Clinical trial NCT03684044
Conditions: Influenza
Sponsor: Hoffmann-La Roche
Start date: 2019-01-08; Completion date: 2020-03-16
Enrollment: 363 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study will evaluate the efficacy, safety, and pharmacokinetics of baloxavir marboxil 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 patients with influenza.

Detailed description:

Arms: arm 1: Participants will receive at least two doses of baloxavir marboxil on Days 1 and 4. A third dose of Baloxavir will be given on Day 7 for participants who have not improved according to protocol defined criteria on Day 5.

Study treatment will be given in combination with SOC NAI (i.e., oseltamivir, zanamivir, or peramivir) in accordance with local clinical practice. arm 2: Participants will receive at least two doses of placebo on Day 1 and 4. A third dose of placebo will be given on Day 7 for participants who have not improved according to protocol defined criteria on Day 5.

Study treatment will be given in combination with SOC NAI (i.e., oseltamivir, zanamivir, or peramivir) in accordance with local clinical practice.
Interventions: intervention 1: Baloxavir Marboxil intervention 2: Placebo
Intervention descriptions: intervention 1: Baloxavir marboxil will be administered as a weight-based dose on Days 1 and 4. A third dose will be given on Day 7 for participants who have not improved according to protocol defined criteria on Day 5. intervention 2: Participants will receive matching placebo on Days 1, 4 and 7.

Protocol documents:
Prot_000.pdf: 
 
Official Title: 
A Phase III, Randomized, Double-Blind Placebo-Controlled, 
Multicenter Study To Evaluate the Efficacy and Safety of Baloxavir 
Marboxil in Combination With Standard-of-Care Neuraminidase 
Inhibitor in Hospitalized Participants With Severe Influenza 
NCT Number: 
NCT03684044 
Document Date: 
Protocol Version 2: 30-May-2019 
 
 


FINAL PROTOCOL APPROVAL
CONFIDENTIAL
This clinical study is being sponsored globally by F. Hoffmann-La Roche Ltd of Basel, 
Switzerland. However, it may be implemented in individual countries by Roche’s local affiliates, 
including Genentech, Inc. in the United States.  The information contained in this document, especially 
any unpublished data, is the property of F. Hoffmann-La Roche Ltd (or under its control) and therefore 
is provided to you in confidence as an investigator, potential investigator, or consultant, for review by 
you, your staff, and an applicable Ethics Committee or Institutional Review Board.  It is understood that 
this information will not be disclosed to others without written authorization from Roche except to the 
extent necessary to obtain informed consent from persons to whom the drug may be administered.
Baloxavir Marboxil—F. Hoffmann-La Roche Ltd
Protocol CP40617, Version 2
PROTOCOL
TITLE:
A PHASE III, RANDOMIZED, DOUBLE-BLIND 
PLACEBO-CONTROLLED, MULTICENTER STUDY 
TO EVALUATE THE EFFICACY AND SAFETY OF 
BALOXAVIR MARBOXIL IN COMBINATION WITH
STANDARD-OF-CARE NEURAMINIDASE INHIBITOR 
IN HOSPITALIZED PATIENTS WITH SEVERE 
INFLUENZA
PROTOCOL NUMBER:
CP40617
VERSION NUMBER:
2
EUDRACT NUMBER:
2018-001416-30
IND NUMBER:
126653
TEST PRODUCT:
Baloxavir marboxil (RO7191686)
MEDICAL MONITOR:
 M.D.
SPONSOR:
F. Hoffmann-La Roche Ltd
DATE FINAL:
Version 1: 17 July 2018
DATES AMENDED:
Version 1 (VHP only): 27 November 2018
Version 2:  See electronic date stamp below.
 
30-May-2019 16:10:33
Title
Approver's Name
Company Signatory
Date and Time (UTC)


Baloxavir Marboxil—F. Hoffmann-La Roche Ltd
2/Protocol CP40617, Version 2
PROTOCOL AMENDMENT, VERSION 2:
RATIONALE 
In addition to updates initiated in this Version 2, this amendment contains updates made 
in a Version 1 (VHP only) amendment approved on 27 November 2018 (applicable to 
countries under Voluntary Harmonization Procedure [VHP] only). Protocol Version 2
supersedes Protocol Version 1 and Version 1 VHP.
Changes to the protocol are summarized below:

The study sample size was change from approximately 240 to approximately 366
hospitalized adults and adolescent patients throughout the protocol.  This change 
was based upon a blinded review of the time to clinical improvement (TTCI) data 
from patients recruited during the northern hemisphere 2018/2019 flu season and the 
incorporation of a planned futility interim analysis (see Section 6).

The optional interim analysis was changed to a formal, pre-planned, unblinded, 
non-binding futility analysis.  It will be conducted after approximately 65% of TTCI 
events and will be based on the TTCI and the Lan-DeMets Pocock beta spending 
function (Section 6.7.1).

The endpoint “time to clinical response” was moved from an exploratory endpoint to 
an additional key secondary endpoint at the request of the FDA (Section 2).

The palatability and acceptability endpoint was added to address a request from the 
European Medicines Agency (EMA) Pediatric Committee (PDCO) to assess the 
acceptability of the baloxavir marboxil granules for oral suspension formulation
(Section 2, Section 4.5.15, Section 6.4.5, and Appendix 5).

The number of sites to enroll patients was updated from approximately 215 global 
sites to 250 sites to allow for the increase in sample size (Section 3.1).

Known hypersensitivity to baloxavir marboxil or the drug product excipients was 
added as an exclusion criterion (Section 4.1.2).

A section was added to summarize post-marketing safety data that identified 
hypersensitivity reactions (i.e., anaphylaxis/anaphylactic reactions, angioedema, and 
urticaria) as adverse drug reactions during post-marketing use of baloxavir marboxil 
(Section 1.2.4).  In the event of a anaphylaxis or other form of hypersensitivity 
reaction, advice that patients should be withdrawn from study treatment was included 
(Section 4.6.1).
Other additions and clarifications:

Summary information was added for intravenous zanamivir (Dectova), which 
recently received a positive opinion for use under exceptional circumstances from 
the EMA for the treatment of complicated and potentially life-threatening influenza A 
or B virus infection in adult and pediatric patients (Section 1.1).

A section was added to summarize results from a Phase III, double-blind, 
randomized, placebo- and active-controlled study investigating baloxavir marboxil in 
patients at high risk of developing influenza-related complications (Section 1.2.3). 


Baloxavir Marboxil—F. Hoffmann-La Roche Ltd
3/Protocol CP40617, Version 2

The timing of the vital signs and assessments for National Early Warning Score 2 
(NEWS2) was clarified, as indicated in the clarification letters sent to sites, to ensure 
all vital sign parameters and NEWS2 assessments are collected together and that 
assessment timepoints are spread throughout the study day to reflect the patient’s 
condition over the entire study day, where possible (Sections 4.5.4; Appendix 5 
footnotes).  

The vitals sign data to be utilized during screening to calculate the NEWS2 score 
was clarified, as indicated in the clarification letters sent to sites, to ensure that all 
data collected closest to but before randomization should be used for the NEWS2 
score calculation and assessment of patient eligibility (Section 4.5.6 and Appendix 3).

Clarification was added that the modified intent-to-treat infected (mITTI) population 
would be used in efficacy analyses. Clarification was also added that full details of 
analysis methods will be contained within the Statistical Analysis Plan (Section 6.4).

The following minor revisions were made for clarification or for consistency across 
sections/Schedule of Activities:
–
Study Treatment Preparation (Section 4.3.1.1):  Text was aligned with 
Pharmacy Manual following protocol clarification letter. 
–
Cautionary Therapy (Section 4.4.2):  Dairy products and calcium-fortified 
beverages was added to the list of cautionary therapies. The word “oral” was 
added to laxatives and antacids for clarity. In addition, the phrase “where 
possible” was also added to match wording for this section (i.e., cautionary, not 
prohibited).
–
Pharmacokinetic Analyses (Section 6.6):  The text was updated to describe how 
patients with 2 or 3 study treatment doses will be analyzed separately.  It was 
also stated that population PK model outcomes would be reported in a separate 
report.
–
Schedule of Activities: The End of Study (EOS) column was moved so it is 
included under the Follow-Up Period heading for clarity. 
–
Schedule of Activities: The timing of Visit 8 was clarified in a footnote to ensure 
that Visit 8 did not occur on the same day as Visit 7.
–
Other minor clarifications and corrections were made throughout the protocol for 
clarify, consistency, or to align text with clarification letters. These are indicated 
by italicized text.
Updates in line with Xofluza® (baloxavir marboxil) approvals and documentation: Core 
Data Sheets (CDS), Investigator’s Brochure, Drug Safety Update Report (DSUR).

Rationale for patient population (Section 3.3.2): Text was updated to align with
approvals as well as current and potentially future Clinical Development Plan (CDP).

Safety plan update (Section 5.1):  Text was updated to align with the Sponsor’s
documentation and approvals.


Baloxavir Marboxil—F. Hoffmann-La Roche Ltd
4/Protocol CP40617, Version 2
The following updates were made to bring the protocol into alignment with recent 
updates to the company’s protocol model document:

Text has been modified to account for the fact that special situations (i.e., accidental 
overdoses and medication errors) are not required to be reported within 24 hours 
(Sections 5.3.5.11 and 5.4).  Note that serious adverse events associated with 
special situations are still required to be reported within 24 hours.

Language has been updated to indicate that therapeutic or elective abortions are not 
considered adverse events unless performed because of an underlying maternal or 
embryofetal toxicity.  In such cases, the underlying toxicity should be reported as a 
serious adverse event.  Language has also been added to clarify that all abortions 
are to be reported on the paper Clinical Trial Pregnancy Reporting Form 
(Section 5.4.3.3).

Language has been added for consistency with Roche's current data retention policy 
and to accommodate more stringent local requirements (if applicable) (Section 7.5).

Language has been added to indicate that the study will comply with applicable local, 
regional, and national laws (Section 8.1).

Language has been revised to clarify that data posting will not be limited to clinical
trial registries and to clarify that redacted Clinical Study Reports are provided only if 
requirements of Roche's global policy on data sharing have been met (Section 9.5).
The following updates were made in the Version 1 (VHP only) amendment per VHP 
request, except where noted, and are being carried forward into this Version 2 
amendment:

Known hypersensitivity to baloxavir marboxil or the drug product excipients has been 
added as an exclusion criterion (Section 4.1.2).

The Medical Monitor has changed and updated contact information has been 
provided (Section 5.4.1).

Language regarding written informed consent for adolescents unable to legally 
provide consent was revised to accommodate situations where a local regulatory or 
Independent Review Board/Ethics Committee policy requires written informed 
consent from both parents (Section 4.5.1).  Section 8.2 has been amended 
accordingly.

The type of pregnancy test at screening has been changed from a urine pregnancy 
test to a serum pregnancy test (Section 4.5.7 and Appendix 1).  In this Version 2 
amendment, the requirement at screening was clarified as follows:  serum pregnancy 
tests for VHP sites and serum or urine pregnancy tests for sites in the rest of the 
world.

In order to correct an error in Version 1, text was added stating that patients who 
discontinue study treatment should continue in the study and complete all scheduled 
study assessments/visits per protocol, where possible (Section 4.6.1).

In order to correct an error in Version 1, text was updated to clarify that patients who 
discontinue from the study will be asked to complete a study discontinuation visit, at 


Baloxavir Marboxil—F. Hoffmann-La Roche Ltd
5/Protocol CP40617, Version 2
which time the assessments per the end of study visit should be conducted 
(Section 4.6.2). 

Text was added to clarify the censoring of patients who discontinue for any reason 
prior to achieving a clinical response event.  Text has been added stating that a 
sensitivity analysis for subjects who discontinue for any reason prior to achieving a 
clinical response event will be performed to investigate potential confounding factors 
and detailed in the SAP along with any further sensitivity analyses (Section 6.4.1).
The Schedule of Activities was updated to reflect updates made in the body of the text 
and to correct minor typographical errors.  
Substantive new information from both amendments (i.e., Version 2 and Version 1 [VHP 
only]) appears in italics.  This amendment represents cumulative changes to the original 
protocol.  


Baloxavir Marboxil—F. Hoffmann-La Roche Ltd
6/Protocol CP40617, Version 2
TABLE OF CONTENTS
PROTOCOL AMENDMENT ACCEPTANCE FORM .......................................... 12
PROTOCOL SYNOPSIS .................................................................................... 13
1.
BACKGROUND .......................................................................................... 22
1.1
Background on Influenza....................................................... 22
1.2
Background on Baloxavir Marboxil ........................................ 23
1.2.1
Phase II Proof-of-Concept and Dose-Finding 
Study (Study 1518T0821)...................................................... 24
1.2.2
Phase III Double-Blind Study in Otherwise 
Healthy Patients 
(Study 1601T0831, CAPSTONE 1)....................................... 24
1.2.3
Phase III Double-Blind Study in Patients at 
High Risk of Developing Influenza-Related 
Complications (Study 1602 T0832, 
CAPSTONE II) ..................................................................... 25
1.2.4
Post-Marketing Safety Data .................................................. 27
1.3
Study Rationale and Benefit–Risk Assessment..................... 27
2.
OBJECTIVES AND ENDPOINTS ............................................................... 27
3.
STUDY DESIGN......................................................................................... 30
3.1
Description of the Study......................................................... 30
3.2
End of Study and Length of Study......................................... 31
3.3
Rationale for Study Design.................................................... 31
3.3.1
Rationale for Baloxavir Marboxil Dose and 
Schedule................................................................................ 31
3.3.2
Rationale for Patient Population ............................................ 32
3.3.3
Rationale for Control Group................................................... 33
3.3.4
Rationale for Endpoints ......................................................... 33
4.
MATERIALS AND METHODS .................................................................... 35
4.1
Patients.................................................................................. 35
4.1.1
Inclusion Criteria.................................................................... 35
4.1.2
Exclusion Criteria................................................................... 36
4.2
Method of Treatment Assignment and Blinding..................... 37


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7/Protocol CP40617, Version 2
4.3
Study Treatment and Other Treatments Relevant 
to the Study Design ............................................................... 38
4.3.1
Study Treatment and NAI Formulation, 
Packaging, and Handling....................................................... 38
4.3.1.1
Baloxavir Marboxil and Matching Placebo 
(Study Treatment).................................................................. 38
4.3.1.2
Standard-of-Care Neuraminidase Inhibitor ............................ 39
4.3.2
Study Treatment and SOC NAI Dosage, 
Administration, and Compliance............................................ 39
4.3.2.1
Baloxavir Marboxil and Matching Placebo (Study 
treatment) .............................................................................. 39
4.3.2.2
Standard-of-Care Neuraminidase Inhibitor ............................ 39
4.3.3
Investigational Medicinal Product Accountability ................... 40
4.3.4
Continued Access to Baloxavir Marboxil................................ 41
4.4
Concomitant Therapy and Additional Restrictions................. 41
4.4.1
Permitted Therapy................................................................. 41
4.4.2
Cautionary Therapy ............................................................... 41
4.4.3
Prohibited Therapy ................................................................ 41
4.5
Study Assessments ............................................................... 41
4.5.1
Informed Consent Forms and Screening Log........................ 42
4.5.2
Medical History, Concomitant Medication, and 
Demographic Data................................................................. 43
4.5.3
Physical Examinations........................................................... 43
4.5.4
Vital Signs.............................................................................. 43
4.5.5
Assessments Specific to National Early Warning 
Score 2 .................................................................................. 44
4.5.6
National Early Warning Score 2............................................. 44
4.5.7
Laboratory and Other Biological Samples ............................. 44
4.5.8
Liver Function Monitoring ...................................................... 45
4.5.9
Electrocardiograms................................................................ 46
4.5.10
Chest X-Rays/CT scan .......................................................... 46
4.5.11
Rapid Influenza Diagnostic Test............................................ 46
4.5.12
Nasopharyngeal Samples...................................................... 47
4.5.13
Endotracheal Aspirates.......................................................... 47
4.5.14
Meals..................................................................................... 47


Baloxavir Marboxil—F. Hoffmann-La Roche Ltd
8/Protocol CP40617, Version 2
4.5.15
Palatability and Acceptability Assessment............................ 47
4.5.16
Ordinal Scale Determination.................................................. 48
4.6
Treatment, Patient, Study, and Site 
Discontinuation...................................................................... 48
4.6.1
Study Treatment Discontinuation........................................... 48
4.6.2
Patient Discontinuation from Study........................................ 49
4.6.3
Study Discontinuation............................................................ 49
4.6.4
Site Discontinuation............................................................... 49
5.
ASSESSMENT OF SAFETY....................................................................... 50
5.1
Safety Plan ............................................................................ 50
5.1.1
Management of Patients Who Experience 
Adverse Events ..................................................................... 50
5.1.1.1
Dose Modifications ................................................................ 50
5.1.1.2
Treatment Interruption ........................................................... 50
5.2
Safety Parameters and Definitions ........................................ 50
5.2.1
Adverse Events ..................................................................... 51
5.2.2
Serious Adverse Events (Immediately Reportable 
to the Sponsor)...................................................................... 51
5.2.3
Adverse Events of Special Interest (Immediately 
Reportable to the Sponsor).................................................... 52
5.3
Methods and Timing for Capturing and 
Assessing Safety Parameters................................................ 52
5.3.1
Adverse Event Reporting Period ........................................... 52
5.3.2
Eliciting Adverse Event Information....................................... 53
5.3.3
Assessment of Severity of Adverse Events ........................... 53
5.3.4
Assessment of Causality of Adverse Events ......................... 54
5.3.5
Procedures for Recording Adverse Events............................ 55
5.3.5.1
Diagnosis versus Signs and Symptoms................................. 55
5.3.5.2
Adverse Events That Are Secondary to Other 
Events.................................................................................... 55
5.3.5.3
Persistent or Recurrent Adverse Events................................ 56
5.3.5.4
Abnormal Laboratory Values ................................................. 56
5.3.5.5
Abnormal Vital Sign Values ................................................... 57
5.3.5.6
Abnormal Liver Function Tests.............................................. 57


Baloxavir Marboxil—F. Hoffmann-La Roche Ltd
9/Protocol CP40617, Version 2
5.3.5.7
Deaths ................................................................................... 58
5.3.5.8
Preexisting Medical Conditions.............................................. 58
5.3.5.9
Lack of Efficacy or Worsening of Influenza............................ 58
5.3.5.10
Hospitalization or Prolonged Hospitalization.......................... 59
5.3.5.11
Reporting Requirements for Cases of Accidental 
Overdose or Medication Error................................................ 59
5.4
Immediate Reporting Requirements from 
Investigator to Sponsor.......................................................... 60
5.4.1
Emergency Medical Contacts................................................ 61
5.4.2
Reporting Requirements for Serious Adverse 
Events and Adverse Events of Special Interest..................... 61
5.4.2.1
Events That Occur prior to Study Drug Initiation.................... 61
5.4.2.2
Events That Occur after Study Drug Initiation........................ 61
5.4.3
Reporting Requirements for Pregnancies.............................. 62
5.4.3.1
Pregnancies in Female Patients............................................ 62
5.4.3.2
Pregnancies in Female Partners of Male Patients................. 62
5.4.3.3
Abortions ............................................................................... 63
5.4.3.4
Congenital Anomalies/Birth Defects ...................................... 63
5.5
Follow-Up of Patients after Adverse Events .......................... 63
5.5.1
Investigator Follow-Up........................................................... 63
5.5.2
Sponsor Follow-Up ................................................................ 64
5.6
Adverse Events That Occur after the Adverse 
Event Reporting Period.......................................................... 64
5.7
Expedited Reporting to Health Authorities, 
Investigators, Institutional Review Boards, and 
Ethics Committees................................................................. 64
6.
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN....................... 65
6.1
Determination of Sample Size ............................................... 65
6.1.1
Blinded Sample Size Re-Assessment ..................................... 66
6.2
Summaries of Conduct of Study............................................ 66
6.3
Summaries of Demographic and Baseline 
Characteristics....................................................................... 66
6.4
Efficacy Analyses .................................................................. 66
6.4.1
Primary Efficacy Endpoint...................................................... 67
6.4.2
Key Secondary Endpoints...................................................... 68


