourse) or use contraceptive measures as defined below:
Women must remain abstinent or use contraceptive methods with a failure 
rate of 1% per year during the treatment period and for 21 days after the 
final dose of study treatment. 
A woman is considered to be of childbearing potential if she is 
postmenarcheal, has not reached a postmenopausal state (12 continuous 
months of amenorrhea with no identified cause other than menopause), and is 
not permanently infertile due to surgery (i.e., removal of ovaries, fallopian 
tubes, and/or uterus) or another cause as determined by the investigator 
(e.g., Müllerian agenesis). 
Examples of contraceptive methods with a failure rate of 1% per year 
include bilateral tubal ligation, male sterilization, hormonal contraceptives that 
inhibit ovulation, hormone-releasing intrauterine devices, and copper 
intrauterine devices.
Hormonal contraceptive methods must be supplemented by a barrier method.
The reliability of sexual abstinence should be evaluated in relation to the 
duration of the clinical trial and the preferred and usual lifestyle of the patient. 
Periodic abstinence (e.g., calendar, ovulation, symptothermal, or 
postovulation methods) and withdrawal are not acceptable methods of 
contraception. If required per local guidelines or regulations, locally 
recognized acceptable methods of contraception and information about the 
reliability of abstinence will be described in the local Informed Consent Form.
Inclusion Criteria: All Household Contacts 
Each HHC living in the home at any time during the study must meet criteria 16 below. 
The screening visit should start within 24 hours after IP randomization unless the HHC is 
a late-arrival HHC (see Section 4.5.9):
1. Signed ICF. In the case of minors, a parent or authorized adult will be required to sign 
the ICF on behalf of the HHC. The informed consent/assent of voluntary participation 
should be obtained in accordance with local requirements. All late-arrival HHCs 
(as defined in Section 4.5.9) must be willing to be consented for screening as soon as 
possible after their arrival.
2. PCR () or RIDT () based on cobas SARS-CoV-2 & Influenza A/B test or other 
local point-of-care/local laboratory result.
3. PCR () or antigen test () for SARS-CoV-2 based on cobas SARS-CoV-2 & 
Influenza A/B test or other POC/local laboratory result.
4. HHC lives with no HHC who will be present in the home at any time during the study 
and who meets any HHC exclusion criteria.
5. HHC lives with no HHC (except late-arrival HHCs) who does not meet HHC inclusion 
criteria 16.


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6. HHC lives in a household where 1 or more HHCs meet all of the following: 
a) Start screening within 24 hours after IP randomization.
b) Have NOT received the influenza vaccine within 6 months prior to screening.
c) Fulfill full study HHC inclusion criteria 714.
Inclusion Criteria: Full Study Household Contacts
Each HHC intended for full study must meet the following additional criteria:
7. Agree to participate in the full study (i.e., participate in all assessments after 
screening).
8. Able to comply with the study protocol per investigator judgment.
9. No influenza symptoms within 7 days prior to screening. Alternatively, mild symptoms 
(at worst) are permissible if determined by the investigator to be due to a preexisting 
condition (e.g., mild nasal congestion due to seasonal allergies).
a) Symptoms for HHC 12 years old: cough, sore throat, nasal congestion, 
headache, feverishness or chills, muscle or joint pain, fatigue.
b) Symptoms for HHC 2 to 12 years old: cough, nasal congestion or 
rhinorrhea.
10. Temperature 38.0C (tympanic).
11. Will reside in the IP's house for at least 7 of the next 9 days and will be present for 
scheduled study visits.
12. Willing and able to measure and record temperature, or have another household 
member perform the task on his or her behalf. Furthermore, a responsible adult will 
assume responsibility to oversee or perform this task on behalf of minors.
13. In the 6 months prior to screening:
a) Has not been diagnosed with influenza by a healthcare professional
b) Has not received BXM, peramivir, laninamivir, oseltamivir, zanamivir, 
rimantadine, umifenovir, amantadine, or favipiravir
14. Does not have a moderate or worse active infections OR infections requiring
systemic (e.g., oral or intravenous) or otherwise internally administered (e.g., inhaled, 
intrathecal) antibiotic/antiviral/antifungal therapy, (topical therapies for mild external 
infections allowed).
4.1.2
Exclusion Criteria
Exclusion Criteria: Index Patients
An IP meeting any of the following criteria will be excluded from the study:
1. IP with severe influenza virus infection requiring inpatient treatment.
2. IP judged by the investigator to be at high risk for complications of influenza, after 
consideration of the following* or other potential risk factors:
a) Women who are pregnant or within 2 weeks post-partum;


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b) Chronic respiratory diseases including chronic obstructive pulmonary disease,
current asthma, and cystic fibrosis;
c) Neurological and neurodevelopmental disorders including disorders of the 
brain, spinal cord, peripheral nerve, and muscle (e.g., cerebral palsy, epilepsy 
[seizure disorders], stroke, intellectual disability, moderate to severe 
developmental delay, muscular dystrophy, or spinal cord injury);
d) Heart disease (such as congenital heart disease, congestive heart failure, or 
coronary artery disease);
e) Blood disorders (such as sickle cell disease);
f)
Endocrine disorders (such as diabetes mellitus);
g) Kidney disorders;
h) Liver disorders;
i)
Metabolic disorders (such as inherited metabolic disorder and mitochondrial 
disorders);
j)
Compromised immune system due to disease (such as people with HIV or 
AIDS, or some cancers such as leukemia) or medications (such as those 
receiving chemotherapy or radiation treatment for cancer, or persons with 
chronic conditions requiring chronic corticosteroids or other drugs that 
suppress the immune system);
k) Morbid obesity (body mass index [BMI] 40);
l)
People younger than 19 years of age on long-term aspirin- or salicylate-
containing medications;
m) People from certain racial and ethnic minority groups are at increased risk 
for hospitalization with influenza, including non-Hispanic Black persons, 
Hispanic or Latino persons, and American Indian or Alaska Native persons. 
The investigator should consider the overall risk of the individual.;
n) People who live in nursing homes and other long-term care facilities.
* Adapted from the definition of “People at Higher Risk of Flu Complications” 
provided by the Centers for Disease Control and Prevention (CDC 2021)
3. IP is 12 years old and unable to swallow tablets (not applicable to IPs 5 to 12 year 
olds who will receive oral suspension).
4. Women who are breastfeeding or have a positive pregnancy test in the pre-dose 
examinations. Female patients with documentation of at least one of the following 
items are exempt from pregnancy testing:
a) Postmenopausal women (defined as cessation of regular menstrual periods 
for 12 continuous months).
b) Women who are surgically sterile by hysterectomy, bilateral oophorectomy, or 
tubal ligation.
c) Females 12 years old and pre-menarcheal.


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5. IP with concurrent (non-influenza) infections requiring systemic antimicrobial and/or 
antiviral therapy at the pre-dose examinations.
6. IP who has received BXM, peramivir, laninamivir, oseltamivir, zanamivir, rimantadine, 
umifenovir, amantadine, or favipiravir within 30 days prior to screening.
7. IP who has received an investigational monoclonal antibody for a viral disease in the 
last year.
8. IP who has received an investigational therapy within 30 days or 5 drug-elimination 
half-lives, whichever is longer, prior to screening.
9. IP lives with an HHC who, based on available information, is:
a) Pregnant or within 2 weeks post-partum.
b) Immunocompromised (including patients receiving immunosuppressant 
therapy, or those with cancer or HIV infection).
c) 2 years old.
d) Unwilling to sign informed consent.
e) Diagnosed with influenza or SARS-CoV-2 infection by a healthcare 
professional in the past 4 weeks.
f)
Previously included in the study.
g) Plan to arrive home from after 24 hours post IP randomization to Day 9 and 
(late-arrival HHC defined in Section 4.5.9) is not willing to be consented as 
soon as possible upon arrival.
10. Known hypersensitivity to BXM or the drug product excipients.
11. Any other contraindication for treatment with BXM as deemed by the treating 
physician or Principal Investigator.
12. IP previously included in the study.
Exclusion Criteria: All Household Contacts
An HHC (living in the home at any time during the study) meeting any of the following 
criteria will be excluded from study entry:
1. Pregnant or within 2 weeks post-partum at screening.
2. Immunocompromised (including patients receiving immunosuppressant therapy, or 
those with cancer or HIV infection).
3. 2 years old.
4. Received an investigational therapy within 30 days or 5 drug-elimination half-lives, 
whichever is longer, prior to screening.
5. Diagnosed with influenza or SARS-CoV-2 infection by a healthcare professional in 
the past 4 weeks.
6. HHC previously included in the study.


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7. HHC who plans to arrive home after 24 hours post IP randomization to Day 9 and 
(late-arrival HHC defined in Section 4.5.9) is not willing to be consented as soon as 
possible upon arrival.
4.2
METHOD OF TREATMENT ASSIGNMENT AND BLINDING
Study site personnel and patients will be blinded to treatment assignment (active drug or 
placebo) during the study. The Sponsor and its agents will also be blinded to treatment 
assignment, with the exception of individuals who require access to patient treatment 
assignments to fulfill their job roles during a clinical trial. These roles include the clinical 
supply chain managers, the interactive voice or web-based response system (IxRS) 
service provider, the iDMC, and central laboratory staff responsible for assessments 
conducted in BXM-treated patients only.
Allocation to one of the two treatment arms will be randomized in a 1:1 proportion and 
will consider the following stratification factors:

Region: United States or Europe; Asia; and rest of world

Number of HHCs: 2; 3

Age: 5 to 12 years; 12 to 30 years; 30 years

Duration of symptoms: 24; 24 to 48 hours
If unblinding is necessary for a medical emergency (e.g., in the case of a serious 
adverse event for which patient management might be affected by knowledge of 
treatment assignment), the investigator will be able to break the treatment code by 
contacting the IxRS. The investigator is not required to contact the Medical Monitor prior 
to breaking the treatment code. However, the investigator should inform the 
Medical Monitor that the treatment code has been broken.
If the investigator wishes to know the identity of the study drug for any reason other than 
a medical emergency, he or she should contact the Medical Monitor directly. Unblinding 
may be permitted if an investigator is deciding whether a patient should withdraw from 
the study and initiate treatment with a proven therapy. However, unblinding will not be 
permitted if an investigator is deciding whether a patient should withdraw from the study 
and initiate treatment with an unproven therapy. The investigator should document and 
provide an explanation for any non-emergency unblinding. The investigator will be able 
to break the treatment code by contacting the IxRS.
As per health authority reporting requirements, the Sponsor's Drug Safety representative 
will break the treatment code for all serious, unexpected suspected adverse reactions 
(see Section 5.7) that are considered by the investigator or Sponsor to be related to 
study drug. The patient may continue to receive treatment, and the investigator, patient, 
and Sponsor personnel, with the exception of the Drug Safety representative and 
personnel who must have access to patient treatment assignments to fulfill their roles 
(as defined above), will remain blinded to treatment assignment.


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4.3
STUDY TREATMENT AND OTHER TREATMENTS RELEVANT 
TO THE STUDY DESIGN
The investigational medicinal product (IMP) for this study is BXM/matching placebo.
4.3.1
Study Treatment Formulation, Packaging, and Handling
4.3.1.1
Baloxavir Marboxil and Placebo
BXM and placebo for IPs will be supplied by the Sponsor as tablets or granules for oral 
suspension.
To maximize the study blind, each site must delegate the constitution of BXM and 
placebo oral suspensions (from the supplied granule) to dedicated site personnel who 
are not involved in any other study-related assessments or procedures. The 
administration of the oral suspension can be performed by study personnel.
For information on the formulation, packaging and handling of BXM and placebo, see the 
pharmacy manual.
4.3.2
Study Treatment Dosage, Administration, and Compliance
IPs will receive either a single dose of BXM or matching placebo.
Any dose modification should be noted on the Study Drug Administration electronic 
Case Report Form (eCRF). Cases of overdose or medication error, along with any 
associated adverse events, should be reported as described in Section 5.3.5.10.
Guidelines for treatment interruption or discontinuation for patients who experience 
adverse events are provided in Section 5.1.
4.3.2.1
Baloxavir Marboxil and Placebo
This is a single, oral dose study.
IPs will receive the initial and only dose of study drug (BXM or matching placebo) to be
taken in tablet or oral suspension form at the study center within 2 hours of 
randomization.
See Table 1 and Table 2 for study drug (BXM or matching placebo) administration. 
Table 1
Study Drug Administration and Dose for Index Patients 
12 Years Old
Weight
Dose, Formulation
20 kg 
2 mg/kg, oral suspension
20 kg 
40 mg, oral suspension


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Table 2
Study Drug Administration and Dose for Index Patients 
12 Years Old
Weight
Dose, Formulation
80 kg
40 mg, (two 20 mg tablets)
80 kg 
80 mg, (four 20 mg tablets)
IPs who are morbidly obese are not eligible for the study (see Section 4.1.2).
4.3.3
Additional Medication
The further treatment of HHCs diagnosed with influenza A/B during the study will be 
determined by the investigator according to local standards (see Section 4.4.2). The 
study sponsor will not provide further treatment.
4.3.4
Investigational Medicinal Product Accountability
All IMPs required for completion of this study (BXM and placebo) will be provided by the 
Sponsor. The study site will acknowledge receipt of IMPs supplied by the Sponsor using 
the IxRS to confirm the shipment condition and content. Any damaged shipments will be 
replaced. The investigator or his or her designee must confirm that appropriate 
temperature conditions have been maintained during transit, either by time monitoring 
(shipment arrival date and time) or temperature monitoring, for all IMPs received and 
that any discrepancies have been reported and resolved before use of the IMPs. All 
IMPs must be stored in a secure, environmentally controlled, and monitored (manual 
or automated) area in accordance with the labeled storage conditions, with access 
limited to the investigator and authorized staff.
IMPs will either be disposed of at the study site according to the study site's institutional 
standard operating procedure or be returned to the Sponsor with the appropriate 
documentation. The site's method of destroying Sponsor-supplied IMPs must be agreed 
to by the Sponsor. The site must obtain written authorization from the Sponsor before 
any Sponsor-supplied IMP is destroyed, and IMP destruction must be documented on 
the appropriate form.
Accurate records of all IMPs received at, dispensed from, returned to, and disposed of by 
the study site should be recorded on the Drug Inventory Log.
4.3.5
Continued Access to Baloxavir Marboxil
Currently, the Sponsor does not have any plans to provide the Roche IMP (BXM) or any 
other study treatments or interventions to patients who have completed the study. The 
Sponsor may evaluate whether to continue providing BXM in accordance with the Roche 


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Global Policy on Continued Access to Investigational Medicinal Product, available at the 
following website:
http://www.roche.com/policy_continued_access_to_investigational_medicines.pdf
4.4
CONCOMITANT THERAPY
Concomitant therapy consists of any medication (e.g., prescription drugs, 
over-the-counter drugs, vaccines, herbal or homeopathic remedies, nutritional 
supplements) used by an IP or HHC in addition to protocol-mandated treatment from 
7 days prior to 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 and Prohibited Therapy for the Index Patient
All medications (including symptomatic therapy for their influenza, oral contraceptives, 
and hormone replacement therapy) are permitted in the IPs during the study except for:

Investigational therapy (other than protocol-mandated study treatment) 

Traditional Chinese medicine or other herbal remedies with antiviral properties for 
the treatment or prevention of influenza (e.g., the product’s label clearly states that 
the product is for the treatment or prevention of influenza or there exists at least 
two scientific studies [in vitro or in vivo] published in peer-reviewed medical 
journals demonstrating a specific antiviral effect against influenza for the product 
or for one of the main ingredients)

Influenza antiviral drugs (BXM, [other than protocol-mandated study treatment], 
peramivir, laninamivir, oseltamivir, zanamivir, rimantadine, umifenovir, amantadine,
or favipiravir)

Immunosuppressants (including biologics)
4.4.2
Permitted and Prohibited Therapy for the Full Study HHCs
All medications are permitted in HHCs except for:

Investigational therapy 

Traditional Chinese medicine or other herbal remedies with antiviral properties for 
the treatment or prevention of influenza (e.g., the product’s label clearly states that 
the product is for the treatment or prevention of influenza or there exists at least 
two scientific studies [in vitro or in vivo] published in peer-reviewed medical 
journals demonstrating a specific antiviral effect against influenza for the product 
or for one of the main ingredients)

Influenza antiviral drugs (BXM, peramivir, laninamivir, oseltamivir, zanamivir, 
rimantadine, umifenovir, amantadine, or favipiravir)

Immunosuppressants (including biologics)


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Local SOC (including antivirals) are only permitted in HHCs, IF the HHC is diagnosed 
with influenza as confirmed by local testing or the investigator diagnoses influenza 
despite negative test results, AND one of the below:
1) HHC is symptomatic as per the secondary “Symptomatic transmission endpoint” 
(see Section 2.1.2.1), or
2) HHC is asymptomatic but considered by the investigator to be at high risk for 
complications of influenza.
4.4.3
Cautionary Therapy and Foods for Index Patients
BXM is not expected to affect the PK of co-administered drugs, nor are co-administered 
drugs expected to affect the PK of baloxavir. See the Baloxavir Marboxil Investigator’s 
Brochure for more information.
No specific food is prohibited in this study.
BXM co-administration with dairy products, calcium-fortified beverages, polyvalent 
cation-containing laxatives, antacids, or oral supplements (e.g., calcium, iron, 
magnesium, selenium, or zinc) should be avoided. Therefore, study medication should 
not be co-administered with any of the aforementioned foods, liquids, or medications.
4.5
STUDY ASSESSMENTS
The schedule of activities to be performed for IPs during the study is provided in 
Appendix 1a. The schedule of activities to be performed for HHCs during the study is 
provided in Appendix 1b.
All activities should be performed and documented for each IP and HHC.
Study assessments indicated in Appendix 1a (IPs) and Appendix 1b (HHCs) will be 
performed at the study site, at the home, or via remote visit (e.g., via telephone or 
computer). The IP screening visit must be conducted at the study site. All respiratory 
swabs must be obtained by a healthcare professional. Home and remote visits may 
improve access and convenience for all subjects participating in the study. Applicable 
study assessments may be performed by staff from study site (if local processes are in 
place) at the patient's home or another suitable location, to improve access and 
convenience. 
The Sponsor will select a healthcare company that will be responsible for providing 
home nurse services for participating sites (the home nurse vendor). Alternatively, 
investigators may delegate a professional home nurse affiliated with a home nurse 
vendor (approved by the Sponsor). The home nurse vendor is responsible for ensuring 
that all home nurse professionals are licensed, qualified, and in good standing, as per 
applicable regulations, and that appropriate background checks have been performed.


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Study visits (at the study site, home, or remote) will occur on scheduled and 
unscheduled visit days, as defined in Appendix 1a and Appendix 1b.
All information collected at home or remote visits will be reviewed by the investigator. All 
respiratory samples collected offsite will be returned to the site for local analysis and/or 
for preparation for shipment to the central laboratory.
4.5.1
Informed Consent Forms and Screening Log
Written informed consent for participation in the study must be obtained 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. In addition, Informed Consent Forms for enrolled 
HHCs and for HHCs who are not subsequently enrolled will be maintained at the study 
site.
All screening evaluations must be completed and reviewed to confirm that patients and 
HHCs meet all eligibility criteria before enrollment. The investigator will maintain a 
screening log to record details of all patients and HHCs 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 for the IP will be obtained in the study site at screening to confirm 
inclusion and exclusion criteria. Medical history will include clinically significant diseases, 
history of influenza symptoms, reproductive status, influenza vaccination status, history 
of local laboratory results. In addition, all medications (e.g., prescription drugs, 
over-the-counter drugs, vaccines, herbal or homeopathic remedies, nutritional 
supplements) used by the IP during the study and within 7 days prior to initiation of study 
treatment will be recorded.
IPs will also provide, to the best of their knowledge, information on the vaccination status 
of their HHC, and an assessment of whether any of their HHCs have exhibited influenza 
like-illness (and the severity of the symptoms) in the last 7 days (see inclusion/exclusion 
criteria).
Medical history for the HHCs will be obtained at the screening visit to confirm inclusion 
and exclusion criteria, including establishing influenza vaccination status and to rule out 
influenza-like illness in the previous 7 days (mild influenza-like symptoms are permitted 
in HHCs if determined by the investigator to be due to a preexisting condition). In 
addition, all medications (e.g., prescription drugs, over-the-counter drugs, vaccines, 
herbal or homeopathic remedies, nutritional supplements) used by the HHC during the 
study and within 7 days prior to enrollment will be recorded. Demographic data will 
include age, sex, self-reported race/ethnicity (where allowed according to local 
regulations) and size of the household (number of HHCs).


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4.5.3
Physical Examinations
A limited physical examination of IPs should be performed at screening to evaluate the 
patient for symptoms related to complications of influenza comprising assessment of the 
eyes, ears, nose, throat, and respiratory system. Any abnormality identified at baseline 
should be recorded on the General Medical History and Baseline Conditions eCRF.
4.5.4
Vital Signs
Vital signs will be assessed at screening in IPs and will comprise measurement of 
temperature, blood pressure, and heart rate. Temperature measurement can be done 
using tympanic, rectal, axillary, oral or forehead/temporal thermometers. Blood pressure 
and heart rate should be taken in sitting position after 5 minutes of rest.
Height and weight will also be recorded at screening in IPs only to calculate the BMI for 
eligibility criteria and to determine the dose of study drug.
4.5.5
Laboratory and Other Biological Samples
The collection and analysis of respiratory and urine samples are described in the 
sections below.
4.5.5.1
Respiratory Samples
Respiratory samples will be collected at the timepoints indicated in the schedule of 
activities for IPs (see Appendix 1a) and for HHCs (see Appendix 1b). Detailed 
instructions for collecting respiratory samples (via “swabbing”) are provided in the 
laboratory manual and must be followed.

IP samples collected at screening
Two samples will be collected (one for local and one for central laboratory analysis) 
by the investigator or site staff. A respiratory sample for local analysis 
(see Section 4.5.5.2) is not needed if the medical record documents show 
influenza A/B positive and SARS-CoV-2 negative test results based on respiratory 
samples collected within 24 hours prior to signed ICF (as part of SOC).

HHC samples collected at screening
Two samples will be collected (one for local and one for central laboratory analysis) 
from all HHCs present in the household within 24 hours of the IP's treatment with 
study medication.
Late-arrival HHCs (as defined in Section 4.5.9) should be swabbed (to collect 
2 samples [one for local and one for central laboratory analysis]) as soon as 
possible at an unscheduled visit, after signing ICF.

IP samples collected post-randomization
One sample is collected for central laboratory analysis on Days 3, 5, and 9. 
Furthermore, the investigator may at any time collect a sample for local analysis of 
SARS-CoV-2 if the investigator suspects co-infection. If this collection occurs during 


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an unscheduled visit, an additional sample should be obtained for central laboratory 
analysis of SARS-CoV-2.

Full study HHC samples collected post-screening
Post-screening samples will only be obtained from HHCs participating in the full 
study at Days 5, 9, and any unscheduled visits. Two samples will be collected at 
each visit (one for local and one for central laboratory analysis). HHCs unable to 
participate in the full study will not receive any post-screening swabs.

Early discontinuation of sample collection for IPs and HHCs
Any HHC with a positive influenza A/B result based on local analysis will no longer 
receive subsequent swabs (i.e., respiratory sample collection is discontinued). 
However, such HHCs will continue to undergo other assessments as described in 
Appendix 1b. If any IP or HHC has a positive SARS-CoV-2 result based on local 
analysis, all swabbing (i.e., respiratory sample collection) will stop for all subjects 
(IP and HHCs) in the same household, and all subjects will be discontinued 
(see Section 4.6.2).
4.5.5.2
Local Analysis of Respiratory Samples
This study will use the cobas Liat System (preferred system) that consists of the 
cobas Liat Analyzer together with a disposable assay tube that holds the reagents 
required to perform a test on the cobas Liat System. Sites will be provided with the 
analyzer and cobas SARS-CoV-2 & Influenza A/B test (a combination assay).
When sites use the cobas SARS-CoV-2 & Influenza A/B test, both influenza and 
SARS-CoV-2 results are generated from a single respiratory sample. Both results are 
expected to be recorded on the eCRF, including when testing for SARS-CoV-2 is not 
mandated by the protocol.
If the preferred system is not available at the study site, the RIDT or other POC test for 
influenza A/B or POC test for SARS-CoV-2 can be used instead. If an IP or HHC is 
tested using an RIDT or other POC test, the site will record the use of the alternative 
test.
Samples locally analyzed are as follows:

Screening samples
Local analysis at screening informs the assessment of IP and HHC inclusion criteria 
(Section 4.1.1). IPs will be randomized based on the local test results that confirm 
the IP is influenza A/B positive and SARS-CoV-2 negative.
All HHCs must be screen failed if local test results confirm that any single HHC 
is influenza A/B positive. All HHCs must be screen failed and the IP 
discontinued if any single HHC is SARS-CoV-2 positive (see Section 4.6.2).