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10/Protocol CP40617, Version 2
6.4.2.1
6-Point Ordinal Scale Measured at Day 7 ............................ 68
6.4.2.2
Time to Clinical Response ..................................................... 69
6.4.3
Secondary Efficacy Endpoints............................................... 70
6.4.4
Virology Endpoints................................................................. 71
6.4.5
Exploratory Palatability and Acceptability 
Endpoint................................................................................ 72
6.5
Safety Analyses..................................................................... 72
6.6
Pharmacokinetic Analyses..................................................... 73
6.7
Interim Analysis ..................................................................... 74
6.7.1
Planned Interim Analysis ....................................................... 74
6.8
China Subpopulation Analyses.............................................. 74
7.
DATA COLLECTION AND MANAGEMENT ............................................... 74
7.1
Data Quality Assurance......................................................... 74
7.2
Electronic Case Report Forms............................................... 75
7.3
Source Data Documentation.................................................. 75
7.4
Use of Computerized Systems .............................................. 76
7.5
Retention of Records............................................................. 76
8.
ETHICAL CONSIDERATIONS.................................................................... 76
8.1
Compliance with Laws and Regulations ................................ 76
8.2
Informed Consent.................................................................. 77
8.3
Institutional Review Board or Ethics Committee.................... 78
8.4
Confidentiality........................................................................ 78
8.5
Financial Disclosure .............................................................. 79
9.
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION ..................................................................................... 79
9.1
Study Documentation ............................................................ 79
9.2
Protocol Deviations................................................................ 79
9.3
Site Inspections ..................................................................... 79
9.4
Administrative Structure......................................................... 80
9.5
Publication of Data and Protection of Trade 
Secrets .................................................................................. 80
9.6
Protocol Amendments ........................................................... 81
10. REFERENCES ........................................................................................... 82


Baloxavir Marboxil—F. Hoffmann-La Roche Ltd
11/Protocol CP40617, Version 2
LIST OF TABLES
Table 1
Objectives and Corresponding Endpoints................................... 28
Table 2
Guidance for Dose and Dosing Regimen for Neuraminidase 
Inhibitors ..................................................................................... 40
Table 3
Adverse Event Severity Grading Scale for Events Not 
Specifically Listed in NCI CTCAE ............................................... 54
LIST OF FIGURES
Figure 1
Study Schema............................................................................. 31
LIST OF APPENDICES
Appendix 1
Schedule of Activities................................................................. 83
Appendix 2
Schedule of Pharmacokinetic Samples...................................... 87
Appendix 3
National Early Warning Score 2 (NEWS2)................................. 88
Appendix 4
Management Criteria for Abnormal Liver Function Tests........... 90
Appendix 5
Palatability and Acceptability Assessment of Study Drug ................ 91


Baloxavir Marboxil—F. Hoffmann-La Roche Ltd
12/Protocol CP40617, Version 2
PROTOCOL AMENDMENT ACCEPTANCE FORM
TITLE:
A PHASE III, RANDOMIZED, DOUBLE-BLIND 
PLACEBO-CONTROLLED, MULTICENTER STUDY 
TO EVALUATE THE EFFICACY AND SAFETY OF 
BALOXAVIR MARBOXIL IN COMBINATION WITH 
STANDARD-OF-CARE NEURAMINIDASE INHIBITOR 
IN HOSPITALIZED PATIENTS WITH SEVERE 
INFLUENZA
PROTOCOL NUMBER:
CP40617
VERSION NUMBER:
2
EUDRACT NUMBER:
2018-001416-30
IND NUMBER:
126653
TEST PRODUCT:
Baloxavir marboxil (RO7191686)
MEDICAL MONITOR:
 M.D.
SPONSOR:
F. Hoffmann-La Roche Ltd
I agree to conduct the study in accordance with the current protocol.
Principal Investigator’s Name  (print)
Principal Investigator’s Signature
Date
Please retain the signed original of this form for your study files.  Please return a copy of 
the signed form as instructed by the CRO.


Baloxavir Marboxil—F. Hoffmann-La Roche Ltd
13/Protocol CP40617, Version 2
PROTOCOL SYNOPSIS
TITLE:
A PHASE III, RANDOMIZED, DOUBLE-BLIND 
PLACEBO-CONTROLLED, MULTICENTER STUDY TO EVALUATE 
THE EFFICACY AND SAFETY OF BALOXAVIR MARBOXIL IN 
COMBINATION WITH STANDARD-OF-CARE NEURAMINIDASE 
INHIBITOR IN HOSPITALIZED PATIENTS WITH SEVERE 
INFLUENZA
PROTOCOL NUMBER:
CP40617
VERSION NUMBER:
2
EUDRACT NUMBER:
2018-001416-30
IND NUMBER:
126653
TEST PRODUCT:
Baloxavir marboxil (RO7191686)
PHASE:
III
INDICATION:
Influenza
SPONSOR:
F. Hoffmann-La Roche Ltd
Objectives and Endpoints
This study will evaluate the efficacy, safety, and pharmacokinetics of baloxavir marboxil 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 patients with influenza.  Specific objectives and corresponding endpoints for the 
study are outlined below.
In this protocol, "study treatment" refers to baloxavir marboxil or its matching placebo.  Study 
treatment is given in combination with a SOC NAI.


Baloxavir Marboxil—F. Hoffmann-La Roche Ltd
14/Protocol CP40617, Version 2
Primary Objective
Corresponding Endpoint
To evaluate the clinical efficacy of 
baloxavir marboxil plus a SOC NAI 
compared with matching placebo plus a 
SOC NAI 
TTCI defined as:
Time to hospital discharge OR
Time to NEWS2 of 2 maintained for 24 hours
Efficacy Objectives
Corresponding Endpoints
To evaluate the clinical efficacy of 
baloxavir marboxil plus a SOC NAI 
compared with matching placebo plus a 
SOC NAI 
Key Secondary Endpoints:
Response rates of the 6-point ordinal scale at Day 7
Time to clinical response based on temperature 
ranges, oxygen saturation, respiratory status, heart 
rate, and hospitalization status a
Other Secondary Endpoints:
Incidence of mechanical ventilation
Duration of mechanical ventilation
Incidence of ICU stay 
Duration of ICU stay
Time to clinical failure, defined as the time to death, 
mechanical ventilation, or ICU admission, 
corresponding to ordinal scale categories 6, 5, and 4, 
respectively, from baseline
Time to hospital discharge 
Incidence of post-treatment influenza-related 
complications b
Mortality rate at Day 7 
Mortality rate at Day 28
Time to NEWS2 of 2 maintained for 24 hours
Virology Objectives
Corresponding Endpoints
To evaluate the virological activity of 
baloxavir marboxil plus a SOC NAI 
compared with matching placebo plus a 
SOC NAI 
Time to cessation of viral shedding by virus titer
Time to cessation of viral shedding by RT-PCR
Change from baseline in influenza virus titer and in 
the amount of virus RNA (RT-PCR) at each 
timepoint
Proportion of patients with positive influenza virus 
titer and proportion of patients positive by RT-PCR 
at each timepoint
AUC in virus titer and in the amount of virus RNA 
(RT-PCR)
To evaluate the polymorphic and 
treatment-emergent amino acid 
substitutions in the PA, PB1, PB2, and 
NA genes and drug susceptibility in 
patients with evaluable virus
Polymorphic and treatment-emergent amino acid 
substitutions in the PA, PB1, PB2, and NA genes
Drug susceptibility in patients with evaluable virus


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Safety Objective (cont.)
Corresponding Endpoints (cont.)
To evaluate the safety of baloxavir 
marboxil plus a SOC NAI compared with 
matching placebo plus a SOC NAI in 
hospitalized patients with influenza
Compare the incidence and severity of AEs and 
SAEs
Incidence of AEs leading to discontinuation
Proportion of patients with any post-treatment ALT 
and AST above baseline and 3ULN, 5ULN, 
10ULN
Pharmacokinetic Objective
Corresponding Endpoints
To evaluate the single- and multiple-dose 
pharmacokinetics of baloxavir 
Plasma concentrations of baloxavir (active 
metabolite) at specified timepoints
After each dose, concentration at predose and 
24 hours postdose will be summarized 
Non-compartmental PK parameters such as AUC, 
Cmax and t1/2 (only for patients undergoing sequential 
PK sampling) 
Exploratory Palatability and 
Acceptability Objective
Corresponding Endpoint

To describe the palatability and 
acceptability of the oral suspension 
in hospitalized patients with 
influenza

Number and proportion of patients reporting 
each palatability and acceptability response at 
each timepoint
AE adverse event; AUC area under the concentrationtime curve; Cmaxmaximum plasma concentration; 
COPD chronic obstructive pulmonary disease;  ICU intensive care unit; NAI neuraminidase inhibitor; 
NEWS2 National Early Warning Score 2; PK pharmacokinetic; RT-PCR reverse transcriptase 
polymerase chain reaction; SAE serious adverse event; SOC standard-of-care; TTCI time to clinical 
improvement; t1/2half-life; ULN upper limited normal
a
Criteria for each parameter (i.e., temperature, oxygen saturation, respiratory status, heart rate, 
systolic blood pressure, and hospital discharge) as defined in the protocol.
b
Incidence of post-treatment influenza-related complications as defined as pneumonia, myositis or
rhabdomyolysis, encephalitis or encephalopathy, myocarditis and/or pericarditis, otitis media, sinusitis, 
exacerbation of COPD/asthma, sepsis, acute lung injury, or acute respiratory distress syndrome.
Study Design
Description of Study
This is a Phase III, randomized, double-blind, placebo-controlled, multicenter study to assess 
the efficacy, safety, and pharmacokinetics of baloxavir marboxil in combination with a SOC NAI 
(i.e., oseltamivir, zanamivir, or peramivir), compared with a matching placebo in combination 
with a SOC NAI in approximately 366 hospitalized adults and adolescent patients (aged 
12 years) with influenza.
Patients will be randomized as soon as possible after screening (ideally within 12 hours),
providing they are within 96 hours of symptom onset and hospitalized (includes assessment in 
emergency centers pending admission to a hospital ward).  Patients will be assigned in a 
2:1 ratio to receive baloxavir marboxil or matching placebo.  Study treatment must be given in 
combination with a SOC NAI according to investigator preference (i.e., oseltamivir, zanamivir, or 
peramivir).  Re-screening of patients who fail to meet the inclusion and exclusion criteria will be 
permitted only once, providing the time from symptom onset to randomization is still within 96 
hours.
Baloxavir marboxil will be administered as a 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 also on Day 7 if clinical 
improvement has not occurred at Day 5, per protocol defined criteria.  Treatment with a SOC 
NAI (i.e., oseltamivir, zanamivir, or peramivir) should be administered in accordance with local 
clinical practice.  To fully explore the utility of the combination with baloxavir marboxil, or 


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matching placebo, the dosing regimen of the SOC NAI should aim to ensure that anti-viral 
activity is maintained from Day 1 to Day 5.  The SOC NAI treatment may be extended to Day 10 
or beyond at the discretion of the investigator and in accordance with local clinical practice.  The 
study consists of two periods:  a 10-day treatment period and a 25-day follow-up period.  
Therefore, the maximum study duration for each patient will be 35 days.
The study assessments to be conducted include the following:  physical examination, vital signs, 
assessment of consciousness, presence, or absence of respiratory support, adverse events, 
concomitant therapies, clinical laboratory tests, nasopharyngeal swabs, and the palatability 
and acceptability questionnaire.  
An external independent Data Monitoring Committee (iDMC) will evaluate safety according to 
policies and procedures detailed in an iDMC Charter.
Number of Patients
Approximately 366 hospitalized adults and adolescent patients (aged 12 years) are planned 
for enrollment at approximately 250 global sites in both Northern and Southern hemispheres.
Target Population
Inclusion Criteria
Patients must meet the following criteria for study entry:

Adult patients:  Signed informed consent by any patient capable of giving consent, or, 
where the patient is not capable of giving consent, by his or her legal/authorized 
representative

Adolescent patients not able to legally consent:  written informed consent for study 
participation is obtained from patient’s parents or legal guardian, with assent as 
appropriate by the patient, depending on the patient’s level of understanding and capability 
to provide assent. 

Age 12 years at the time of signing the Informed Consent Form/Assent Form

Ability to comply with the study protocol, in the investigator’s judgment

Patients who require hospitalization for severe influenza or acquire influenza during 
hospitalization, the severity of which requires an extension of hospitalization

Diagnosis of influenza A and/or B by a positive Rapid Influenza Diagnostic Test (RIDT) or 
reverse transcriptase-polymerase chain reaction (RT-PCR) 
Positive results from local tests are acceptable if conducted within the 24 hours prior to 
screening.
A patient with a negative RIDT may be enrolled if influenza is suspected based on local 
surveillance data or if the patient reports contact with a known case of influenza within 
the prior 7 days and all other inclusion criteria are met

The time interval between the onset of symptoms and randomization is within 96 hours
The onset of symptoms is defined as the time when the patient experiences at least 
one new general symptom (e.g., headache, feverishness or chills, muscle or joint pain, 
fatigue), respiratory symptom (e.g., cough, sore throat, nasal congestion), or fever.

A score of 4 based on the National Early Warning Score 2 (NEWS2)

Patients will require objective criteria of seriousness defined by at least one of the following 
criteria: 

Requires ventilation or supplemental oxygen to support respiration

Has a complication related to influenza that requires hospitalization (e.g., pneumonia, 
CNS involvement, myositis, rhabdomyolysis, acute exacerbation of chronic kidney 
disease, asthma or chronic obstructive pulmonary disease [COPD], severe dehydration, 
myocarditis, pericarditis, exacerbation of ischemic heart disease)

For women of childbearing potential:  Agreement to remain abstinent (refrain from 
heterosexual intercourse)
Women must remain abstinent or use contraceptive methods with a failure rate of 1% 
per year during the treatment period and for 28 days after the last dose of study 


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treatment.  Hormonal contraceptive methods must be supplemented by a barrier 
method.
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 has not undergone surgical sterilization 
(removal of ovaries and/or uterus).
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.
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.
Exclusion Criteria
Patients who meet any of the following criteria will be excluded from study entry:

Patients who have received more than 48 hours of antiviral treatment for the current 
influenza infection prior to screening

Patients who have received baloxavir marboxil for the current influenza infection

Known contraindication to neuraminidase inhibitors

Patients hospitalized for exclusively social reasons (e.g., lack of caregivers at home)

Patients expected to die or be discharged within 48 hours, according to the investigator’s 
judgement

Patients weighing 40 kg

Patients with known severe renal impairment (estimated glomerular filtration rate 
30 mL/min/1.73 m2) or receiving continuous renal replacement therapy, hemodialysis, 
peritoneal dialysis

Patients with any of the following laboratory abnormalities detected within 24 hours prior to 
or during screening (according to local laboratory reference ranges: 

ALT or AST level 5 times the upper limit of normal (ULN) 
OR

ALT or AST 3 times the ULN and total bilirubin level 2 times the ULN 

Pregnant or breastfeeding, or positive pregnancy test in a predose examination, or 
intending to become pregnant during the study or within 28 days after the last dose of study 
treatment

Exposure to an investigational drug within 5 half-lives or 30 days (whichever is longer) of 
randomization 

Any serious medical condition or abnormality in clinical laboratory tests that, in the 
investigator’s judgment, precludes the patient’s safe participation in and completion of the 
study

Known hypersensitivity to baloxavir marboxil or the drug product excipients
End of Study
The end of this study is defined as the date when the last patient, last visit (LPLV) occurs or the 
date at which the last data point required for statistical analysis or safety follow-up is received
from the last patient, whichever occurs later.  The LPLV is expected to occur 35 days after the 
last patient is enrolled. 
Length of Study
The total length of the study, from screening of the first patient to the LPLV, is expected to be 
approximately 2.5 years.


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Investigational Medicinal Products
The investigational medicinal products (IMPs) for this study are baloxavir marboxil and its 
matching placebo as the comparator.
Test Product (Investigational Drug)
Baloxavir marboxil or its matching placebo will be administered orally according to body weight 
(40 mg for patients weighing 40 to 80 kg; 80 mg for patients weighing 80 kg), either in tablet 
form or granules for oral suspension for patients unable to swallow or with a nasogastric tube in 
situ (e.g., in intubated patients).  Dosing will occur on Day 1 and Day 4, with a further dose at 
Day 7 for patients who have not improved according to at least 1 of the following specific 
criteria at Day 5: ongoing mechanical ventilation, persistent fever, severely 
immunocompromised, pneumonia, or confirmed/suspected influenza-related complication.
Non-Investigational Medicinal Product
Standard-of-Care Neuraminidase Inhibitor
The protocol-defined SOC NAIs are oseltamivir, zanamivir, or peramivir.
An open-label SOC NAI should be administered according to local clinical practice (i.e., 
oseltamivir, peramivir, or zanamivir) to ensure anti-viral activity is maintained from Day 1 
through Day 5.  The SOC NAI treatment may be extended to Day 10 or beyond at the discretion 
of the investigator and in accordance with local clinical practice.  Special attention is required for 
dosing in patients with renal impairment, as dose adjustment may be needed.
Statistical Methods
Primary Analysis
The primary efficacy objective for this study is to evaluate the efficacy of baloxavir marboxil plus 
a SOC NAI, compared with matching placebo plus SOC NAI on the basis of the following 
endpoint:

Time to clinical improvement (TTCI; defined as time to hospital discharge or time to NEWS2 
of 2 and maintained for 24 hours, whichever comes first)
The median TTCI will be compared between the baloxavir marboxil plus SOC NAI and matching 
placebo plus SOC NAI arms using the stratified log-rank test within three regions (i.e., North 
America; Europe, Middle East, and Africa [EMEA]; rest of world [ROW]), NEWS2 (7, 7), and 
time from symptom onset to study treatment (48 hours, 48 hours) included as the 
stratification factors.  The Kaplan-Meier plot, median time to response, and their 95% CI, and a 
p-value will be presented.
The log-rank test requires the assumption of proportional hazards to be met.  The proportional 
hazards assumption will be tested graphically using the log cumulative hazard plot by treatment 
group.  The plots for each treatment group will be parallel if the proportional hazard assumption 
holds.  Using a Cox model, the slope of a linear regression will also be tested and a plot of 
scaled Schoenfeld residuals against the Kaplan-Meier estimator will be investigated.  Should 
the proportional hazards assumption be violated, the Gehan-Wilcoxon test will be used to 
analyze the data as the logrank test can be under powered in this situation. All investigations 
will be detailed in the statistical section of the CSR.  
The estimand is the median change in TTCI.  This absolute measure will be assessed over the 
duration of the study (35 days).  Intercurrent events are those that occur after treatment 
initiation and either preclude observation of the variable or affect its interpretation.  Intercurrent 
events will be accounted for through censoring rules.  Patients who are lost to follow-up, who do 
not have a clinical response event, who die or discontinue for any reason prior to achieving a 
clinical response event will be censored at their last contact date or date of death, whichever is 
applicable.  No dose reductions or treatment cross-overs are anticipated.  
The primary efficacy analysis population will be characterized through the inclusion/exclusion 
criteria and will be the modified intent-to-treat (influenza-)infected (mITTI) population, which 
consists of all patients who were randomized to treatment, received a dose of study drug, and 
were RT-PCR positive for influenza (centrally assessed) at any timepoint.
A sensitivity analysis will be conducted where patients who are lost to follow-up or who do not 
have a clinical response event will be assumed to have had an event at 28 days.  A sensitivity


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analysis for patients who discontinue for any reason prior to achieving a clinical response 
event will be performed to investigate potential confounding factors. A sensitivity analysis, 
considering death as a competitive event, using a competing risk model will be conducted if 
there are a sufficient number of deaths or an imbalance between groups in deaths and reason 
attributed.  These and any further sensitivity analyses will be fully detailed in the SAP. 
Missing data handling rules for the components of the NEWS2 score will be specified in the 
SAP.
Determination of Sample Size
Two new factors influenced the revised sample size:  1) the revised assumption for the placebo 
plus NAI control-arm TTCI following blinded data review and 2) the faster than anticipated 
enrollment rate.  Integration of these two factors informed a sample size readjustment to 
approximately 366 randomized patients.  Assuming that the RT-PCRpositive rate (tested in 
a central laboratory) will be 75% of the randomized population and a dropout rate of 4% the 
mITTI population will be 264 patients (i.e., 176 patients in the baloxavir marboxil group and 
88 in the placebo group).  
The total number of randomized patients may change based on the percentage of patients who 
are RT-PCR positive during the study.
The total mITTI sample size of 264 patients provides at least 80% power using the Logrank 
Chi-Square test to detect a 31-hour difference in TTCI between treatment groups under the 
following assumptions:  median TTCI in the placebo plus NAI group is 94 hours, 840 hours 
follow-up (35 days) using 5% alpha. The minimal detectable difference is expected to be 
around 23 hours.  The alteration of the TTCI in the placebo plus NAI group to 94 hours was 
selected after consideration of the response rates observed in a blinded review of TTCI 
including data from 127 patients.
The increased sample size has the consequential benefit of a larger population for safety 
analysis of the combination and multiple dose regimen specifically tested in this study for the 
severely ill hospitalized patient group.
The study power is calculated based on the primary endpoint incorporating a group sequential 
design (GSD) using a beta spending function with non-binding rule, to allow for one futility 
interim, without increasing the overall experiment-wise error rate.
Interim Analyses
After approximately 65% of TTCI events, a formal unblinded non-binding futility interim 
analysis based on the TTCI will be performed.  The futility interim analysis will use a Lan-
DeMets Pocock beta spending function.  If the hazard ratio seen at the interim is below the 
calculated futility bound, the trial may be declared futile and recruitment will be stopped. 
The futility interim is non-binding on the Sponsor, and any deviation from the iDMC 
recommendation will be fully documented in the CSR.  If the study is stopped for futility, at 
that point the study results will be reported.  Full operating characteristics of the IA will be 
detailed in the SAP.
The interim analysis will be conducted by an unblinded external statistical group (independent 
Data Coordinating Centre, iDCC) and reviewed by the iDMC (also unblinded), whilst the 
Sponsor will remain blinded until the end of study.  Interactions between the iDMC/iDCC and 
Sponsor will be carried out as specified in the iDMC Charter. 
The iDMC Charter will be updated to document this pre-planned interim analysis and
potential recommendations the iDMC can make to the Sponsor as a result of the analysis (e.g., 
stop the study for futility or continue the study), and the iDMC Charter will also be made 
available to relevant health authorities.


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviation
Definition
ANCOVA
analysis of covariance
AUC
area under the concentration–time curve or 
area under the curve (as appropriate)
AUCinf
area under the concentration–time curve from time 0 to infinity
AUCtau
area under the plasma concentrationtime curve for a dosing interval
BID
twice daily
C24
concentration 24 hours postdose
Cmax
maximum plasma concentration
Ctrough
minimum plasma concentration
CL/F
apparent clearance
COPD
chronic obstructive pulmonary disease
CTCAE
Common Terminology Criteria for Adverse Events
EC
Ethics Committee
eCRF
electronic Case Report Form
EDC
electronic data capture
EMEA
Europe, Middle East, and Africa
FiO2
fraction of inspired oxygen
GSD
Group Sequential Design
HA
hemagglutinin complex 
HIPAA
Health Insurance Portability and Accountability Act
ICH
International Council for Harmonisation
ICU
intensive care unit
iDCC
independent Data Coordinating Centre
iDMC
independent Data Monitoring Committee
IMP
investigational medicinal product
IND
Investigational New Drug (Application)
IRB
Institutional Review Board
IxRS
interactive voice or web-based response system
LPLV
last patient, last visit
M2
matrix-2
mITTI
modified intent-to-treat (influenza) infected (population)
MN
mobile nursing
NA
neuraminidase
NAI
neuraminidase inhibitor
NCI
National Cancer Institute
NCI CTCAE
National Cancer Institute Common Terminology Criteria for Adverse 
Events
NEWS2
National Early Warning Score 2


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Abbreviation
Definition
NMPA
National Medical Products Administration
PCR
polymerase chain reaction
PK
pharmacokinetic
PRO
patient-reported outcome
RIDT
Rapid Influenza Diagnostic Test
ROW
rest of world
RT-PCR
reverse transcriptase-polymerase chain reaction
SAP
Statistical Analysis Plan
SOC
standard of care
TCID50
50% tissue culture infectious dose
TQT
Thorough QT
TTAS
time to alleviation of symptoms
TTCI
time to clinical improvement
ULN
upper limit of normal
Vc/F
apparent volume of distribution for the central compartment


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1.
BACKGROUND
1.1
BACKGROUND ON INFLUENZA
Influenza is an acute respiratory infectious disease caused by a virus of the 
orthomyxovirus family.  Two forms are known to infect humans, influenza A and B.  
These viruses cause an acute febrile infection of the respiratory tract after an incubation 
period of 1 to 4 days, characterized by the sudden onset of fever, cough, fatigue, 
headache, and myalgia.  Annual influenza epidemics are thought to result in between 
3 and 5 million cases of severe illness, and between 250,000 and 500,000 deaths every 
year around the world (WHO 2017).
Although the condition is usually self-limiting in healthy adults, it can be associated with 
substantial morbidity and occasional mortality in children, the elderly, and the 
immunocompromised (Paules and Subbarao 2017).  Hospitalization due to severe 
influenza is associated with high mortality (4%8%), intensive care unit (ICU) admission 
(5%17%), and prolonged hospital stays of between 5 and 9 days.  During a pandemic 
season, the outcomes may be more serious, with up to 34% of patients requiring ICU 
care and a mortality rate as high as 15% (Lee and Ison 2012).
The influenza viruses have a segmented, negative-sense, single-stranded, 
lipid-encapsulated RNA genome; they range between 80 and 100 nm in size.  Subtypes 
are defined according to glycoproteins present in the viral lipid coat.  The hemagglutinin 
complex (HA) is the major surface protein of the virus.  The neuraminidase (NA) proteins 
are the second major surface proteins in the virion and play a role in enhancing virus 
penetration of the mucus layer around the target cell and in release of virus from the cell 
surface.  The matrix-2 (M2) protein triggers the disintegration of the virion during virus 
entry into the cell and may also be involved in protecting the HA prior to assembly of 
new virus particles.
The following anti-influenza virus drugs are currently available for treatment of acute, 
uncomplicated influenza in different countries:  the M2 ion channel inhibitors amantadine 
and rimantadine, the RNA polymerase inhibitor favipiravir, and the NA inhibitors 
(i.e., oseltamivir, zanamivir, and peramivir).  Many cases of seasonal influenza infection 
are resistant to amantadine and rimantadine, hence their use in clinical practice is limited.  
NA inhibitor (NAI) oral formulations need to be administered for 5 days, potentially 
resulting in poor patient compliance and convenience, while inhalation formulations can 
only be used in patients who are able to inhale the drug.  These factors contribute to an 
unmet medical need for new antiviral influenza drugs that can be easily and less 
frequently administered, particularly in patients who are severely ill and possibly
intubated.
In February 2019, intravenous zanamivir (Dectova) received a positive opinion for use
under exceptional circumstances from the European Medicines Agency for the 
treatment of complicated and potentially life-threatening influenza A or B virus 


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infections in adult and pediatric patients (aged 6 months).  Zanamivir is only 
indicated when the influenza virus is resistant to other antiviral drugs, or when other 
antiviral drugs are not suitable, and, therefore, have limited scope in treating influenza 
in hospitalized patients.  Currently, there are no other licensed drugs specifically 
approved for the treatment of influenza in hospitalized patients. Despite this, NAIs are 
widely used as the mainstay of treatment for hospitalized patients, and evidence shows
a potential reduction in mortality in hospitalized patients treated with NAIs, especially if 
initiated as early as possible (Muthuri et al. 2014).
Influenza viruses are known to mutate during the course of replication and can mutate 
into a strain resistant to existing antiviral influenza drugs or a strain to which most people 
are not immune.  Certain strains of avian influenza have been found to be highly 
pathogenic with high rates of NAI-resistance (Hu et al. 2013). New antiviral influenza 
treatments with novel mechanisms of action may provide alternative therapy options, 
particularly when used in combination with NAIs, to overcome such highly pathogenic 
organisms.
1.2
BACKGROUND ON BALOXAVIR MARBOXIL
Baloxavir marboxil is a compound that exerts antiviral effects against influenza.  
Baloxavir marboxil (also referred to as S-033188) is a pro-drug, which is converted to an 
active form baloxavir (also referred to BALOXAVIR) through a metabolic process called 
hydrolysis, in the blood, liver, and small intestine.
Baloxavir marboxil acts on cap-dependent endonuclease, an enzyme specific to 
influenza viruses, and inhibits viral cap-snatching, thereby suppressing the replication of 
influenza viruses.
To date, one Phase II study in otherwise healthy adults and two Phase III studies in 
adults and adolescents (i.e., one in otherwise healthy patients and one in patients with 
high risk of influenza-related complications) have been completed and are summarized 
below. Currently, the clinical development plan is designed to investigate additional
indications for post-exposure prophylaxis, the reduction of influenza transmission, and
otherwise healthy pediatrics (12 years of age). The studies for these additional
indications are not discussed in this protocol.
Baloxavir marboxil is approved for use in Japan (since February 2018) for the treatment 
of influenza A or B virus infection in all age groups (10 kg) and in the United States
(since October 2018), Hong Kong (since February 2019), and Thailand (since March 
2019).  It is approved for the treatment of influenza in otherwise healthy patients aged 
12 years and above who have been symptomatic for no more than 48 hours.  In addition, 
baloxavir marboxil is approved in Thailand and Japan for the treatment of influenza in 
patients aged 12 years and above who have been symptomatic for no more than 48 hours 
and are at high risk of developing influenza-related complications. Regulatory filings 


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in other global regions are either completed, ongoing, or planned to gain market 
authorization for the use of baloxavir marboxil for the treatment of influenza.
Detailed profiles of baloxavir marboxil and its active form, baloxavir, derived from 
nonclinical and clinical studies are provided in the Baloxavir Marboxil Investigator’s 
Brochure.  
1.2.1
Phase II Proof-of-Concept and Dose-Finding Study 
(Study 1518T0821)
In this Phase II, double-blind, randomized, placebo-controlled study, the efficacy and 
safety of baloxavir marboxil in otherwise healthy Japanese patients with influenza virus
infection was investigated.  A single dose of 10, 20, or 40 mg baloxavir marboxil or 
placebo was administered to 400 patients with influenza virus infection (100 per dose 
group).
The median times to alleviation of influenza symptoms in the 10-mg, 20-mg, and 40-mg 
groups were 54.2, 51.0, and 49.5 hours, respectively, compared with 77.7 hours in the 
placebo group. Using the stratified generalized Wilcoxon test, the prespecified
secondary analysis, all three dose groups of baloxavir marboxil showed a significantly 
greater reduction in the time to alleviation of symptoms compared with the placebo 
group (2-sided p-values:  p0.0085 for the 10-mg group, p0.0182 for the 20-mg group, 
and p0.0046 for the 40-mg group).
Compared with the placebo group, all of the baloxavir marboxil groups showed a greater 
reduction in the proportion of patients with positive influenza virus titer, change from 
baseline in influenza virus titer, and change in amount of influenza virus on Days 2 and 3 
using the stratified Wilcoxon test.
Baloxavir marboxil was well tolerated in the study.  No deaths, serious adverse events,
or treatment-emergent adverse events leading to study withdrawal were reported in any 
of the groups.  Adverse events were reported in 27 of 100 patients (27%, 34 events) in 
the 10-mg group, 23 of 100 patients (23%, 29 events) in the 20-mg group, and 26 of 
100 patients (26%, 29 events) in the 40-mg group compared with 29 of 100 patients 
(29%, 40 events) in the placebo group. No dose-dependent adverse events were 
observed. Most adverse events were of mild intensity and resolved. No severe 
treatment-emergent adverse events were reported in the study.
1.2.2
Phase III Double-Blind Study in Otherwise Healthy Patients 
(Study 1601T0831, CAPSTONE 1)
In this Phase III, double-blind, double-randomized, placebo- and active 
(oseltamivir)controlled study, the efficacy and safety of baloxavir marboxil- was 
investigated in otherwise healthy Japanese and US adults and adolescents 
12 to 64 years of age with influenza.  The doses studied were a single dose of 40 mg for 
patients weighing 40 to 80 kg and a single dose of 80 mg for patients weighing 80 kg.  


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Patients randomized to the active-control arm received 75 mg oseltamivir, twice daily 
(BID) for 5 days.  A total of 1432 patients received the study drug:  610 in the baloxavir 
marboxil group, 309 in the placebo group, and 513 in the oseltamivir group.
The baloxavir marboxil group showed a significantly greater reduction in the time to 
alleviation of symptoms (TTAS) compared with the placebo group (median difference 
26.5 hours [95% CI: -35.8, -17.8]; p0.0001).  In the adult stratum of patients, the 
median TTAS was 53.5 hours in the baloxavir marboxil group compared with 53.8 hours 
in the oseltamivir group.  Of the secondary endpoints, significant decreases in both virus 
titer and the amount of virus RNA were observed in the baloxavir marboxil group 
compared with the placebo group.  
In addition, the median time to cessation of viral shedding, as determined by virus titer, 
was significantly shorter (p0.0001) in the baloxavir marboxil group (24 hours) than in 
the placebo group (96 hours) and in the oseltamivir group (72 hours).
Beneficial effects of baloxavir marboxil on fever were also demonstrated.  The proportion 
of patients who had fever was reduced more rapidly in the baloxavir marboxil group than 
in the placebo group following the study drug administration.  The median time to 
resolution of fever was shortened by 17.5 hours in the baloxavir marboxil group 
compared with the placebo group (p0.0001).
Baloxavir marboxil was well tolerated in this study.  No deaths were reported in any 
group.  Two serious adverse events (i.e., aseptic meningitis and incarcerated inguinal 
hernia) were reported in 2 of 610 patients (0.3%) in the baloxavir marboxil group.  Both 
serious adverse events resolved and were considered not related to study drug by the 
investigators.  Adverse events were reported in 126 of 610 patients (20.7%, 172 events) 
in the baloxavir marboxil group, 76 of 309 patients (24.6%, 118 events) in the placebo 
group, and 127 of 513 patients (24.8%, 179 events) in the oseltamivir group. 
The relatively common adverse events (incidence2% or greater) in any of the groups 
were bronchitis, sinusitis, diarrhea, and nausea; however, the incidence of each adverse 
event in the baloxavir marboxil group was lower than or equal to that in the placebo 
group.  In all groups, the majority of the adverse events were categorized as 
Grade 1 or 2 and resolved.
1.2.3
Phase III Double-Blind Study in Patients at High Risk of 
Developing Influenza-Related Complications 
(Study 1602 T0832, CAPSTONE II) 
In this global, Phase III, double-blind, randomized placebo-, and active 
(oseltamivir)-controlled study, the efficacy and safety of baloxavir marboxil was 
investigated in adults and adolescents at high risk of developing influenza-related 
complications. The patients had to have at least one high-risk factor for developing 
influenza-related complications (adapted from the Centers for Disease Control and 


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Prevention’s [CDC] criteria). The doses studied were a single dose of 40 mg for 
patients weighing 40 to 80 kg and a single dose of 80 mg for patients weighing 
80 kg. Patients randomized to the active-control arm received 75 mg oseltamivir, 
BID for 5 days.  A total of 2178 patients received the study drug: 730 in the baloxavir 
marboxil group, 727 in the placebo group, and 721 in the oseltamivir group.
The primary endpoint was the time to improvement of influenza symptoms (TTIS) in 
patients with influenza. Since high-risk individuals may have underlying chronic 
diseases that share some symptoms with those of influenza (e.g., cough in a patient with 
chronic lung disease), a modification of the TTAS was used to permit assessment of 
improvement of a symptom that may have been present before the onset of influenza but 
worsened by influenza, or maintenance of a preexisting symptom that had not been 
worsened by the onset of acute influenza. 
The study met its primary endpoint, demonstrating a clinically meaningful and 
statistically significant reduction in TTIS in the baloxavir marboxil group compared 
with the placebo group (median difference 29.1 [95% CI: 42.8, 14.6] hours, 
p 0.0001). The difference in TTIS between the baloxavir marboxil group and the 
oseltamivir group was not statistically significant (median difference 7.7 [95% CI: 
22.7, 7.9] hours, p 0.8347).
The results for the secondary clinical efficacy and virologic endpoints were supportive 
of the results for the primary endpoint. There were clinically meaningful reductions in 
TTAS and time to resolution of fever in the baloxavir marboxil group compared to the 
placebo group, and no notable differences in the secondary clinical efficacy endpoints 
between the baloxavir marboxil and oseltamivir groups. The median time to cessation 
of viral shedding, as determined by virus titer, showed a clear reduction in the 
baloxavir marboxil group compared with the placebo group (median difference of 
48.0 hours, p 0.0001) and also when compared to the oseltamivir group (median 
difference of 48.0 hours, p 0.0001).
Baloxavir marboxil was well tolerated in patients at high risk of influenza-related 
complications.  Two deaths were reported in the study, one in the oseltamivir group due 
to a SAE of pneumonia unrelated to study treatment (0.1%) and one in the baloxavir 
marboxil group due to acute myocardial infarction that developed on Day 1 prior to 
receiving study treatment (0.1%). SAEs (0.7% to 1.2%) and AEs leading to 
withdrawal from treatment (0.6% to 0.7%) were reported by similar proportions of 
patients in all groups. All SAEs in the baloxavir marboxil group were considered to be 
unrelated to treatment. Approximately 25% of patients experienced at least one AE in 
the baloxavir marboxil group compared with 30% and 28% of patients in the placebo 
and oseltamivir groups, respectively.  The relatively common AEs (incidence 2% or 
greater) in any of the groups were bronchitis, sinusitis, diarrhea, and nausea; however, 
the incidence of each AE in the baloxavir marboxil group was lower than or equal to 
that in the placebo and oseltamivir groups.


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1.2.4
Post-Marketing 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 urticarial.  
Refer to Section 6 of the Baloxavir Marboxil Investigator’s Brochure for current details
related to post-marketing safety information.
1.3
STUDY RATIONALE AND BENEFIT–RISK ASSESSMENT
Influenza virus infection can lead to severe outcomes in patients with underlying medical 
comorbidities or in other vulnerable groups at risk of complications. For example, 
influenza predisposes individuals to secondary bacterial infection, which may progress in 
severity leading to poor prognosis (Rothberg and Haessler 2010).  Other serious 
complications can also develop, including cardiac and neurological complications. 
There are no approved drugs licensed for the treatment of patients hospitalized with 
influenza; however, treatment guidelines endorse the use of NAIs, such as oseltamivir,
in the hospitalized population (Harper et al. 2009; CDC 2018). Baloxavir marboxil 
appears to have significant virological efficacy, offering the potential to treat influenza in 
the hospitalized population more effectively than currently available treatments.
Preclinical studies of baloxavir marboxil used in combination with NAIs have shown 
synergistic effects on inhibition of viral replication (Kitano et al. 2017). Baloxavir 
marboxil in combination with a NAI is expected to produce a greater reduction in viral 
load than either baloxavir marboxil or a NAI alone.  
The results of the clinical studies outlined above have demonstrated clinical efficacy and 
safety of baloxavir marboxil in the treatment of influenza virus infections in otherwise 
healthy adult and adolescent patients, and in adult and adolescent patients at high risk 
of developing influenza-related complications supporting a positive benefit-risk 
assessment in both populations.  With demonstrated clinical efficacy and well tolerated 
safety profile, a placebo-controlled study in combination with a standard-of-care (SOC) 
NAI to assess the efficacy and safety of baloxavir marboxil in hospitalized patients with
influenza is justified to address the high unmet need and burden of disease in this 
severely ill population.
2.
OBJECTIVES AND ENDPOINTS
This study will evaluate the efficacy, safety, and pharmacokinetics of baloxavir marboxil 
in combination with a SOC NAI (i.e., oseltamivir, zanamivir, or peramivir) compared with 
a matching placebo in combination with a SOC NAI in hospitalized patients with influenza.  
Specific objectives and corresponding endpoints for the study are outlined in Table 1.