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
IP samples post-randomization
No samples will be collected for local analysis except samples collected for 
SARS-CoV-2 local testing by investigators as needed (see Section 4.5.5.1). 
If any IP or HHC tests positive for SARS-CoV-2, all subjects (IP and HHCs) in 
the same household must be discontinued (see Section 4.6.2).

HHC samples post-screening 
HHCs participating in the full study will have all post-screening respiratory samples 
tested for influenza A/B using the cobas SARS-CoV-2 & Influenza A/B test. If the 
preferred system is not available at the study site, a RIDT or other POC test for 
influenza A/B can be used.
HHCs who test positive for influenza A/B may be treated as per Section 4.4.2.
HHCs participating in the full study are assessed for symptoms of influenza and 
fever at all visits (see Section 4.5.6 and Appendix 2). Once an HHC is assessed to 
have worsened or new influenza symptoms or fever, then all their remaining 
samples will be required to additionally be tested for SARS-CoV-2 using the
cobas SARS-CoV-2 & Influenza A/B test or other POC test for SARS-CoV-2 if the 
preferred system is not available at the study site (NB other POC tests for 
SARS-CoV-2 may need an additional sample if this POC test is not a combination 
assay). No SARS-CoV-2 local testing is required after criteria have been met for 
early discontinuation of sample collection (see Section 4.5.5.1 for early 
discontinuation of sample collection for IPs and HHCs). (Note: if worsened or new 
influenza symptoms or fever occur after discontinuation of sample collection, no 
local SARS-CoV-2 testing is conducted).
If any HHC or IP tests positive for SARS-CoV-2, all subjects (HHCs and IP) in 
the same household must be discontinued (see Section 4.6.2).
NOTE: All IP and HHC samples collected after signed ICF and used for local analysis 
will also be sent to the central laboratory. 
4.5.5.3
Central Laboratory Analyses 
All respiratory samples collected from the IPs and HHCs during the study will be sent to 
a central laboratory for analysis of the measures below (see Table 3).
The rationales for these central laboratory assessments are described in Section 3.4.6.
Confirmation of influenza infection for all enrolled households
Respiratory samples obtained at screening from all IPs and all HHCs will be analyzed by 
quantitative PCR to confirm that the IP was PCR-positive for influenza A/B and all HHCs
were PCR-negative for influenza A/B. The central laboratory test result will be used to 
confirm eligibility to define the analysis populations.
Respiratory samples obtained post-screening from HHCs participating in the full study 
will be analyzed by quantitative PCR to determine if the HHC has become PCR-positive 


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for influenza A/B. The central laboratory test result will be used to determine if the 
primary and secondary efficacy endpoints have been met. 
Viral type and subtype assessment
Respiratory samples obtained from IPs on Day 0 and from HHCs who become central 
laboratory PCR-positive for influenza will be analyzed by PCR in the central laboratory to 
determine the influenza type (A or B) and influenza A subtype (H1N1 and H3N2).
Only HHCs with a virus type/subtype that is consistent with that of the IP (i.e., consistent 
with within-household transmission) will be considered for the primary efficacy endpoint 
and secondary efficacy endpoints.
Viral titer assessment
Samples from IPs only will be assessed in the central laboratory to determine viral titer:

at all timepoints using CT (threshold cycle) values from viral RNA PCR (with results 
reported as particles or copies per mL).

at all timepoints using 50% tissue culture infectious dose (TCID50) values.
Analysis of viruses with reduced susceptibility to BXM
Viral RNA sequencing of the PA protein gene to identify amino acid substitutions 
conferring reduced susceptibility to BXM (see Section 3.4.6.4) will be done for IPs
randomized to BXM and their HHCs if the HHC becomes central laboratory PCR-positive 
for influenza A/B during the study.
Additional sequencing of polymerase basic (PB) protein 1 (PB1) and PB2 may be 
conducted in case an I38X substitution (or other identified substitution) is found in the PA 
protein in the IP and the corresponding HHC (i.e., transmission of a viral variant with 
reduced susceptibility).
Samples from IPs who experience a rebound in viral titers and/or show 
treatment-emergent amino acid substitutions in PA identified by sequencing analysis will 
be assayed for phenotypic reduced susceptibility.
Viral genome sequencing
Viral genome sequencing will be conducted for IPs and HHCs at selected sites which 
provide adequate numbers of IPs.
The methods for additional sequenced-based transmission identification are currently 
being developed and will be described in a separate methodological document.


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Testing for SARS-CoV-2 infection for all enrolled households
Respiratory samples obtained from IPs or HHCs and submitted to the central laboratory 
will be subsequently analyzed by qualitative or quantitative PCR for SARS-CoV-2, if 
deemed necessary for accurate assessment of co-infection.
Table 3
Central Laboratory Assessments on Respiratory Samples 
Obtained From Index Patients and Household Contacts on the 
Visits Indicated
Index Patients
Household Contacts
Visit Day
0
3
5
9
0
5
9
UV
Confirmatory PCR influenza A/B testing
x
x
x
x
x
Subtype PCR Influenza A
x
x a
x a
x a
Viral titer b, c
x
x
x
x
Sequencing to evaluate reduced-susceptibility 
substitutions d
x
x
x
x
x a
x a
x a
Additional genome sequencing 
(selected sites only) 
x
x
x
x
x a
x a
x a
Phenotypic resistance assay for selected 
samples e
x
x
x
x
SARS-CoV-2
x f
x f
x f
x f
UV unscheduled visit.
a. Only for household contacts who are central laboratory PCR positive for influenza A/B.
b. 50% tissue culture infectious dose (TCID50).
c. Quantitative viral RNA PCR.
d. Only for index patients randomized to BXM and their household contacts.
e. Only for index patients randomized to BXM who have a rebound in viral titer and/or a 
treatment-emergent amino acid substitution.
f. SARS-CoV-2 testing will be conducted at screening and Day 9 or last evaluable visit, 
if deemed necessary for accurate assessment of co-infection.
4.5.5.4
Other Laboratory Samples
A urine sample will be taken from female IPs for pregnancy testing as indicated in 
Appendix 1a.
The following female IPs are exempt from providing a urinary sample:

Postmenopausal women (defined as cessation of regular menstrual periods for 
12 continuous months).

Women who are surgically sterile by hysterectomy, bilateral oophorectomy, or tubal 
ligation.

Females 12 years old and pre-menarcheal.


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4.5.5.5
Sample Procedures and Storage
For sampling procedures, storage conditions, and shipment instructions, see the 
laboratory manual.
Respiratory samples (from IPs and HHCs) collected for analysis of viral parameters will 
be destroyed no later than 5 years after the final Clinical Study Report has been 
completed.
When an IP or HHC withdraws from the study, samples collected prior to the date of 
withdrawal may still be analyzed, unless the IP/HHC 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.
Given the complexity of viral genome sequencing, data derived from these analyses will 
generally not be provided to study investigators or IPs/HHCs unless required by law. The 
aggregate results of any conducted research will be available in accordance with the 
effective Sponsor policy on study data publication.
4.5.6
Household Contact Symptoms and Temperature
Assessment of symptoms of influenza and temperature measurement will be conducted 
as part of screening.
Starting at Day 0 through to Day 9, all full study HHCs aged 12 years old will be 
instructed in the symptoms of early influenza (Appendix 2). HHCs will record their 
temperature every day at bedtime, as well as any time they feel feverish, in a paper 
diary. For HHC aged 12 years old, the responsible adult will record the child’s 
temperature every day at bedtime, as well as any time the child appears feverish, in a 
paper diary. On Day 9, body temperature must be measured during the visit conducted 
either at the study site or at the HHC’s home.
HHCs will be instructed to contact the site in case of symptoms of influenza, fever 
38°C, or any other concern. Responsible adults (parents, legal guardians) will be 
responsible for contacting the site on behalf of HHCs 18 years old. The site will assess 
the incoming telephone call and may arrange an unscheduled visit within 24 hours.
The nurse or site staff will review the temperature log and assess symptoms of influenza 
at scheduled and unscheduled visits (see Appendix 2).
Note: Symptom and temperature assessments may be conducted at home or at the 
study site. Home visits may be performed by home nurses or by site staff (if local 


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practices are in place). Symptom assessment interview and temperature log review may 
be conducted remotely (e.g., via telephone or computer).
4.5.7
Patient-Reported Outcomes
Patient-reported outcome (PRO) data will be collected via paper questionnaires at the 
timepoints indicated in Appendix 1a to document the treatment benefit of BXM in IPs
12 years old only. The questionnaires, translated into the local language as 
appropriate, will be completed in their entirety at specified timepoints during the study.
The EQ-5D-5L (see Appendix 3) is a validated self-report health status questionnaire 
that is used to calculate a health status utility score for use in health economic analyses 
(EuroQol Group 1990; Brooks 1996; Herdman et al. 2011; Janssen et al. 2013). There 
are two components to the EQ-5D-5L: a five-item health state profile that assesses 
mobility, self-care, usual activities, pain/discomfort, and anxiety/depression, as well as a 
visual analogue scale that measures health state. Published weighting systems allow for 
creation of a single composite score of the patient's health status. The EQ-5D-5L takes 
approximately 5 minutes to complete. It will be used in this study for informing 
pharmacoeconomic evaluations.
The Work Productivity and Activity Impairment Questionnaire plus Classroom 
Impairment Questions (WPAICIQ) will be used to measure lost work or school days 
(adapted from Reilly et al. 1996; see Appendix 4). This validated, self-reported 
questionnaire quantifies both the amount of absenteeism (work time missed) and 
presenteeism (reduced on-the-job effectiveness) due to health problems.
4.5.8
Palatability and Acceptability
IPs 12 years old who receive study drug (BXM or matching placebo) as an oral 
suspension will be assessed for perceived palatability and acceptability of the study 
drug. A two-question palatability and acceptability questionnaire (completed by the IP
or with assistance from a responsible adult permitted for children who cannot read) will 
be used to record palatability and acceptability (see Appendix 5).
4.5.9
Household Contact Screening (including Late-Arrival HHCs)
In line with the eligibility criteria (see Section 4.1), any HHC may only be enrolled for the 
full study if a total of 1 or more unvaccinated HHCs agree and are eligible to participate 
in the full study. These 1 or more full study HHCs should be identified and screened at 
the Day 0 visit, and respiratory swabs should be obtained 24 hours after the IP receives
study drug. If a full study HHC cannot be screened at the Day 0 visit, then no HHC can 
be enrolled (even if potential full study HHCs may arrive home 24 hours after IP 
randomization [late-arrival HHCs]). 


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HHCs in the home within 24 hours after IP randomization 
All consenting HHCs present at any time in the home during the first 24 hours after IP 
randomization must undergo the Day 0 visit, and respiratory swabs should be obtained 
24 hours after IP study medication administration. HHCs intended for the full study and 
present within 24 hours after IP randomization should be enrolled together for the full 
study only after all HHCs (who were present at the Day 0 visit) have completed the 
Day 0 screening and have tested negative for both influenza and SARS-CoV-2 per local 
test.
If the investigator identifies during IP screening (i.e., prior to randomization and dosing) 
that timely Day 0/1 screening of HHCs cannot be achieved (as described above), then 
the IP should be screen failed. If after IP randomization and dosing the associated 
household is screen failed, the IP should not be discontinued, and will follow 
assessments as per Appendix 1a.
HHCs not present in the home at any time within 24 hours after IP randomization 
(late-arrival HHC)
If an HHC arrives home 24 hours after IP randomization where HHCs have already 
been enrolled in the full study, the late-arrival HHC should be screened as soon as 
possible at an unscheduled visit. If the late-arrival HHC meets all study eligibility criteria, 
they can also be enrolled in the full study. If the late-arrival HHC refuses screening or is 
influenza positive, the IP and HHCs enrolled will remain in the study. Note that all HHCs 
(including late-arrival HHCs) intended for the full study must reside in the IP’s home for 
at least 7 of the following 9 days and be present for scheduled study visits (i.e., a 
late-arrival HHC must arrive no later than Day 2 to potentially qualify for the full study).
If an HHC arrives home 24 hours after IP randomization where HHCs have already 
been enrolled and the late-arrival HHC refuses to be screened or is influenza A/B 
positive at screening, all the enrolled subjects (IP and the existing enrolled HHCs) 
should not be discontinued.
If a late-arrival HHC or any subject is determined to be SARS-CoV-2 positive at any time 
during the study, all enrolled subjects (IP and HHCs) should be discontinued from the 
study.
4.6
TREATMENT, PATIENT, STUDY, AND SITE DISCONTINUATION
4.6.1
Study Treatment Discontinuation
Not applicable – this is a single-dose study.
4.6.2
Subject Discontinuation from Study
HHCs who develop influenza symptoms before the Day 9 visit may be tested for 
infection at an earlier unscheduled visit (see Appendix 1b for additional details). If an
HHC tests positive for influenza A/B before the Day 9 visit they would not undergo any 


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further respiratory swabbing; however, these HHCs would continue to complete their 
daily temperature measurement and monitor for symptoms until the end of the study 
(Day 9 visit) and would not be early discontinued from the study.
As of March 2020 because of the ongoing COVID-19 pandemic, many countries and 
communities advise or require patients with suspected or confirmed SARS-CoV-2 
infection to self-quarantine or to visit only designated healthcare facilities. Therefore, 
consistent with these public health measures, if any study subject (IPs and full study 
enrolled HHCs) or other person living in the household is diagnosed with the 
SARS-CoV-2 infection by a healthcare professional, the entire enrolled household will be 
discontinued from the study, with cessation of study site and/or home visits. Following 
discontinuation from the study and if not already assessed that day, an early 
discontinuation visit should be conducted remotely (e.g., via telephone) for all IPs and 
full study HHCs. Collection of a respiratory sample will not be required.
IPs and HHCs have the right to voluntarily withdraw 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:

IP/HHC withdrawal of consent

Study termination or site closure

Any medical condition that the investigator or Sponsor determines may jeopardize 
the IP’s or HHC's safety if he or she continues in the study

Investigator or Sponsor determines it is in the best interest of the IP/HHC.
Every effort should be made to obtain information through the end of the safety-reporting 
period on IPs who withdraw from the study but have not withdrawn consent
(see Section 5.3.1). The primary reason for withdrawal from the study should be 
documented on the appropriate eCRF. If an IP/HHC requests to be withdrawn from the 
study, this request must be documented in the source documents and signed by the 
investigator.
If an IP/HHC discontinues the study early, they will undergo the assessments shown in 
Appendix 1a or Appendix 1b, respectively.
IPs/HHCs who withdraw 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.


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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
BXM has been approved in many countries, including in Japan since February 2018, in
the United States since October 2018, and in the European Union since January 2021. 
Clinical development is ongoing. The safety plan for IPs in this study is based on clinical 
experience with BXM in completed and ongoing studies. The anticipated important 
safety risks for BXM are outlined below. 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 IPs participating in this study. 
Eligibility criteria have been designed to exclude IPs at higher risk for toxicities. Patients 
will undergo safety monitoring during the study, including assessment of the nature, 
frequency, and severity of adverse events. In addition, guidelines for managing adverse 
events, including criteria for treatment interruption or discontinuation, are provided 
below.
No blood samples will be taken from IPs/HHCs during the study, minimizing the risk of 
adverse events related to study procedures. While nasopharyngeal swabs are preferred, 
the laboratory manual allows that less invasive mid-turbinate or nasal swabs to be used 
if a nasopharyngeal swab is not possible or the IP/HHC (or responsible adult) refuses a 
nasopharyngeal swab.
Furthermore, HHCs who participate in this study will benefit from free, convenient home 
monitoring and early/rapid diagnosis. HHCs who develop influenza will be allowed to be 
treated with SOC by their physician.
5.1.1
Risks Associated with Baloxavir Marboxil
BXM is generally well tolerated and no important identified or potential safety concerns 
associated with BXM have been identified from clinical studies conducted, to date. 


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Hypersensitivity reactions have been identified in the post marketing setting. Refer to 
Postmarketing Safety Data section (Section 1.2.3) for further details.
Exclusion criteria for patients with known hypersensitivity to BXM or the drug product 
excipients are included in this protocol, as re-exposure must be avoided.
5.1.2
Management of Study Participants Who Experience Adverse 
Events
5.1.2.1
Dose Modifications
This is a single dose study; therefore, the dose of BXM cannot be reduced.
5.1.2.2
Treatment Interruption
This is a single dose study; therefore, the dose of BXM cannot be interrupted.
5.2
SAFETY PARAMETERS AND DEFINITIONS
Safety assessments in IPs will consist of recording adverse events, including serious 
adverse events, at the timepoints indicated in Appendix 1a.
Certain types of events require immediate reporting to the Sponsor, as outlined in 
Section 5.4.
For HHCs, only adverse events related to the study procedures indicated in Appendix 1b
will be considered.
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 subject 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 Sections 5.3.5.7
and 5.3.5.8 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

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 
IP/HHC 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 5.3.5.9)

Results in persistent or significant disability/incapacity (i.e., the adverse event 
results in substantial disruption of the IP's/HHC’s ability to conduct normal life 
functions)

Is a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to 
study drug

Is a significant medical event in the investigator's judgment (e.g., may jeopardize the 
IP/HHC 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). There are no BXM-specific adverse events 
of special interest. Adverse events of special interest for this study are limited to:

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 5.3.5.5)


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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 an IP 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 Sections 5.4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).
Adverse events that may occur in the HHCs (relating to the study procedures) should be 
collected in the eCRF only and not reported to the global safety database.
5.3.1
Adverse Event Reporting Period
Investigators and their delegates will seek information on adverse events at each subject 
contact. All adverse events, whether reported by the IPs/HHCs or noted by study 
personnel, will be recorded in the subject's medical record and on the Adverse Event 
eCRF.
After informed consent has been obtained from the IP, but prior to initiation of study 
drug, only serious adverse events caused by a protocol-mandated intervention (e.g., the 
respiratory swab) 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 for IPs 12 years old 
until the Day 9 visit and for IPs 12 years old (at randomization) until the Day 21 safety 
visit.
Instructions for reporting adverse events that occur after the adverse event reporting 
period are provided in Section 5.6.


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5.3.2
Eliciting Adverse Event Information
A consistent methodology of non-directive questioning should be adopted for eliciting 
adverse event information at all IP/HHC evaluation timepoints. Examples of 
non-directive questions include the following:
"How have you felt since your last study site visit?"
"Have you had any new or changed health problems since you were last here?"
5.3.3
Assessment of Severity of Adverse Events
The adverse event severity grading scale for the NCI CTCAE (v5.0) will be used for 
assessing adverse event severity. Table 4 will be used for assessing severity for 
adverse events that are not specifically listed in the NCI CTCAE.
Table 4
Adverse Event Severity Grading Scale for Events Not Specifically 
Listed in NCI CTCAE
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 subjects 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 IP, 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" 


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accordingly. The following guidance should be taken into consideration (see also 
Table 5):

Temporal relationship of event onset to the initiation of study drug

Course of the event, with special consideration of the effects of dose reduction, 
discontinuation of study drug, or reintroduction of study drug (as applicable)

Known association of the event with the study drug or with similar treatments

Known association of the event with the disease under study

Presence of risk factors in the patient or use of concomitant medications known to 
increase the occurrence of the event

Presence of non-treatment-related factors that are known to be associated with the 
occurrence of the event.
Table 5
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 the HHCs, only those adverse events should be collected in the eCRF which are 
assessed to be related to any study procedure. These events will not be reported to the 
global safety database.
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
Infusion-Related or Injection Reactions
Not applicable.


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5.3.5.2
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.
5.3.5.3
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.
5.3.5.4
Persistent or Recurrent Adverse Events
A persistent adverse event is one that extends continuously, without resolution, between 
subject 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.


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A recurrent adverse event is one that resolves between subject evaluation timepoints 
and subsequently recurs. Each recurrence of an adverse event should be recorded as a 
separate event on the Adverse Event eCRF.
5.3.5.5
Abnormal Liver Function Tests
As no blood samples will be taken during this study, liver function tests would only be 
conducted if an adverse event occurs that warrants further work up.
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 5.3.5.2) 
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).
5.3.5.6
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 virus infection.
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 solely to progression of influenza virus infection, "influenza virus 
infection 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.


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5.3.5.7
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.
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").
5.3.5.8
Lack of Efficacy or Worsening of Influenza Virus Infection
Medical occurrences or symptoms of deterioration that are anticipated as part of 
influenza virus infection should 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 virus infection 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 virus infection").
5.3.5.9
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 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 IP/HHC has not experienced an adverse event
An event that leads to hospitalization under the following circumstances is not 
considered to be a serious adverse event, but should be reported as an adverse event 
instead:

Hospitalization that was necessary because of IP/HHC requirement for outpatient 
care outside of normal outpatient study site operating hours.