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In this protocol, "study treatment" refers to baloxavir marboxil or its matching placebo.
Study treatment is given in combination with a SOC NAI.
Table 1
Objectives and Corresponding Endpoints
Primary Objective
Corresponding Endpoint
To evaluate the clinical efficacy of 
baloxavir marboxil plus a SOC NAI 
compared with matching placebo 
plus a SOC NAI 
TTCI defined as:

Time to hospital discharge OR

Time to NEWS2 of 2 maintained for 24 hours
Efficacy Objectives
Corresponding Endpoints
To evaluate the clinical efficacy of 
baloxavir marboxil plus a SOC NAI
compared with matching placebo plus 
a SOC NAI
Key Secondary Endpoints:
Response rates of the 6-point ordinal scale at Day 7
Time to clinical response based on temperature 
ranges, oxygen saturation, respiratory status, heart 
rate, and hospitalization status a
Other Secondary Endpoints:
Incidence of mechanical ventilation
Duration of mechanical ventilation
Incidence of ICU stay 
Duration of ICU stay
Time to clinical failure, defined as the time to death, 
mechanical ventilation, or ICU admission, 
corresponding to ordinal scale categories 6, 5, and 4, 
respectively, from baseline
Time to hospital discharge 
Incidence of post-treatment influenza-related 
complications b
Mortality rate at Day 7 
Mortality rate at Day 28
Time to NEWS2 of 2 maintained for 24 hours


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Table 1
Objectives and Corresponding Endpoints (cont.)
Virology Objectives
Corresponding Endpoints
To evaluate the virological activity of 
baloxavir marboxil plus a SOC NAI 
compared with matching placebo 
plus a SOC NAI 
Time to cessation of viral shedding by virus titer
Time to cessation of viral shedding by RT-PCR
Change from baseline in influenza virus titer and in the 
amount of virus RNA (RT-PCR) at each timepoint
Proportion of patients with positive influenza virus titer 
and proportion of patients positive by RT-PCR at each 
timepoint
AUC in virus titer and in the amount of virus RNA 
(RT-PCR)
To evaluate the polymorphic and 
treatment-emergent amino acid 
substitutions in the PA, PB1, PB2,
and NA genes and drug 
susceptibility in patients with 
evaluable virus
Polymorphic and treatment-emergent amino acid 
substitutions in the PA, PB1, PB2, and NA genes
Drug susceptibility in patients with evaluable virus
Safety Objective
Corresponding Endpoints
To evaluate the safety of baloxavir 
marboxil plus a SOC NAI compared 
with matching placebo plus a SOC 
NAI in hospitalized patients with 
influenza
Compare the incidence and severity of AEs and SAEs
Incidence of AEs leading to discontinuation
Proportion of patients with any post-treatment ALT and 
AST above baseline and 3 ULN, 5ULN, 
10ULN
Pharmacokinetic Objective
Corresponding Endpoints
To evaluate the single- and 
multiple-dose pharmacokinetics of 
baloxavir 
Plasma concentrations of baloxavir (active metabolite) 
at specified timepoints
After each dose, concentration at predose and 
24 hours postdose will be summarized 
Non-compartmental PK parameters such as AUC, 
Cmax and t1/2 (only for patients undergoing sequential 
PK sampling) 
Exploratory Palatability and 
Acceptability Objective
Corresponding Endpoint

To describe the palatability and 
acceptability of the oral 
suspension in hospitalized 
patients with influenza

Number and proportion of patients reporting each 
palatability and acceptability response at each 
timepoint
AEadverse event; AUCarea under the concentrationtime curve; Cmaxmaximum plasma 
concentration; ICUintensive care unit; NAIneuraminidase inhibitor; NEWS2National Early 
Warning Score 2; PKpharmacokinetic; RT-PCRreverse transcriptase polymerase chain 
reaction; SAEserious adverse event; SOCstandard-of-care; t1/2half-life; TTCItime to 
clinical improvement; t1/2half-life; ULNupper limited normal.
a
Criteria for each parameter noted in Section 6.4.2.
b
Incidence of post-treatment influenza-related complications as defined in Section 6.4.3.


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3.
STUDY DESIGN
3.1
DESCRIPTION OF THE STUDY
This is a Phase III, randomized, double-blind, placebo-controlled, multicenter study to 
assess the efficacy, safety, and pharmacokinetics of baloxavir marboxil in combination 
with a SOC NAI (i.e., oseltamivir, zanamivir, or peramivir), compared with a matching 
placebo in combination with a SOC NAI in approximately 366 hospitalized adults and 
adolescent patients (aged 12 years) with influenza.
Patients will be randomized as soon as possible after screening (ideally within 
12 hours), providing they are within 96 hours of symptom onset and hospitalized
(includes assessment in emergency centers pending admission to a hospital ward).  
Patients will be assigned in a 2:1 ratio to receive baloxavir marboxil or matching placebo. 
Study treatment must be given in combination with a SOC NAI according to investigator 
preference (i.e., oseltamivir, zanamivir, or peramivir).  Re-screening of patients who fail 
to meet the inclusion and exclusion criteria will be permitted only once, providing the 
time from symptom onset to randomization is still within 96 hours.
Baloxavir marboxil will be administered as a 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 also 
on Day 7 if clinical improvement has not occurred at Day 5, per protocol defined criteria
(see Section 4.3.2.1).  Treatment with a SOC NAI (i.e., oseltamivir, zanamivir, or 
peramivir) should be administered in accordance with local clinical practice. To fully 
explore the utility of the combination with baloxavir marboxil, or matching placebo, the 
dosing regimen of the SOC NAI should aim to ensure that anti-viral activity is maintained 
from Day 1 to Day 5. The SOC NAI treatment may be extended to Day 10 or beyond at 
the discretion of the investigator and in accordance with local clinical practice.  
The study consists of two periods: a 10-day treatment period and a 25-day follow-up 
period.  Therefore, the maximum study duration for each patient will be 35 days.
The study assessments to be conducted include the following:  physical examination, 
vital signs, assessment of consciousness, presence or absence of respiratory support,
adverse events, concomitant therapies, clinical laboratory tests, nasopharyngeal swabs, 
and the palatability and acceptability questionnaire.  Please see Appendix 1 for details 
concerning the timing of these assessments.  
This study will be conducted at approximately 250 global sites in both Northern and 
Southern hemispheres.
An external independent Data Monitoring Committee (iDMC) will evaluate safety 
according to policies and procedures detailed in an iDMC Charter.


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Figure 1 presents an overview of the study design.  A schedule of activities is provided in
Appendix 1.
Figure 1
Study Schema
NAIneuraminidase inhibitor; SOCstandard-of-care.
a All patients will receive at least two doses of baloxavir marboxil or its matching placebo
(i.e., Days 1 and 4).  A third dose may also be administered on Day 7 if clinical improvement is 
not observed at Day 5 according to protocol defined criteria (Section 4.3.2.1).
b A SOC NAI should be administered to cover a minimum of treatment exposure from Day 1 to 
Day 5. This treatment may be extended to Day 10 or beyond, at the discretion of the 
investigator and in accordance with local clinical practice.
3.2
END OF STUDY AND LENGTH OF STUDY
The end of this study is defined as the date when the last patient, last visit (LPLV) occurs 
or the date at which the last data point required for statistical analysis or safety follow-up 
is received from the last patient, whichever occurs later.  The LPLV is expected to occur 
35 days after the last patient is enrolled. 
The total length of the study, from screening of the first patient to the LPLV, is expected 
to be approximately 2.5 years.
In addition, the Sponsor may decide to terminate the study at any time.
3.3
RATIONALE FOR STUDY DESIGN
3.3.1
Rationale for Baloxavir Marboxil Dose and Schedule
The safety and efficacy of baloxavir marboxil in otherwise healthy and high-risk adult 
and adolescent patients with influenza virus infection have been demonstrated in 


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previous studies using baloxavir marboxil tablets (10 mg and 20 mg) dosed at 40 mg 
and 80 mg according to body weight.
In this study, baloxavir marboxil will be available in two forms.  A tablet formulation will 
be administered to patients who can swallow. Granules for oral suspension formulation 
will be administered to patients who are intubated and have a nasogastric tube in situ as 
well as to patients who are unable to swallow tablets for other reasons.  
Baloxavir marboxil will be administered as a 40-mg dose in patients weighing 
40 to 80 kg or an 80-mg dose in patients weighing 80 kg.  Dosing of baloxavir 
marboxil will be given, on Day 1 and Day 4 for all patients, with an additional dose on
Day 7 in the absence of clinical improvement when assessed on Day 5. Specific criteria 
for extended dosing to Day 7 include ongoing mechanical ventilation, persistence of 
fever, severely immunocompromised, pneumonia, or confirmed/suspected
influenza-related complication.
Seriously ill patients who are hospitalized with influenza demonstrate prolonged viral 
shedding compared with otherwise healthy patients with influenza (Lee et al. 2009).  
Therefore, the repeat-dose regimen is to ensure that plasma baloxavir concentrations 
remain above a target-threshold concentration for a longer duration in severely ill 
patients owing to the greater potential of a protracted influenza illness. 
Administration of up to three doses of baloxavir marboxil separated by 3 days is 
planned (i.e., Days 1, 4, and 7).  The dosing interval of 3 days approximates terminal 
disposition half-life (~70 hours) of baloxavir, thus higher drug exposure on Day 4 or 7 
relative to the first dose is expected, under the assumption of linear pharmacokinetics.  
Model-based simulation indicates that the population-median accumulation in terms of 
maximum plasma concentration (Cmax) and minimum plasma concentration (Ctrough) prior
to next dose on Day 7 (third consecutive dose) would be approximately 1.5 and 
1.7 times greater than after the first dose, respectively.  Based on the worst-case 
arithmetic mean Bayesian estimate of 126 ng/mL for Cmax in Phase III (Asian 80 kg), 
the highest peak plasma concentration after a third consecutive dose (Day 7) is not 
expected to exceed the peak drug levels observed in Japanese patients receiving 80 mg 
in the Thorough QT (TQT) study.  Likewise, total drug exposure simulated on Day 7 area 
under the plasma concentrationtime curve for a dosing interval (AUCtau) is not expected 
to exceed area under the concentrationtime curve from Time 0 to infinity (AUCinf) of the 
TQT, regardless of dose.  However, for certain individual Asian patients receiving 80 mg, 
total drug exposure on Day 7 (AUCtau) may approach similar overall exposures as seen 
in the TQT.
3.3.2
Rationale for Patient Population
The safety and efficacy of baloxavir marboxil has been investigated in otherwise healthy 
adult and adolescent populations, and in adult and adolescent patients at high risk of 
influenza-related complications. Baloxavir marboxil has been approved in several 


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countries, including Japan and the United States.  Given the significant unmet need in 
patients hospitalized with severe influenza, this study is designed to evaluate the efficacy 
and safety of baloxavir marboxil in this population.
Baloxavir marboxil has been well tolerated in adults and adolescents in previous studies, 
with a pharmacokinetic (PK) profile supportive of the inclusion of these age groups in 
this study. There are a number of pediatric studies in progress that are designed to
confirm the safety and pharmacokinetics of baloxavir marboxil in otherwise healthy 
children with influenza aged 12 years. Depending on the outcome of these additional
pediatric studies and this current study in hospitalized patients, younger hospitalized 
patients may be studied in a future protocol.
Morbidity and mortality are particularly high for elderly patients and 
immunocompromised patients admitted to hospital with influenza. This study will,
therefore, include both of these groups, with no upper age limit or restriction on the 
degree of immunocompromise.  Patients with severe renal or severe liver impairment will 
be excluded based on the current unknown PK profile and tolerability of repeated doses 
of baloxavir marboxil.
3.3.3
Rationale for Control Group
It is not ethical to withhold active treatment from patients hospitalized with influenza,
given the potential severity and poor outcomes in this patient group. NAIs are 
well-established and well-characterized antiviral agents used as the SOC in many
patients hospitalized with influenza and are supported in published guidelines for 
antiviral treatment of these patients (Harper et al. 2009; Fiore et al. 2011).  All patients in 
this study will receive a SOC NAI treatment (i.e., oseltamivir, zanamivir, or peramivir).  
In addition, patients will be randomized in a 2:1 ratio to receive baloxavir marboxil or its 
matching placebo.  Therefore, at a minimum, all patients will be treated with a SOC NAI 
for influenza.  
3.3.4
Rationale for Endpoints
There is no validated clinical end-point for assessing improvement in patients 
hospitalized due to influenza.  Consequently, three measures of clinical improvement are 
used in this study:  “time to clinical improvement” as the primary endpoint, “response
rates of the 6-point ordinal scale” and “time to clinical response” as key secondary 
endpoints. The primary and both key secondary endpoints will be tested in a 
hierarchical chain to control the experiment-wise error rate (alpha). 
The primary endpoint for this study will be the time to clinical improvement (TTCI),
defined as time to hospital discharge or time to National Early Warning Score 2 (NEWS2) 
of 2 maintained for 24 hours, whichever occurs first. This endpoint will provide
objective evidence of improvement in a patient’s condition, which is likely to be a 
reasonable surrogate to overall clinical status improvement. 


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The original NEWS was created in the United Kingdom by the Royal College of 
Physicians in 2012 to standardize the process of recording, scoring, and responding to 
changes in routinely measured physiological parameters in acutely ill patients. The 
score has been widely implemented across the National Health Service in the United 
Kingdom, and in other healthcare settings across the world. NEWS2 is a similar but 
updated score (Royal College of Physicians 2017) to incorporate an additional oxygen 
scale for patients at risk of hypercapnic respiratory failure (target oxygen saturation of 
88%92%, rather than the standard target of 96%).
Six physiological parameters are routinely recorded: 

Respiration rate

Oxygen saturation

Systolic blood pressure

Pulse rate

Level of consciousness and new confusion (ACVPU: Aalert, Cnew confusion, 
Vresponsive to voice, Presponsive to pain, Uunconscious)

Temperature
In addition, a weighting score of 2 is added for patients requiring supplemental oxygen to 
maintain their prescribed oxygen saturation range.
NEWS2 was developed for patients aged 16 years; however, children aged 
1216 years have very similar physiological parameter ranges as adults. In this study, 
NEWS2 is not being used as an early warning system to identify patients who may need 
escalating levels of care; rather, it is being used to standardize vital sign collection which 
will facilitate setting severity levels for inclusion and demonstrating response to 
treatment.  Most pediatric early warning scores are complex and designed to detect 
critical illness in younger children. For the purposes of this study, a patient achieving a 
NEWS2 of 2 is likely to represent a meaningful degree of clinical improvement
(i.e., clinically stable and potentially eligible for discharge). Importantly as well, the 
method of statistical analysis and the selection of a clinically meaningful difference 
between treatment groups are possible for an endpoint of this design. 
The first key secondary endpoint will be the proportion of patients per category in the 
6-point ordinal scale at Day 7. The categories within this scale (see Section 4.5.16)
reflect the clinical status of patients during their hospital stay.  The clinical status should 
be assessed to reflect the most accurate condition of the patient from a medical 
perspective, to minimize the effects of administrative or non-medical factors (e.g., the 
hospital bed availability may lead to patients not being cared for in the ward most 
suitable for their condition).  This endpoint has received considerable interest for use in 
this patient population. There is as yet no definition of a minimum clinically relevant
difference between treatment groups; however, the 6-point ordinal scale will be used in 


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this study to investigate the change in clinical state of patients as the key secondary 
endpoint.
The second of the two key secondary endpoints will be “time to clinical response”.  This 
endpoint is defined by the time to hospital discharge or the time to vital sign parameter 
stabilization.  Vital sign stabilization is based on achieving a set temperature, combined 
with achieving a set oxygen saturation, plus two out of three other parameters related 
to respiratory status, blood pressure or heart rate (see Section 6.5).  
This endpoint was defined in a previous intravenous zanamivir or oral oseltamivir 
clinical study, the largest randomized, double-blind clinical trial of any NAI in 
hospitalized patients with severe influenza to date (Marty et al. 2017).  In the study by 
Marty et al., the “time to clinical response” (primary endpoint) was not met, and 
numerical non-significant differences were noted and warrant further investigation. 
4.
MATERIALS AND METHODS
4.1
PATIENTS
This study aims to enroll approximately 366 adult and adolescent patients.  The study is 
designed to assess the safety and clinical activity of baloxavir marboxil when given in 
combination with a SOC NAI in patients hospitalized due to severe influenza.  
4.1.1
Inclusion Criteria
Patients must meet the following criteria for study entry:

Adult patients:  Signed informed consent by any patient capable of giving consent, or, 
where the patient is not capable of giving consent, by his or her legal/authorized 
representative

Adolescent patients not able to legally consent: written informed consent for study 
participation is obtained from patient’s parents or legal guardian, with assent as 
appropriate by the patient, depending on the patient’s level of understanding and 
capability to provide assent

Age 12 years at the time of signing the Informed Consent Form/Assent Form

Ability to comply with the study protocol, in the investigator’s judgment

Patients who require hospitalization for severe influenza or acquire influenza during 
hospitalization, the severity of which requires an extension of hospitalization

Diagnosis of influenza A and/or B by a positive Rapid Influenza Diagnostic Test 
(RIDT) or reverse transcriptase-polymerase chain reaction (RT-PCR) 
Positive results from local tests are acceptable if conducted within the 24 hours
prior to screening.
A patient with a negative RIDT may be enrolled if influenza is suspected based 
on local surveillance data or if the patient reports contact with a known case of 
influenza within the prior 7 days and all other inclusion criteria are met


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
The time interval between the onset of symptoms and randomization is within
96 hours
The onset of symptoms is defined as the time when the patient experiences at 
least one new general symptom (e.g., headache, feverishness or chills, muscle 
or joint pain, fatigue), respiratory symptom (e.g., cough, sore throat, nasal 
congestion), or fever.

A score of 4 based on the NEWS2 (see Appendix 3)

Patients will require objective criteria of seriousness defined by at least one of the 
following criteria: 
−
Requires ventilation or supplemental oxygen to support respiration  
−
Has a complication related to influenza that requires hospitalization 
(e.g., pneumonia, CNS involvement, myositis, rhabdomyolysis, acute 
exacerbation of chronic kidney disease, asthma or chronic obstructive 
pulmonary disease [COPD], severe dehydration, myocarditis, pericarditis, 
exacerbation of ischemic heart disease)

For women of childbearing potential:  Agreement to remain abstinent (refrain from 
heterosexual intercourse):
Women must remain abstinent or use contraceptive methods with a failure rate 
of 1% per year during the treatment period and for 28 days after the last dose 
of study treatment.  Hormonal contraceptive methods must be supplemented by 
a barrier method.
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 has not 
undergone surgical sterilization (removal of ovaries and/or uterus).
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.
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.
4.1.2
Exclusion Criteria
Patients who meet any of the following criteria will be excluded from study entry:

Patients who have received more than 48 hours of antiviral treatment for the current 
influenza infection prior to screening

Patients who have received baloxavir marboxil for the current influenza infection

Known contraindication to neuraminidase inhibitors

Patients hospitalized for exclusively social reasons (e.g., lack of caregivers at home)


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
Patients expected to die or be discharged within 48 hours, according to the 
investigator’s judgement

Patients weighing 40 kg

Patients with known severe renal impairment (estimated glomerular filtration rate
30 mL/min/1.73 m2) or receiving continuous renal replacement therapy, 
hemodialysis, peritoneal dialysis

Patients with any of the following laboratory abnormalities detected within 24 hours
prior to or during screening (according to local laboratory reference ranges: 
–
ALT or AST level 5 times the upper limit of normal (ULN) 
OR
–
ALT or AST 3 times the ULN and total bilirubin level 2 times the ULN 

Pregnant or breastfeeding, or positive pregnancy test in a predose examination, or 
intending to become pregnant during the study or within 28 days after the last dose 
of study treatment

Exposure to an investigational drug within 5 half-lives or 30 days (whichever is longer)
of randomization

Any serious medical condition or abnormality in clinical laboratory tests that, in the 
investigator’s judgment, precludes the patient’s safe participation in and completion 
of the study

Known hypersensitivity to baloxavir marboxil or the drug product excipients
4.2
METHOD OF TREATMENT ASSIGNMENT AND BLINDING 
Following completion of screening and after all patient eligibility requirements are 
confirmed, patients will undergo randomization in a 2:1 ratio stratified by three regions 
(i.e., North America; Europe, Middle East, and Africa [EMEA]; and rest of world [ROW]), 
NEWS2 score (7, 7; see Appendix 3), and time from symptom onset to study 
treatment (48 hours, 48 hours). 
All patients will receive either baloxavir marboxil or its matching placebo.  
A permuted-block randomization method will be used to obtain an approximate 2:1 ratio 
between the active treatment arm and the placebo arm within each stratum. The 
placebo and active kits are filled and packaged to look identical.
All study site personnel and patients will be blinded to the baloxavir marboxil versus 
placebo treatment assignment throughout the study; the SOC NAI will be open label.  
The Sponsor and its agents will also be blinded to the baloxavir marboxil assignment, 
with the exception of individuals who require access to patient treatment assignments to 
fulfill their responsibilities during a clinical trial. These roles include the unblinding group 
responsible, clinical supply chain managers, sample handling staff, operational assay 
group personnel, IxRS service provider, and iDMC members.