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5.3.5.10
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 
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 BXM or matching placebo, 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 BXM or matching placebo, 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 two 
entries on the Adverse Event eCRF, one entry to report the accidental overdose and one 


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entry to report the headache. The "Accidental overdose" and "Medication error" boxes 
would need to be checked for both entries.
5.3.5.11
Patient-Reported Outcome Data
Adverse event reports will not be derived from PRO data by the Sponsor, and safety 
analyses will not be performed using PRO data. Sites are not expected to review the 
PRO data for adverse events.
5.4
IMMEDIATE REPORTING REQUIREMENTS FROM 
INVESTIGATOR TO SPONSOR
Certain events require immediate reporting to allow the Sponsor to take appropriate 
measures to address potential new risks in a clinical trial. The investigator must report 
such events to the Sponsor immediately; under no circumstances should reporting take 
place more than 24 hours after the investigator learns of the event. The following is a list 
of events that the investigator must report to the Sponsor within 24 hours after learning 
of the event, regardless of relationship to study drug:

Serious adverse events (defined in Section 5.2.2; see Section 5.4.2 for details on 
reporting requirements). Grade 4 and 5 events must be reported as serious adverse 
events

Adverse events of special interest (defined in Section 5.2.3; see Section 5.4.2 for 
details on reporting requirements)

Pregnancies (see Section 5.4.3 for details on reporting requirements).
The investigator must report new significant follow-up information for these events to the 
Sponsor immediately (i.e., no more than 24 hours after becoming aware of the 
information). New significant information includes the following:

New signs or symptoms or a change in the diagnosis

Significant new diagnostic test results

Change in causality based on new information

Change in the event's outcome, including recovery

Additional narrative information on the clinical course of the event.
Investigators must also comply with local requirements for reporting serious adverse 
events to the local health authority and Institutional Review Board (IRB)/Ethics 
Committee (EC).
5.4.1
Emergency Medical Contacts
To ensure the safety of study IPs/HHCs, 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, 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 


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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 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.
5.4.2.2
Events That Occur after Study Drug Initiation (Index Patients 
Only)
After initiation of the single dose of study drug to IPs on Day 0, serious adverse events 
and adverse events of special interest will be reported in IPs 12 years old until Day 9 
and for IPs 12 years old (at randomization) until the Day 21 safety visit.
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 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 after the adverse event 
reporting period are provided in Section 5.6.
5.4.3
Reporting Requirements for Pregnancies
5.4.3.1
Pregnancies in Female Index Patients
Female IPs of childbearing potential will be instructed through the Informed Consent 
Form to immediately inform the investigator if they become pregnant during the study or 
within 21 days after the initial and only dose of study drug. A paper Clinical Trial 
Pregnancy Reporting Form should be completed and submitted to the Sponsor or its 
designee immediately (i.e., no more than 24 hours after learning of the pregnancy), 
either by faxing or by scanning and emailing the form using the fax number or email 
address provided to investigators. Pregnancy should not be recorded on the Adverse 
Event eCRF. The investigator should counsel the IP, discussing the risks of the 


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pregnancy and the possible effects on the fetus. Monitoring of the IP should continue 
until conclusion of the pregnancy. Any serious adverse events associated with the 
pregnancy (e.g., an event in the fetus, an event in the mother during or after the 
pregnancy, or a congenital anomaly/birth defect in the child) should be reported on the 
Adverse Event eCRF. In addition, the investigator will submit a Clinical Trial Pregnancy 
Reporting Form when updated information on the course and outcome of the pregnancy 
becomes available.
5.4.3.2
Pregnancies in Female Partners of Male Index Patients
Male IPs will be instructed through the Informed Consent Form to immediately inform the 
investigator if their partner becomes pregnant during the study or within 21 days after the 
initial and only dose of study drug. The investigator should report the pregnancy on the
paper Clinical Trial Pregnancy Reporting Form and submit the form to the Sponsor or its 
designee immediately (i.e., no more than 24 hours after learning of the pregnancy), 
either by faxing or by scanning and emailing the form using the fax number or email 
address provided to investigators. Attempts should be made to collect and report details 
of the course and outcome of any pregnancy in the partner of a male IP exposed to 
study drug. When permitted by the site, the pregnant partner would need to sign an 
Authorization for Use and Disclosure of Pregnancy Health Information to allow for 
follow-up on her pregnancy. If the authorization has been signed, the investigator should 
submit a Clinical Trial Pregnancy Reporting Form with additional information on the 
pregnant partner and the course and outcome of the pregnancy as it becomes 
available. An investigator who is contacted by the male IP or his pregnant partner may 
provide information on the risks of the pregnancy and the possible effects on the fetus, 
to support an informed decision in cooperation with the treating physician and/or 
obstetrician.
5.4.3.3
Abortions
A spontaneous abortion should be classified as a serious adverse event (as the Sponsor 
considers abortions to be medically significant), recorded on the Adverse Event eCRF, 
and reported to the Sponsor immediately (i.e., no more than 24 hours after learning of 
the event; see Section 5.4.2). 
If a therapeutic or elective abortion was performed because of an underlying maternal or 
embryofetal toxicity, the toxicity should be classified as a serious adverse event, 
recorded on the Adverse Event eCRF, and reported to the Sponsor immediately (i.e., no 
more than 24 hours after learning of the event; see Section 5.4.2). A therapeutic or 
elective abortion performed for reasons other than an underlying maternal or 
embryofetal toxicity is not considered an adverse event.
All abortions should be reported as pregnancy outcomes on the paper Clinical Trial 
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5.4.3.4
Congenital Anomalies/Birth Defects
Any congenital anomaly/birth defect in a child born to a female IP exposed to study drug 
(or the female partner of a male IP exposed to study drug) should be classified as a 
serious adverse event, recorded on the Adverse Event eCRF, and reported to the 
Sponsor immediately (i.e., no more than 24 hours after learning of the event; 
see Section 5.4.2).
5.4.4
Reporting Requirements for Medical Device Complaints
Not applicable.
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 IP/HHC is lost to 
follow-up, or the IP/HHC 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 IP's/HHC's medical record to facilitate source data 
verification.
All pregnancies reported during the study should be followed until pregnancy outcome.
5.5.2
Sponsor Follow-Up
For serious adverse events, adverse events of special interest, and pregnancies, 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 
Visit Day 9 for IPs 12 years old and Visit Day 21 for IPs 12 years old), if the event is 
believed to be related to prior study drug treatment. These events should be reported 
through use of the Adverse Event eCRF. However, if the EDC system is not available, 
the investigator should report these events directly to the Sponsor or its designee, either 
by faxing or by scanning and emailing the paper Clinical Trial Adverse Event/Special 
Situations Form using the fax number or email address provided to investigators.


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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.
6.
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN
The present section outlines the planned statistical analysis of the study. Full details will 
be specified in a separate Statistical Analysis Plan (SAP), which will be finalized prior to 
locking of the study database and unblinding at the end of the study. The SAP may 
include additional analyses not explicitly mentioned in this section.
The primary efficacy analysis population will consist of all unvaccinated in the primary 
analysis will be defined in a blinded review meeting before database lock and 
documented in the SAP.
Supportive analyses including all full study HHCs of all randomized IPs will be 
performed.
Treatment groups will be defined based on the arm to which the respective IP was 
randomized.
The efficacy analysis based on households will primarily use the set of households with 
all full study HHCs of the randomized IPs, if all the HHCs were PCR negative at 
screening.
The safety population will consist of all IPs who received at least one dose of study drug, 
with patients grouped according to the received treatment.


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6.1
DETERMINATION OF SAMPLE SIZE
The proposed sample size for this study is 2,030 evaluable HHCs. Assuming a 15% 
drop-out for inclusion of HHCs into the primary analysis population, an average of 
2.5 HHCs per IP and a 15% exclusion rate on the household level, this equates to an 
approximate number of IPs of 1,130.
A transmission rate in the placebo arm of approximately 20% is assumed based on data 
from the literature, including work by Welliver et al. (2001). For a 30% relative risk 
reduction with BXM, which is considered clinically meaningful, the transmission rate in 
the active treatment group is expected to be 14%. Under these assumptions and for a 
two-sided test for binary proportions at the 5% significance level, the power for the 
between-arm comparison based on the primary endpoint will be approximately 90%. 
For the secondary “Symptomatic transmission endpoint” (symptomatic influenza) the 
power will be 80% for an assumed 65% proportion of symptomatic cases among 
infected HHCs, and not considering the hierarchical testing procedure. The literature 
reports a variety of values for the proportion of influenza cases that are symptomatic. 
The assumption of 65% was authorized by the study steering committee; however, this 
assumption has limitations.
The effect of clustering was examined in simulations and using analysis methods 
accounting for the household effect. The power was largely maintained in simulations 
that assumed the existence of a random variation of the background transmission rate 
between households with a standard deviation up to 5% (i.e., with about 95% of the 
values for the BXM and placebo groups in the [4.2, 23.8] and [10.2, 29.8] range, 
respectively). This is compatible with the inclusion of a large number of small clusters 
and a small expected intra-cluster correlation, resulting in a negligible design effect and 
related reduction in effective sample size.
6.2
SUMMARIES OF CONDUCT OF STUDY
The number of patients and HHCs who enroll, participate in the full study, discontinue, or 
complete the study will be summarized. Reasons for premature study withdrawal will be 
listed and summarized. Enrollment, participation in the full study, and major protocol 
deviations will be listed and evaluated for their potential effects on the interpretation of 
study results.
6.3
SUMMARIES OF DEMOGRAPHIC AND BASELINE 
CHARACTERISTICS
Demographic and baseline characteristics (including age, sex, number of HHCs, and 
duration of symptoms) will be summarized overall and by treatment group.
6.4
EFFICACY ANALYSES
6.4.1
Primary Efficacy Endpoint
The primary efficacy endpoint is presented in Section 2.1.1.1.


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The primary analysis will compare the transmission rate for the primary endpoint 
between the two arms and express the effect by an adjusted odds ratio. The comparison 
will be based on a model providing population-averaged estimates using a generalized 
estimating equations approach and accounting for the stratification factors used at 
randomization (see Section 4.2). The primary test for the treatment effect will be 
two-sided and the significance level will be 5%. For this analysis, missing values will not 
be imputed. The SAP will specify sensitivity analyses performed with different imputation 
methods and alternative definitions of the analysis population.
A supportive analysis for robustness will employ a two-sided Cochran-Mantel-Haenszel 
test accounting for the stratification factors used at randomization.
The same approach will be used for the secondary endpoints considering the 
hierarchical testing strategy described in the following section.
6.4.2
Secondary Efficacy Endpoints
Secondary efficacy endpoints are listed in Section 2.1.2.1.
If the primary outcome reaches significance, a hierarchical, sequential testing procedure 
is planned for the analysis of secondary efficacy endpoints. The secondary efficacy 
endpoints will be tested at the alpha0.05 significance level as part of a confirmatory 
analysis in hierarchal order as listed in Table 6. A given endpoint will be tested if and 
only if the all endpoints listed ahead of it have reached significance at the 0.05 level. All 
tests not part of the confirmatory analysis will be considered non-confirmatory.
Table 6
Confirmatory Hierarchical Order for Secondary Efficacy 
Endpoints
Order
Secondary Efficacy Analysis
1
Symptomatic transmission by Day 5
2
Virological transmission at the household level by Day 5
3
Symptomatic transmission at the household level by Day 5
4
Virological transmission by Day 9
5
Symptomatic transmission by Day 9
6
Any virological infection by Day 9
7
Any virological infection at the household level by Day 9
8
Any symptomatic infection by Day 9
9
Any symptomatic infection at the household level by Day 9
The rate of direct transmission, as a by-household measure, will be analyzed by means 
of a Cochran-Mantel-Haenszel test accounting for the stratification factors used at 


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randomization. The rate of symptomatic influenza in HHCs will be analyzed as described
for the primary endpoint.
6.4.3
Other Efficacy Endpoints
Other efficacy endpoints are listed in Section 2.1.3.1. 
The analysis of other endpoints will be primarily descriptive and documented within the 
SAP.
The rate of direct transmission of either influenza A/B to HHCs in relation to viral titer for 
the IP at Day 0 will be analyzed by means of models similar to those used for the 
primary analysis but including other explanatory variables of interest that will be 
specified in the SAP.
6.5
SAFETY ANALYSES
A descriptive analysis of safety parameters will be performed in the safety population.
Safety analyses will include the assessment of the incidence, severity, and timing of 
treatment-emergent adverse events and serious adverse events by treatment group.
Safety data collected from included HHCs will be summarized by treatment group based 
on the respective IP.
6.6
PHARMACOKINETIC ANALYSES 
Not applicable.
6.7
IMMUNOGENICITY ANALYSES
Not applicable. 
6.8
ANALYSIS OF SUBGROUPS
A subgroup analysis will be conducted in patients from selected sites to assess the 
accuracy of matching IP to HHC transmission based on influenza subtype for the 
primary/secondary endpoints. Sequencing will be performed for samples from selected 
sites and countries based on feasibility, including availability of reference sequence for a
specific community.
Other subgroups of interest are defined by:

The stratification factors used for randomization.

IPs with influenza A versus influenza B.

Influenza seasons.


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Subgroup analyses will be primarily descriptive. Where applicable, the heterogeneity of 
treatment effects across subgroups will be addressed by testing treatment-by-subgroup 
effects added to the respective models. Details will be provided in the SAP.
6.9
INTERIM ANALYSES
6.9.1
Planned Interim Analyses
There are no planned interim efficacy analyses for this study. Section 6.9.2 describes 
optional interim analyses of efficacy.
Safety interim analyses will be performed regularly by an iDMC. Efficacy data will only 
be provided if requested by the iDMC. Further details on the function and logistics 
(e.g., frequency of the meetings) of the iDMC will be provided in the iDMC Charter.
6.9.2
Optional Interim Analyses
To adapt to information that may emerge during the course of this study, the Sponsor 
may choose to conduct one or more interim efficacy analyses. Possible goals of these 
interim analyses include assessing the futility of study continuation or reassessing the 
sample size in case the overall transmission rates (calculated in a blinded manner) are 
smaller than anticipated. If recruitment projections indicate that a large proportion of the 
currently planned sample can be recruited by the end of the 2020/2021 or subsequent 
Northern hemisphere influenza seasons (e.g., 70%), the Sponsor will determine 
whether to perform an interim analysis with stopping rules based on efficacy endpoints in 
accordance to a group-sequential design. Below are the specifications in place to ensure 
the study continues to meet the highest standards of integrity when an 
optional interim analysis is executed.
Any interim analyses would be conducted by an external statistical group and reviewed 
by the iDMC. Interactions between the iDMC and Sponsor will be carried out as 
specified in the iDMC charter, and the Sponsor will remain blinded throughout the study. 
The decision to conduct optional interim analyses, along with the rationale, timing, and 
statistical details for these analyses, will be documented in a specific interim analysis
SAP. The iDMC charter will document potential recommendations the iDMC can make to 
the Sponsor as a result of the analyses and the iDMC charter will also be made available 
to relevant health authorities, if applicable.
If a group-sequential interim analysis will be performed, a Lan-DeMets alpha-spending 
function with O’Brien-Fleming or similar boundaries will be used to define the 
null-hypothesis rejection region for the primary and key secondary endpoints. Tests will 
be conducted at the one-sided 2.5% significance level (alternative hypothesis: odds ratio
1 for the comparison of BXM vs. placebo). The iDMC will review interim analysis 
results and provide a recommendation concerning the continuation of the study. The 
hierarchical testing procedure will ensure control of the overall type I error rate at the 
pre-defined level (Hung et al. 2007; Glimm et al. 2010). A recommendation to stop the 


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study with rejection of the null-hypothesis should be considered if the rejection 
boundaries are crossed for both the primary and the first secondary endpoint 
(symptomatic influenza in HHCs).
7.
DATA COLLECTION AND MANAGEMENT
7.1
DATA QUALITY ASSURANCE
A contract research organization (CRO) will be responsible for the 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 CRO will request data clarification from the 
sites, which the sites will resolve electronically in the EDC system. 
The Sponsor will perform oversight of the data management of this study. The Sponsor 
will produce an EDC Study Specification document that describes the quality checking to 
be performed on the data. Central laboratory data and other electronic data will be sent 
securely directly to the Sponsor (Roche) using the Sponsor’s (Roche) 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.
HHC data will be recorded in a paper diary, and data collected by the home nurse or site 
staff will be recorded on worksheets. The data from the diaries and worksheets will be 
entered into the EDC system by site staff.
PRO data from IPs will be collected on paper questionnaires. The data from the 
questionnaires will be entered into the EDC system by site staff.
7.2
ELECTRONIC CASE REPORT FORMS 
eCRFs are to be completed through use of a Sponsor-designated EDC system. Sites will 
receive training and have access to a manual for appropriate eCRF completion. eCRFs 
will be submitted electronically to the Sponsor and should be handled in accordance with 
instructions from the Sponsor.
All eCRFs should be completed by designated, trained site staff. eCRFs should be 
reviewed and electronically signed and dated by the investigator or a designee.
At the end of the study, the investigator will receive patient eCRF data for his or her site 
in a readable format that must be kept with the study records. Acknowledgement of 
receipt of the data is required.


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7.3
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 IP/HHC 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, subject-reported outcomes, 
evaluation checklists, pharmacy dispensing records, recorded data from automated 
instruments, copies of transcriptions that are certified after verification as being accurate 
and complete, microfiche, photographic negatives, microfilm or magnetic media, X-rays, 
patient files, and records kept at pharmacies, laboratories, and medico-technical 
departments involved in a clinical trial.
Before study initiation, the types of source documents that are to be generated will be 
clearly defined in the Trial Monitoring Plan. This includes any protocol data to be entered 
directly into the eCRFs (i.e., no prior written or electronic record of the data) and 
considered source data.
Source documents that are required to verify the validity and completeness of data 
entered into the eCRFs must not be obliterated or destroyed and must be retained per 
the policy for retention of records described in Section 7.5.
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.
7.4
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.
7.5
RETENTION OF RECORDS
Records and documents pertaining to the conduct of this study and the distribution of 
IMP, including eCRFs, paper PRO and HHC data, 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 


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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 final study results have been reported 
or for the length of time required by relevant national or local health authorities, 
whichever is longer.
8.
ETHICAL CONSIDERATIONS
8.1
COMPLIANCE WITH LAWS AND REGULATIONS
This study will be conducted in full conformance with the ICH E6 guideline for Good 
Clinical Practice and the principles of the Declaration of Helsinki, or the 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 
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 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 Forms for IPs and HHCs (and ancillary sample 
Informed Consent Forms such as a Child's Informed Assent Form) 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.
The investigator or authorized designee will explain to each IP/HHC the objectives, 
methods, and potential risks associated with each optional procedure. IPs/HHCs will be 
told that they are free to refuse to participate and may withdraw their consent at any time 
for any reason. 
The Consent Forms must be signed and dated by the IP/HHC or the IP’s/HHC's legally 
authorized representative before his or her participation in the study. The case history or 
clinical records for each IP/HHC shall document the informed consent process and that 
written informed consent was obtained prior to participation in the study.


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The Consent Forms should be revised whenever there are changes to study procedures 
or when new information becomes available that may affect the willingness of the patient 
to participate. The final revised IRB/EC-approved Consent Forms must be provided to 
the Sponsor for health authority submission purposes.
IPs/HHCs 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 their participation in the study. For any updated or revised 
Consent Forms, the case history or clinical records for each patient shall document the 
informed consent process and that written informed consent was obtained using the 
updated/revised Consent Forms for continued participation in the study.
A copy of each signed Consent Form must be provided to the IP/HHC or the IP's/HHC'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.
For sites in the United States, each Consent Form may also include IP/HHC
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 IP/HHC 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 IP/HHC, 
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 IP/HHC 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 9.7).
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. 


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8.4
CONFIDENTIALITY
The Sponsor maintains confidentiality standards by coding each IP/HHC enrolled in the 
study through assignment of a unique subject identification number. This means that 
IP/HHC names are not included in data sets that are transmitted to any Sponsor 
location.
IP/HHC 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 
IP/HHC, unless permitted or required by law.
Medical information may be given to an IP's/HHC's personal physician or other 
appropriate medical personnel responsible for the IP's/HHC's welfare, for treatment 
purposes.
Given the complexity of viral genome sequencing, data derived from these analyses will 
generally not be provided to study investigators or IPs/HHCs unless required by law. The 
aggregate results of any conducted research will be available in accordance with the 
effective Sponsor policy on study data publication (see Section 9.6).
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).


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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 IP/HHC 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 IP/HHC safety and 
data integrity to the Sponsor and to the IRB/EC in accordance with established IRB/EC 
policies and procedures. The Sponsor will review all protocol deviations and assess 
whether any represent a serious breach of Good Clinical Practice guidelines and require 
reporting to health authorities. As per the Sponsor's standard operating procedures, 
prospective requests to deviate from the protocol, including requests to waive protocol 
eligibility criteria, are not allowed.
9.3
MANAGEMENT OF STUDY QUALITY
The Sponsor has implemented a system to manage the quality of the study, focusing on 
processes and data that are essential to ensuring patient safety and data integrity. The 
Sponsor identified potential risks associated with critical trial processes and data and 
implemented plans for evaluating and controlling these risks. Risk evaluation and 
control included the selection of risk-based parameters (e.g., adverse event rate, protocol 
deviation rate) and the establishment of quality tolerance limits for these parameters. 
Detection of deviations from quality tolerance limits will trigger an evaluation to 
determine if action is needed. Details on the establishment and monitoring of quality 
tolerance limits are provided in a Quality Tolerance Limit Management Plan.
9.4
SITE INSPECTIONS
Site visits will be conducted by the Sponsor or an authorized representative for 
inspection of study data, IPs’ 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.
9.5
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.


Baloxavir Marboxil—F. Hoffmann-La Roche Ltd
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Approximately 200 sites globally will participate to enroll approximately 1,130 IPs and 
2,030 HHCs. Enrollment will occur through an IxRS. 
Central facilities will be used for certain study assessments throughout the study as 
specified in Section 4.5. 
An iDMC will be employed to monitor and evaluate IP/HHC safety throughout the study. 
9.6
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 details), and 
redacted Clinical Study Reports and other summary reports will be made available upon 
request. 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 
country, the Sponsor aims to publish results from analyses of additional endpoints and 
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.


Baloxavir Marboxil—F. Hoffmann-La Roche Ltd
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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.
9.7
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 IPs/HHCs or changes that involve logistical or 
administrative aspects only (e.g., change in Medical Monitor or contact information).


Baloxavir Marboxil—F. Hoffmann-La Roche Ltd
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Appendix 1a
Schedule of Activities for the Index Patient
Screening 
Study 
Site Visit
Day 3 
Visit 1
Day 5 
Visit 1
Unscheduled or
Early 
Discontinuation 1, 2, 3 
Day 9 Visit
(End of Study) 1
Safety Follow-Up 
Visit
(511 Year Olds 
Only) 1
Day
0
3 (1)
5 (1)
Unscheduled
9 (1)
Day 21 (2)
Informed consent
x
Demographic data
x
Medical history
x
Limited physical assessment
x
Vital signs
x
Height and weight
x
Urine pregnancy test (see Section 4.5.5.4)
x
Respiratory sample (swabbing) 4
x
x 5
x 5
x 6
x 5
Review of inclusion/exclusion criteria
x
Randomization (performed after all above 
activities completed) followed by study drug 
administration (performed latest 2 hours 
post-randomization) 
x
EQ-5D-5L questionnaire 8
x
x
x
WPAICIQ questionnaire 8
x
Palatability and acceptability 
questionnaire 9
x
Concomitant medications
x
x
x
x
x
x
Adverse events 7
x
x
x
x
x
x


Appendix 1a:
Schedule of Activities for the Index Patient (cont.)
Baloxavir Marboxil—F. Hoffmann-La Roche Ltd
107/Protocol MV40618, Version 4
AE adverse event; HHC household contact; IP index patient; SAE serious adverse event; SARS-CoV-2 severe acute respiratory syndrome 
coronavirus 2; WPAICIQWork Productivity and Activity Impairment Questionnaire plus Classroom Impairment Questions.
1. All assessments (except sample collection) for these visits can be conducted remotely (e.g., via telephone or computer), in study site or at 
home.
2. If the IP is discontinued early because a subject in their household tests positive for SARS-CoV-2 (see Section 4.6.2), then this visit must be 
conducted remotely, and no swabbing is performed.
3. If the IP is discontinued early, the IP should be followed until the end of their safety reporting period (Day 9 for IPs 12 years old or Day 21 for 
IPs 12 years old) (see Section 5.3.1).
4. Follow instructions in the laboratory manual (see Section 4.5.5).
5. Samples for central laboratory only. If SARS-CoV-2 co-infection suspected, collect additional sample for local testing (see Section 4.5.5.1).
6. If SARS-CoV-2 co-infection suspected, collect a sample for central laboratory testing and a sample for local testing (see Section 4.5.5.1). 
7. After informed consent is obtained and prior to study drug administration, only SAEs caused by a protocol-mandated intervention should be 
reported. After study drug administration, all AEs will be reported until Day 9 for IPs aged 12 to 64 years old, and until Day 21 for IPs aged 
12 years old at randomization.
8. Only to be completed by IPs 12 years and older.
9. Palatability and acceptability questions are to be completed as soon as possible after swallowing the study drug by IPs who are less than
12 years old and who receive study drug as granules for oral suspension. The questionnaire will be completed by the IP or with the assistance 
of a responsible adult for IPs who cannot read.


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Appendix 1b
Schedule of Activities for Each Household Contact
All HHCs
Full Study HHCs Only
Screening 
Visit 1, 2
Day 5 Visit 1
HHC 
Sick Visit 1, 3, 4
Early 
Discontinuation 1, 5
Day 9 Visit 1
(End of Study 4)
Day
0 or 1
5 (1)
Unscheduled
Unscheduled
9 (1)
Informed consent
x
Demographic data
x
Medical history
x
Respiratory sample (swabbing) 6
x 7
x 8, 9
x 8, 9
x 8, 9
x 8, 9
Review of inclusion/exclusion criteria
x
Symptoms assessment
x
x 10
x 10
x 10
x 10
Body temperature recording 11
x
x
x
x
x
Concomitant medications
x
x
x
x
x
Enrollment IxRS
x
Dispensing/reviewing/collecting subject diary
x 12
x 13
x 13
x 13
x 13
AEs due to study procedures
(e.g., nurse-administered swabs)
x
x
x
x
x
AE adverse event; HHC household contact; IP index patient; IxRs interactive voice or web-based response system; SAE serious adverse 
event; SARS-CoV-2 severe acute respiratory syndrome coronavirus 2; WPAICIQ Work Productivity and Activity Impairment Questionnaire plus 
Classroom Impairment Questions.
1. All assessments (except swabbing) can be conducted remotely (e.g., via telephone or computer), at the study site or at home.
2. Visit must be initiated within 24 hours of IP randomization (see Section 4.5.9 for details regarding late-arrival HHCs).
3. HHC is seen within 24 hours of informing the study site of influenza symptoms or fever (Section 4.5.6).
4. HHC must be discontinued if IP or any HHC tests positive for SARS-CoV-2 (see Section 4.6.2 for subject discontinuation criteria). 
5. If HHC is discontinued early because a subject in their household tests positive for SARS-CoV-2, then this visit must be conducted remotely, and 
no swabbing is performed.


Appendix 1b:
Schedule of Activities for Each Household Contact (cont.)
Baloxavir Marboxil—F. Hoffmann-La Roche Ltd
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6. Two samples will be collected at each visit (one for local and one for central laboratory). Follow instructions in the laboratory manual 
(see Section 4.5.5).
7. Swab must be performed within 24 hours after IP study drug administration (see Section 4.5.9).
8. Sample collection is discontinued after the HHC’s sample locally tests positive for influenza A/B or if any subject’s (IP or HHC) sample tests 
positive for SARS-CoV-2 (see Section 4.5.5.1).
9. If an HHC is determined to have new or worsened symptoms or fever, the local respiratory sample collected at this and future visits should also 
be tested for SARS-CoV-2 (see Section 4.5.5.2) in addition to influenza A/B (unless sample collection discontinued; see Section 4.5.5.1).
10. Symptoms assessed according to Section 4.5.6 and Appendix 2.
11. HHCs will measure their temperature daily at bedtime, and any time they feel feverish and record values in a paper diary. At the Day 9 visit, 
body temperature must be measured during the visit either at the study site or at home.
12. This assessment is for full study HHCs only.
13. Daily temperature diary reviewed at each scheduled/unscheduled visit.


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Appendix 2
Symptoms Assessed in the Full Study Household Contacts
Starting at Day 0, full study household contacts (HHCs; or the responsible adult of the 
children 12 years of age) will be instructed in the symptoms of early influenza. 
Qualifying symptoms for household contacts are shown below:
Symptoms assessed in household contacts aged 12 years of age
Qualifying respiratory symptoms

Cough

Sore throat

Nasal congestion
Qualifying general systemic symptoms

Headache

Feverishness or chills

Muscle or joint pain

Fatigue
Symptoms assessed in household contacts aged 2 to 12 years of age
Qualifying upper respiratory tract infection 
symptoms

Cough

Nasal congestion or rhinorrhea
Assessment of influenza symptoms for full study HHC 12 years old
DAY 0 prior to enrollment
HCP asks HHC ►
about symptom (x) ▼
Have you had 
(x) in the last 
7 days?
Is your (x) mild or 
is it worse than 
mild?
What is causing your (x)? 
(record the cause or write “not 
known”)
Action
Cough
Y or N
Mild or Worse
Cause:
Do NOT enroll 
if any symptom 
is (1) worse 
than mild or 
(2) cause is 
not known or 
likely 
infection.
Sore throat
Y or N
Mild or Worse
Cause: 
Nasal congestion
Y or N
Mild or Worse
Cause: 
Headache
Y or N
Mild or Worse
Cause: 
Feverishness or chills
Y or N
Mild or Worse
Cause: 
Muscle or joint pain
Y or N
Mild or Worse
Cause: 
Fatigue
Y or N
Mild or Worse
Cause: 
Record Day 0 temperature.
__ __ . __°C
Do NOT enroll 
if ≥38.0 °C
Site:
HCP obtains swab
Is local influenza A/B, or local SARS-CoV-2 positive? Y or N
Do NOT enroll 
if Y




Appendix 2:
Symptoms Assessed in the Full Study Household Contacts 
(cont.)
Baloxavir Marboxil—F. Hoffmann-La Roche Ltd
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DAYS 5, 9, AND UNSCHEDULED for full study HHC ages 2 to 12 years old
HCP asks adult ►
about symptom (x) ▼
For symptoms present at 
baseline: is your child’s (x) 
worse since your child enrolled?
For symptoms not present at baseline: 
does your child have (x)?
Cough
Y or N
Y or N
Nasal congestion or rhinorrhea 
(stuffy or runny nose)
Y or N
Y or N
Review HHC temperature log. Obtain child’s temperature if not 
yet done.* Record highest temperature here ►
__ __ . __°C 
Date:
Site:
Time:
HCP obtains 
swab
Is local 
influenza A/B
positive?
Y or N **
If Y, refer HHC to investigator for standard of care (including anti-viral 
medicine). No more samples for this HHC needed. Continue to monitor 
for symptoms at subsequent visit if symptoms endpoint not yet met.
If N, continue sampling at next visit. However, investigator may initiate 
standard of care if suspicion for influenza is high due to symptoms.
*  Temperature obtained from tympanic thermometers provided to households (or exceptionally 
from other thermometers/locations in case of tympanic thermometer failure for any reason).
** Test SARS-CoV-2 via local test if HHC develops symptoms or fever versus baseline.
If positive, withdraw all study subjects in household from the study.


Baloxavir Marboxil—F. Hoffmann-La Roche Ltd
113/Protocol MV40618, Version 4
Appendix 3
EQ-5D-5L to Measure Quality of Life
Under each heading, please check the ONE box that best describes your health 
TODAY.
MOBILITY
I have no problems walking

I have slight problems walking

I have moderate problems walking

I have severe problems walking

I am unable to walk

SELF-CARE
I have no problems washing or dressing myself

I have slight problems washing or dressing myself

I have moderate problems washing or dressing myself

I have severe problems washing or dressing myself

I am unable to wash or dress myself

USUAL ACTIVITIES (e.g. work, study, housework, family or 
leisure activities)
I have no problems doing my usual activities

I have slight problems doing my usual activities

I have moderate problems doing my usual activities

I have severe problems doing my usual activities

I am unable to do my usual activities

PAIN / DISCOMFORT
I have no pain or discomfort

I have slight pain or discomfort

I have moderate pain or discomfort

I have severe pain or discomfort

I have extreme pain or discomfort

ANXIETY / DEPRESSION
I am not anxious or depressed

I am slightly anxious or depressed

I am moderately anxious or depressed

I am severely anxious or depressed

I am extremely anxious or depressed

USA (English) © 2009 EuroQol Group EQ-5D™ is a trade mark of the EuroQol Group


Appendix 3:
EQ-5D-5L to Measure Quality of Life (cont.)
Baloxavir Marboxil—F. Hoffmann-La Roche Ltd
114/Protocol MV40618, Version 4

We would like to know how good or bad 
your health is TODAY.

This scale is numbered from 0 to 100.

100 means the best health you can 
imagine.
0 means the worst health you can 
imagine.

Mark an X on the scale to indicate how 
your health is TODAY.

Now, please write the number you 
marked on the scale in the box below.
USA (English) © 2009 EuroQol Group EQ-5D™ 
is a trade mark of the EuroQol Group
YOUR HEALTH TODAY =


Baloxavir Marboxil—F. Hoffmann-La Roche Ltd
115/Protocol MV40618, Version 4
Appendix 4
Work Productivity and Activity Impairment Questionnaire 
plus Classroom Impairment Questions: SHP, Version 2 
(WPAICIQ:SHP, V2) 
The following questions ask about the effect of your influenza/flu on your ability 
to work, attend classes, and perform regular daily activities. Please fill in the 
blanks or circle a number, as indicated.
1)
Are you currently employed (working for pay)?
____NO
___YES
If NO, check “NO” and skip to question 6.
The next questions are about the past seven days, not including today.
2)
During the past seven days, how many hours did you miss from work 
because of problems associated with your influenza/flu? Include hours you 
missed on sick days, times you went in late, left early, etc., because of 
influenza/flu. Do not include time you missed to participate in this study.
______HOURS
3)
During the past seven days, how many hours did you miss from work 
because of any other reason, such as vacation, holidays, time off to 
participate in this study?
______HOURS
4)
During the past seven days, how many hours did you actually work? 
______HOURS (If “0”, skip to question 6)


Appendix 4:
Work Productivity and Activity Impairment Questionnaire 
plus Classroom Impairment Questions: 
SHP, Version 2 (WPAICIQ:SHP, V2) (cont.)
Baloxavir Marboxil—F. Hoffmann-La Roche Ltd
116/Protocol MV40618, Version 4
5)
During the past seven days, how much did influenza/flu affect your 
productivity while you were working?
Think about days you were limited in the amount or kind of work you could 
do, days you accomplished less than you would like, or days you could not 
do your work as carefully as usual. If influenza/flu affected your work only a 
little, choose a low number. Choose a high number if influenza/flu affected 
your work a great deal.
Consider only how much influenza/flu affected 
productivity while you were working.
Influenza/flu
had no effect
on my work
Influenza/flu
completely 
prevented me
0
1
2
3
4
5
6
7
8
9
10
from working
Circle a number
6)
Do you currently attend classes in an academic setting (middle school, high 
school, college, graduate school, additional course work, etc.)?  
___NO
___YES
If NO, check “NO” and skip to question 10.
7)
During the past seven days, how many hours did you miss from class or 
school because of problems associated with your influenza/flu? Do not 
include time you missed to participate in this study.
_____ HOURS
8)
During the past seven days, how many hours did you actually attend class or 
school?
_____ HOURS (If “0”, skip to question 10.)


Appendix 4:
Work Productivity and Activity Impairment Questionnaire 
plus Classroom Impairment Questions: 
SHP, Version 2 (WPAICIQ:SHP, V2) (cont.)
Baloxavir Marboxil—F. Hoffmann-La Roche Ltd
117/Protocol MV40618, Version 4
9)
During the past seven days, how much did your influenza/flu affect your 
productivity while in school or attending classes in an academic setting? 
Think about days your attention span was limited, you had trouble with 
comprehension or days in which you could not take tests as effectively as 
usual. If influenza/flu affected your productivity at school or in class only a 
little, choose a low number. Choose a high number if influenza/flu affected 
your productivity at school or in class a great deal.
Consider only how much influenza/flu affected
productivity while in school or attending classes.
Influenza/flu
had no effect 
on my class 
work
Influenza/flu
completely 
prevented me 
from doing my 
0
1
2
3
4
5
6
7
8
9
10
class work
Circle a number
10) During the past seven days, how much did influenza/flu affect your ability to 
do your regular daily activities, other than work at a job or attending classes?
By regular activities, we mean the usual activities you do, such as work 
around the house, shopping, child care, exercising, studying, etc. Think 
about times you were limited in the amount or kind of activities you could do 
and times you accomplished less than you would like. If influenza/flu
affected your activities only a little, choose a low number. Choose a high 
number if influenza/flu affected your activities a great deal.
Consider only how much influenza/flu affected your ability 
to do your regular daily activities, other than work at a job or attending classes.
Influenza/flu
had no effect 
on my daily
Influenza/flu
completely 
prevented me
activities
0
1
2
3
4
5
6
7
8
9
10
from doing my 
daily activities
Circle a number
Adapted from: Reilly MC, Tanner A, Meltzer EO: Work, classroom and activity impairment instruments: 
validation studies in allergic rhinitis. Clin Drug Invest 1996;11:278-88.


Baloxavir Marboxil—F. Hoffmann-La Roche Ltd
118/Protocol MV40618, Version 4
Appendix 5
Palatability and Acceptability Questionnaire of Study Drug 
(Index Patients Aged 5 Years Old to 12 Years Old)
Instructions: Please answer the following questions to help us understand your 
experience with the study medicine. For the question with a face, indicate which 
of the faces best matches how you felt about the medicine.
For children who cannot read yet, parents or caregiver, please help us 
understand your child’s experience with the study medicine. Invite your child to 
look at the cartoon, ask him or her the questions, and record his or her answer. 
If your child cannot answer the question, please skip the question.
The questions below are to be answered as soon as possible after swallowing the 
medicine.
1. How was the taste of the medicine?
□
□
□
□
□
Like very much
Like a little
Not sure
Dislike a little
Dislike very 
much
2.
Would you be happy to take the medicine again?
□Yes
□No
□Not sure/no answer

SAP_001.pdf: 
 
Official Title: 
A Phase IIIB, Multicenter, Randomized, Double-Blind, Placebo-
Controlled, Clinical Efficacy Study of Baloxavir Marboxil for the 
Reduction of Direct Transmission of Influenza From Otherwise 
Healthy Patients to Household Contacts 
NCT Number: 
NCT03969212 
Document Date: 
SAP Version 4: 06-August-2024 
 
 
 


STATISTICAL ANALYSIS PLAN AMENDMENT APPROVAL 
 
 
SPONSOR: 
LEGAL REGISTERED 
ADDRESS: 
F. Hoffmann-La Roche Ltd 
Grenzacherstrasse 124 
4070 Basel, Switzerland 
DATE FINAL: 
See electronic date stamp on the last page of this 
document  
CONFIDENTIAL 
 
This is an F. Hoffmann-La Roche Ltd document that contains confidential information.  Nothing 
herein is to be disclosed without written consent from F. Hoffmann-La Roche Ltd. 
 
Baloxavir marboxil—F. Hoffmann-La Roche Ltd 
Statistical Analysis Plan MV40618, Version 4 
STATISTICAL ANALYSIS PLAN 
STUDY TITLE: 
A PHASE IIIb, MULTICENTER, RANDOMIZED, DOUBLE-BLIND, 
PLACEBO-CONTROLLED, CLINICAL EFFICACY STUDY OF 
BALOXAVIR MARBOXIL FOR THE REDUCTION OF DIRECT 
TRANSMISSION OF INFLUENZA FROM OTHERWISE HEALTHY 
PATIENTS TO HOUSEHOLD CONTACTS 
STUDY NUMBER: 
MV40618 
VERSION NUMBER: 
4 
ROCHE COMPOUND 
Baloxavir Marboxil (RO7191686) 
EUDRACT NUMBER: 
2018-004056-37 
IND NUMBER: 
126653 
NCT NUMBER: 
NCT03969212 
PLAN PREPARED BY: 
, MD, Ph.D. 
, Ph.D. 
, MSc 
, MSc 
, Ph.D. 
 
 


 
Baloxavir marboxil—F. Hoffmann-La Roche Ltd  
Statistical Analysis Plan MV40618, Version 4 
2 
STATISTICAL ANALYSIS PLAN VERSION HISTORY 
This Statistical Analysis Plan (SAP) was developed based on Roche SAP model 
document V2.0. 
SAP Version 
Approval Date 
Based on Protocol  
(Version, Approval Date) 
Version 4 
see electronic date stamp 
on the last page of this 
document 
Version 4, 29 March 2022 
Version 3 
7-June-2024 
Version 4, 29 March 2022 
Version 2 
19-July-2023 
Version 4, 29 March 2022 
Version 1 
28-September-2022 
Version 4, 29 March 2022 
 
 
 


 
Baloxavir marboxil—F. Hoffmann-La Roche Ltd  
Statistical Analysis Plan MV40618, Version 4 
3 
STATISTICAL ANALYSIS PLAN AMENDMENT RATIONALE 
Key changes to the SAP, along with the rationale for each change, are summarized 
below. 
Section 
Description of Change 
Rationale for Change 
4.2 
Updated description of inter-current 
event of death 
Clarification on handling of 
death of an IP and strategy for 
both HHC and IP deaths 
4.2 
Removed RR from population-level 
summary measures 
The odds ratio is the main 
population-level summary and 
the RR is supportive  
4.2.2 
Updated CI for RRR to use bootstrap 
method 
To address concerns with the 
Zhang and Yu (1998) 
approach for the CI 
4.3.1 
Updated significance level (and 
associated confidence interval width) for 
all secondary endpoints in the testing 
hierarchy 
To ensure strong control of the 
type I error 
4.6.2 
Updated the analysis sets for the 
summaries of treatment group 
comparability 
Clarification on the analysis 
sets that will be used for 
demography, vital signs, 
medical history and 
concomitant medication 
summaries 
4.7.1 
Updated description of testing at interim 
and final analysis 
Clarification that interim 
analysis was one-sided but 
final analysis is two-sided 
Additional minor changes have been made throughout to improve clarity and 
consistency. 
 


 
Baloxavir marboxil—F. Hoffmann-La Roche Ltd  
Statistical Analysis Plan MV40618, Version 4 
4 
 
TABLE OF CONTENTS 
STATISTICAL ANALYSIS PLAN VERSION HISTORY ........................................ 2 
STATISTICAL ANALYSIS PLAN AMENDMENT RATIONALE ............................. 3 
1. 
INTRODUCTION ............................................................................. 9 
1.1 
Objectives and Endpoints .......................................................... 9 
1.2 
Study Design ........................................................................... 13 
1.2.1 
Treatment Assignment and Blinding ........................................ 15 
1.2.2 
Randomization ......................................................................... 18 
1.2.3 
Independent Review Facility .................................................... 18 
1.2.4 
Data Monitoring ....................................................................... 18 
2. 
STATISTICAL HYPOTHESES AND SAMPLE SIZE 
DETERMINATIONS ...................................................................... 18 
2.1 
Statistical Hypotheses ............................................................. 18 
2.2 
Sample Size Determination ..................................................... 18 
2.2.1 
Sample Size for China Population ........................................... 19 
3. 
ANALYSIS SETS .......................................................................... 19 
3.1 
Screened Populations .............................................................. 19 
3.2 
Randomized Populations ......................................................... 19 
3.2.1 
Handling of Late Arrival HHCs and Screen Failed HHCs for 
PAS-HC. .................................................................................. 21 
3.3 
Pharmacokinetic-Evaluable Population ................................... 21 
3.4 
Safety Populations ................................................................... 21 
4. 
STATISTICAL ANALYSES ........................................................... 22 
4.1 
General Considerations ........................................................... 22 
4.1.1 
Missing Data ............................................................................ 23 
4.2 
Primary Endpoint Analysis ....................................................... 24 
4.2.1 
Definition of Primary Endpoint ................................................. 25 
4.2.2 
Main Analytical Approach for Primary Endpoint(s) ................... 26 
4.2.3 
Sensitivity Analyses ................................................................. 27 
4.2.4 
Supplementary Analyses ......................................................... 29 
4.3 
Secondary Endpoints Analysis(ses) ........................................ 30 


 
Baloxavir marboxil—F. Hoffmann-La Roche Ltd  
Statistical Analysis Plan MV40618, Version 4 
5 
4.3.1 
Confirmatory Secondary Endpoints ......................................... 30 
4.3.1.1 
Symptomatic Transmission by Day 5 (Primary Endpoint 
and Symptoms) ........................................................................ 31 
4.3.1.2 
Virological Transmission at the HH Level by Day 5 
(Primary Endpoint for the Primary Estimand at HH Level) ....... 31 
4.3.1.3 
Symptomatic Transmission at HH Level by Day 5 (Primary 
Endpoint and Symptom for the Primary Estimand at HH 
Level) ....................................................................................... 32 
4.3.1.4 
Virological Transmission by Day 9 ........................................... 32 
4.3.1.5 
Symptomatic Transmission by Day 9 ....................................... 32 
4.3.1.6 
Any Virological Infection by Day 9 ........................................... 32 
4.3.1.7 
Any Virological Infection at the HH Level by Day 9 .................. 33 
4.3.1.8 
Any Symptomatic Infection by Day 9 ....................................... 33 
4.3.1.9 
Any Symptomatic Infection at the HH Level by Day 9 .............. 33 
4.3.2 
Supportive Secondary Endpoints ............................................. 33 
4.3.2.1 
Health Status Utility Endpoints ................................................. 33 
4.3.2.2 
Palatability and Acceptability of Baloxavir ................................ 34 
4.4 
Exploratory Endpoints Analysis ............................................... 34 
4.5 
Safety Analyses ....................................................................... 34 
4.5.1 
Extent of Exposure .................................................................. 34 
4.5.2 
Adverse Events ........................................................................ 34 
4.5.3 
Additional Safety Assessments ................................................ 36 
4.6 
Other Analyses ........................................................................ 36 
4.6.1 
Summaries of Conduct of Study .............................................. 36 
4.6.2 
Summaries of Treatment Group Comparability ........................ 37 
4.6.3 
Virological Analyses ................................................................. 37 
4.6.4 
Baloxavir Resistance Analysis ................................................. 39 
4.6.5 
Analyses of Subgroups of Interest ........................................... 41 
4.7 
Interim Analyses ...................................................................... 42 
4.7.1 
Planned Interim Analysis ......................................................... 42 
4.7.2 
Changes to Protocol-planned Analyses ................................... 44 
5. 
SUPPORTING DOCUMENTATION .............................................. 45 
5.1 
Symptoms Assessed in the Full Study Household Contacts ... 45 
5.2 
EQ-5D-5L to Measure Quality of Life ....................................... 49 


 
Baloxavir marboxil—F. Hoffmann-La Roche Ltd  
Statistical Analysis Plan MV40618, Version 4 
6 
5.3 
Work Productivity And Activity Impairment Questionnaire 
Plus Classroom Impairment Questions: SHP, Version 2 
(WPAI  CIQ:SHP, V2) ............................................................ 52 
5.4 
Palatability and Acceptability Questionnaire of Study Drug 
(Index Patients Aged 5 Years Old to  12 Years Old) .............. 54 
5.5 
Local Laboratory Sample Testing for Influenza at the 
Central Laboratory ................................................................... 55 
6. 
REFERENCES.............................................................................. 57 
 
LIST OF TABLES 
Table 1 
Primary and Selected Secondary Endpoints ................................. 9 
Table 2 
Other Secondary Objectives and Endpoints ............................... 12 
Table 3 
Study Drug Administration and Dose for Index 
Patients  12 Years Old .............................................................. 16 
Table 4 
Study Drug Administration and Dose for Index 
Patients  12 Years Old .............................................................. 16 
Table 5 
Analysis Periods ......................................................................... 22 
Table 6 
Confirmatory Hierarchical Order for the Secondary Endpoints ... 30 
Table 7 
Projected Interim and Final Analyses Characteristics ................. 43 
Table 8 
Outcomes Following Local Sample Testing at Central 
Laboratory for Scenario 2 and 3. ................................................. 56 
 
LIST OF FIGURES 
Figure 1 
Study Schema ............................................................................. 17 
 


 
Baloxavir marboxil—F. Hoffmann-La Roche Ltd  
Statistical Analysis Plan MV40618, Version 4 
7 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation or Term 
Description 
AE 
adverse event 
BLOQ 
below the limit of quantification 
BXM 
baloxavir marboxil 
CI 
confidence interval 
CMH 
cochran-mantel-haenszel 
COVID-19 
Coronavirus Disease 2019 
CSR 
Clinical Study Report 
CTCAE 
common terminology criteria for adverse events 
DAP M2 
Data Analysis Plan Module 2 
eCRF 
electronic Case Report Form 
EQ-5D-5L 
Euroqol 5-dimension Questionnaire 
FAS-HC 
full household contacts analysis set 
FASi-HC 
full household contacts infected analysis set 
FAS-HH 
full household analysis set 
FASi-HH 
full household infected analysis set 
FAS-IP 
full index patients analysis set 
GCP 
Good Clinical Practice 
GEE 
generalized estimating equations 
HCP 
healthcare professional 
HHC 
household contact 
I38X 
substitution of isoleucine for another amino acid at position 38 (of the 
polymerase acidic protein) 
IA 
interim analysis 
iDMC 
independent Data Monitoring Committee 
IMP 
investigational medicinal product 
IP 
index patient 
IxRS 
interactive voice or web-based response system 
MDD 
minimum detectable difference 
MedDRA 
The Medical Dictionary for Regulatory Activities 
NCI  National Cancer Institute 
OR 
odds ratio 
OwH 
otherwise healthy 
PA 
polymerase acidic (protein) 
PAS-HC 
primary household contacts analysis set 
PAS-HH 
primary households analysis set 


 
Baloxavir marboxil—F. Hoffmann-La Roche Ltd  
Statistical Analysis Plan MV40618, Version 4 
8 
Abbreviation or Term 
Description 
PAS-IP 
primary index patients analysis set 
PCR 
polymerase chain reaction 
POC 
point of care 
PT 
preferred terms 
RAS 
resistance associated substitution (PA/I38X or PA/T20K [influenza B 
only] and other USPI defined substitutions) 
RIDT 
rapid influenza diagnostic test 
RNA 
ribonucleic acid 
RT-PCR 
reverse transcription polymerase chain reaction 
RR 
relative risk 
RRR 
relative risk reduction 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SARS-CoV-2 
syndrome coronavirus 2 
SAS 
statistical analysis system 
SCR-HHC 
screened household contacts population 
SCR-IP 
screened index patients population 
SD 
standard deviation 
SOC 
system organ class 
T20K 
substitution of threonine to lysine at position 20 in the polymerase 
acidic protein 
TCID50 
50% tissue culture infectious dose 
US 
United States 
USPI 
United States Package Insert 
VAS 
Visual Analogue Scale 
WPAI  CIQ 
Work Productivity and Activity Impairment Questionnaire plus 
Classroom Impairment Questions 


 
Baloxavir marboxil—F. Hoffmann-La Roche Ltd  
Statistical Analysis Plan MV40618, Version 4 
9 
1. 
INTRODUCTION 
This Statistical Analysis Plan (SAP) describes the analyses that are planned to be 
performed for the Clinical Study Report (CSR) of Study MV40618 (Centerstone).  
Additional detailed algorithms for endpoint derivation and tables, listings and figures 
shells are provided in the Data Analysis Plan Module 2 (DAP M2). 
1.1 
OBJECTIVES AND ENDPOINTS 
This study will evaluate the efficacy of a single, oral dose of baloxavir marboxil (BXM) 
compared with placebo for the reduction of the direct transmission rate of influenza A or 
B from otherwise healthy index patients (IPs) to household contacts.  Only household 
contacts (HHCs) with influenza type A and B will be considered for primary and 
secondary efficacy endpoints.  Specific objectives and corresponding endpoints for the 
study based on the study protocol are outlined in Table 1 and Table 2.  
Table 1 
Primary and Selected Secondary Endpoints 
Primary Objective(s) 
Definition 
 
To evaluate the efficacy of a 
single, oral dose of BXM 
compared with placebo to prevent 
secondary within‑household 
transmission of influenza A or B 
 
Virological transmission by Day 5: Proportion of 
HHCs who become PCR(  ) [confirmed at central 
laboratory] for influenza by Day 5 Visit, with virus 
subtype consistent with IP 
Selected Secondary Objective(s) 
Definition 
 
To evaluate the efficacy of a 
single, oral dose of BXM 
compared with placebo to prevent 
transmission of influenza A/ B 
beyond secondary 
within‑household transmission 
 
Symptomatic transmission by Day 5: Proportion of 
HHCs who become PCR (  ) [confirmed at central 
laboratory] for influenza by Day 5 Visit, with virus 
subtype consistent with IP, AND:  
1. 
For HHC aged  12 years: 
– 
Temperature  38.0 °C*1 and one respiratory 
symptom, OR 
– 
One respiratory symptom and one general 
systemic symptom (with or without fever). 
2. 
For HHC aged  2 to  12 years: 
– 
Temperature  38.0 °C* AND signs or 
symptoms of an upper respiratory tract 
infection. 
 