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While PK samples must be collected from patients assigned to the comparator placebo 
arm, PK assay results for these patients are not needed for the safe conduct or proper 
interpretation of this study.  Laboratories responsible for performing study drug PK 
assays will be unblinded to patients' treatment assignments in order to identify 
appropriate samples to be analyzed.  PK samples from patients assigned to the placebo 
arm will not be analyzed for study drug PK concentration except by request (e.g., to 
evaluate a possible error in dosing).  
If unblinding is necessary for a medical emergency (e.g., in the case of a serious 
adverse event for which patient management might be affected by knowledge of 
treatment assignment), the investigator will be able to break the treatment code by 
contacting the IxRS.  The investigator is not required to contact the Medical Monitor prior 
to breaking the treatment code; however, the treatment code should not be broken 
except in emergency situations.
If the investigator wishes to know the identity of the study drug for any reason other than 
a medical emergency, he or she should contact the Medical Monitor directly (see 
Section 5.4.1 for contact information).  The investigator should document and provide an 
explanation for any non-emergency unblinding.  After discussion and agreement with the 
Medical Monitor, the investigator will subsequently be allowed to break the treatment 
code by contacting the IxRS.
In accordance with health authority reporting requirements, the Sponsor's Drug Safety 
representative will break the treatment code for all suspected unexpected serious 
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.
4.3
STUDY TREATMENT AND OTHER TREATMENTS RELEVANT 
TO THE STUDY DESIGN
The investigational medicinal products (IMPs) for this study are baloxavir marboxil and 
its matching placebo as the comparator.
4.3.1
Study Treatment and NAI Formulation, Packaging, and 
Handling
4.3.1.1
Baloxavir Marboxil and Matching Placebo (Study Treatment) 
Baloxavir marboxil and matching placebo will be supplied by the Sponsor as tablets or 
granules for oral suspension.  In order to maximize the study blind, it is mandated that 
each site delegates the preparation of baloxavir marboxil and placebo granules to 
dedicated site personnel that are not involved in any other study related assessments or 
procedures.  The administration of the granule formulation can be performed by study 
personnel.


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For information on the formulation and handling of baloxavir marboxil and matching 
placebo, see the pharmacy manual.
4.3.1.2
Standard-of-Care Neuraminidase Inhibitor
For sites where the SOC NAI is oseltamivir, the oseltamivir will be supplied by the 
Sponsor as capsules or powder for oral suspension. For information on the formulation 
and handling of oseltamivir, see local prescribing information.
All other SOC NAIs (i.e., zanamivir or peramivir) will be supplied by the study sites and 
will be reimbursed by the Sponsor.  For information on the formulation, packaging, and 
handling of SOC NAIs, see local prescribing information.
4.3.2
Study Treatment and SOC NAI Dosage, Administration, and 
Compliance
The treatment regimens are summarized in Section 3.1.
Any dose modification should be noted on the Study Drug Administration electronic 
Case Report Form (eCRF).  Cases of overdose or medication error, along with any 
adverse events, should be reported as described in Section 5.3.5.11. 
Guidelines for dosage modification and treatment interruption or discontinuation for 
patients who experience adverse events are provided in Section 5.1.1.
4.3.2.1
Baloxavir Marboxil and Matching Placebo (Study treatment) 
Baloxavir marboxil or matching placebo will be administered orally according to body 
weight (40 mg for patients weighing 40 to 80 kg; 80 mg for patients weighing 80 kg) 
either in tablet form (20-mg tablets) or granules for oral suspension for patients unable to 
swallow or with a nasogastric tube in situ (e.g., in intubated patients).  
Dosing will occur on Day 1 and Day 4, with a further dose at Day 7 for patients who have 
not improved according to at least 1 of the following specific criteria at Day 5:

Ongoing mechanical ventilation

Persistent fever

Severely immunocompromised

Pneumonia

Confirmed/suspected influenza-related complication
4.3.2.2
Standard-of-Care Neuraminidase Inhibitor
In general, choice of dose, regimen, and any period of extended dosing or dose 
alterations for the SOC NAI (i.e., oseltamivir, zanamivir, or peramivir) should be made in 
accordance with local clinical practice.  However, due to the design of the trial, wherever 
possible, treatment with the chosen SOC NAI should be sufficient to ensure exposure of 
active drug such that anti-viral activity is maintained from Day 1 through Day 5. Table 2


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provides guidance on the choice of dose and regimen to achieve this goal.  If required, 
the investigator may choose to follow local practice instead of these guidelines.  Special 
attention is required for dosing in patients with renal impairment, as dose adjustment 
may be needed.
The above recommendation is regardless of whether the patient has already received 
antiviral treatment within 48 hours prior to screening (i.e., a minimum of 5 days 
administration of the NAI beginning at Day 1 is recommended).  
Table 2
Guidance for Dose and Dosing Regimen for Neuraminidase 
Inhibitors
NAI
Dose
Regimen
Duration of Dosing 
from Day 1
Comments
Oseltamivir
75 mg
BID 
5 days
Zanamivir
10 mg
BID
5 days
Lowest age for dosing to be in line 
with local prescribing information
Peramivir
Adults: 600 mg 
Adolescents:
10 mg/kg up to, 
a maximum of 
600 mg
QD
5 days
Peramivir dosing regimen has been 
selected in line with the study 
conducted in hospitalized patients 
(deJong et al. 2014) and is, therefore,
higher than the generally approved 
dose in uncomplicated influenza
BID twice daily; NAI neuraminidase inhibitor; QD once daily.
Treatment with all NAIs may be extended to Day 10 or beyond, at the discretion of the 
investigator and in accordance with local clinical practice.  Special attention is required 
for dosing in patients with renal impairment, as dose adjustment may be needed.
Note: For sites where the SOC NAI is oseltamivir; from the point of randomization, 
Sponsored-supplied capsules or suspension should be used, where possible.
4.3.3
Investigational Medicinal Product Accountability
The IMPs to be used in this study (i.e., baloxavir marboxil and its matching 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 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 investigational medicinal product (IMP) is 
destroyed, and IMP destruction must be documented on the appropriate form.


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Accurate records of the IMPs received at, dispensed from, returned to, and disposed of 
by the study site should be recorded on the Drug Inventory Log.
4.3.4
Continued Access to Baloxavir Marboxil
Currently, the Sponsor does not have any plans to provide the Roche IMP (baloxavir 
marboxil) or any other study treatments or interventions to patients who have completed 
the study.  The Roche Global Policy on Continued Access to Investigational Medicinal 
Product is available at the following website:
http://www.roche.com/policy_continued_access_to_investigational_medicines.pdf
4.4
CONCOMITANT THERAPY AND ADDITIONAL RESTRICTIONS
Concomitant therapy consists of any medication (e.g., prescription drugs, 
over-the-counter drugs, vaccines, herbal or homeopathic remedies, nutritional 
supplements) used by a patient in addition to protocol-mandated treatment from 7 days 
prior to initiation of study drug until the study completion/discontinuation visit.  All such 
medications should be reported to the investigator and recorded on the Concomitant 
Medications eCRF.
4.4.1
Permitted Therapy 
All therapies required for the management of the patient’s acute illness are permitted 
except for those listed below in Section 4.4.3 (Prohibited Therapy).
4.4.2
Cautionary Therapy
Polyvalent cationcontaining products may decrease plasma concentrations of baloxavir.  
Thus, dairy products, calcium-fortified beverages, polyvalent cationcontaining oral 
laxatives or oral antacids, and oral supplements containing iron, zinc, selenium, calcium, 
or magnesium should not be taken with baloxavir marboxil, where possible.
4.4.3
Prohibited Therapy
Use of the following concomitant therapies is prohibited as described below:

Investigational therapy (other than the protocol-mandated study treatment) is 
prohibited within 5 half-lives or 30 days (whichever is longer) prior to initiation of 
study treatment and during the study 

Approved or experimental influenza treatments other than the protocol-mandated 
NAIs (i.e., oseltamivir, zanamivir, or peramivir) from the point of randomization

Concomitant use of herbal therapies is prohibited as their pharmacokinetics, safety 
profiles, and potential drugdrug interactions are generally unknown
4.5
STUDY ASSESSMENTS 
The schedule of activities to be performed during the study is provided in Appendix 1.  
All activities must be performed and documented for each patient.  


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Patients will be closely monitored for safety and tolerability throughout the study.  
Patients’ liver function should be assessed prior to each dose of baloxavir marboxil or 
matching placebo; therefore, dosing will occur only if the clinical assessment and local 
laboratory test values are acceptable.
At applicable sites, certain study assessments may be performed by a mobile nursing 
(MN) professional or 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 for 
patients participating in the study following hospital discharge.
The Sponsor may select a healthcare company that will be responsible for providing MN 
services for participating sites (the MN vendor).  The MN vendor is responsible for 
ensuring that all MN professionals are licensed, qualified, and in good standing, as per 
applicable regulations, and that appropriate background checks have been performed.  
If the investigator at a participating site determines that MN services are appropriate for 
a patient and the patient gives written informed consent to participate in MN visits, the 
MN network will communicate with the patient and the patient’s site.  MN visits will be 
scheduled on specified visit days, to allow for relevant assessments to be performed by 
the MN professional.  The schedule of activities (see Appendix 1) specifies the 
assessments that may not be performed by an MN professional.
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). If a patient 
cannot provide consent on his or her own, informed consent by legal/authorized 
representatives may be obtained only if allowed by and in accordance with local 
regulations and Independent Review Board (IRB)/Ethics Committee (EC) policies and 
procedures.  If a patient gains the ability to consent on his or her own during the course 
of the study, he or she must re-consent. For adolescents unable to legally provide 
consent, written informed consent for participation in the study must be obtained from 
the child’s parent(s) or legal guardian in accordance with local regulations and IRB/EC 
policies and procedures before performing any study-related procedures (including 
screening evaluations).  The written Assent Form should also be signed and dated by 
those children who are considered to have a sufficient level of understanding as well as 
the capability to provide assent. 
Informed Consent Forms (and Assent Forms where appropriate) for enrolled patients 
and for patients who are not subsequently enrolled will be maintained at the study site.
All screening evaluations must be completed and reviewed to confirm that patients meet 
all eligibility criteria before enrollment.  The investigator will maintain a screening log to 
record details of all patients screened and to confirm eligibility or record reasons for 
screening failure, as applicable.


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4.5.2
Medical History, Concomitant Medication, and Demographic 
Data
Medical history, including clinically significant diseases, surgeries, cancer history 
(including prior cancer therapies and procedures), reproductive status, smoking history,
home oxygen use, and use of alcohol and drugs of abuse will be recorded at the 
baseline visit.  In addition, all medications (e.g., prescription drugs, over-the-counter 
drugs, vaccines, herbal or homeopathic remedies, nutritional supplements) used by the 
patient within 7 days prior to initiation of study treatment will be recorded.  At the time of 
each follow-up physical examination, an interval medical history should be obtained and 
any changes in medications and allergies should be recorded.
Recorded demographic data will include age, sex, and self-reported race/ethnicity.
Race/ethnicity data is to be obtained only if allowed by and in accordance with local 
regulations. Race/ethnicity data, where collected, will be used as a variable within the 
PK analysis. In the Phase III study (1601T0831), a difference was observed in the 
baloxavir plasma concentration 24 hours postdose (C24) measurement when assessed 
according to reported race (see Baloxavir Marboxil Investigator’s Brochure for details).
Influenza vaccination history for the 12 months before screening will be recorded, 
including the type of vaccine (e.g., live, inactivated) and date administered, if known.
4.5.3
Physical Examinations
A complete physical examination should be conducted at screening and include an 
evaluation of the head, eyes, ears, nose, and throat, and the cardiovascular, 
dermatologic, musculoskeletal, respiratory, gastrointestinal, genitourinary, and 
neurologic systems.  Any abnormality identified at the baseline visit should be recorded 
on the General Medical History and Baseline Conditions eCRF.  
Limited, symptom-directed physical examinations should be performed at specified 
postbaseline visits and as clinically indicated.  Changes from baseline abnormalities 
should be recorded in patient notes.  New or worsened clinically significant abnormalities 
should be recorded as adverse events on the Adverse Event eCRF.
Limited, symptom-directed physical examinations may be performed by an MN 
professional.
4.5.4
Vital Signs
Vital signs will include measurements of respiratory rate, pulse rate, peripheral oxygen 
saturation, systolic and diastolic blood pressures, and body temperature.  Body 
temperature should be measured using the same methodology throughout the study.  
For patients requiring supplemental oxygen, the oxygen flow rate (L/min) and/or fraction 
of inspired oxygen (FiO2) should be recorded.


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All of the vital sign parameters should be recorded together four times per day for the 
duration of the hospitalization throughout the treatment period (Day 1/Visit 1 to Day 10).  
It is recommended that the collection timepoints for vital signs and assessments 
(specific to NEWS2, Section 4.5.4) are spread throughout the study day to reflect the 
patient’s condition over the entire study day, where possible.  Following hospital 
discharge during the treatment period (Day 1 to Day 10) these parameters should be 
recorded once at each return visit to the clinic.  Patients who remain hospitalized during 
the follow-up period (Day 11+) require daily collection of vital signs for the purpose of the
study.  During the follow-up period in patients who have been discharged, vital sign 
measurements and temperature are to be recorded at the investigators’ discretion 
(e.g., if symptoms and signs persist during follow-up).  Vital sign measurements may be 
performed by an MN professional.
4.5.5
Assessments Specific to National Early Warning Score 2
In addition to the vital measurements, the patient’s consciousness level and the presence 
or absence of respiratory support must be recorded. The NEWS2 parameter for respiratory 
support is the selection of either air or oxygen “oxygen” can include other forms of 
ventilation to maintain oxygen saturation (see Appendix 3). 
These should be recorded at the same time points as the vital sign measurements (see 
Section 4.5.4 and Appendix 1).
4.5.6
National Early Warning Score 2
The NEWS2 should be calculated by the site at screening only based upon vital sign 
values and assessments related to National Early Warning Score 2 (see Section 4.5.5) 
recorded during the patient assessment.  Should these assessments be conducted more 
than once during the screening period (per site patient care), all data collected closest to 
but before randomization should be used for the NEWS2 score calculation and 
assessment of patient eligibility.  See Appendix 3 for calculation instructions.  
After screening, the NEWS2 values do not need to be calculated by the site, but will be 
calculated electronically by the Sponsor based on vital sign parameters and 
NEWS2-related assessments recorded by the investigator in the appropriate eCRF.
4.5.7
Laboratory and Other Biological Samples
Samples for the following laboratory tests will be sent to local laboratories for analysis:

Hematology:  WBC count, RBC count, hemoglobin, hematocrit, platelet count, 
differential count (neutrophils, eosinophils, basophils, monocytes, lymphocytes, other 
cells)

Chemistry panel (serum or plasma):  sodium, potassium, chloride, bicarbonate, 
glucose, BUN or urea, creatinine, total protein, albumin, phosphorus, calcium, total 
bilirubin, ALP, ALT, and/or AST, uric acid, LDH

Liver chemistry panel: total bilirubin, ALP, ALT and/or AST


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
Pregnancy test
–
All women of childbearing potential will have a pregnancy test at screening
(urine or serum). For those countries under VHP (i.e., Belgium, Czech 
Republic, Estonia, Finland, France, Germany, Hungary, Romania, Spain, and 
Sweden), as well as Netherlands, a serum pregnancy test is mandated at 
screening.  Urine pregnancy tests will be performed at specified subsequent 
visits.  If a urine pregnancy test is positive, it must be confirmed by a serum 
pregnancy test.
The following samples will be sent to the Sponsor or a designee for analysis:

Plasma samples for PK analysis (see Appendix 2)

Serum antibody titers for influenza A and B viruses 

Nasopharyngeal swabs for influenza virology tests (i.e., RT-PCR, 50% tissue culture 
infectious dose [TCID50], phenotyping and genotyping according to the resistance 
analysis plan, drug susceptibility testing) and non-influenza respiratory bacterial and 
virus coinfections panel (only at the screening visit)
Blood and urine sample collection may be performed by an MN professional.  For 
sampling procedures, storage conditions, and shipment instructions, see the laboratory 
manual.
These samples will be destroyed when the final Clinical Study Report has been 
completed, with the following exception:

Plasma samples collected for PK analysis may be needed for additional PK assay 
development and validation; therefore, these samples will be destroyed no later than 
5 years after the final Clinical Study Report has been completed.
When a patient withdraws from the study, samples collected prior to the date of 
withdrawal may still be analyzed, unless the patient specifically requests that the 
samples be destroyed or local laws require destruction of the samples.  However, if 
samples have been tested prior to withdrawal, results from those tests will remain as 
part of the overall research data.
Data arising from sample analysis will be subject to the confidentiality standards 
described in Section 8.4.
4.5.8
Liver Function Monitoring
Patients should be assessed for liver function prior to each dose of baloxavir marboxil or 
matching placebo.  
On Day 1 and Day 4, the assessment is mandatory.  On Day 1, the local laboratory full 
blood chemistry panel required as part of screening can be used for this assessment or 
prior blood results if tests conducted within 24 hours prior to screening.  On Day 4, the 


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protocol-required local laboratory blood liver chemistry panel should be used for this 
assessment. 
On Day 7, the local laboratory blood liver chemistry panel and associated review of 
liver chemistry is only required if the patient will receive baloxavir marboxil or 
matching placebo on this study day.
Results must be reviewed by the investigator before dose administration.  Dosing will 
occur only if the clinical assessment and local laboratory liver chemistry panel values are 
acceptable (see Appendix 4).
4.5.9
Electrocardiograms
Single ECG recordings will be obtained at specified timepoints, as outlined in the 
schedule of activities (see Appendix 1) and may be obtained at unscheduled timepoints.  
All ECG recordings must be performed using a standard high-quality, high-fidelity digital 
electrocardiograph machine equipped with computer-based interval measurements.  
Lead placement should be as consistent as possible.  ECG recordings must be 
performed after the patient has been resting in a supine position for at least 10 minutes.  
All ECGs are to be obtained prior to other procedures scheduled at that same time 
(e.g., vital sign measurements, blood draws) and, if possible, should not be obtained 
within 3 hours after any meal.  Circumstances that may induce changes in heart rate, 
including environmental distractions (e.g., television, radio, conversation) should be 
avoided during the pre-ECG resting period and during ECG recording.
For safety monitoring purposes, the investigator must review, sign, and date all ECG 
tracings.  Paper copies of ECG tracings will be kept as part of the patient's permanent 
study file at the site.  
4.5.10
Chest X-Rays/CT scan
If a chest X-ray has not been taken within the 24 hours prior to screening, it must be 
performed on Day 1. If a chest X-ray was performed within 24 hours prior to screening, 
no additional chest X-ray needs to be performed.  If the SOC is a chest CT scan, this 
can be used as alternative to the chest X-ray. 
Chest X-ray/CT scan findings should be recorded on the appropriate eCRF at baseline.  
If additional chest X-rays/CT scans are taken per local practice, this information should 
be provided in the CRF. 
4.5.11
Rapid Influenza Diagnostic Test  
For patients to be eligible for this study, a RIDT or RT-PCR is required to be performed 
to inform a diagnosis of influenza. A patient with a negative RIDT may be enrolled if 
influenza is suspected based on local surveillance data or the patient reports contact 


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with a known case of influenza within the prior 7 days and this is documented; the 
patient must meet all other inclusion criteria.  
The RIDT will be provided by the Sponsor for sites that do not have access to a local 
RIDT kit or who do not perform RIDT as standard of care. If a site has performed a 
RIDT or RT-PCR test within the 24 hours prior to screening, the local RIDT or RT-PCR 
result can be used, and the test result will be entered into the eCRF.
4.5.12
Nasopharyngeal Samples 
Nasopharyngeal samples collected from both nostrils will be used for influenza virology 
tests for all patients and sent to a central laboratory.  It may only be possible to access 
one nostril if a patient has a nasogastric tube in place, in which case sites may collect a 
sample from one nostril only.
Nasopharyngeal samples should be taken at screening and sent to a central laboratory 
in addition to any local swabs taken for RIDT or RT-PCR used for patient eligibility 
purposes.  Phenotyping and genotyping will be performed according to the resistance 
analysis plan.
4.5.13
Endotracheal Aspirates
For patients who are intubated, endotracheal aspirates should be taken on the same day
as nasopharyngeal samples (see Appendix 1), in accordance with local techniques for 
endotracheal aspiration. If bronchoalveolar lavage is being performed for reasons not 
related to the study, samples should also be collected for influenza RT-PCR assessment,
if possible, for central laboratory testing.
4.5.14
Meals
Study treatment can be taken with or without food. The time of last food intake prior to 
each study treatment on Days 1, 4, and 7 (if additional treatment administered on Day 7)
as well as the fasting period after each study treatment intake will be recorded in the 
eCRF.
It is recommended that dairy products and calcium-fortified beverages should not be 
taken with baloxavir marboxil, where possible. (see Section 4.4.2).
4.5.15
Palatability and Acceptability Assessment
Patients that are awake, compos mentis, and take the study treatment (baloxavir 
marboxil or matching placebo) oral suspension will be asked to assess palatability and 
acceptability through a questionnaire (Appendix 5).  The time of assessment completion 
should be approximately 1 minute after swallowing the study treatment solution, and 
before rinsing the mouth, on Day 1 and Day 4 (as well as Day 7 if an additional dose is 
required).