1 Temperature obtained from tympanic thermometers provided to households (or exceptionally 
from other thermometers/locations in case of tympanic thermometer failure for any reason) 


 
Baloxavir marboxil—F. Hoffmann-La Roche Ltd  
Statistical Analysis Plan MV40618, Version 4 
10 
Table 1 
Primary and Selected Secondary Endpoints 
 
3. 
Symptoms must be either new, or have 
worsened versus baseline in HHC with 
baseline symptoms due to a pre-existing 
comorbidity 
 
Virological transmission at the household level by 
Day 5: Proportion of households with at least one 
HHC who meets the primary endpoint 
 
Symptomatic transmission at the household level 
by Day 5: Proportion of households with at least 
one HHC who meets the “Symptomatic 
transmission by Day 5 endpoint. 
 
Virological transmission by Day 9: Proportion of 
HHCs who become PCR (  ) (confirmed at central 
laboratory) for influenza by Day 9 Visit, with virus 
subtype consistent with IP, including: 
 
all HHC meeting primary endpoint, AND 
 
all HHC cases detected after Day 5 Visit 
meeting the following criteria: 
– 
Included HHC case is in a household where 
another HHC has already met the primary 
endpoint, OR 
– 
Included HHC case is PCR(  ) [confirmed at 
central laboratory] for influenza bearing an 
amino acid substitution of isoleucine for 
another amino acid at position 38 (I38X) in 
the polymerase acidic (PA) protein (PA/I38X 
substitution) or amino acid substitution of 
threonine to lysine at position 20 in the 
polymerase acidic (PA) protein for influenza 
B only (PA/T20K) 
 
 
Symptomatic transmission by Day 9: Proportion of 
HHCs who meet the “Virological transmission by 
Day 9” endpoint AND are symptomatic per the 
definition for symptoms in the “Symptomatic 
transmission by Day 5” endpoint. 
 
Any virological infection by Day 9: Proportion of 
HHCs who become PCR (  ) for influenza 
(confirmed at central laboratory) by Day 9. 
 
Any virological infection at the household level by 
Day 9: Proportion of households with at least one 


 
Baloxavir marboxil—F. Hoffmann-La Roche Ltd  
Statistical Analysis Plan MV40618, Version 4 
11 
Table 1 
Primary and Selected Secondary Endpoints 
HHC who meets the “Any virological infection by 
Day 9” endpoint. 
 
Any symptomatic infection by Day 9: Proportion of 
HHCs who meet the “Any virological infection by 
Day 9” endpoint AND are symptomatic per the 
definition for symptoms in the “Symptomatic 
transmission by Day 5” endpoint. 
 
Any symptomatic infection at the household level 
by Day 9: Proportion of households with at least 
one HHC who meets the “Any symptomatic 
infection by Day 9” endpoint. 
BXM  baloxavir marboxil; HHC  household contacts; IP  index patient; PA/I38X  polymerase 
acidic (protein)/ substitution of isoleucine for another amino acid at position 38 (of the polymerase 
acidic protein); PA/T20K  polymerase acidic (protein)/ substitution of threonine to lysine at 
position 20; PCR  polymerase chain reaction.  
  
 
 


 
Baloxavir marboxil—F. Hoffmann-La Roche Ltd  
Statistical Analysis Plan MV40618, Version 4 
12 
Table 2 
Other Secondary Objectives and Endpoints 
Additional Efficacy Objectives 
Corresponding Endpoints 
 
To further evaluate the efficacy of 
a single, oral dose of BXM 
compared with placebo to prevent 
transmission of influenza A or B.  
 
The effect of IP baseline viral titer on the rate of 
direct transmission of influenza A or influenza B 
to HHCs.  
 
Baloxavir arm only: Proportion of IPs who 
are PCR(  ) [confirmed at central laboratory] 
for influenza bearing a PA/I38X or substitution 
of threonine to lysine at position 20 in the 
polymerase acidic protein (T20K) (influenza B 
only) substitution (or other identified 
substitution) post randomization.  
 
Baloxavir arm only: Proportion of HHCs who 
become PCR(  ) [confirmed at central laboratory] 
for influenza bearing a PA/I38X or T20K 
(influenza B only) substitution (or other identified 
substitution) with matched PA substitution with 
their IP by Day 9 Visit.  
 
Baloxavir arm only: Proportion of symptomatic 
cases among HHCs who become PCR(  ) 
[confirmed at central laboratory] for influenza 
bearing a PA/I38X or T20K (influenza B only) 
substitution (or other identified substitution) with 
matched PA substitution with their IP by Day 9 
Visit (utilizing same symptoms definition as used 
for secondary symptomatic transmission 
endpoint).  
 
Proportion of HHC who become PCR(  ) 
[confirmed at central laboratory] for influenza by 
Day 9 Visit, with virus subtype consistent with IP.  
 
Measurement of viral titer by PCR and 50% 
tissue culture infectious dose (TCID50) in IPs 
over the Day 0, 3, 5, and 9 Visits 
 
Subgroup analysis: in a post-hoc analysis, 
endpoints requiring a subtype match will be 
assessed with a match based on sequencing in a 
subset of households (sequencing will be 
performed for samples from selected sites and 
countries based on feasibility, including 
availability of adequate number of IP sequences 
for specific community). 


 
Baloxavir marboxil—F. Hoffmann-La Roche Ltd  
Statistical Analysis Plan MV40618, Version 4 
13 
Table 2 
Other Secondary Objectives and Endpoints 
Safety Objectives 
Corresponding Endpoints 
 
To evaluate the safety and 
tolerability of a single, oral dose of 
BXM compared with placebo. 
 
Index patient only: The incidence, severity, and 
timing of adverse events, and serious adverse 
events. 
Health Status Utility Objectives 
Corresponding Endpoints 
 
To evaluate index patients treated 
with BXM compared with those 
receiving placebo. 
 
Index patient aged 12 and above only: Change 
from baseline in health-related quality of life 
according to EuroQol 5 dimensions 5 (EQ-5D-5L) 
Questionnaire at Day 3 and Day 9 Visits.  
 
Index patient age 12 and above only: Work 
Productivity and Activity Impairment 
Questionnaire plus Classroom Impairment 
Questions: SHP, Version 2 (WPAI  CIQ:SHP, V 
2) to measure lost work or school day assessed 
at Day 9 Visit. 
Additional Objective 
Palatability and Acceptability Endpoints 
 
To describe the palatability and 
acceptability of BXM oral 
suspension 
 
Index patient aged 12 and below only: 
Distribution of responses to the Palatability and 
Acceptability Questionnaire of Study Drug 
BXM  baloxavir marboxil; HHC  household contacts; IP  index patient; PA/I38X  polymerase 
acidic (protein)/ substitution of isoleucine for another amino acid at position 38 (of the polymerase 
acidic protein); PA/T20K  polymerase acidic (protein)/ substitution of threonine to lysine at 
position 20; PCR  polymerase chain reaction; EQ‑5D‑5L  EuroQoL 5‑Dimension Questionnaire 
(see Section 5.2); WPAI  CIQ  Work Productivity and Activity Impairment Questionnaire plus 
Classroom Impairment Questions (see Section 5.3); Palatability and Acceptability Questionnaire 
of Study Drug (see Section 5.4). 
  
1.2 
STUDY DESIGN 
This is a randomized, double-blind, multicenter, parallel group, placebo-controlled study 
designed to evaluate the clinical efficacy of BXM for the reduction of direct transmission 
of influenza A or B from otherwise healthy (OwH) IPs to their HHCs. 
For this household study, IPs with influenza will be randomized to receive BXM or 
placebo, and their HHCs will be repeatedly tested for influenza virus and assessed for 
influenza symptoms during the next 9 days.  The total number of new HHC infections 
(symptomatic and asymptomatic) and total number of new HHC infections associated 
with symptoms will be key measures used to evaluate the “virological transmission” and 
“symptomatic transmission” endpoints (see Section 2.2). 


 
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Approximately 1130 IPs with influenza and approximately 2030 evaluable HHCs are 
planned to participate (assuming an average of 2.5 HHCs per IP, a 15% exclusion rate 
at the household level, and a 15% drop-out rate) in the study.  The total study duration 
for each household will be up to 9 (  1) days (IPs aged 511 years old will have a safety 
follow‑up visit at 21 [  2] days).  This study will be conducted at approximately 200 sites 
globally in the Northern and Southern hemispheres. 
At the end of the 2022/2023 Northern hemisphere influenza season, an interim efficacy 
analysis will be conducted with early stopping rules for proven efficacy (based on a 
group sequential design) and futility.  See Section 4.7.1 for details.  
Figure 1 presents an overview of the study design.  A schedule of activities for the IPs 
and HHCs is provided in study protocol. 
Index Patient: Screening and Randomization 
Eligible IPs must be aged from  5 to  64 years old, have influenza symptom onset 
within 48 hours, test positive for influenza A/B, and be OwH (i.e., not at high risk for 
complications of influenza).  Screening assessments informing IP eligibility include 
physical examination, vital signs, height and weight, medical history and concomitant 
therapies, urine pregnancy testing, and respiratory sampling for influenza testing. 
With regard to the household, IPs should be determined at screening to live 
with  1 HHCs who have not received an influenza vaccine in the past 6 months 
(“unvaccinated HHCs”), are likely to fulfill all HHC eligibility criteria, and are expected to 
participate in the “full study” (i.e., participate in all study assessments). 
IPs who meet the eligibility criteria (see Protocol Section 4.1) will be randomized in a 
1:1 ratio to receive a single dose of either BXM or placebo within 2 hours of 
randomization.  The dose and formulation of BXM is based on weight and age (see 
Section 1.2.1). 
Index Patient: Post-Randomization 
Respiratory samples and adverse events (AEs) will be collected.  IPs who are   12 years 
old will also complete questionnaires describing their health status and absence from 
work or school (see Section 5.2 and Section 5.3).  IPs who are  12 years old will be 
asked to complete a questionnaire on the palatability and acceptability of the study drug 
oral suspension. 
Household Contacts: Screening and Enrollment 
All HHCs present in the home must have their screening visit start within 24 hours of IP 
randomization (see Protocol Section 4.5.8 for details).  If any HHC tests positive for 
influenza A/B, then all HHCs fail screening.  If  1 unvaccinated HHCs meet all HHC 
eligibility criteria and agree to participate in the full study, it is allowable for additional 
HHCs to not participate beyond the screening visit (even if they meet all HHC eligibility 


 
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criteria).  There is no maximum number of vaccinated and unvaccinated HHCs that can 
participate in the full study. 
HHCs who agree to participate in the full study (“full study HHCs”) must meet the full 
study criteria (HHC inclusion criteria 7 to 14; see Protocol Section 4.1.1, including that 
they must reside in the household for 7 of the 9 study days, and must not have any 
influenza symptoms at screening (mild symptoms determined by the investigator to be 
due to a pre-existing condition are allowed). 
Screening assessments informing HHC eligibility include influenza symptoms (see 
Section 5.1), medical history, concomitant medications, and respiratory sampling for 
influenza testing. 
Full Study Household Contacts: Post-Screening 
Only full study HHCs participate in visits and assessments post-screening.  Full study 
HHCs are monitored for new or worsening influenza symptoms (see Section 5.1) and will 
also maintain a daily temperature diary (see Protocol Section 4.5.6).  HHCs will be 
instructed to telephone the site if they develop influenza symptoms or fever so that a 
scheduled or unscheduled visit occurring within 24 hours can be arranged (see Protocol 
Section 4.5.6).  Respiratory samples, adverse events due to study procedures, and 
concomitant medications will be collected. 
SARS-CoV-2 Testing 
Given overlapping influenza and Coronavirus disease 2019 (COVID-19) symptoms, 
severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) testing will be 
conducted at screening and as needed during study conduct (see Protocol 
Section 4.5.5.2).  If any subject (IP or HHC) tests positive for SARS-CoV-2, then all 
subjects in the household should be discontinued (see Protocol Section 4.6.2). 
Independent Data Monitoring Committee 
An external independent Data Monitoring Committee (iDMC) will evaluate safety 
according to policies and procedures detailed in an iDMC Charter.  The involvement of 
the iDMC in interim efficacy evaluations is described in Section 4.7. 
1.2.1 
Treatment Assignment and Blinding 
This is a single, oral dose study.  IPs will receive the initial and only dose of study drug 
(BXM or matching placebo) to be taken in tablet or oral suspension form at the study 
center.  See Table 3 and Table 4 for study drug (BXM or matching placebo) 
administration.  


 
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Table 3 
Study Drug Administration and Dose for Index Patients  12 Years 
Old 
Weight 
Dose, Formulation 
  20 kg  
2 mg/kg, oral suspension 
  20 kg 
40 mg, oral suspension 
  
Table 4 
Study Drug Administration and Dose for Index Patients  12 Years 
Old 
Weight 
Dose, Formulation 
   80 kg 
40 mg, two 20 mg tablets 
  80 kg 
80 mg, four 20 mg tablets 
  
See details in study Protocol Section 4.2 “Method of Treatment Assignment and 
Blinding”.




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1.2.2 
Randomization 
IPs will be allocated to one of the two treatment arms in a 1:1 proportion with predefined 
stratification factors: region (US or Europe, Asia, Rest of the World), number of 
household contacts living in the household during the study (  2,   3), age ( 5 
to   12 years;   12 to   30 years,   30 years) and duration of symptoms (  24,   24 
to  48 hours).  A placebo for BXM will be used in the control arm.  Patients, 
investigators, and the Sponsor will be blinded to treatment assignment. 
At study completion, stratification factors recorded in the Interactive voice or web-based 
response system (IxRS) will be compared to the stratification factors derived from data 
recorded on the electronic Case Report Form (eCRF), which will be used in the analysis, 
to identify any mis-stratifications.  These will be listed for all patients. 
1.2.3 
Independent Review Facility 
Not Applicable. 
1.2.4 
Data Monitoring 
Safety interim analyses will be performed regularly and reviewed by an iDMC.  Efficacy 
data will be provided for interim analysis purposes (see Section 4.7) or if requested by 
the iDMC.  Further details on the function and logistics (e.g., frequency of the meetings) 
of the iDMC are provided in the iDMC Charter.   
2. 
STATISTICAL HYPOTHESES AND SAMPLE SIZE 
DETERMINATIONS 
2.1 
STATISTICAL HYPOTHESES 
The hypothesis for the primary analysis is as follows: 
 
H0: No difference in virological influenza transmission rate between study treatments 
(odds ratio  1). 
 
HA: The virological influenza transmission rate in Baloxavir arm is different from 
Placebo (odds ratio ≠ 1) 
 
2.2 
SAMPLE SIZE DETERMINATION 
The proposed sample size for this study is 2,030 evaluable household contacts.  
Assuming a 15% drop-out for inclusion of household contacts into the primary analysis 
population, an average of 2.5 household contacts per IP and a 15% exclusion rate on 
the household level, this equates to an approximate number of IPs of 1,130. 
A transmission rate in the placebo arm of approximately 20% is assumed based on data 
from the literature, including work by Welliver et al. 2001.  For a 30% relative risk 
reduction with BXM, which is considered clinically meaningful, the transmission rate in 
the active treatment group is expected to be 14%.  Under these assumptions and for a 
two-sided test for binary proportions at the 5% significance level, the power for the 


 
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between-arm comparison based on the primary endpoint is expected to be  90%.  For 
the secondary “Symptomatic transmission endpoint” (symptomatic influenza) the power 
will be approximately 80% for an assumed 65% proportion of symptomatic cases among 
infected household contacts, and not considering the hierarchical testing procedure.  
Computations were performed using a normal approximation to the binomial distributions 
(R function “power.prop.test”).  The literature reports a variety of values for the 
proportion of influenza cases that are symptomatic.  The assumption of 65% was 
authorized by the study steering committee. 
The effect of clustering was examined in simulations and using analysis methods 
accounting for the household effect.  The power was largely maintained in simulations 
that assumed the existence of a random variation of the background transmission rate 
between households with a standard deviation up to 5% (i.e., with about 95% of the 
values for the BXM and placebo groups in the [4.2, 23.8] and [10.2, 29.8] range, 
respectively).  This is compatible with the inclusion of a large number of small clusters 
and a small expected intra-cluster correlation, resulting in a negligible design effect and 
related reduction in effective sample size. 
2.2.1 
Sample Size for China Population 
This study will enroll participants across all sites including participants in China.  No cap 
on sample size is currently planned in China subpopulation.  
3. 
ANALYSIS SETS 
The primary study analysis will occur when the last subject has either withdrawn or 
completed their last visit and will be based on cleaned data for all subjects up to and 
including this point.  The end of the study for all patients (except IPs  12 years old) is 
expected to occur 9 days after the last IP is enrolled.  For IPs  12 years old, the last visit 
will be Day 21.  Interim analyses are described in Section 4.7. 
3.1 
SCREENED POPULATIONS 
Screened Index Patients Population (SCR-IP): will include all IPs screened at 
investigational sites with signed Informed Consent.  
Screened Household Contacts Population (SCR-HHC): will include all household 
contacts of the SCR-IP set, screened at investigational sites or at nurse house visits, 
with signed Informed Consent. 
3.2 
RANDOMIZED POPULATIONS  
Household Contacts Analysis sets: 
 
Full Household Contacts Analysis set (FAS-HC) will include all HHCs who are 
enrolled for the full study and linked to a randomized IP. 
Note: household contacts with Baseline collected later than 2 days after IP 


 
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randomization cannot be part of the FAS-HC because they would not be eligible to 
be enrolled for the full study. 
 
Full Household Contacts infected Analysis set (FASi-HC): subset of all FAS-HC 
whose IPs are polymerase chain reaction (PCR)   for influenza A or B at Baseline 
(see Section 4.1).   
 
Primary Household Contacts Analysis Set (PAS-HC) is a subset of FASi-HC 
including all HHCs: 
– 
From households where the IP is PCR   for influenza A or B at Baseline (see 
Section 4.1), and received study drug 
– 
who are unvaccinated (i.e., that have not received the influenza vaccine within 
6 months prior to screening), and  
– 
from households where all contacts are PCR negative at Baseline (see 
Section 4.1).  Additional criteria for late arrivals HHCs and screened failed 
HHCs are reported in Section 3.2.1. 
 
Index Patients Analysis sets: 
 
Full Index Patients Analysis Set (FAS-IP): will include all randomized IPs.   
 
Primary Index Patients Analysis Set (PAS-IP): will include all index patients from 
FAS-IP with at least one HHC in the PAS-HC. 
 
Full Index Patients Analysis Set for BXM Resistance Analysis (RES-IP): will include 
all IPs randomized to BXM and exposed to BXM, having at least one PA sequencing 
result 
 
Households Analysis sets: 
 
Full Household Analysis Set (FAS-HH) will include all household (HH) of 
randomized IPs. 
 
Full Households infected Analysis Set (FASi-HH): All households in FAS-HH with 
the IP PCR positive at screening and with at least one HHC enrolled for the full 
study.  Of note, this corresponds to the HHs of all subjects in FASi-HHC. 
 
Primary Households Analysis Set (PAS-HH): subset of FASi-HH where IPs are in 
PAS-IP. 
 
For analysis set derivation purposes, where a central laboratory sample result is missing 
for any reason, the local laboratory sample would be tested at the central laboratory in 
an attempt to avoid missing data, this is applicable to any index patient and household 
contact (see Section 5.5, Local laboratory sample testing for influenza at the central 
laboratory, scenario 1).  If a central laboratory result remains missing following an 
attempt to retest the local samples centrally (Section 5.5 scenario  1), the local 
laboratory result will be utilized for the analysis set derivation if the conducted assay was 
a PCR method (see Section 4.1.1).  For index patients where baseline central laboratory 
result is missing and the local laboratory test result was conducted by a non PCR 


 
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method e.g., RIDT, the central laboratory result on protocol Day 3 will be utilized for 
analysis set derivation (Section 5.5 scenario 1).   
In the situation of specific cases where there is a mismatch between the results from the 
local and central laboratory sample for the IP baseline influenza testing the selection of 
the value for analysis set derivation is described in Section 5.5 scenario 2  
Treatment groups will be defined for all analysis sets above based on the arm to which 
the respective IP was randomized. 
3.2.1 
Handling of Late Arrival HHCs and Screen Failed HHCs for 
PAS-HC.  
For HHCs with Baseline PCR values collected after IP randomization  2 day (see 
Section 4.1), the full household will be excluded from PAS-HC if: 
 
HHC has informed consent form (ICF) date  IP randomization  7 days (prior to 
protocol study Day 7) and at least one of the following holds true: 
– 
HHC has no PCR assessment date  IP randomization  7 days, or 
– 
HHC has at least one positive PCR assessment, with date  IP 
randomization  7 days, having type/subtype matching with IP or with 
type/subtype missing 
 
The full household would also be excluded from the PAS-HC if a HHC is screen failed 
with date  IP randomization  7 days and is screen failed because of influenza test 
positive result.  These cases will be detected from IxRS screen fail reasons (INC02 for 
protocol v3 and v4, and INC03 for protocol v1 and v2) as the local influenza test data are 
not collected on the CRF nor samples are analyzed by central laboratory. 
3.3 
PHARMACOKINETIC-EVALUABLE POPULATION 
Not Applicable. 
3.4 
SAFETY POPULATIONS 
The Safety Index Patients Population will include all subjects from the SCR-IP who are 
randomized and receive any amount of study drug.  Patients will be grouped for analysis 
according to the received treatment.  Additional analysis will be conducted in the: 
 
Pediatric Safety set: composed of the subset of patients in Safety IP set who are 
less than 12 years old. 
 
Adolescent Safety set: composed of the subset of patients in Safety IP set with 
12  age  18 years. 
 
Adult Safety set: composed of the subset of patients in Safety IP set with 
age  18 years. 
 
The Safety Household Contacts Population will include all partial or full study enrolled 
subjects.  Safety data for HHCs will be summarized overall. 


 
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4. 
STATISTICAL ANALYSES 
The analyses outlined in this SAP supersede those specified in the protocol.  Unless 
otherwise specified (e.g., in the context of group-sequential analyses, see Section 4.7), 
statistical hypotheses will be tested at the 5% significance level (alpha  0.05) against 
two-sided alternatives.  A confirmatory testing strategy for the primary and selected 
secondary endpoints is described in Section 4.2 and Section 4.3. 
All statistical analyses will be performed using SAS statistical software (Version 9.4), 
unless otherwise specified. 
4.1 
GENERAL CONSIDERATIONS 
All summaries will be produced for the FAS-IP and FAS-HC, unless otherwise specified. 
Unless otherwise specified, the Clinical Data Interchange Standards Consortium 
(CDISC) standard will be used for the analysis and presentation of study days, which 
correspond to protocol study Day  1, apart from days prior to randomization, where 
analysis days and study protocol days are the same, as shown in Table 5. 
Table 5 
Analysis Periods 
 
Study Days 
Protocol 
Days 
0(1) 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11   
Analysis 
Days 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12   
IP Periods 
B(2) 
Before Day 5 
Day 5 
After Day 5 
HHC 
Periods 
B(2) 
Up to Day 5 
After Day 5 
HHC  household contact; IP  index patient. 
Note: (1) Protocol study Day 0 Baloxavir Marboxil (MV40618) SAP v2  randomization (2) 
Baseline for a HHC is not later than IP randomization Day  2 day, to accommodate for late 
arrival still eligible for inclusion in FASi-HC (Section 3.2).  
  
Summaries over time of data including selected symptoms/signs and viral titer will be 
produced by visit, and for HHC symptoms, by the post Baseline analysis periods 
provided in table above. 
Baseline values are defined as: 
 
For IPs: the last assessment prior to study treatment dosing.  For baseline influenza 
status (positive/negative) and type/subtype and any parameters where time is not 
collected, assessments on or prior to the day of study treatment dosing will be 
considered as detailed in the DAP-M2.  Information on local and central laboratory 
sample testing related to the baseline definition is provided in Section 5.5. 


 
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 
For HHCs: the earliest assessment recorded not later than IP randomization day  2 
days.  Baseline data collected later than IP randomization day  2 will be taken from 
late screening visits if occurring before any documented post-baseline visit of the 
HHC 
 
Full details on Baseline derivation will be provided in the DAP-M2 Section 3.1.6.2. 
Descriptive statistics (mean, median, SD, range) will be presented for continuous 
variables, and frequencies and percentages will be presented for categorical variables, 
unless otherwise specified.  The percentages will be calculated based on the number of 
non-missing values. 
4.1.1 
Missing Data 
The primary focus of this section is on missing influenza assessment data because of 
their direct impact on key efficacy study endpoints and analysis set derivation. 
Missing influenza test data can arise both at the IP/household and HHC level: 
 
If the IP or at least one household contact have baseline influenza result missing, 
(unless the late arrival HHC joined the HH after Day 7 - see SAP Section 3.2.1 for 
details), the whole household will be excluded from the primary analysis set (PAS-
HC) because it would be unclear if any HHC infections detected post-baseline would 
originate from the IP. 
 
In case of missing influenza type/subtype in positive PCR measurements in HHC (or 
in IP), the influenza transmission endpoint is considered positive. 
 
In the absence of PCR measurements post-baseline in HHCs in the relevant time 
window, the transmission by Day 5 endpoints would be considered non-evaluable.  
More specifically, the endpoint would be considered as non-evaluable if no 
post-baseline assessment is taken prior to study Day 7 or if the latest post-baseline 
assessment is taken prior to study Day 4 and is negative for influenza.  Handling of 
non-evaluable/missing data is described below for the key analyses. 
 
Where a central laboratory sample result is missing for any reason, the local 
laboratory sample would be tested at the central laboratory in an attempt to avoid 
missing data, this is applicable to any index patient and household contact (see 
Section 5.5, local laboratory sample testing for influenza at the central laboratory, 
scenario 1).  Unless otherwise specified, the point of care (POC) tests or other local 
laboratory test results for influenza will be used for the analysis, and for analysis 
sets derivation, if the local assay was a PCR method (i.e., if local test type is PCR or 
LIAT) when no central lab assessment is available for qualitative PCR (see 
Chen  et  al. 2015).  These data will be provided in listings.  Section 5.5 (scenario 2 
and 3) describes the selection of the value for analysis in specific cases where there 
is a mismatch between the results from the local and central laboratory. 
 
For the symptomatic transmission by Day 5 endpoint, missing data may also arise in 
case of no symptoms collected post-baseline. 


 
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Missing endpoint data or missing scheduled assessments may mainly arise because of: 
 
Subjects lost to follow-up or discontinued prior to the assessment visit (e.g., prior to 
Day 5).  A conservative 15% drop-out rate was assumed for sample size 
considerations.  Protocol compliance is however expected to be higher because of 
the short study duration and the possibility to perform study visits at the clinic or by 
nurse home visits, as per subjects’ preference.  
 
As per protocol, respiratory samples from HHCs only will be tested using the POC 
system and if any sample is positive, no further respiratory swabs will be taken.  In 
this case, the primary endpoint will be evaluable unless the central assessment is 
negative.  Data will not be collected at Day 5 and/or Day 9 because of prior 
POC/local laboratory positive test (e.g., at unscheduled visit) not eventually 
confirmed by central laboratory measurements.  A minor impact is expected on 
primary endpoint, because of the high specificity of POC test and the limited number 
of unscheduled visits expected by Day 5 visit.  
 
Missing data due to sample mishandling or other laboratory issues. 
 
For the primary estimand (see Section 4.2), missing/non-evaluable values will be 
imputed by considering any existing out-of-window post-baseline PCR assessment, or 
imputing negative if no post-baseline PCR assessment is available. 
Other analysis will be conducted on complete cases.  This approach was suggested by 
(Ma et al. 2013) for any clinical trials with a small percentage of missing outcomes 
(   15%).  Sensitivity analyses will however be conducted for the primary endpoint as 
specified in Section 4.2.3. 
4.2 
PRIMARY ENDPOINT ANALYSIS 
PAS-HC will be the primary efficacy analysis set.  Supportive and secondary analyses 
will also be conducted on the other analysis sets described in Section 3.2 and 
Section 3.3.  
The primary estimand for the analysis of the primary endpoint and for the first of the 
secondary endpoints (see 4.3.1.1) is defined as follows (details are provided in the DAP 
M2): 
a) Treatment regimens for patients to be evaluated 
One dose of oral BXM or placebo given to the IP at baseline. 
b) Populations of patients targeted by the clinical question (e.g., patients 
meeting inclusion/exclusion criteria, grouped according to randomized 
treatment assignment) 
PAS-HC, i.e., unvaccinated HHCs who are included in the full study (requirements 
include that the HHC joins the household no later than on Day 2), who are linked to 
a baseline PCR positive randomized IP and are from a completely PCR negative 
HH (except for the IP) at baseline.  The PCR test status for the IP and household 
contacts at baseline need to be confirmed by the central laboratory.  HHCs are 


 
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grouped for analysis according to the randomized treatment assignment of the 
respective IP. 
c) 
Patient-level outcome to be measured 
PCR-confirmed infection (primary endpoint) by Day 5, Symptomatic PCR-confirmed 
infection by Day 5 (Symptomatic Transmission first secondary endpoint).  The 
window for the Day 5 visit extends to study Day 6.  For the definition of symptomatic 
cases refer to Protocol Section 2.1.2.1. 
d) How intercurrent events will be handled (e.g., regardless of protocol 
violations) 
 
Protocol violations, including BXM dosing issues (e.g. wrong dose), use of 
prohibited medication, out-of-window assessments (especially after Day 6), or 
other events impacting the evaluability of the respiratory samples: treatment 
policy.  All available PCR samples will be used for the evaluation of HHCs for 
the analysis.  For HHCs without evaluable post-baseline samples, the status 
will be defined according to the baseline sample (i.e., negative for the primary 
analysis).  In case no post-baseline symptoms are collected, the HHC will be 
considered asymptomatic. 
 
COVID-19 positivity in the HH: while on treatment (outcome measures used 
until discontinuation) 
 
Positive PCR in HHC not matching IP’s influenza type/subtype: while on 
treatment strategy (primary endpoint considered negative unless there are 
subsequent positive assessments that match the IP’s influenza type/subtype) 
 
Death: Death of a HHC will be treated as a transmission event, death of an IP 
will also result in their associated HHCs being imputed as transmission events 
(composite strategy). 
e) Population-level summary measure (e.g., Proportion of HHCs who become PCR(  ) 
for influenza by Day 5 Visit). 
Odds ratio (primary model) 
 
4.2.1 
Definition of Primary Endpoint 
The primary endpoint will be derived at the HHC level based on central laboratory 
influenza test results (or local test results if central laboratory results are missing, see 
Section 4.1.1 and 3.2), as: 
 
A HHC will be considered positive, if an influenza test is positive within 6 days post 
IP randomization, with virus type and subtype matching with that of the respective IP 
 
A HHC will be considered negative, if they do not meet the criteria for positivity and 
an influenza test is negative at Day 5  1 
 
Missing otherwise 
 
Detailed endpoint derivation specifications in case of missing data on virus type/subtype 
are provided in DAP M2 Section 3.2.2. 


 
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4.2.2 
Main Analytical Approach for Primary Endpoint(s) 
The primary analysis will be performed on the PAS-HC with imputed missing primary 
endpoint information as described in Section 4.1.1 and will compare the transmission 
rate for the primary endpoint between the two treatment arms and express the effect by 
an adjusted odds ratio (OR).  The comparison will be based on a model providing 
population-averaged estimates using a generalized estimating equations (GEE) 
approach and accounting for clustering within households and the stratification factors 
(see Section 1.2.2) based on eCRF data, or IxRS in case of missing eCRF data.  
An exchangeable variancecovariance structure will be applied to model the 
within‑household errors, assuming that the correlation between any pair of HHCs within 
the same household is the same given the absence of a natural order of HHCs within 
households.  If the model doesn’t converge, other variancecovariance structures (in the 
following order: unstructured, independent) or other starting estimates of the model 
parameters can be considered. 
Adjusted point and 100×(1-α*)% CI estimates of the incidence proportions and odds ratio 
for the treatment effect at Day 5 and the pvalue for the treatment effect as well as for 
each covariate will be provided (see Section 2.1), where α* is the significance level at 
the final analysis.   
The primary test for the treatment effect at the final analysis will be two-sided and the 
significance level will be derived based on the alpha spend at the interim analysis and 
the size of the primary analysis population (PAS-HC) at the time of the analysis using 
the R package rpact (Wassmer and Pahlke 2019), as described in Section 4.7.1.  The 
number of available data for analysis will be tabulated. 
Sample SAS code can be found below (SAS code is regarded as “draft” until fully 
validated at the analysis stage): 
proc genmod data=PAS_HC; 
   class region nbhhc agecat dursymp trt household influenza; 
   model influenza = trt region nbhhc agecat dursymp / dist=bin 
link=logit type3; 
   repeated subject=household / type=exch covb; 
   lsmeans trt / ilink exp diff cl alpha=; 
run; 
 
In addition to adjusted odds ratio, the treatment effect will also be summarized by the 
relative risk (RR) as a supportive population-level summary.  The point estimate of the 
relative risk reduction (RRR) will be estimated as 1-RR, where RR is the relative risk 
derived by means of the formula published in Zhang and Yu 1998: 
𝑅𝑅 = 
𝑂𝑅
(1 −𝑃0) + (𝑃0 × 𝑂𝑅) 


 
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with OR and P0 being the adjusted odds ratio and incidence rate for Placebo obtained 
from the primary GEE model, respectively.  The confidence interval for the RRR will be 
calculated using the bootstrap method, where the sampling is conducted at the 
household level to maintain the correlation structure and the RRR for each sample is 
calculated as described above using the OR and P0 obtained from the GEE model. 
4.2.3 
Sensitivity Analyses 
The primary analysis will be conducted adjusting for stratification factors derived from 
eCRF data as described in Section 4.2.  If it is found that a large number of 
mis-stratifications occurred, a sensitivity analysis will be carried out on the primary 
endpoint, using the IxRS stratification factors in the model. 
Sensitivity analysis will be conducted to evaluate the robustness of the results of the 
primary analysis with respect to different assumptions regarding missing endpoint data.  
Sensitivity Analysis 
Approach 
Rationale 
Complete case analysis (no 
missing data imputation) 
To evaluate the effect under the assumption of 
data missing completely at random, i.e., 
assuming that the probability of missing 
transmission data is unrelated to any other 
measured variable and also unrelated to the 
values of the actual transmission itself (National 
Research Council 2010) 
Missing transmission 
endpoint will be imputed as 
negative 
To evaluate the effect using an approach in line 
with the FDA guidance “Influenza: Developing 
Drugs for Treatment and/or Prophylaxis” (April 
2011, Section 8) HHCs with insufficient data for 
the evaluation of the primary endpoint are 
considered as not having PCR-confirmed 
influenza 
Multiple Missing Data 
Imputation (MI) 
To evaluate the effect imputing missing 
transmission endpoints using the placebo 
response rates.  Further details are given below 
the table.   
Excluding data from Study 
sites with health authority 
identified Good Clinical 
Practice (GCP) violations 
US site 320035 was inspected by the FDA and 
issued a Form 483, Inspectional Observations 
and later warning letter for investigator lack of 
oversight and supervision of the clinical study 
and failure to ensure that subjects met 


 
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Sensitivity Analysis 
Approach 
Rationale 
protocol-required inclusion criteria for a 
non-Roche study.  While no findings identified 
by the FDA for Study MV40618, data from this 
site is excluded due to FDA concerns regarding 
inadequate investigator oversight.  
A site management organisation Medipharma 
Co ltd was inspected by the Japanese Ministry 
of Health, Labor and Welfare (MHLW) and 
reported to have committed GCP violations, 
including data falsification.  Medipharma 
supported Japanese sites 325126 and site 
323607 in the conduct of study MV40619.  Data 
from the sites supported by medipharma are 
excluded due to failings in GCP conduct by 
Medipharma. 
FDA  Food and Drug Administration; HHC  house hold contact; PCR  polymerase chain 
reaction. 
  
Multiple Missing Data Imputation (MI): will consist of the following 3 phases: 
Imputation: The missing endpoint data will be filled in with values estimated by a logistic 
regression model fitted using placebo patients to predict the value of the missing 
endpoint and thus derive complete data set for analysis.  Model terms will include those 
of the primary analysis model.  This imputation process will be repeated 50 times.  
Example SAS code is provided below (to be validated): 
proc mi data= PAS_HC nimpute=50 out=mi_PAS_HC seed=&seed; ; 
   class region nbhhc agecat dursymp trt influenza;  
   fcs logistic (influenza= region nbhhc age_ip age_hhc dursymp 
/link=logit); 
mnar model(influenza /modelobs=(trt='PLACEBO')) 
run; 
proc sort; data= mi_PAS_HC; by _imputation_; run; 
  
Analysis: each of the complete data sets generated during imputation is then analyzed 
using the primary analysis model.  Example SAS code is provided below (to be 
validated): 
proc genmod data=mi_PAS_HC; 
   class region nbhhc agecat dursymp influenza trt household; 
   model influenza = trt region nbhhc agecat dursymp / dist=bin 
link=logit type3; 
   repeated subject=household / type=exch  ecovb; 
   lsmeans trt / pdiff ; 
by _imputation_; 
    ods output ParameterEstimates=gmparms ParmInfo=gmpinfo 
CovB=gmcovb Diffs = gmlmd Lsmeans=gmlsm; 
run; 
 


 
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Pooling: The parameter estimates derived from each analyzed data set are combined for 
the derivation of final results.  Log OR will be combined because their distribution can be 
better approximated by normal distribution.  The final point and 100× (1- α*)% CI 
estimate of the OR, where α* is the significance level at the final analysis, will be 
obtained by taking anti-log transformation on the corresponding statistics for the log OR, 
further transformation to relative risk will be done as with the primary analysis.  Example 
SAS code is provided below (to be validated): 
proc mianalyze parms(classvar=full)= gmlmd alpha=; 
   class trt; modeleffects trt; 
   ods output ParameterEstimates=es_mi_final, 
run; 
data es_mi_final; set es_mi_final; 
   OR=exp(Estimate); 
   OR_upper=exp(UCLMean); 
   OR_lower=exp(LCLMean); 
run; 
  
4.2.4 
Supplementary Analyses  
A supportive analysis will be conducted on the primary endpoint imputed as per primary 
estimand: 
 
Repeating the primary analysis model on the FASi-HC.  Rationale is to evaluate to 
what extent the BXM effect can be generalized to a wider population which also 
includes HHCs who are vaccinated or not confirmed negative for influenza at 
Baseline.  This analysis will also evaluate if the BXM effect is robust to the inclusion 
of HHCs from households where the related IP was not treated as per protocol.  
 
Additional sensitivity analysis of the primary estimand for robustness of the primary 
endpoint analysis will include: 
 
To evaluate the treatment effect expressed as relative risk by repeating the primary 
analysis by means of the modified Poisson regression model adjusting for 
stratification factors (Zou 2004, Yelland et al. 2011) and using the log link-function 
instead of the logit link-function (dist  poisson link  log in the SAS model 
statement).  Similar to the primary analysis of odds ratio, an exchangeable 
variance-covariance structure will be applied to model the within‑household errors.  
Convergence and stability of estimates will be evaluated. 
 
Repeating the primary analysis of the primary endpoint derived using only central 
lab results, if local PCR influenza test results are used for the derivation of the 
primary analysis in more than 5% of the PAS-HC (see Section 3.2).  Rationale is to 
evaluate the extent to which the BXM effect is dependent on the inclusion of local 
PCR results. 
 
Repeat the primary analysis model on the PAS-HC excluding households where a 
HHC met the primary endpoint at or before protocol day 2, if more than 10% of the 
events occur at or before protocol Day 2.  Rationale is to evaluate the extent to 
which the BXM effect is dependent on the inclusion of infections which might 
represent primary cases rather than secondary transmissions from the IP. 


 
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 
A two-sided Cochran-Mantel-Haenszel (CMH) test to compare each treatment arm, 
stratified by the same factors used for the primary analysis.  The adjusted proportion 
ratios (relative risks) and ORs will be presented at Day 5 along with the 
corresponding 100×(1-α*)% CI, where α* is the significance level at the final 
analysis. 
Rationale is to evaluate the impact of not accounting for within-household 
correlation when evaluating the BXM effect and other assumptions behind the 
validity of the GEE model used for the primary analyses. 
Sample SAS code can be found below (SAS code is regarded as “draft” until fully 
validated at the analysis stage): 
 
proc freq data=PAS-HC; 
   tables  region*nbhhc*agecat*dursymp*trt*influenza / cmh 
relrisk nocol nopercent; 
run; 
  
Subgroup Analyses for Primary Endpoint(s) 
The generalizability of primary endpoint results when comparing BXM to placebo is 
investigated by estimating the treatment effect in subgroups as described in 
Section 4.6.5. 
4.3 
SECONDARY ENDPOINTS ANALYSIS(SES) 
4.3.1 
Confirmatory Secondary Endpoints 
If the primary outcome reaches significance (see Section 4.2), a hierarchical, sequential 
testing procedure is planned for the analysis of secondary efficacy endpoints.  The 
secondary efficacy endpoints (see derivation details in DAP M2 Section 3.2.3) will be 
tested at the same significance level as the primary endpoint as part of a confirmatory 
analysis in hierarchical order as listed in Table 6.  A given endpoint will be tested for 
confirmatory purposes if and only if all endpoints preceding it have reached significance 
at the defined level.  All tests not part of the confirmatory analysis will be considered 
exploratory.  Confidence intervals for the endpoints in the testing hierarchy will be 
adjusted based on the significance level at the final analysis in the same way as for the 
primary endpoint (Section 4.2.2). 
Table 6 
Confirmatory Hierarchical Order for the Secondary Endpoints 
Order 
Secondary Analysis 
1 
Symptomatic Transmission by Day 5 (Primary Endpoint and Symptoms). 
2 
Virological Transmission at the HH Level by Day 5 (Primary Endpoint at HH Level). 
3 
Symptomatic Transmission at HH Level by Day 5 (Primary Endpoint and Symptom at 
HH Level). 
4 
Virological Transmission by Day 9. 
5 
Symptomatic Transmission by Day 9. 
6 
Any Virological Infection by Day 9 
7 
Any Virological Infection at the HH Level by Day 9. 


 
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Order 
Secondary Analysis 
8 
Any Symptomatic Infection by Day 9. 
9 
Any Symptomatic Infection at the HH Level by Day 9. 
HH  household. 
  
4.3.1.1 
Symptomatic Transmission by Day 5 (Primary Endpoint and 
Symptoms) 
This analysis is part of the confirmatory strategy and evaluates the treatment effect on 
the rates of symptomatic transmission by Day 5 (with a visit window extending to Day 6).  
It will be conducted on an endpoint which restricts the definition of the primary endpoint 
to only transmissions of influenza with specific new signs or symptoms, (or worsened 
versus baseline) at any time post baseline.  This analysis will be conducted for the 
PAS-HC by means of the same model used for the primary analysis.   
Sensitivity analyses detailed in Section 4.2.3 will be conducted also for the symptomatic 
transmission by Day 5 endpoint. 
Subgroup analyses detailed in Section 4.6.5 will be conducted for the symptomatic 
transmission by Day 5 endpoint. 
A supportive analysis will be conducted by repeating this model on the FASi-HC. 
4.3.1.2 
Virological Transmission at the HH Level by Day 5 (Primary 
Endpoint for the Primary Estimand at HH Level) 
This analysis is part of the confirmatory strategy and evaluates the treatment effect on 
the rates of transmission by Day 5 at the household level.  If one HHC in the household 
meets the primary endpoint for the primary estimand, then the household is counted as 
having met the endpoint.  The analysis will be conducted by means of a CMH approach 
on the PAS-HH.  
If appropriate, the analysis will be repeated as sensitivity for the FASi-HH.  Additional 
sensitivity (not confirmatory) analyses will be conducted on PAS-HH and may also be 
provided for FASi-HH by using a generalized linear model (GLM) similar to the model 
used for the primary analysis.  Sample SAS code can be found below (SAS code is 
regarded as “draft” until fully validated at the analysis stage): 
   proc genmod data= PAS_HH; 
      class region nbhhc agecat dursymp influenza trt; 
      model influenza = trt region nbhhc agecat dursymp /  
      dist=bin link=logit type3; 
      lsmeans trt / ilink exp diff cl; 
   run; 
 
The model for the analysis conducted on the FASi-HH will include a covariate term 
indicating whether at least one of the HHC was PCR positive at screening. 