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4.5.16
Ordinal Scale Determination
Assessment of patient status using an ordinal scale will be recorded at baseline on 
Day 1, and again once daily every morning (between 8 am and 12 pm) while 
hospitalized.  The ordinal scale categories are as follows: 
1. Discharged (or “ready for discharge”)
2. Non-ICU hospital ward (or “ready for hospital ward”) not requiring supplemental 
oxygen/non-invasive ventilation  
3. Non-ICU hospital ward (or “ready for hospital ward”) requiring supplemental 
oxygen/non-invasive ventilation  
4. ICU without mechanical (invasive) ventilation (or “ready for ICU admission”)
5. Mechanical (invasive) ventilation
6. Death
Patients who are ready to be discharged (e.g., still hospitalized due to non-medical or 
administrative reasons) will be assigned an ordinal scale of 1
Patients in non-ICU hospital ward that are eligible for ICU care based on clinical 
presentation but awaiting ICU care will be assigned an ordinal scale of 4.
Patients in ICU for administrative or non-medical reasons, who are ready for a non-ICU 
hospital ward, will be assigned an ordinal scale of 2 (if not requiring supplemental 
oxygen/ non-invasive ventilation) or 3 (requiring supplemental oxygen/ non-invasive 
ventilation).
4.6
TREATMENT, PATIENT, STUDY, AND SITE DISCONTINUATION
4.6.1
Study Treatment Discontinuation
Patients must permanently discontinue study treatment if they experience any of the 
following:

Any medical condition that the investigator or Sponsor determines may jeopardize 
the patient’s safety if he or she continues to receive study treatment

Investigator or Sponsor determines it is in the best interest of the patient

Abnormal liver function test results (please refer to Appendix 4

Anaphylaxis or other form of hypersensitivity reaction 

Pregnancy
The primary reason for study treatment discontinuation should be documented on the 
appropriate eCRF.  Patients who discontinue study treatment will not be replaced.
Patients who discontinue study treatment should be continued in the study and 
complete all scheduled study assessments/visits per protocol, where possible. 


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4.6.2
Patient Discontinuation from Study
Patients who discontinue from the study will be asked to complete a study 
discontinuation visit. At study discontinuation, assessments per the end of study (EOS) 
visit should be conducted.
Patients 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:

Patient withdrawal of consent

Study termination or site closure

Patient non-compliance, defined as failure to comply with protocol requirements as 
determined by the investigator or Sponsor
Every effort should be made to obtain information on patients who withdraw from the 
study.  The primary reason for withdrawal from the study should be documented on the 
appropriate eCRF.  If a patient requests to be withdrawn from the study, this request 
must be documented in the source documents and signed by the investigator. Patients 
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
The Sponsor will notify the investigator if the Sponsor decides to discontinue the study.  
4.6.4
Site Discontinuation
The Sponsor has the right to close a site at any time.  Reasons for closing a site may 
include, but are not limited to, the following:

Excessively slow recruitment

Poor protocol adherence

Inaccurate or incomplete data recording

Non-compliance with the International Council for Harmonisation (ICH) guideline for 
Good Clinical Practice

No study activity (i.e., all patients have completed the study and all obligations have 
been fulfilled)


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5.
ASSESSMENT OF SAFETY
5.1
SAFETY PLAN
The safety and efficacy of baloxavir marboxil has been investigated in otherwise healthy 
adult and adolescent populations as well as adult and adolescent patients at high risk of 
influenza-related complications.  Baloxavir marboxil has been approved in several 
countries, including Japan and the United States (see Section 1.2). The safety plan for 
patients in this study is based on clinical experience with baloxavir marboxil in completed 
and ongoing studies, as well as analysis of cumulative adverse events reporting from 
post-marketing surveillance.  Please refer to the Baloxavir Marboxil Investigator's 
Brochure for a complete summary of safety information.
Several measures will be taken to ensure the safety of patients participating in this study.  
Eligibility criteria have been designed to exclude patients 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.
5.1.1
Management of Patients Who Experience Adverse Events
5.1.1.1
Dose Modifications
No dose modification will be permitted during the study.
5.1.1.2
Treatment Interruption
Treatment interruption is not allowed in this study.  Study treatment should be 
discontinued in patients who meet the criteria listed in Section 4.6.1.
5.2
SAFETY PARAMETERS AND DEFINITIONS
Safety assessments will consist of monitoring and recording adverse events, including 
serious adverse events and adverse events of special interest, performing 
protocol-specified safety laboratory assessments, measuring protocol-specified vital 
signs, and conducting other protocol-specified tests that are deemed critical to the safety 
evaluation of the study.
Certain types of events require immediate reporting to the Sponsor, as outlined in 
Section 5.4.


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5.2.1
Adverse Events
According to the ICH guideline for Good Clinical Practice, an adverse event is any 
untoward medical occurrence in a clinical investigation 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 Section 5.3.5.8 and 
Section 5.3.5.9 for more information)

Recurrence of an intermittent medical condition (e.g., headache) not present at 
baseline

Any deterioration in a laboratory value or other clinical test (e.g., ECG, X-ray) that is 
associated with symptoms or leads to a change in study treatment or concomitant 
treatment or discontinuation from study drug

Adverse events that are related to a protocol-mandated intervention, including those 
that occur prior to assignment of study treatment (e.g., screening invasive 
procedures such as biopsies)
5.2.2
Serious Adverse Events (Immediately Reportable to the 
Sponsor)
A serious adverse event is any adverse event that meets any of the following criteria:

Is fatal (i.e., the adverse event actually causes or leads to death)

Is life threatening (i.e., the adverse event, in the view of the investigator, places the 
patient at immediate risk of death)
This does not include any adverse event that, had it occurred in a more severe 
form or was allowed to continue, might have caused death.

Prolongs inpatient hospitalization or non-elective re-hospitalization (see 
Section 5.3.5.10)

Results in persistent or significant disability/incapacity (i.e., the adverse event results 
in substantial disruption of the patient’s ability to conduct normal life functions)

Is a congenital anomaly/birth defect in a neonate/infant born to a mother exposed to 
study drug

Is a significant medical event in the investigator's judgment (e.g., may jeopardize the 
patient or may require medical/surgical intervention to prevent one of the outcomes 
listed above)
The terms "severe" and "serious" are not synonymous.  Severity refers to the intensity of 
an adverse event (e.g., rated as mild, moderate, or severe, or according to National 
Cancer Institute Common Terminology Criteria for Adverse Events [NCI CTCAE]; see 


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Section 5.3.3); the event itself may be of relatively minor medical significance (such as 
severe headache without any further findings).
Severity and seriousness need to be independently assessed for each adverse event 
recorded on the eCRF.
Serious adverse events are required to be reported by the investigator to the Sponsor 
immediately (i.e., no more than 24 hours after learning of the event; see Section 5.4.2 for 
reporting instructions).
5.2.3
Adverse Events of Special Interest (Immediately Reportable to 
the Sponsor)
Adverse events of special interest are required to be reported by the investigator to the 
Sponsor immediately (i.e., no more than 24 hours after learning of the event; see 
Section 5.4.2 for reporting instructions).  Adverse events of special interest for this study 
are as follows:

Cases of potential drug-induced liver injury that include an elevated ALT or AST in 
combination with either an elevated bilirubin or clinical jaundice, as defined by Hy's 
Law (see Section 5.3.5.6)

Suspected transmission of an infectious agent by the study drug, as defined as 
follows:
Any organism, virus, or infectious particle (e.g., prion protein transmitting 
transmissible spongiform encephalopathy), pathogenic or non-pathogenic, is 
considered an infectious agent.  A transmission of an infectious agent may be 
suspected from clinical symptoms or laboratory findings that indicate an infection in 
a patient exposed to a medicinal product.  This term applies only when a 
contamination of the study drug is suspected.
5.3
METHODS AND TIMING FOR CAPTURING AND ASSESSING 
SAFETY PARAMETERS
The investigator is responsible for ensuring that all adverse events (see Section 5.2.1 for 
definition) are recorded on the Adverse Event eCRF and reported to the Sponsor in 
accordance with instructions provided in this section and in Section 5.4, Section 5.5, and
Section 5.6.  The investigator is also responsible for reporting any occurrence of 
accidental overdose or medication error (see Section 5.3.5.11).  
For each adverse event recorded on the Adverse Event eCRF, the investigator will make 
an assessment of seriousness (see Section 5.2.2 for seriousness criteria), severity (see 
Section 5.3.3), and causality (see Section 5.3.4).  
5.3.1
Adverse Event Reporting Period
Investigators will seek information on adverse events at each patient contact.  All 
adverse events, whether reported by the patient or noted by study personnel, will be 
recorded in the patient’s medical record and on the Adverse Event eCRF.


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After informed consent has been obtained but prior to initiation of study drug, only 
serious adverse events caused by a protocol-mandated intervention (e.g., invasive 
procedures such as biopsies, discontinuation of medications) should be reported 
(see Section 5.4.2 for instructions for reporting serious adverse events).
After initiation of study drug, all adverse events will be reported until 28 days after the 
final dose of study drug.
Instructions for reporting adverse events that occur after the adverse event reporting 
period are provided in Section 5.6.
5.3.2
Eliciting Adverse Event Information
A consistent methodology of non-directive questioning should be adopted for eliciting 
adverse event information at all patient evaluation timepoints.  Examples of non-directive 
questions include the following:
"How have you felt since your last clinic visit?"
"Have you had any new or changed health problems since you were last here?"
5.3.3
Assessment of Severity of Adverse Events
The adverse event severity grading scale for the NCI CTCAE (v5.0) will be used for 
assessing adverse event severity.  Table 3 will be used for assessing severity for 
adverse events that are not specifically listed in the NCI CTCAE.


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Table 3
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 patients who are 
not bedridden.
c If an event is assessed as a "significant medical event," it must be reported as a serious 
adverse event (see Section 5.4.2 for reporting instructions), per the definition of serious 
adverse event in Section 5.2.2.
d Grade 4 and 5 events must be reported as serious adverse events (see Section 5.4.2 for 
reporting instructions), per the definition of serious adverse event in Section 5.2.2.
5.3.4
Assessment of Causality of Adverse Events
Investigators should use their knowledge of the patient, the circumstances surrounding 
the event, and an evaluation of any potential alternative causes to determine whether an 
adverse event is considered to be related to the study drug, indicating "yes" or "no" 
accordingly.  The following guidance should be taken into consideration:

Temporal relationship of event onset to the initiation of study drug

Course of the event, with special consideration of the effects of dose reduction, 
discontinuation of study drug, or reintroduction of study drug (as applicable)

Known association of the event with the study drug or with similar treatments

Known association of the event with the disease under study

Presence of risk factors in the patient or use of concomitant medications known to 
increase the occurrence of the event

Presence of non-treatment-related factors that are known to be associated with the 
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For patients receiving combination therapy, causality will be assessed individually for 
each protocol-mandated therapy.
5.3.5
Procedures for Recording Adverse Events
Investigators should use correct medical terminology/concepts when recording adverse 
events on the Adverse Event eCRF.  Avoid colloquialisms and abbreviations.
Only one adverse event term should be recorded in the event field on the Adverse Event 
eCRF.
5.3.5.1
Diagnosis versus Signs and Symptoms
A diagnosis (if known) should be recorded on the Adverse Event eCRF rather than 
individual signs and symptoms (e.g., record only liver failure or hepatitis rather than 
jaundice, asterixis, and elevated transaminases).  However, if a constellation of signs 
and/or symptoms cannot be medically characterized as a single diagnosis or syndrome 
at the time of reporting, each individual event should be recorded on the Adverse Event 
eCRF.  If a diagnosis is subsequently established, all previously reported adverse events 
based on signs and symptoms should be nullified and replaced by one adverse event 
report based on the single diagnosis, with a starting date that corresponds to the starting 
date of the first symptom of the eventual diagnosis.
5.3.5.2
Adverse Events That Are Secondary to Other Events
In general, adverse events that are secondary to other events (e.g., cascade events or 
clinical sequelae) should be identified by their primary cause, with the exception of 
severe or serious secondary events.  A medically significant secondary adverse event 
that is separated in time from the initiating event should be recorded as an independent 
event on the Adverse Event eCRF.  For example:

If vomiting results in mild dehydration with no additional treatment in a healthy adult, 
only vomiting should be reported on the eCRF.

If vomiting results in severe dehydration, both events should be reported separately 
on the eCRF.

If a severe gastrointestinal hemorrhage leads to renal failure, both events should be 
reported separately on the eCRF.

If dizziness leads to a fall and consequent fracture, all three events should be 
reported separately on the eCRF.

If neutropenia is accompanied by an infection, both events should be reported 
separately on the eCRF.
All adverse events should be recorded separately on the Adverse Event eCRF if it is 
unclear as to whether the events are associated.


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5.3.5.3
Persistent or Recurrent Adverse Events
A persistent adverse event is one that extends continuously, without resolution, between 
patient evaluation timepoints.  Such events should only be recorded once on the 
Adverse Event eCRF.  The initial severity (intensity or grade) of the event will be 
recorded at the time the event is first reported.  If a persistent adverse event becomes 
more severe, the most extreme severity should also be recorded on the Adverse Event 
eCRF.  If the event becomes serious, it should be reported to the Sponsor immediately 
(i.e., no more than 24 hours after learning that the event became serious; see 
Section 5.4.2 for reporting instructions).  The Adverse Event eCRF should be updated 
by changing the event from "non-serious" to "serious," providing the date that the event 
became serious, and completing all data fields related to serious adverse events.
A recurrent adverse event is one that resolves between patient evaluation timepoints 
and subsequently recurs.  Each recurrence of an adverse event should be recorded as a 
separate event on the Adverse Event eCRF.
5.3.5.4
Abnormal Laboratory Values
Not every laboratory abnormality qualifies as an adverse event.  A laboratory test result 
must be reported as an adverse event if it meets any of the following criteria:

Is accompanied by clinical symptoms

Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation)

Results in a medical intervention (e.g., potassium supplementation for hypokalemia) 
or a change in concomitant therapy

Is clinically significant in the investigator’s judgment 
It is the investigator’s responsibility to review all laboratory findings.  Medical and 
scientific judgment should be exercised in deciding whether an isolated laboratory 
abnormality should be classified as an adverse event.
If a clinically significant laboratory abnormality is a sign of a disease or syndrome 
(e.g., ALP and bilirubin 5ULN associated with cholestasis), only the diagnosis 
(i.e., cholestasis) should be recorded on the Adverse Event eCRF.
If a clinically significant laboratory abnormality is not a sign of a disease or syndrome, 
the abnormality itself should be recorded on the Adverse Event eCRF, along with a 
descriptor indicating whether the test result is above or below the normal range 
(e.g., "elevated potassium," as opposed to "abnormal potassium").  If the laboratory 
abnormality can be characterized by a precise clinical term per standard definitions, the 
clinical term should be recorded as the adverse event.  For example, an elevated serum 
potassium level of 7.0 mEq/L should be recorded as "hyperkalemia."


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Observations of the same clinically significant laboratory abnormality from visit to visit 
should only be recorded once on the Adverse Event eCRF (see Section 5.3.5.3 for 
details on recording persistent adverse events).
5.3.5.5
Abnormal Vital Sign Values
Not every vital sign abnormality qualifies as an adverse event.  A vital sign result must
be reported as an adverse event if it meets any of the following criteria:

Is accompanied by clinical symptoms

Results in a change in study treatment (e.g., dosage modification, treatment 
interruption, or treatment discontinuation)

Results in a medical intervention or a change in concomitant therapy

Is clinically significant in the investigator’s judgment 
It is the investigator’s responsibility to review all vital sign findings.  Medical and scientific 
judgment should be exercised in deciding whether an isolated vital sign abnormality 
should be classified as an adverse event.
If a clinically significant vital sign abnormality is a sign of a disease or syndrome 
(e.g., high blood pressure), only the diagnosis (i.e., hypertension) should be recorded on 
the Adverse Event eCRF.
Observations of the same clinically significant vital sign abnormality from visit to visit 
should only be recorded once on the Adverse Event eCRF (see Section 5.3.5.3 for 
details on recording persistent adverse events).
5.3.5.6
Abnormal Liver Function Tests
The finding of an elevated ALT or AST (3ULN) in combination with either an elevated 
total bilirubin (2ULN) or clinical jaundice in the absence of cholestasis or other 
causes of hyperbilirubinemia is considered to be an indicator of severe liver injury (as 
defined by Hy's Law).  Therefore, investigators must report as an adverse event the 
occurrence of either of the following:

Treatment-emergent ALT or AST 3ULN in combination with total bilirubin 
2ULN

Treatment-emergent ALT or AST 3ULN in combination with clinical jaundice
The most appropriate diagnosis or (if a diagnosis cannot be established) the abnormal 
laboratory values should be recorded on the Adverse Event eCRF (see Section 5.3.5.1) 
and reported to the Sponsor immediately (i.e., no more than 24 hours after learning of 
the event) either as a serious adverse event or an adverse event of special interest (see 
Section 5.4.2).


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In addition, liver function abnormalities meeting any of the following criteria need to be 
managed according to Appendix 4:

AST or ALT 5ULN

AST or ALT 3ULN and total bilirubin 2ULN or INR 1.5, if INR is measured

AST or ALT 3ULN with signs and symptoms compatible with hepatitis or 
hypersensitivity
5.3.5.7
Deaths
All deaths that occur during the protocol-specified adverse event reporting period (see 
Section 5.3.1), regardless of relationship to study drug, must be recorded on the 
Adverse Event eCRF and immediately reported to the Sponsor (see Section 5.4.2).  This 
includes death attributed to progression of influenza.  
Death should be considered an outcome and not a distinct event.  The event or condition 
that caused or contributed to the fatal outcome should be recorded as the single medical 
concept on the Adverse Event eCRF.  Generally, only one such event should be 
reported. If the cause of death is unknown and cannot be ascertained at the time of 
reporting, "unexplained death" should be recorded on the Adverse Event eCRF.  If the 
cause of death later becomes available (e.g., after autopsy), "unexplained death" should 
be replaced by the established cause of death.  The term "sudden death" should not be 
used unless combined with the presumed cause of death (e.g., "sudden cardiac death").
If the death is attributed to progression of influenza, "influenza progression" should be 
recorded on the Adverse Event eCRF.  
Deaths that occur after the adverse event reporting period should be reported as 
described in Section 5.6.
5.3.5.8
Preexisting Medical Conditions
A preexisting medical condition is one that is present at the screening visit for this study.  
Such conditions should be recorded on the General Medical History and Baseline 
Conditions eCRF.
A preexisting medical condition should be recorded as an adverse event only if the 
frequency, severity, or character of the condition worsens during the study.  When 
recording such events on the Adverse Event eCRF, it is important to convey the concept 
that the preexisting condition has changed by including applicable descriptors 
(e.g., "more frequent headaches").
5.3.5.9
Lack of Efficacy or Worsening of Influenza
Medical occurrences or symptoms of deterioration that are anticipated as part of 
influenza, such as fluctuations in symptoms, should only be recorded as an adverse 
event if judged by the investigator to have unexpectedly worsened in severity or 
frequency or changed in nature at any time during the study.  When recording an 


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unanticipated worsening of influenza on the Adverse Event eCRF, it is important to 
convey the concept that the condition has changed by including applicable descriptors 
(e.g., "accelerated worsening of influenza").
5.3.5.10
Hospitalization or Prolonged Hospitalization
Any adverse event that results in hospitalization following initial discharge (i.e., in-patient 
admission to a hospital) or prolonged hospitalization (i.e., after the current study 
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 the prolongation of hospitalization under the following 
circumstances should not be reported as an adverse event or a serious adverse event:

Hospitalization for respite care

Hospitalization for a preexisting condition, provided that all of the following criteria 
are met:
–
The hospitalization was planned prior to the study or was scheduled during the 
study when elective surgery became necessary because of the expected 
normal progression of the disease.
The patient has not experienced an adverse event.
An event that leads to the prolongation of 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 patient requirement for outpatient 
care outside of normal outpatient clinic operating hours

Adverse events that would otherwise not require hospitalization
5.3.5.11
Reporting Requirements for Cases of Accidental Overdose or 
Medication Error
Accidental overdose and medication error (hereafter collectively referred to as "special 
situations"), are defined as follows:

Accidental overdose:  accidental administration of a drug in a quantity that is higher 
than the assigned dose

Medication error:  accidental deviation in the administration of a drug 
In some cases, a medication error may be intercepted prior to administration of 
the drug.
Special situations are not in themselves adverse events but may result in adverse 
events.  Each adverse event associated with a special situation should be recorded 
separately on the Adverse Event eCRF.  If the associated adverse event fulfills 
seriousness criteria, the event should be reported to the Sponsor immediately 
(i.e., no more than 24 hours after learning of the event; see Section 5.4.2).  For baloxavir 


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marboxil and 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 baloxavir marboxil and matching 
placebo, regardless of whether they result in an adverse event, should be recorded on
the Adverse Event eCRF and reported to the Sponsor immediately (i.e., no more than 
24 hours after learning of the event).  Special situations should be recorded as described 
below:

Accidental overdose:  Enter the adverse event term.  Check the "Accidental 
overdose" and "Medication error" boxes.