 
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4.3.1.3 
Symptomatic Transmission at HH Level by Day 5 (Primary 
Endpoint and Symptom for the Primary Estimand at HH Level) 
The analysis defined in Section 4.3.1.2 will be performed as part of the confirmatory 
strategy on the symptomatic transmission endpoint (see endpoint defined in 
Section 4.3.1.1) for the Primary Estimand, at the household level for the PAS-HH. 
A supportive (not confirmatory) analysis will be conducted by repeating this analysis on 
the FASi‑HH. 
4.3.1.4 
Virological Transmission by Day 9 
This analysis is part of the confirmatory strategy and evaluates the treatment effect on 
the rate of influenza transmission by Day 9 visit, including 1 day of tolerance (see 
DAP-M2).  It will be conducted on an endpoint which extends the primary endpoint to 
include all occurrences of possible tertiary (within household) transmission (i.e., 
transmission from an influenza infected HHC to a further HHC) and all cases of 
transmission of virus with reduced susceptibility (i.e., influenza bearing a PA/I38X or 
T20K (influenza B only) substitution).  This composite endpoint (see Table 1) will be 
analyzed by means of the same model used in the primary analysis for the PAS HC, and 
summarized by time of transmission and subtype match with IP.  
A supportive (not-confirmatory) analysis will be conducted by repeating this model on the 
FASi‑HC. 
4.3.1.5 
Symptomatic Transmission by Day 9  
This analysis is part of the confirmatory strategy and evaluates the treatment effect on 
the rate of symptomatic influenza transmissions by Day 9 visit, including 1 day of 
tolerance (see DAP-M2).  The endpoint restricts the definition in Section 4.3.1.4 to 
symptomatic cases by considering only transmission of influenza with specific new signs 
or symptoms (or worsened versus baseline) at any time post baseline (see Table 1).  
This analysis will be conducted for the PAS-HC by means of the same model used for 
the primary analysis. 
A supportive (not-confirmatory) analysis will be conducted by repeating this model on the 
FASi‑HC. 
4.3.1.6 
Any Virological Infection by Day 9 
This analysis is part of the confirmatory strategy and evaluates the treatment effect on 
the rate of all influenza infections by Day 9 visit (endpoint is positive following any 
positive influenza test between baseline and Day 10).  This endpoint will be analyzed by 
means of the same model used in the primary analysis for the PAS-HC, and 
summarized by time of transmission and subtype match with IP for PAS-HC. 
A supportive (not-confirmatory) analysis will be conducted by repeating this model on the 
FASi‑HC. 


 
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4.3.1.7 
Any Virological Infection at the HH Level by Day 9 
This analysis is part of the confirmatory strategy and evaluates the treatment effect on 
the rate of all influenza transmissions by Day 9 visit.  It will be conducted on the endpoint 
in Section 4.3.1.6 at the household level.  This endpoint will be analyzed using the same 
confirmatory analysis method used in Section 4.3.1.2 for the PAS-HH. 
4.3.1.8 
Any Symptomatic Infection by Day 9 
This analysis is part of the confirmatory strategy and evaluates the treatment effect on 
the rate of all symptomatic influenza transmissions by Day 9 visit at the HHC level.  It will 
be conducted on an endpoint which restricts the endpoint in Section 4.3.1.6 to only 
transmissions of influenza with specific new signs or symptoms, (or worsened versus 
baseline) which may depend on HHC age (see Table 1).  This analysis will be conducted 
for the PAS-HC by means of the same model used for the primary analysis. 
A supportive (not-confirmatory) analysis will be conducted by repeating this model on the 
FASi‑HC. 
4.3.1.9 
Any Symptomatic Infection at the HH Level by Day 9 
This analysis is part of the confirmatory strategy and evaluates the treatment effect on 
the rate of all symptomatic influenza transmissions by Day 9 visit.  It will be conducted 
on the endpoint in Section 4.3.1.8 at the household level.  This endpoint will be analyzed 
by means of the same model used in Section 4.3.1.2 for the PAS-HH. 
4.3.2 
Supportive Secondary Endpoints 
 
4.3.2.1 
Health Status Utility Endpoints 
4.3.2.1.1 
EQ-5D-5L Questionnaire  
EQ-5D-5L is the questionnaire used to measure Quality of Life of IPs age 12 and above 
at Baseline, Day 3 and Day 9 visits (see Van Hout et al. 2012).  The EQ-5D-5L consists 
of a descriptive system of 5 items (i.e., mobility, self-care, usual activity, pain/discomfort 
and anxiety/depression) and an EQ Visual Analogue Scale (VAS; vertical graduated 
scale [0-100], with 100 at the top representing “best imaginable health state” and 0 at the 
bottom representing “worst imaginable health state”).  It will be used in this study for 
informing pharmacoeconomic evaluations.  Analyses will be documented separately in a 
pharmacoeconomic report 
4.3.2.1.2 
Work Productivity and Activity Impairment Questionnaire  
Work Productivity and Activity Impairment Questionnaire plus Classroom Impairment 
Questions: SHP, Version 2 (WPAI    CIQ: SHP, V2) is the questionnaire used to assess 
working status and the impact of influenza on absenteeism, presentism, and the ability to 
perform regular activities.  It will be used in this study for informing pharmacoeconomic 
evaluations.  Analyses will be documented separately in a pharmacoeconomic report.  


 
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4.3.2.2 
Palatability and Acceptability of Baloxavir 
IPs who are  12 years’ old who have received the oral suspension will be asked to 
answer a questionnaire regarding the palatability and acceptability of the study drug.  IPs 
responses will be summarized for the FAS-IP. 
4.4 
EXPLORATORY ENDPOINTS ANALYSIS 
Not Applicable. 
4.5 
SAFETY ANALYSES 
Safety data collected from IPs will be analyzed in the Safety IP Population.  Selected 
safety analyses will be repeated in the Adult, Adolescent and Pediatric Safety set.  
Safety data collected from included HHCs will be analyzed in the Safety HHC 
Population. 
4.5.1 
Extent of Exposure 
Actual dose and dose intensity (% of planned dose administered) will be summarized 
with descriptive statistics for Safety IP set.  
4.5.2 
Adverse Events 
Verbatim description of adverse events (AEs) will be mapped to Medical Dictionary for 
Regulatory Activities (MedDRA) thesaurus terms and graded according to the National 
Cancer Institute Common Terminology Criteria for Adverse Events Version 5.0 (NCI 
CTCAE v5.0).  
Adverse Events for index patients 
For IPs, all AEs with an observed or imputed date of onset on or after the start date of 
trial treatment will be considered as treatment-emergent.  If the onset date of the AE is 
prior to the day of single dose, the AE will be considered treatment-emergent if its end 
date is on or after the date of administration of investigational medicinal product (IMP) 
and worsened in NCI CTCAE grading (initial grade  most extreme grade, or most 
extreme intensity is not missing and initial intensity is missing).  An AE with a completely 
missing start date will be assumed to be treatment-emergent unless the AE has a 
complete non-imputed end date that is prior to study visit Day 0.  
All AEs will be provided in listings, but only treatment-emergent AEs will be summarized.  
Additional listings will be provided for all AEs associated with COVID-19, and for the 
subset of those leading to study discontinuation.  
An AE summary table will be provided which presents by treatment arm the number and 
percentage of patients in Safety IP set reporting at least one event within the following 
categories: 
 
All AEs 


 
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 
Serious AEs 
 
AEs suspected to be caused by study medication 
 
AEs by most extreme NCI CTCAE grade 
 
AEs of special interest, defined as AEs reported as of special interest in the eCRF 
 
AEs of COVID-19  
 
AEs leading to study discontinuation 
 
This table will be repeated in the Pediatric, Adolescent, and Adult Safety sets.  This table 
will also be repeated using the Safety IP set, but excluding data from Study sites with 
health authority identified GCP violations (US site 320035 and Japanese sites 325126 
and 323607), further details of the violations are given in Section 4.2.3. 
AEs and SAEs will also be summarized by date of first onset according to the following 
categories: Day 0 after IMP, Day 1-3, Day 4-5, Day 6-9, After Day 9. 
Summaries of AEs will be tabulated by MedDRA term, appropriate MedDRA levels (by 
system organ class [SOC] and preferred term [PT]), and when specified by 
NCI CTCAE grade.  At each level of summarization (at least one event, SOC and PT), 
patients reporting more than one AE will be counted only once.  For each patient, if 
multiple incidences of the same adverse events occur, the maximum severity reported 
will be used in the summaries.  In particular, summaries will be presented by SOC and 
PT for IPs who presented at least one event for the following: 
 
All AEs 
 
Serious AEs 
 
AEs resulting in death 
 
AE suspected to be caused by study medication 
 
AE by most extreme NCI CTCAE grade 
 
AE of special interest  
 
AE leading to study discontinuation 
 
AE associated with COVID-19 leading to study discontinuation  
 
AEs (non-serious only) occurring in  5% of patients in at least one treatment group 
 
AEs occurring in  5% of patients in at least one treatment group 
 
AEs occurring in  1% of patients in at least one treatment group 
 
AE by outcome 
 
AE by body weight  80 kg and  80 kg 
 
AE by race  
 
AE by region 
 
Overdose 


 
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The following AE tables will be presented for the Adult, Adolescent and Pediatric Safety 
sets by SOC and PT: 
 
AE 
 
Serious AEs 
 
AEs resulting in death 
 
AE suspected to be caused by study medication 
 
AE leading to study discontinuation 
 
AE by most extreme NCI CTCAE grade 
 
AE of special interest  
 
AE occurring in n  1% of patients in at least one treatment group. 
 
Adverse Events for Household Contacts 
Only study procedure related AEs will be collected for HHCs.  A summary of all AEs will 
be provided for the household contacts. 
4.5.3 
Additional Safety Assessments 
Vital Signs 
Vital signs be assessed at screening in IPs only and will be summarized as described in 
Section 4.6.2. 
4.6 
OTHER ANALYSES 
4.6.1 
Summaries of Conduct of Study 
The number of IPs and HHCs who enroll, discontinue, or complete the study will be 
summarized by treatment arm and overall in FAS-IP and FAS-HC sets.  Reason for 
screening failure will be summarized for the SCR-IP and SCR-HHC. 
Reasons for premature study withdrawal will be listed and summarized by treatment arm 
and overall for both IPs and HHCs. 
Major protocol deviations will be listed and summarized by treatment arm and overall to 
be evaluated for their potential effects on the interpretation of study results (see 
Section 3.3). 
Major Protocol Deviations Related to COVID-19 will be listed and summarized by 
treatment arm and overall for both IPs and HHCs to evaluate the impact of the 
COVID-19 pandemic on study conduct.  
Listings of influenza and COVID-19 tests will be provided. 
The number and percentage of IPs and household contacts at each visit will be 
provided. 
 


 
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4.6.2 
Summaries of Treatment Group Comparability 
Demographic and baseline characteristics of IPs (including, but not limited to, age, sex, 
region, race, ethnicity, number of household contacts, duration of symptoms) will be 
summarized overall and by treatment arm in PAS-IP and may also be presented in the 
FAS-IP and Safety Populations.  Medical history will be summarized in FAS-IP.  
Descriptive summaries of baseline vital signs will be provided by treatment arm for the 
PAS-IP set and will comprise measurement of temperature, blood pressure and heart 
rate.  Demographics and baseline characteristics will be produced also for the Pediatric, 
Adolescent, and Adult Safety sets. 
Demographic and baseline characteristics of HHCs (including age of the HHC, sex of the 
HHC, number of household contacts of the respective IP, duration of symptoms of the 
respective IP) will be summarized overall and by treatment arm in the PAS-HC (see 
Section 3.3) and may also be presented in the FASi-HC.  Medical history will be 
summarized in FAS-HC. 
Prior and Concomitant medication 
All medications (e.g., prescription drugs, over-the-counter drugs, vaccines, herbal or 
homeopathic remedies, nutritional supplements) used by the IPs and HHCs will be 
recorded.  
Prior and concomitant medications will be summarized by treatment group for the 
FAS-IP and FAS-HC and show the number (%) of subjects who used the medication at 
least once by Anatomic Therapeutic Chemical (ATC; level 2) and preferred term (PT) 
classification system using the WHO Drug Dictionary.  
4.6.3 
Virological Analyses 
Effect of IP baseline viral titer: the rate of direct transmission of either influenza A or B to 
HHCs in relation to viral titer for the IPs at Baseline will be analyzed on the primary 
endpoint by including terms for the logarithm of IP baseline virus load in the main 
analysis model (see Section 4.2).  Only the amount of virus titer of the transmitted virus 
matching with IP will be used for analysis, summing the viral titers of all transmitted 
viruses in case of co-infection in both IP and HHC subjects.  The analysis will be 
conducted by subgroups defined on quartiles of the distribution of IP baseline virus titer 
across the overall PAS-HC.  Point and 95% interval estimates of rates of transmission by 
treatment arm and the treatment effects will be presented.  The analysis will also be 
conducted by including the interaction between baseline virus load and treatment arm in 
the model and results will also present the p-value for interaction term.  The analysis will 
be performed for the PAS-HC, with baseline viral titer assessed using vp/mL values from 
viral RNA PCR.  The analysis will be repeated for the baseline viral titer measured using 
50% tissue culture infectious dose (TCID50) values.  The effect of IP symptoms at 
Baseline will be explored in supportive models.  


 
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Similar analyses will be performed using symptomatic transmission as the target 
variable.  
Proportion of HHCs with virus subtype consistent with IP (both treatment arms): the 
number (%) of HHCs with laboratory assessed PCR   influenza and virus subtype 
consistent with IP in at least one post-baseline time point, will be tabulated by treatment 
arm and baseline IP influenza type/subtype for the PAS-HC.  
Measurement of virus in IPs:  
 
Change from Baseline in influenza virus titer (TCID50) and in amount of virus RNA 
(RT‑PCR) at each timepoint:   
Viral titer assessments of IPs will be summarized in the logarithmic scale together with 
the change from baseline, by treatment arm at all time-points (Day 0, 3, 5, and 9 visits) 
for the PAS‑IP for virology assessments expressed in vp/mL (amount of virus RNA) and 
TCID50/mL.  If a patient is infected with multiple virus types, the sum of those amounts of 
virus RNA will be used for analysis (sum performed in the original scale and result 
transformed in the logarithmic scale).  Change from baseline will be presented in graphs 
and analyzed by means of analysis of covariance (ANCOVA) model adjusted for 
baseline titer and stratification factors.  All analyses will be performed in the logarithmic 
scale. 
Data below the limit of quantification (BLOQ) will be included in the analysis with the 
imputed value equal to the [log10 LLOQ] – 0.001, where the LLOQ is the lower limit of 
quantification reported in the laboratory record in vp/mL or TCID50/mL.  
For RT-PCR (i.e., values in vp/mL), in case of influenza co-infection: 
 
If only one titer is BLOQ, then the overall titer is equal to the non BLOQ titer 
 
If both are BLOQ with limit of quantification LLOQ1 and LLOQ2, the imputed value 
will be log10(10^([log10 LLOQ1] – 0.001)  10^([log10 LLOQ2] – 0.001)).  
 
Virology data expressed in Ct unit will be provided only in listings. 
 
 
Proportion of IPs with positive influenza virus titer according to TCID50 assessment 
at each timepoint. 
Proportion of IPs positive for influenza virus titer using TCID50/mL assessments will be 
presented by treatment arm at Baseline and Days 3,5 and 9 visits, and is defined as the 
percentage of patients whose influenza virus titer is above the limit of quantification.  
Titer values BLOQ (“  0.75”) will be considered as negative value titer.  This analysis will 
use the CMH test stratified by the stratification factors and performed on PAS-IP, with no 
imputed data. 


 
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 
Proportion of IPs with positive influenza virus titer according to RT-PCR assessment 
at each timepoint. 
Proportion of IPs positive as per qualitative result (positive/negative) by RT-PCR central 
lab assessment (or local test results if central laboratory results are missing, see 
Section 4.1.1) will be presented by treatment arm over time.  This analysis will use the 
CMH test stratified by the stratification factors and performed on PAS-IP, with no 
imputed data. 
Measurement of influenza virus in HHCs:  
 
Amount of virus RNA (RT-PCR) at first time point a HHCs is positive by RT-PCR 
central lab assessment. 
 
Amount of virus RNA will be summarized overall, and by IP age group (  12,   12) and 
by influenza virus type, in the logarithmic scale by treatment arm in HHCs positive for 
primary endpoint (see Section 4.2.1) for PAS-HC.  Difference between treatment arms 
will be evaluated by means of the Van Elteren test, stratified by IP age group and 
influenza virus type/subtype.  The analysis will also be presented in HHCs positive for 
symptomatic transmission by Day 5 endpoint (see Section 4.3.1.1) for PAS-HC.  
Example SAS code is provided below (to be validated): 
proc npar1way data=PASHC; 
    strata age_virus_type; 
    class trt; 
    var log_titer; 
run; 
 
 
Exploration of infectivity and of symptoms in relation to viral titers in HHCs 
The association of viral titers and the development of symptoms (as per symptomatic 
endpoint definition or for other combinations the individual symptoms) will be explored by 
means of logistic regression or similar techniques in HHCs who become PCR positive 
post-baseline.  
In an attempt to understand if BXM can reduce transmission beyond its effect on the 
secondary transmission, the statistical transmission model developed in IPs (see above: 
Effect of IP baseline viral titer) will be evaluated for its applicability to infected HHCs.  
This evaluation will consider factors such as viral titers or types and timing of symptoms 
in IPs (used to develop the model) vs HHCs.  If the transmission model can be applied to 
HHCs, the probability of transmitting the virus once infected that will be derived from the 
model will be compared for the two treatment arms. 
4.6.4 
Baloxavir Resistance Analysis  
Polymorphic and treatment-emergent amino acid substitutions in PA will be analysed by 
Sanger sequencing for all BXM treated IPs and associated HHCs.  In addition, 
sequencing of PB1 and PB2 may be performed in IPs or HHCs if a PA/I38X, PA/T20K 
(influenza B only) or United States Package Insert (USPI) defined resistance associated 


 
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substitution (RAS) (see DAP M2 Section 3.2.1.7) is identified in PA of the IP and the 
associated HHC. 
PA data will be listed for all HHCs living in households with at least one contact and/or IP 
with RAS.  If additional sequencing in PB1/PB2 is performed, a listing is produced in 
households with at least one contact and/or IP with any mutation in PB1/PB2, and 
reported in a CSR addendum.  
All USPI defined RAS, including I38X and T20K, will be listed by time point in RES-IP.  
Additional listings by time points will be produced for: 
 
IPs in RES-IP with USPI defined RAS and/or any additional treatment emergent 
mutations 
 
IPs in RES-IP with USPI defined RAS and having only post-baseline PA 
assessments 
 
HHCs in FASi-HC with USPI defined RAS  
 
Proportion of IPs with influenza bearing I38X / T20K and USPI defined RAS 
substitutions (BXM arm only) 
 
The number (%) of IPs in the BXM arm with baseline and/or treatment-emergent 
I38X substitutions or a T20K substitution (influenza B only) (see DAP M2 Section 
3.2.1.7) will be tabulated for the RES-IP, including only IPs having paired 
sequencing, i.e., having both baseline and at least one post‑baseline sequencing 
result.  I38X and T20K summaries will also be presented by age group (  12,   12 
years old) for the RES-IP, having paired sequencing.  
 
The analysis will be repeated for the number (%) of IPs in the BXM arm with 
baseline and / or treatment emergent USPI defined RAS substitutions for the 
RES-IP (see DAP M2 Section 3.2.1.7)  
 
Summaries will be provided for any additional PA substitution identified only in 
post‑baseline time points (treatment-emergent) for the RES-IP having paired 
sequencing. 
 
The I38X/T20K and USPI defined RAS substitutions tables will be repeated to 
summarize the proportion of IPs with at least one transmission with matching I38X/T20K 
/USPI defined RAS in the household. 
Proportion of HHCs with influenza bearing I38X / T20K and USPI defined RAS 
substitutions (BXM arm only) 
The following analysis will be conducted in the FASi-HC population limited to those 
HHCs whose IPs were exposed to BXM: 
 
The number (%) of HHCs with an I38X, or T20K (influenza B only) substitution will 
be presented for all HHCs in the BXM arm and for HHCs in the BXM arm who tested 
positive for influenza with at least one PA sequence.  
Summaries will be also provided for HHCs in the BXM arm meeting the virological 


 
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and symptomatic transmission by Day 9 endpoint (see Section 4.3.1.4) with at least 
one PA sequence.  
The HHC number (%) will be tabulated by HHCs having an IP in BXM arm and by 
HHCs having an IP with matching I38X or T20K substitution.  
 
The number (%) of HHCs with a USPI defined RAS substitution will be presented for 
all HHCs in the BXM arm, HHCs in the BXM arm who tested positive for influenza 
with at least one PA sequence.  
The HHC number (%) will be tabulated by HHCs having an IP in BXM arm and by 
HHCs having an IP with matching USPI defined RAS substitution.  
 
Summaries will also be provided in the FASi-HH. 
Phenotypic Analysis in IPs (BXM arm only)  
Selected samples from BXM-treated IPs who experience a rebound in viral titers and/or 
show novel treatment‑emergent amino acid substitutions (different from the USPI 
defined RAS) in PA identified by sequencing analysis will be assayed for phenotypic 
reduced susceptibility.  
As assessment of the drug susceptibility of the influenza virus, the 50% effective 
concentration (EC50) of BXM will be measured by the ViroSpot™ assay using baseline 
and selected post‑baseline swab samples.  EC50 values from post-baseline samples will 
be compared with baseline values from the same patient, and all EC50 values will be 
compared with values of reference strains.  Respective ratios (EC50 post-baseline / EC50 
baseline, and EC50 / EC50 reference) will be reported. 
The detailed definition of viral rebound and the reference influenza virus strains will be 
documented in the DAP-M2 Section 3.2.1.8 and study CSR.  Mean EC50 value of the 
two B reference strain EC50 values will be used to calculate EC50 ratio. 
Using EC50 reference as denominator for the EC50 ratio, a summary of drug susceptibility 
will be provided for FAS-IP, including only IPs with study drug exposure, randomized to 
BXM, and with at least one post-baseline EC50 result.  All EC50 data will be provided in 
listing for FAS‑IP, indicating if a rebound was observed for the IP.  
The phenotypic analysis will be documented in a CSR addendum. 
4.6.5 
Analyses of Subgroups of Interest 
Subgroup analysis for the primary/secondary endpoints will be conducted in patients 
based on accurate matching of IPs to HHCs influenza virus to assess if the set of viral 
sequences within a household are more similar to each other than to sequences in the 
community (or between households) (see Protocol Section 3.4.6.5).  The analysis will be 
based on whole genome sequencing on influenza A and B virus positive clinical 
specimens and can be accomplished either phylogenetically (in locations with a 
sufficient number of sequences) or using a measurement of genetic distance between 


 
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paired populations.  Full details will be described in a separate analysis plan and 
reported separately. 
Other subgroups of interest are defined by:  
 
The stratification factors used for randomization (as per main analysis approach). 
 
IP age group (Pediatric [Age  12], Non-Pediatric [Age  12])  
 
Influenza type in IPs (A/H1N1 versus A/H3N2 versus B – coinfections in IPs will be 
assessed as a separate category) 
 
Influenza season (2019/2020 vs later seasons grouped according to enrollment)  
 
The analysis will be performed on the primary and the first secondary endpoints for the 
primary estimand using the main analysis model for PAS-HC (see Section 4.2).  
Subgroup analyses will be primarily descriptive and treatment effect will be presented in 
forest plots.  Exploratory treatment by subgroup interaction tests (or treatment by 
continuous covariate interaction, if applicable) will be evaluated to investigate the 
heterogeneity of the treatment effects and results will be included in the study report.  
Only subgroups with at least 10 positive and 10 negative cases will be considered.  If the 
limited sample size available within a subgroup prevents model convergence, the 
smallest subgroup will be excluded (if at least two will remain) and this issue will be 
reported in the study report.  
4.7 
INTERIM ANALYSES 
Unblinded safety analyses will be performed regularly by an external statistical group (an 
independent data coordinating center) and reviewed by iDMC.  In the context of these 
safety reviews, efficacy data will only be provided if requested by the iDMC.  Further 
details on the function and logistics (e.g., frequency of the meetings) of the iDMC will be 
provided in the iDMC Charter.  Note that an interim analysis was conducted on 
July 27, 2023 by the iDMC using the methodology and process described in 
Section 4.7.1 below and in the iDMC charter.  The outcome is described in Section 4.7.2 
below. 
4.7.1 
Planned Interim Analysis  
An interim analysis of efficacy data will be performed at the end of the 2022/2023 
Northern hemisphere influenza season, when recruitment rates are likely to be very low.  
The aim of this interim analysis is to review, in addition to safety data, the primary (see 
4.2) and the first secondary endpoint (see 4.3.1.1) in order to stop the study in case of 
sufficient evidence of efficacy or for futility for a study with a large uncertainty regarding 
the true effect size.  The analysis will include IPs randomized up to 07 May 2023 and 
their HHCs.  Recruitment will continue while the analysis is being conducted.  In case of 
a decision to stop the double blind phase as a result of the interim analysis, the study will 
be unblinded, otherwise other efficacy interim analyses may be performed at later stages 
of the study based on the same methodology. 


 
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The efficacy analysis with an early stop option will follow a group-sequential design.  A 
Lan-DeMets alpha-spending function with O’Brien-Fleming boundaries will be used to 
define the null-hypothesis rejection region for the primary and the first secondary 
endpoint.  Tests at the interim analysis will be one-sided (alternative hypothesis for the 
interim analysis: OR  1 for the comparison of BXM vs. placebo).. (Note that the test at 
the final analysis will be two-sided and the overall two-sided significance level for the 
study will be controlled at 5%.) 
The iDMC will review interim analysis results and provide a recommendation concerning 
the continuation of the study.  A recommendation to stop the study for efficacy with 
rejection of the null-hypothesis should be considered if the rejection boundaries are 
crossed for both the primary and the first secondary endpoint (based on their respective 
primary estimand).  The hierarchical testing procedure will ensure control of the overall 
type I error rate at the pre-defined level (Hung et al. 2007; Glimm et al. 2010).  
The boundaries for the interim and the final analysis will be derived based on the size of 
the primary analysis population (PAS-HC) at the time of the analysis using the R 
package rpact (Wassmer and Pahlke 2019).   
If 65% of the planned HHC sample is available for the IA, it is projected that an observed 
OR of 0.52 or lower at this analysis will result in a statistically significant difference 
(based on the specific boundary p-value) between treatment arms in the PAS-HC 
population (i.e., an OR of 0.52 will be the MDD for the analysis; this approximately 
corresponds to a relative risk reduction 44% in the BXM arm compared to placebo).  
For the calculations, we used an effective total sample size of 1698 HHCs, using a 
design effect of 1.196, resulting from a mean number of HHCs per household of 2.20 
and an intra-household correlation of 0.163: The effective final sample size was 
calculated as 2030 / design effect, with the design effect being defined as 1  ((HH size – 
1)*intra-household correlation) (Hemming et al. 2011). 
Table 7 illustrates the p-value boundary for early stopping based on the projected 
number of evaluable HHCs at the time of the interim analysis, considering, however, that 
the analysis will be conducted even if the sample size will deviate from this projected 
number. 
Table 7 
Projected Interim and Final Analyses Characteristics 
Analysis 
No. of 
evaluable 
HHCs 
% of the 
planned final 
sample size 
Projected 
Cutoff Date a 
Projected 
MDD b 
Projected Boundary  
(one-sided p-value) c 
Interim 
1320 
65% 
May 2023 
0.52 
p  0.0054 
Final 
2030 
100% 
Apr 2024 
0.74 
p  0.0233 


 
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HHC  house hold contact, MDD  minimally detectable difference. 
a Study month at which the last IP and the associated HHCs included in the interim / final 
analysis are enrolled.  Analysis results will be available after data cleaning. 
b The largest observed odds ratio that is projected to be statistically significant.  For the interim 
analysis the first secondary endpoint determines the MDD.  For the final analysis, the primary 
endpoint. 
c The projected one-sided boundary for statistical significance for the number of evaluable 
HHCs (actual boundary to be calculated at time of analysis based on actual number of 
HHCs).  The boundary for the final analysis assumes that no additional interim analysis is 
conducted.  Note that the two-sided equivalent will be used for the final analysis (2 x 
one-sided boundary), since the tests at the final analysis will be two-sided.  
  
The assessment of futility will be based on the outcome of the analysis of the primary 
endpoint as described in Section 4.2.1 as well as the secondary endpoint: continuation 
of the study will be considered futile for virological efficacy  15% and symptomatic 
efficacy   30% at the interim analysis.  This futility stopping rule is non-binding and the 
iDMC may recommend continuation of the trial accounting for all information at their 
disposal.  
The futility cutoffs for the virological endpoint were computed based on simulations using 
study parameters obtained from a blinded data look performed in May 2023.  
Simulations evaluated the probability of a binary endpoint (a set of Bernoulli trials per 
arms assuming 1:1 randomization in 2 arms with a success probability in the two arms 
reflecting the true efficacy) to meet the futility criterion at the IA and statistical 
significance at study end using Fisher’s exact test.  
Based on simulations of 100,000 trials per condition, the chance of stopping for futility if 
the true efficacy is 0%, 10% and 20% is 82%, 63% and 36%, respectively.  For 30% true 
efficacy, the chance of stopping studies that would achieve a significant effect at study 
end would be ~3%. 
4.7.2 
Changes to Protocol-planned Analyses  
The list of PA substitutions considered relevant for the definition of "Virological 
transmission by Day 9" and related endpoints, including those listed in Protocol Section 
2.1.3.1, will be limited to I38X or T20K (influenza B only).  Other substitutions listed in 
Protocol Section 3.4.6.4 will be included in additional analyses presenting the incidence 
of USPI defined RAS in IPs and in HHCs from the BXM arm.  
PA/I38 mutations demonstrate  10-fold change in the EC50 of baloxavir for the 
recombinant virus harboring the amino acid substitution to that of the wild-type strain for 
type A virus and a  5‑fold change for type B virus.  The other listed mutations display 
smaller EC50 changes. 
An efficacy interim analysis (Section 4.7.1), with a methodology compatible with the 
optional interim analysis described in Protocol Section 6.9.2 was conducted at the end of 
the 2022/2023 season. 


 
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Interim Outcome-The interim was conducted by the iDMC as described in Section 4.7.1 
above and in the iDMC charter on 27 July 2023.  The recommendation from the iDMC 
was not to stop for efficacy nor futility and to continue the trial as planned.  The 
significance level at the final analysis will be derived using the methodology described in 
Section 4.7.1, which accounts for the alpha spend at the interim analysis.  
5. 
SUPPORTING DOCUMENTATION 
5.1 
SYMPTOMS ASSESSED IN THE FULL STUDY HOUSEHOLD 
CONTACTS 
Starting at Day 0, full study household contacts (HHCs; or the responsible adult of the 
children  12 years of age) will be instructed in the symptoms of early influenza.  
Qualifying symptoms for household contacts are shown below: 
Symptoms assessed in household contacts aged  12 years of age 
Symptoms assessed in household contacts aged  12 years of age 
Qualifying respiratory symptoms 
Cough 
Sore throat 
Nasal congestion 
Qualifying general systemic symptoms 
Headache 
Feverishness or chills 
Muscle or joint pain 
Fatigue 
Symptoms assessed in household contacts aged  2 to  12 years of age 
Qualifying upper respiratory tract infection 
symptoms 
Cough 
Nasal congestion or rhinorrhea 
  
 
 


 
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Assessment of influenza symptoms for full study HHC  12 years old 
DAY 0 prior to enrollment 
HCP asks HHC 
► 
about symptom 
(x) ▼  
Have you 
had (x) in 
the last 
7 days? 
Is your (x) mild 
or is it worse 
than mild? 
What is causing your (x)?  
(record the cause or write “not 
known”) 
Action 
Cough 
Y or N 
Mild or Worse 
Cause: 
Do NOT 
enroll if any 
symptom is 
(1) worse 
than mild or 
(2) cause is 
not known 
or likely 
infection. 
Sore throat 
Y or N 
Mild or Worse 
Cause:  
Nasal congestion 
Y or N 
Mild or Worse 
Cause:  
Headache 
Y or N 
Mild or Worse 
Cause:  
Feverishness or 
chills 
Y or N 
Mild or Worse 
Cause:  
Muscle or joint 
pain 
Y or N 
Mild or Worse 
Cause:  
Fatigue 
Y or N 
Mild or Worse 
Cause:  
Record Day 0 temperature. 
__ __ . __°C 
Do NOT 
enroll 
if  38.0 °C 
Site: 
HCP obtains swab 
Is local influenza A/B, or local SARS-CoV-2 positive? Y or N 
Do NOT 
enroll if Y 
 
 
 




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Assessment of influenza symptoms for full study HHC ages  2 to  12 years old 
DAY 0 prior to enrollment 
HCP asks adult ► 
about symptom (x) 
▼  
Has your 
child had (x) 
in the last 7 
days? 
Is (x) mild 
or is it 
worse than 
mild? 
What is causing (x)?  
(record the cause or write 
“not known”) 
Decision 
Cough 
Y or N 
Mild or 
Worse 
Cause: 
Do NOT enroll 
if any symptom 
is (1) worse 
than mild or 
(2) cause is 
not known or 
likely 
infection. 
Nasal congestion or 
rhinorrhea (stuffy or 
runny nose) 
Y or N 
Mild or 
Worse 
Cause: 
Record Day 0 temperature. 
__ __ . 
__°C 
Do NOT enroll 
if ≥38.0 °C 
Site: 
HCP obtains swab 
Is local influenza A/B, or local SARS-CoV-2 positive? Y or 
N 
Do NOT enroll 
if Y 
  
DAYS 5, 9, AND UNSCHEDULED for full study HHC ages  2 to  12 years old 
HCP asks adult ► 
about symptom (x) ▼  
For symptoms present at 
baseline: is your child’s (x) 
worse since your child 
enrolled? 
For symptoms not present at 
baseline: does your child have (x)? 
Cough 
Y or N 
Y or N 
Nasal congestion or 
rhinorrhea (stuffy or runny 
nose) 
Y or N 
Y or N 
Review HHC temperature log.  Obtain child’s temperature if 
not yet done.* Record highest temperature here ► 
__ __ . 
__°C  
Date: 
Site: 
Time: 
HCP 
obtains 
swab 
Is local 
influenza A/B 
positive? 
Y or N ** 
If Y, refer HHC to investigator for standard of care (including anti-
viral medicine).  No more samples for this HHC needed.  Continue 
to monitor for symptoms at subsequent visit if symptoms endpoint 
not yet met. 
If N, continue sampling at next visit.  However, investigator may 
initiate standard of care if suspicion for influenza is high due to 
symptoms. 
* Temperature obtained from tympanic thermometers provided to households (or exceptionally 
from other thermometers/locations in case of tympanic thermometer failure for any reason).  
** Test SARS-CoV-2 via local test if HHC develops symptoms or fever versus baseline.  
If positive, withdraw all study subjects in household from the study. 
 
 
 


 
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5.2 
EQ-5D-5L TO MEASURE QUALITY OF LIFE 
Under each heading, please check the ONE box that best describes your health TODAY. 
MOBILITY 
 
I have no problems walking 
❑ 
I have slight problems walking 
❑ 
I have moderate problems walking 
❑ 
I have severe problems walking 
❑ 
I am unable to walk 
❑ 
SELF-CARE 
 
I have no problems washing or dressing myself 
❑ 
I have slight problems washing or dressing myself 
❑ 
I have moderate problems washing or dressing myself 
❑ 
I have severe problems washing or dressing myself 
❑ 
I am unable to wash or dress myself 
❑ 
 
 
 


 
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USUAL ACTIVITIES (e.g., work, study, housework, family or leisure activities) 
 
I have no problems doing my usual activities 
❑ 
I have slight problems doing my usual activities 
❑ 
I have moderate problems doing my usual activities 
❑ 
I have severe problems doing my usual activities 
❑ 
I am unable to do my usual activities 
❑ 
PAIN / DISCOMFORT 
 
I have no pain or discomfort 
❑ 
I have slight pain or discomfort 
❑ 
I have moderate pain or discomfort 
❑ 
I have severe pain or discomfort 
❑ 
I have extreme pain or discomfort 
❑ 
ANXIETY / DEPRESSION 
 
I am not anxious or depressed 
❑ 
I am slightly anxious or depressed 
❑ 
I am moderately anxious or depressed 
❑ 
I am severely anxious or depressed 
❑ 
I am extremely anxious or depressed 
❑ 
 
USA (English)© 2009 EuroQol Group EQ-5D™ is a trade mark of the EuroQol Group 
 
 




 
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5.3 
WORK PRODUCTIVITY AND ACTIVITY IMPAIRMENT 
QUESTIONNAIRE PLUS CLASSROOM IMPAIRMENT 
QUESTIONS: SHP, VERSION 2 (WPAI  CIQ:SHP, V2) 
The following questions ask about the effect of your influenza/flu on your ability to work, 
attend classes, and perform regular daily activities.  Please fill in the blanks or circle a 
number, as indicated. 
1. 
Are you currently employed (working for pay)? 
 
____NO ___YES (If NO, check “NO” and skip to question 6.) 
The next questions are about the past seven days, not including today. 
 
2. 
During the past seven days, how many hours did you miss from work because of 
problems associated with your influenza/flu?  Include hours you missed on sick 
days, times you went in late, left early, etc. because of influenza/flu.  Do not include 
time you missed to participate in this study. 
______HOURS 
 
3. 
During the past seven days, how many hours did you miss from work because of 
any other reason, such as vacation, holidays, time off to participate in this study? 
______HOURS 
 
4. During the past seven days, how many hours did you actually work? 
______HOURS (If “0”, skip to question 6) 
 
5. 
During the past seven days, how much did influenza/flu affect your productivity while 
you were working?  
 
Think about days you were limited in the amount or kind of work you could do, days you 
accomplished less than you would like, or days you could not do your work as carefully 
as usual.  If influenza/flu affected your work only a little, choose a low number.  Choose 
a high number if influenza/flu affected your work a great deal. 
 
Consider only how much influenza/flu affected productivity while you were working. 
Influenza/flu had 
no effect 
on my work 
 
 
 
 
 
 
 
 
 
 
 
Influenza/flu 
completely 
prevented me 
 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
from working 
 
Circle a number 
 
 


 
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6. 
Do you currently attend classes in an academic setting (middle school, high school, 
college, graduate school, additional course work, etc.)?   
___NO ___YES (If NO, check “NO” and skip to question 10.) 
 
7. 
During the past seven days, how many hours did you miss from class or school 
because of problems associated with your influenza/flu?  Do not include time you 
missed to participate in this study. 
_____ HOURS 
 
8. 
During the past seven days, how many hours did you actually attend class or 
school? 
_____ HOURS (If “0”, skip to question 10.) 
 
9. 
During the past seven days, how much did your influenza/flu affect your productivity 
while in school or attending classes in an academic setting?  
Think about days your attention span was limited, you had trouble with comprehension 
or days in which you could not take tests as effectively as usual.  If influenza/flu affected 
your productivity at school or in class only a little, choose a low number.  Choose a high 
number if influenza/flu affected your productivity at school or in class a great deal. 
Consider only how much influenza/flu affected productivity while in school or attending 
classes. 
 
Influenza/flu had no 
effect on my class 
work 
 
 
 
 
 
 
 
 
 
 
 
Influenza/flu 
completely 
prevented me from 
doing my  
 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
 class work 
Circle a number 
 
10. During the past seven days, how much did influenza/flu affect your ability to do your 
regular daily activities, other than work at a job or attending classes?  
By regular activities, we mean the usual activities you do, such as work around the 
house, shopping, child care, exercising, studying, etc.  Think about times you were 
limited in the amount or kind of activities you could do and times you accomplished less 
than you would like.  If influenza/flu affected your activities only a little, choose a low 
number.  Choose a high number if influenza/flu affected your activities a great deal. 
 
 


 
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Consider only how much influenza/flu affected your ability to do your regular daily 
activities, other than work at a job or attending classes. 
Influenza/flu had no 
effect on my daily 
 
 
 
 
 
 
 
 
 
 
 
Influenza/flu 
completely 
prevented me 
Activities 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
from doing my daily 
activities 
Circle a number 
 
Adapted from: Reilly et al. 1996. 
  
5.4 
PALATABILITY AND ACCEPTABILITY QUESTIONNAIRE OF 
STUDY DRUG (INDEX PATIENTS AGED 5 YEARS OLD TO  12 
YEARS OLD) 
Instructions: Please answer the following questions to help us understand your 
experience with the study medicine.  For the question with a face, indicate which of the 
faces best matches how you felt about the medicine. 
For children who cannot read yet, parents or caregiver, please help us understand 
your child’s experience with the study medicine.  Invite your child to look at the cartoon, 
ask him or her the questions, and record his or her answer.  
If your child cannot answer the question, please skip the question.  The questions below 
are to be answered as soon as possible after swallowing the medicine. 
1. 
How was the taste of the medicine? 
 
 
 
 
□ 
□ 
□ 
□ 
□ 
Like very much 
Like a little 
Not sure 
Dislike a little 
Dislike very 
much 
  
2. 
Would you be happy to take the medicine again? 
□ Yes 
□ No 
□ Not sure/no answer 
 
 


 
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5.5 
LOCAL LABORATORY SAMPLE TESTING FOR INFLUENZA AT 
THE CENTRAL LABORATORY 
There are 3 scenarios where the local laboratory samples will be tested for influenza at 
the central laboratory, including rationale for the testing: 
 
Scenario 1. Where a central laboratory sample result is missing for any reason, 
applicable to any index patient and household contact. 
A sample collected for the central laboratory testing has not arrived and is classed as 
missing or is determined by the central laboratory vendor to not be appropriate for 
testing, such as due to sample handling issues.  The local laboratory sample would be 
tested at the central laboratory in an attempt to avoid missing data.  This would be 
applicable to IP and HHC samples. 
For Index patient Day 0 (screening): In the rare circumstance where the local and central 
sample cannot be tested at the central laboratory (i.e., both judged to be contaminated 
by the central laboratory or both missing) and the local test at conducted at screening 
was a rapid influenza diagnostic tests (RIDT), the index patient post baseline sample at 
or before Day 3 will be evaluated to determine whether the screening sample is 
influenza positive or negative and the virus type/subtype if available.   This decision is 
supported by (a) the timing of the index patient symptom onset and (b) the known time to 
cessation of viral shedding by RT-PCR for otherwise healthy patients treated with 
baloxavir marboxil and placebo from CAPSTONE-1 (median [95% CI]: 216hrs [216, 240 
hrs] vs. 240hrs [240, 336 hrs] respectively). 
Scenario 2. Where the index patient screening local laboratory sample result is 
influenza positive, but the central laboratory sample result is influenza negative. 
 
The development of rapid molecular point-of-care diagnostics provide a fast and 
accurate diagnosis to help inform the clinical management of patients.  The cobas Liat is 
the preferred system for local analysis of respiratory samples and will be provided to 
sites.  When the preferred system is not available, other point of care tests for influenza 
tests such as RIDTs or other molecular/PCR based assays may be used for local 
laboratory sample testing for influenza in CENTERSTONE.  
Local laboratory samples that are positive for influenza, provides evidence that an index 
patient has an influenza infection.  However, when a separate sample collected for PCR 
testing at the central laboratory returns a negative influenza result, the index patient is 
determined to not have an influenza infection, even though there is evidence of infection 
for local laboratory testing.  
Mismatches between a positive local sample result and negative central laboratory 
sample result may lead to an index patient (and household) not being eligible for the 
study, impacting the primary analysis sample size and statistical power.  Therefore, in 
this scenario, testing the local laboratory sample at the central laboratory is warranted. 
 


 
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Scenario 3. Where the household contact post-baseline local laboratory sample 
result is influenza positive, but the central laboratory sample result is influenza 
negative. 
Rationale regarding point-of-care diagnostics and mismatched influenza results between 
local laboratory and central laboratory samples is provided in scenario 2, which is 
broadly applicable to household contacts. 
In the scenario that a household contacts post-baseline time-point has a positive local 
laboratory sample result and negative central laboratory sample result, a household 
contact will not meet efficacy endpoints, even though there is evidence that the local 
sample met the primary endpoint. 
Algorithms for determining the sample result for analysis in scenario 2 and 3 are 
described in below Table 8: 
  
Table 8 
Outcomes Following Local Sample Testing at Central Laboratory 
for Scenario 2 and 3. 
Sample 
collected 
Local sample test 
result by Liat or 
other PCR 
Central sample test 
result at Central lab 
Local sample test 
result at Central 
lab 
Sample result 
for analysis 
IP – 
Screening 
Positive 
Negative 
Negative 
NEGATIVE 
IP – 
Screening 
Positive 
Negative 
Positive 
POSITIVE 
HHC - post 
baseline 
Positive 
Negative 
Negative 
NEGATIVE 
HHC - post 
baseline 
Positive 
Negative 
Positive 
POSITIVE 
HHC  household contact; IP  index patient; PCR  polymerase chain reaction. 
 
The identification of local samples for testing at the central laboratory will be made by 
the Sponsor.  
Note in all scenarios, retesting of identified local samples will be performed if a local 
sample was received by the central laboratory and the received sample was compatible 
with the validated central laboratory assays i.e., local sample was received in the study 
provided universal transport media tubes and of sufficient volume for analysis. 
The local laboratory sample testing at the central laboratory and the transfer of results 
will occur prior to interim analyses or database lock.  For a database lock, all scenarios 
will be completed and results data transferred to the Sponsor prior to treatment 
assignment information unblinding.  The process has been reviewed and approved by 
the CENTERSTONE Steering Committee. 
 


 
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6. 
REFERENCES 
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rapid PCR-based detection of influenza compared to Prodesse ProFlu+ and viral 
culture. Eur J Microbiol Immunol (Bp). 2015;5(4):236-245. 
Glimm E, Maurer W, and Bretz F. Hierarchical testing of multiple endpoints in group‑
sequential trials. 2010; 29(2):219-228. 
Hemming K, Girling AJ, Sitch AJ, et al. Sample size calculations for cluster randomised 
controlled trials with a fixed number of clusters. BMC medical research 
methodology. 2011;11(1):1-1. 
Hung HMJ, Wang SJ, Robert O'Neill R. Statistical Considerations for Testing Multiple 
Endpoints in Group Sequential or Adaptive Clinical Trials, Journal of 
Biopharmaceutical Statistics, 2007; 17:6, 1201-1210, DOI: 
10.1080/10543400701645405. 
Ma J, Raina J, Beyene J, Thabane L. Comparison of population-averaged and cluster-
specific models for the analysis of cluster randomized trials with missing binary 
outcomes: a simulation study. BMC Medical Research Methodology. 2013;9(13). 
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Panel on Handling Missing Data in Clinical Trials, National Research Council. 2010. The 
Prevention and Treatment of Missing Data in Clinical Trials. 2010; ISBN 978-0-
309-15814-5. Available at: https://www.nap.edu/initiative/panel-on-handling-
missing-data-in-clinical-trials. 
Reilly MC, Tanner A, Meltzer EO. Work, classroom and activity impairment instruments: 
validation studies in allergic rhinitis. Clinical drug investigation. 1996;11:278-288.  
Van Hout B, Janssen MF, Feng YS, et al. Interim scoring for the EQ-5D-5L: Mapping the 
EQ-5D-5L to EQ-5D-3L value sets. Value Health 2012;15:708-715. 
Wassmer G, Pahlke F. Rpact: Confirmatory adaptive clinical trial design and analysis. R 
package version 3.0.3. 2020. Available at: https://CRAN.R-
project.org/package=rpact 
Welliver R, Monto AS, Carewicz O, et al. Effectiveness of oseltamivir in preventing 
influenza in household contacts: a randomized controlled trial. JAMA. 
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Yelland LN, Salter AB and Ryan P et al. Performance of the Modified Poisson 
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Zou G. A modified poisson regression approach to prospective studies with binary data. 
Am J Epidemiol. 2004 Apr 1;159(7):702-6. doi: 10.1093/aje/kwh090. PMID: 
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