Medication error that does not qualify as an overdose:  Enter the name of the drug 
administered and a description of the error (e.g., wrong dose administered, wrong 
dosing schedule, incorrect route of administration, wrong drug, expired drug 
administered) as the event term.  Check the "Medication error" box.

Medication error that qualifies as an overdose:  Enter the drug name and "accidental 
overdose" as the event term.  Check the "Accidental overdose" and "Medication 
error" boxes.  Enter a description of the error in the additional case details.

Intercepted medication error:  Enter the drug name and "intercepted medication 
error" as the event term.  Check the "Medication error" box.  Enter a description of 
the error in the additional case details.
As an example, an accidental overdose that resulted in a headache would require the 
completion of two Adverse Event eCRF pages, one to report the accidental overdose 
and one to report the headache.  The "Accidental overdose" and "Medication error" 
boxes would need to be checked on both eCRF pages.
5.4
IMMEDIATE REPORTING REQUIREMENTS FROM 
INVESTIGATOR TO SPONSOR
Certain events require immediate reporting to allow the Sponsor to take appropriate 
measures to address potential new risks in a clinical trial.  The investigator must report 
such events to the Sponsor immediately; under no circumstances should reporting take 
place more than 24 hours after the investigator learns of the event.  The following is a list 
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)


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
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 IRB/EC.
5.4.1
Emergency Medical Contacts
Medical Monitor Contact Information:
PPD 24-Hour Safety Hotline:

North America:
1 888 483 7729

EMEA/APAC:44 (0) 1223 374 240

Latin America:
55 11 4504 4801
Roche Medical Monitor/ Medical Responsible:
 M.D.
Mobile Telephone No.:
5.4.2
Reporting Requirements for Serious Adverse Events and 
Adverse Events of Special Interest
5.4.2.1
Events That Occur prior to Study Drug Initiation
After informed consent has been obtained but prior to initiation of study drug, only 
serious adverse events caused by a protocol-mandated intervention should be reported.  
The paper Clinical Trial Serious Adverse Event/Adverse Event of Special Interest 
Reporting Form provided to investigators should be completed and submitted to the 
Sponsor or its designee immediately (i.e., no more than 24 hours after learning of the 
event), either by faxing or by scanning and emailing the form using the fax number or 
email address provided to investigators.
5.4.2.2
Events That Occur after Study Drug Initiation
After initiation of study drug, serious adverse events and adverse events of special 
interest will be reported until 28 days after the last dose of study drug.  Investigators 
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 


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electronic data capture (EDC) system.  A report will be generated and sent to Roche 
Safety Risk Management by the EDC system.
In the event that the EDC system is unavailable, the paper Clinical Trial Serious Adverse 
Event/Adverse Event of Special Interest Reporting Form provided to investigators should 
be completed and submitted to the Sponsor or its designee immediately (i.e., no more 
than 24 hours after learning of the event), either by faxing or by scanning and emailing 
the form using the fax number or email address provided to investigators.  Once the 
EDC system is available, all information will need to be entered and submitted via the 
EDC system.  
Instructions for reporting serious adverse events that occur 28 days after the last dose 
of study treatment are provided in Section 5.6.
5.4.3
Reporting Requirements for Pregnancies
5.4.3.1
Pregnancies in Female Patients
Female patients of childbearing potential will be instructed to immediately inform the 
investigator if they become pregnant during the study or within 28 days after the last 
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 
discontinue study drug and counsel the patient, discussing the risks of the pregnancy 
and the possible effects on the fetus.  Monitoring of the patient 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 Patients
Male patients will be instructed through the Informed Consent Form to immediately 
inform the investigator if their partner becomes pregnant during the study or within 
28 days after the final 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.  Attempts should be made to collect and report details of the course and 
outcome of any pregnancy in the partner of a male patient 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 


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Pregnancy Reporting Form when updated information on the course and outcome of the 
pregnancy becomes available.  An investigator who is contacted by the male patient 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 SAE, 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 
Pregnancy Reporting Form.
5.4.3.4
Congenital Anomalies/Birth Defects
Any congenital anomaly/birth defect in a child born to a female patient 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).
5.5
FOLLOW-UP OF PATIENTS AFTER ADVERSE EVENTS
5.5.1
Investigator Follow-Up
The investigator should follow each adverse event until the event has resolved to baseline 
grade or better, the event is assessed as stable by the investigator, the patient is lost to 
follow-up, or the patient withdraws consent.  Every effort should be made to follow all 
serious adverse events considered to be related to study drug or trial-related procedures 
until a final outcome can be reported.
During the study period, resolution of adverse events (with dates) should be documented 
on the Adverse Event eCRF and in the patient’s medical record to facilitate source data 
verification.
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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 
28 days after the last dose of study drug), if the event is believed to be related to prior 
study drug treatment.  These events should be reported through use of the Adverse 
Event eCRF.  However, if the EDC system is not available, the investigator should report 
these events directly to the Sponsor or its designee, either by faxing or by scanning and 
emailing the paper Clinical Trial Serious Adverse Event/Adverse Event of Special 
Interest Reporting Form using the fax number or email address provided to investigators.
5.7
EXPEDITED REPORTING TO HEALTH AUTHORITIES, 
INVESTIGATORS, INSTITUTIONAL REVIEW BOARDS, AND 
ETHICS COMMITTEES
The Sponsor will promptly evaluate all serious adverse events and adverse events of 
special interest against cumulative product experience to identify and expeditiously 
communicate possible new safety findings to investigators, IRBs, ECs, and applicable 
health authorities based on applicable legislation.
To determine reporting requirements for single adverse event cases, the Sponsor will 
assess the expectedness of these events using the following reference document:

Baloxavir Marboxil Investigator's Brochure
The Sponsor will compare the severity of each event and the cumulative event 
frequency reported for the study with the severity and frequency reported in the 
applicable reference document.
Reporting requirements will also be based on the investigator's assessment of causality 
and seriousness, with allowance for upgrading by the Sponsor as needed.
An iDMC will monitor the incidence of the events listed in Section 5.2.3 during the study.  
An aggregate report of any clinically relevant imbalances that do not favor the test 
product will be submitted to health authorities.


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6.
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN
Efficacy analyses will be conducted for the modified intent-to-treat infected (mITTI) 
population.  This is defined as all patients randomized who received at least one dose of 
study drug and were centrally assessed as RT-PCR positive for influenza at any 
timepoint, with patients grouped according to the treatment assigned at randomization.
Safety analyses will be conducted for the safety population.  This is defined as all 
patients who received at least one dose of study drug, with patients grouped according 
to the treatment received.
The analysis will occur at the end of the study (as defined in Section 3.2).
Detailed specifications of the statistical methods will be described in the Statistical 
Analysis Plan (SAP).
The global population will include all patients enrolled during the global enrollment phase
(If patients from China are enrolled, a China subpopulation will include all patients 
enrolled at National Medical Products Administration [NMPA]-recognized sites).  
Separate analyses may be performed for the global population and the China 
subpopulation (see Section 6.8 for information on the China subpopulation analyses).
6.1
DETERMINATION OF SAMPLE SIZE
Two new factors influenced the revised sample size:  1) the revised assumption for the 
placebo plus NAI control-arm TTCI following blinded data review (Section 6.1.1) and 
2) the faster than anticipated enrollment rate.  Integration of these two factors informed 
a sample size readjustment to approximately 366 randomized patients.  Assuming that 
the RT-PCRpositive rate (tested in a central laboratory) will be 75% of the randomized 
population and a dropout rate of 4%, the modified intent-to-treat (influenza) infected 
(mITTI) population will be 264 patients (i.e., 176 patients in the baloxavir marboxil 
group and 88 in the placebo group).  The total number of randomized patients may 
change based on the percentage of patients who are RT-PCR positive during the study.
The total mITTI sample size of 264 patients provides at least 80% power using the 
Logrank Chi-Square test to detect a 31-hour difference in TTCI between treatment 
groups under the following assumptions: median TTCI in the placebo plus NAI group is 
94 hours, 840 hours follow-up (35 days) using 5% alpha.  The minimal detectable 
difference is expected to be around 23 hours.  The alteration of the TTCI in the placebo 
plus NAI group to 94 hours was selected after consideration of the response rates 
observed in a blinded review (see Section 6.1.1) of TTCI including data from 
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The increased sample size has the consequential benefit of a larger population for safety 
analysis of the combination and multiple dose regimen specifically tested in this study 
for the severely ill hospitalized patient group.
The study power is calculated based on the primary endpoint incorporating a group 
sequential design (GSD) using a beta spending function with non-binding rule, to 
allow for one futility interim, without increasing the overall experiment-wise error rate.
6.1.1
Blinded Sample Size Re-Assessment
The TTCI of 84 hours for the placebo plus NAI arm was selected in the initial study 
design (i.e., protocol version 1) after consideration of response rates observed in prior 
hospitalized studies with similar clinical response endpoints (Marty et al. 2017; 
de Jong et al. 2014).
After the first northern hemisphere flu season recruitment, a blinded evaluation of the 
protocol defined TTCI for all available data was conducted to improve the accuracy of 
assumptions of the length of TTCI in the placebo plus NAI group. The pooled median 
TTCI of this blinded review (94 hours) was selected as the revised assumption for the 
placebo plus NAI group, which resulted in the adjustment of the study sample size 
(Section 6.1).
Given the blinded nature of the evaluation, this has no impact on the overall alpha for 
the study. 
6.2
SUMMARIES OF CONDUCT OF STUDY
The number of patients who are randomized, who are RT-PCR positive, who are treated, 
and who discontinue or complete the study will be summarized by treatment group.  
Reasons for premature study withdrawal will be summarized.  
Eligibility criteria deviations and other major protocol deviations will be listed and 
summarized by treatment group.  
6.3
SUMMARIES OF DEMOGRAPHIC AND BASELINE 
CHARACTERISTICS
Demographic and baseline characteristics (including age, sex, race, region, NEWS2, 
RT-PCR status, time from symptom onset to study treatment) will be summarized using 
means, standard deviations, medians, and ranges for continuous variables and 
proportions for categorical variables, as appropriate.  Summaries will be presented by 
treatment group.  These will be summarized for the modified-ITTI and safety populations.
6.4
EFFICACY ANALYSES
Efficacy analyses will use the mITTI population, which includes all patients randomized 
who received at least one dose of study drug with patients grouped according to the 


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treatment assigned at randomization and are centrally assessed RT-PCR positive for 
influenza at any timepoint.
In addition to the analyses described in Section 6.4.1 and Section 6.4.2, the following
analyses will be performed for the primary efficacy endpoint and the key secondary 
efficacy endpoints, as appropriate. Details of these analyses will be described in the 
SAP:

Sensitivity analyses to evaluate the robustness of results to the primary analysis
methods (e.g., handling of dropouts)

Descriptive subgroup analyses to evaluate the consistency of results across 
prespecified subgroups (e.g., based on age, sex, race/ethnicity, stratification factors, 
and patients taking anti-influenza drugs prior to enrollment)
Hypothesis tests will be two-sided at the 5% significance level, unless stated otherwise.
To manage the overall type I error, the endpoints will be tested sequentially. The order 
of testing will be as follows:

TTCI

Response rates of the 6-point ordinal scale at Day 7

Time to Clinical Response
If the primary efficacy analysis hypothesis test result is not statistically significant
(i.e. p 0.05), the hypothesis below that result in the hierarchical chain will be 
considered exploratory and no claims of statistical significance will be made. The same 
rules apply to the next endpoint in the chain.
6.4.1
Primary Efficacy Endpoint
The primary efficacy objective for this study is to evaluate the efficacy of baloxavir 
marboxil plus a SOC NAI, compared with matching placebo plus SOC NAI on the basis 
of the following endpoint:

TTCI (defined as time to hospital discharge or  time to NEWS2 of 2 and maintained 
for 24 hours, whichever comes first)
The median TTCI will be compared between the baloxavir marboxil plus SOC NAI and 
matching placebo plus SOC NAI arms using the stratified log-rank test within three
regions (i.e., North America, EMEA, ROW), NEWS2 (7, 7), and time from symptom 
onset to study treatment (48 hours, 48 hours) included as the stratification factors.  
The Kaplan-Meier plot, median time to response, 95% CIs, and p-values will be 
presented.
The log-rank test requires the assumption of proportional hazards to be met.  The 
proportional hazards assumption will be tested graphically using the log cumulative 
hazard plot by treatment group.  The plots for each treatment group will be parallel if the 


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proportional hazard assumption holds. Using a Cox model, the slope of a linear 
regression will also be tested and a plot of scaled Schoenfeld residuals against the 
Kaplan-Meier estimator investigated.
Should the proportional hazards assumption be violated, the Gehan-Wilcoxon test will be 
used to analyze the data as the logrank test can be under powered in this situation. 
All investigations will be detailed in the statistical section of the CSR.  
The estimand is the median change in TTCI.  This absolute measure will be assessed 
over the duration of the study (35 days).  Intercurrent events are those that occur after 
treatment initiation and either preclude observation of the variable or affect its 
interpretation.  Intercurrent events will be accounted for through censoring rules.  
Patients who are lost to follow-up, who do not have a clinical response event, who die or 
discontinue for any reason prior to achieving a clinical response event will be censored 
at their last contact date or date of death, whichever is applicable. No dose reductions 
or treatment cross-overs are anticipated.  
As specified in Section 6.4, the primary efficacy analysis population will be the 
modified-ITTI population, which consists of all patients who were randomized to 
treatment, received a dose of study drug, and were RT-PCR positive for influenza at any 
timepoint.
A sensitivity analysis will be conducted where patients who are lost to follow-up or who
do not have a clinical response event will be assumed to have had an event at 28 days.  
A sensitivity analysis for patients who discontinue for any reason prior to achieving a 
clinical response event will be performed to investigate potential confounding factors.
A sensitivity analysis, considering death as a competitive event, using a competing risk 
model will be conducted if there are a sufficient number of deaths or an imbalance 
between groups in deaths and reason attributed.  These and any further sensitivity 
analyses will be fully detailed in the SAP.
Missing data handling rules for the components of the NEWS2 score will be specified in 
the SAP.
6.4.2
Key Secondary Endpoints
6.4.2.1
6-Point Ordinal Scale Measured at Day 7
For the key secondary endpoint of 6-point ordinal scale the response rate of the scale 
will be measured at Day 7.  The 6-point ordinal scale will be analyzed using the 
Cochran-Mantel-Haenszel test statistic stratified by region (i.e., North America, EMEA, 
ROW), NEWS2 (7, 7), and time from symptom onset to study treatment (48 hours, 
48 hours).
For the ordinal endpoint, missing data will be imputed by using the patient’s last 
non-missing score for any patient with a missing response at Day 7.  If the patient died 


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prior to Day 7, the patient will be included in the death category.  The proportion of 
patients with a response in each category will be summarized by treatment group and 
Cochran-Mantel-Haenszel test statistic result presented.  
A sensitivity analysis will be conducted where missing scores at Day 7 will be replaced 
by the patient’s last non-missing score 1 (i.e., one ordinal category worse).  If the 
patient died prior to or on Day 7, the patient will be included in the death category.  
6.4.2.2
Time to Clinical Response
The additional key secondary endpoint of the “time to clinical response” will be based 
upon hospital discharge, fever, and oxygen saturation, and two or more of the following:  
improved respiratory status, heart rate, or systolic blood pressure.  The exact criteria 
for each parameter are as follows:
Temperature:a

36·6°C (97·9°F)axillary, or 

37·2°C (99°F)oral, or 

37·7°C (99·9°F)rectal, core, or tympanic 
AND 
Oxygen Saturation:b,c

95% (without supplemental oxygen) 
AND two of the following three: 
Respiratory Status:

Return to pre-morbid oxygen requirement (patients with chronic oxygen use), OR 

Need for supplemental oxygen (given in any way–ventilator, non-invasive ventilation, 
facemask, face-tent, or nasal cannula) to no need for supplemental oxygen, OR 

Respiratory rate 24 per min (without supplemental oxygen) 
Heart Rate:

100 beats per min 
Systolic blood pressure:d

90 mmHg 
OR 
Hospital Discharge


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a Without the use of antipyretics within 8 hours. 
b A patient with a history of chronic hypoxia (without supplemental oxygen) will satisfy the 
normalization criteria for oxygen saturation if the value (without supplemental oxygen) is 2% 
from the patient’s historical oxygen saturation before enrollment as documented in the patient’s 
medical records, if available  
c This requirement is waived for patients with a history of chronic supplemental oxygen 
requirement who have an oxygen saturation 95% with supplemental oxygen documented in 
the patients’ medical records within 12 months of enrollment.
d Without inotropic support given within 2 hours of assessment.
For patients who achieve four of the five vital sign resolution criteria above, both the temperature 
and oxygen saturation response criteria must be maintained for 24 hours for the clinical response 
endpoint to be met.
Time to clinical response will be analyzed using similar methods and sensitivity analyses 
as specified for the primary endpoint.  Patients who are lost to follow-up, who do not 
have a clinical response, or who die will be censored at their last contact date or date of 
death, whichever is applicable. Further details on methods and missing data rules will 
be fully detailed in the SAP.
6.4.3
Secondary Efficacy Endpoints
The other secondary endpoints for this study are as follows:

The incidence of mechanical ventilation

Duration of mechanical ventilation

Incidence of ICU stay

Duration of ICU stays

Time to clinical failure (defined as the time to death, mechanical ventilation, or ICU 
admission, corresponding to ordinal scale categories 6, 5, and 4, respectively, from 
baseline)

Time to hospital discharge

Incidence of influenza-related complications (pneumonia, myositis or rhabdomyolysis, 
encephalitis or encephalopathy, myocarditis and/or pericarditis, otitis media, sinusitis, 
exacerbation of COPD/asthma, sepsis, acute lung injury, or acute respiratory 
distress syndrome)*

Mortality rate at Day 7

Mortality rate at Day 28

Time to NEWS2 of 2 maintained for 24 hours
* Specific complication eCRF pages with diagnostic criteria for the complications of pneumonia, 
myositis or rhabdomyolysis, encephalitis or encephalopathy, myocarditis and/or pericarditis, 
otitis media, sinusitis, exacerbation of COPD/asthma, sepsis, acute lung injury, or acute 
respiratory distress syndrome will be utilized for these events reported as adverse events after 
the initiation of study treatment.  This data will be subject to a blinded manual medical review 
of events together with other related eCRF data (e.g., serious adverse event forms as 
applicable and medical history).


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Secondary efficacy incidence and rate endpoints will be analyzed using the 
Cochran-Mantel-Haenszel test statistic stratified by region (North America, EMEA, 
ROW), NEWS2 (7, 7) and time from symptom onset to study treatment (48 hours, 
48 hours).
Time to event secondary efficacy endpoints will be analyzed using similar methods as 
specified for the primary endpoint.  Patients who are lost to follow-up, who do not have a 
response, or who die will be censored at their last contact date or date of death, 
whichever is applicable.
Mortality rates and duration of ICU stays and ventilation will be analyzed descriptively.
6.4.4
Virology Endpoints
The virology endpoints for this study are as follows:

Time to cessation of viral shedding by virus titer and by RT-PCR
The time to cessation of viral shedding will be analyzed using similar methods as 
specified for the primary endpoint.  Patients who are lost to follow-up, who do not 
have cessation of viral shedding, or who die will be censored at their last contact 
date or date of death, whichever is applicable.

Change from baseline in influenza virus titer and in the amount of virus RNA 
(RT-PCR) at each timepoint

Proportion of patients with positive influenza virus titer and proportion of patients 
positive by RT-PCR at each time point

Area under the curve (AUC) over time in virus titer and amount of virus RNA 
(RT-PCR)
For the incidence and rate endpoints, missing data imputations will be specified in the 
SAP.
For incidence and rate endpoints, the difference in proportions, 95% CIs, and the 
p-values will be presented.  
Continuous endpoints, such as change from baseline endpoints, will be analyzed using 
an analysis of covariance (ANCOVA) model with region (North America, EMEA, ROW), 
NEWS2 (7, 7), and time from symptom onset to study treatment (48 hours, 
48 hours) as stratification variables, and the baseline value of the studied measure as 
a covariate.
The additional virology endpoints are as follows:

Polymorphic and treatment-emergent amino acid substitutions in the PA, PB1, PB2, 
and NA genes

Drug susceptibility in patients with evaluable virus


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The additional virology endpoints will be summarized descriptively. Further details will 
be described in a resistance analysis plan.
6.4.5
Exploratory Palatability and Acceptability Endpoint
The palatability and acceptability endpoint for patients that receive the study treatment 
(baloxavir marboxil or matching placebo) oral suspension on Days 1, 4, and 7 
(if additional study treatment is administered on Day 7) will be summarized 
descriptively. 
The number and proportion of patients within each response category for the 
palatability and acceptability questions from the questionnaire ( Appendix 5) will be 
presented for the following:

Overall taste on a scale of 1 to 5

Whether the patient would be happy to take the medicine again (yes, no, not sure/no 
answer)
No formal statistical analyses will be performed.
6.5
SAFETY ANALYSES
The safety analysis population will consist of all randomized patients who received at 
least one dose of study drug, with patients grouped according to treatment received. 
All verbatim adverse event terms will be mapped to MedDRA thesaurus terms, and 
adverse event severity will be graded according to the NCI CTCAE v5.0 scale.
Safety will be assessed through descriptive summaries of adverse events, vital sign 
measurements, and laboratory test results (serum chemistry and hematology including 
complete blood count with differential and platelet counts).
A treatment-emergent adverse event is defined as any new adverse event reported or 
any worsening of an existing condition on or after the first dose of study drug. 
Separate summaries will be generated for serious adverse events, deaths, adverse 
events leading to discontinuation of study drug, and adverse events of special interest. 
Adverse events will be summarized by MedDRA term, appropriate thesaurus level, and 
toxicity grade.
Descriptive summaries of laboratory values at baseline and throughout the study will be 
tabulated by treatment arm. For selected parameters, changes from baseline and the 
proportion of patients experiencing clinically significant changes relative to baseline will 
be summarized by treatment arm.


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6.6
PHARMACOKINETIC ANALYSES
The PK analysis population will consist of patients who provided at least one measurable 
postdose concentration at a scheduled visit timepoint. Patients may be excluded from 
the PK analysis population only if they significantly violate the inclusion or exclusion 
criteria or deviate significantly from the protocol, or if data are unavailable or incomplete.  
Decisions on patient exclusion from the PK analysis population will be made prior to 
database closure by the clinical pharmacologist.  Excluded patients will be documented, 
together with the reason for exclusion.
For all patients, individual baloxavir concentration data will be listed by day and by 
timepoint postdose.  Plasma levels of baloxavir will be summarized (i.e., mean, standard 
deviation, coefficient of variation, median, minimum, and maximum) by day and 
timepoint postdose.  Individual and mean plasma baloxavir concentrations versus time 
data will be plotted (i.e., a separate figure panel for each of the three doses).  In addition, 
for patients who provided sparse PK data, the distribution of plasma baloxavir 
concentrations will also be presented by means of a boxplot (i.e., a separate figure for 
each dose, X-axis category time postdose).
Non-compartmental PK parameters (e.g., AUC, time to maximum concentration, Cmax, 
half-life) will only be derived for patients who underwent the non-sparse (sequential) PK 
sampling regimen (Appendix 2) and who provided sufficient data to allow estimation of 
such parameters.  The following non-compartmental PK parameters will be derived for 
each individual after the first and second dose:  AUC0-72h, Cmax, C24, and terminal 
half-life (as appropriate for data collected).  AUCinf and clearance at steady state will be 
reported after the first dose, only.  Drug accumulation will be assessed based on the 
AUC0-72h ratio between the second and first baloxavir marboxil dose.  Estimates for 
these parameters will be tabulated and summarized (i.e., mean, standard deviation, 
coefficient of variation, median, minimum, and maximum).  Inter-patient variability 
will be evaluated based on the summary statistics of the individual PK parameter 
estimates.
All tables, listings, and figures derived from PK data (concentrations or parameters) 
obtained from patients who underwent the sequential PK sampling (Appendix 2) will be 
presented separately (i.e., not pooled with data from patients who underwent sparse PK
sampling).
Non-linear mixed effect modelling will be used to characterize the population 
pharmacokinetics of baloxavir in the target population.  The population typical PK 
model parameters (e.g., apparent clearance [CL/F], apparent volume of distribution for 
the central compartment [Vc/F]), and their covariates will be estimated.  Individual PK 
parameters may also calculated using post hoc Bayesian estimation for each patient, 
and plotted against significant covariates identified (e.g., body weight, age). The derived 
PK parameters will be tabulated and summarized (i.e., by mean, standard deviation, 
coefficient of variation, median, and minimum and maximum). PK exposure and 


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response (e.g., virus titers) relationships will be explored.  The population PK model 
outcomes will be reported in a stand-alone report outside of the clinical report.
Additional PK analyses will be conducted as appropriate.
6.7
INTERIM ANALYSIS
6.7.1
Planned Interim Analysis
After approximately 65% of TTCI events, a formal unblinded non-binding futility 
interim analysis based on the TTCI will be performed.  The futility interim analysis 
will use a Lan-DeMets Pocock beta spending function.  If the hazard ratio seen at the 
interim is below the calculated futility bound, the trial may be declared futile and 
recruitment will be stopped. 
The futility interim is non-binding on the Sponsor, and any deviation from the iDMC 
recommendation will be fully documented in the CSR.  If the study is stopped for 
futility, at that point the study results will be reported.  Full operating characteristics 
of the interim analysis will be detailed in the SAP.
The interim analysis will be conducted by an unblinded external statistical group 
(independent Data Coordinating Centre [iDCC]) and reviewed by the iDMC (also 
unblinded), whilst the Sponsor will remain blinded until the end of study.  Interactions 
between the iDMC/iDCC and Sponsor will be carried out as specified in the iDMC 
Charter. 
The iDMC Charter will be updated to document this pre-planned interim analysis and
potential recommendations the iDMC can make to the Sponsor as a result of the 
analysis (e.g., stop the study for futility or continue the study), and the iDMC Charter will 
also be made available to relevant health authorities.
6.8
CHINA SUBPOPULATION ANALYSES
If patients in China are enrolled, the China subpopulation will include all patients enrolled 
at NMPA-recognized sites.  Results from these analyses may be summarized in a 
separate clinical study report.
7.
DATA COLLECTION AND MANAGEMENT
7.1
DATA QUALITY ASSURANCE
The Sponsor will be responsible for data management of this study, including quality 
checking of the data.  Data entered manually will be collected via EDC through use of 
eCRFs.  Sites will be responsible for data entry into the EDC system.  In the event of 
discrepant data, the Sponsor will request data clarification from the sites, which the sites 
will resolve electronically in the EDC system.


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The Sponsor will produce an EDC Study Specification document that describes the 
quality checking to be performed on the data. Central laboratory data and IxRS data will 
be sent directly to the Sponsor, using the Sponsor’s standard procedures to handle and 
process the electronic transfer of these data.
eCRFs and correction documentation will be maintained in the EDC system’s audit trail.  
System backups for data stored by the Sponsor and records retention for the study data 
will be consistent with the Sponsor’s standard procedures.
7.2
ELECTRONIC CASE REPORT FORMS 
eCRFs are to be completed through use of a Sponsor-designated EDC system.  Sites 
will receive training and have access to a manual for appropriate eCRF completion.  
eCRFs will be submitted electronically to the Sponsor and should be handled in 
accordance with instructions from the Sponsor.
All eCRFs should be completed by designated, trained site staff.  eCRFs should be 
reviewed and electronically signed and dated by the investigator or a designee.
At the end of the study, the investigator will receive patient data for his or her site in a 
readable format on a compact disc that must be kept with the study records.  
Acknowledgement of receipt of the compact disc is required.
7.3
SOURCE DATA DOCUMENTATION
Study monitors will perform ongoing source data verification and review to confirm that 
critical protocol data (i.e., source data) entered into the eCRFs by authorized site 
personnel are accurate, complete, and verifiable from source documents. 
Source documents (paper or electronic) are those in which patient data are recorded 
and documented for the first time.  They include, but are not limited to, hospital records, 
clinical and office charts, laboratory notes, memoranda, patient-reported outcomes
(PROs), evaluation checklists, pharmacy dispensing records, recorded data from 
automated instruments, copies of transcriptions that are certified after verification as 
being accurate and complete, microfiche, photographic negatives, microfilm or magnetic 
media, X-rays, patient files, and records kept at pharmacies, laboratories, and 
medico-technical departments involved in a clinical trial.
Before study initiation, the types of source documents that are to be generated will be 
clearly defined in the Trial Monitoring Plan.  This includes any protocol data to be 
entered directly into the eCRFs (i.e., no prior written or electronic record of the data) and 
considered source data.
Source documents that are required to verify the validity and completeness of data 
entered into the eCRFs must not be obliterated or destroyed and must be retained per 
the policy for retention of records described in Section 7.5.


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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, electronic or paper patient-reported outcome (PRO) data 
(if applicable), Informed Consent Forms, laboratory test results, and medication 
inventory records, must be retained by the Principal Investigator for 15 years after 
completion or discontinuation of the study or for the length of time required by relevant 
national or local health authorities, whichever is longer.  After that period of time, the 
documents may be destroyed, subject to local regulations.  
No records may be disposed of without the written approval of the Sponsor.  Written 
notification should be provided to the Sponsor prior to transferring any records to 
another party or moving them to another location.
Roche will retain study data for 25 years after the final Clinical Study Report has been 
completed or for the length of time required by relevant national or local health 
authorities, whichever is longer.
8.
ETHICAL CONSIDERATIONS
8.1
COMPLIANCE WITH LAWS AND REGULATIONS
This study will be conducted in full conformance with the ICH E6 guideline for Good 
Clinical Practice and the principles of the Declaration of Helsinki, or the applicable laws 
and regulations of the country in which the research is conducted, whichever affords the 
greater protection to the individual.  The study will comply with the requirements of the
ICH E2A guideline (Clinical Safety Data Management:  Definitions and Standards for 
Expedited Reporting).  Studies conducted in the United States or under a U.S. 
Investigational New Drug (IND) Application will comply with U.S. Food and Drug 
Administration regulations and applicable local, state, and federal laws.  Studies 


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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 Form (and ancillary sample Informed Consent 
Forms such as a Child’s Informed Assent Form or Mobile Nursing Informed Consent 
Form, if applicable) will be provided to each site.  If applicable, it will be provided in a 
certified translation of the local language.  The Sponsor or its designee must review and 
approve any proposed deviations from the Sponsor's sample Informed Consent Forms 
or any alternate consent forms proposed by the site (collectively, the "Consent Forms") 
before IRB/EC submission.  The final IRB/ECapproved Consent Forms must be 
provided to the Sponsor for health authority submission purposes according to local 
requirements.
If applicable, the Informed Consent Form will contain separate sections for any optional 
procedures.  The investigator or authorized designee will explain to each patient the 
objectives, methods, and potential risks associated with each optional procedure.  
Patients will be told that they are free to refuse to participate and may withdraw their 
consent at any time for any reason.  A separate, specific signature will be required to 
document a patient's agreement to participate in optional procedures.  Patients who 
decline to participate will not provide a separate signature.
The Informed Consent Forms must be signed and dated by the patient or the patient’s 
legally authorized representative(s) before his or her participation in the study.  The case 
history or clinical records for each patient shall document the informed consent process 
and that written informed consent was obtained prior to participation in the study.
The Consent Forms should be revised whenever there are changes to study procedures 
or when new information becomes available that may affect the willingness of the patient 
to participate.  The final revised IRB/EC-approved Consent Forms must be provided to 
the Sponsor for health authority submission purposes.
Patients 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 Informed Consent Form must be provided to the patient or the 
patient’s legally authorized representative(s).  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.


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For sites in the United States, each Consent Form may also include patient 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 patient 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 patient, 
and relevant supporting information must be submitted to the IRB/EC by the Principal 
Investigator and reviewed and approved by the IRB/EC before the study is initiated.  
In addition, any patient recruitment materials must be approved by the IRB/EC. 
The Principal Investigator is responsible for providing written summaries of the status of 
the study to the IRB/EC annually or more frequently in accordance with the requirements, 
policies, and procedures established by the IRB/EC.  Investigators are also responsible 
for promptly informing the IRB/EC of any protocol amendments (see Section 9.6).
In addition to the requirements for reporting all adverse events to the Sponsor, 
investigators must comply with requirements for reporting serious adverse events to the 
local health authority and IRB/EC.  Investigators may receive written IND safety reports 
or other safety-related communications from the Sponsor.  Investigators are responsible 
for ensuring that such reports are reviewed and processed in accordance with health 
authority requirements and the policies and procedures established by their IRB/EC, and 
archived in the site’s study file. 
8.4
CONFIDENTIALITY
The Sponsor maintains confidentiality standards by coding each patient enrolled in the 
study through assignment of a unique patient identification number.  This means that 
patient names are not included in data sets that are transmitted to any Sponsor location.
Patient medical information obtained by this study is confidential and may be disclosed 
to third parties only as permitted by the Informed Consent Form (or separate 
authorization for use and disclosure of personal health information) signed by the patient, 
unless permitted or required by law.
Medical information may be given to a patient’s personal physician or other appropriate 
medical personnel responsible for the patient’s welfare, for treatment purposes.
Given the complexity and exploratory nature of exploratory biomarker analyses, data 
derived from these analyses will generally not be provided to study investigators or 
patients unless required by law.  The aggregate results of any conducted research will 


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be available in accordance with the effective Roche policy on study data publication (see
Section 9.5).
Data generated by this study must be available for inspection upon request by 
representatives of national and local health authorities, Sponsor monitors, 
representatives, and collaborators, and the IRB/EC for each study site, as appropriate.
8.5
FINANCIAL DISCLOSURE
Investigators will provide the Sponsor with sufficient, accurate financial information in 
accordance with local regulations to allow the Sponsor to submit complete and accurate 
financial certification or disclosure statements to the appropriate health authorities.  
Investigators are responsible for providing information on financial interests during the 
course of the study and for 1 year after completion of the study (see definition of end of 
study in Section 3.2).
9.
STUDY DOCUMENTATION, MONITORING, AND 
ADMINISTRATION
9.1
STUDY DOCUMENTATION
The investigator must maintain adequate and accurate records to enable the conduct of 
the study to be fully documented, including, but not limited to, the protocol, protocol 
amendments, Informed Consent Forms, and documentation of IRB/EC and 
governmental approval.  In addition, at the end of the study, the investigator will receive 
the patient data, including an audit trail containing a complete record of all changes to 
data.
9.2
PROTOCOL DEVIATIONS
The investigator should document and explain any protocol deviations. The investigator 
should promptly report any deviations that might have an impact on patient safety and 
data integrity to the Sponsor and to the IRB/EC in accordance with established IRB/EC 
policies and procedures.  The Sponsor will review all protocol deviations and assess 
whether any represent a serious breach of Good Clinical Practice guidelines and require 
reporting to health authorities.  As per the Sponsor's standard operating procedures, 
prospective requests to deviate from the protocol, including requests to waive protocol 
eligibility criteria, are not allowed.
9.3
SITE INSPECTIONS
Site visits will be conducted by the Sponsor or an authorized representative for 
inspection of study data, patients' medical records, and eCRFs.  The investigator will 
permit national and local health authorities; Sponsor monitors, representatives, and 
collaborators; and the IRBs/ECs to inspect facilities and records relevant to this study.


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9.4
ADMINISTRATIVE STRUCTURE
This trial will be sponsored and managed by F. Hoffmann-La Roche Ltd.  The Sponsor 
will provide clinical operations management, data management, and medical monitoring.
Approximately 250 sites globally in both Northern and Southern hemispheres will 
participate to enroll approximately 366 patients.  Enrollment will occur through an IxRS.  
Central facilities will be used for certain study assessments throughout the study 
(e.g., specified laboratory tests and PK analyses), as specified in Section 4.5.  
Accredited local laboratories will be used for routine monitoring; local laboratory ranges 
will be collected.
An iDMC will be employed to monitor and evaluate patient safety throughout the study.
9.5
PUBLICATION 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), and redacted 
Clinical Study Reports and other summary reports will be made available upon request, 
provided the requirements of Roche's global policy on data sharing have been met.  For 
more information, refer to the Roche Global Policy on Sharing of Clinical Trials Data at 
the following website:
www.roche.com/roche_global_policy_on_sharing_of_clinical_study_information.pdf
The results of this study may be published or presented at scientific congresses.  For all 
clinical trials in patients involving an IMP for which a marketing authorization application 
has been filed or approved in any country, the Sponsor aims to submit a journal 
manuscript reporting primary clinical trial results within 6 months after the availability of 
the respective Clinical Study Report.  In addition, for all clinical trials in patients involving 
an IMP for which a marketing authorization application has been filed or approved in any 
country, the Sponsor aims to publish results from analyses of additional endpoints and 
exploratory data that are clinically meaningful and statistically sound.
The investigator must agree to submit all manuscripts or abstracts to the Sponsor prior 
to submission for publication or presentation.  This allows the Sponsor to protect 
proprietary information and to provide comments based on information from other 
studies that may not yet be available to the investigator.
In accordance with standard editorial and ethical practice, the Sponsor will generally 
support publication of multicenter trials only in their entirety and not as individual center 
data.  In this case, a coordinating investigator will be designated by mutual agreement.


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Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements.  Any formal publication 
of the study in which contribution of Sponsor personnel exceeded that of conventional 
monitoring will be considered as a joint publication by the investigator and the 
appropriate Sponsor personnel.
Any inventions and resulting patents, improvements, and/or know-how originating from 
the use of data from this study will become and remain the exclusive and unburdened 
property of the Sponsor, except where agreed otherwise.
9.6
PROTOCOL AMENDMENTS
Any protocol amendments will be prepared by the Sponsor.  Protocol amendments will 
be submitted to the IRB/EC and to regulatory authorities in accordance with local 
regulatory requirements.
Approval must be obtained from the IRB/EC and regulatory authorities (as locally 
required) before implementation of any changes, except for changes necessary to 
eliminate an immediate hazard to patients or changes that involve logistical or 
administrative aspects only (e.g., change in Medical Monitor or contact information).


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10.
REFERENCES
Centers for Disease Control and Prevention (CDC), National Center for Immunization 
and Respiratory Diseases (NCIRD). Influenza Antivirial Medications: Summary for 
Clinicians. Retreived from 
https://www.cdc.gov/flu/professionals/antivirals/summary-clinicians.htm. Revised 
February 23, 2018. Accessed March 30, 2018.
de Jong ME, Ison MG, Monto AS, et al. Evaluation of Intravenous Peramivir for 
Treatment of Influenza in Hospitalized Patients. Clin Infect Dis 
2014;59(12):e172-85.
Fiore AE, Fry A, Shay D, et al. Centers for Disease Control and Prevention (CDC). 
Antiviral agents for the treatment and chemoprophylaxis of influenza—
recommendations of the Advisory Committee on Immunization Practices (ACIP). 
MMWR Recomm Rep 2011;60:124.
Harper SA, Bradley JS, Englund JA, et al. Expert Panel of the Infectious Diseases 
Society of America. Seasonal influenza in adults and childrendiagnosis, 
treatment, chemoprophylaxis, and institutional outbreak management: clinical 
practice guidelines of the Infectious Diseases Society of America. Clin Infect Dis 
2009;48:100332.
Hu Y, Lu S, Song Z, et al. Association between adverse clinical outcome in human 
disease caused by novel influenza A H7N9 virus and sustained viral shedding and 
emergence of antiviral resistance. Lancet 2013;381:22739.
Kitano M, Yamamoto A, Noshi T, et al. Synergistic antiviral activity of 
S-033188/S-033447, a novel inhibitor of influenza virus cap-dependent 
endonuclease, in combination with neuraminidase inhibitors in vitro. Open Forum 
Infect Dis 2017;4(Suppl 1):S371.
Lee N, Chan PK, Hui DS, et al. Viral loads and duration of viral shedding in adult 
patients hospitalized with influenza. J Infect Dis 2009,200:492500.
Lee N, Ison MG. Diagnosis, management and outcomes of adults hospitalized with 
influenza. Antivir Ther 2012;17(1 Pt B):14357.
Marty FM, Vidal-Puigserver J, Clark C, et al. Intravenous zanamivir or oral oseltamivir for 
hospitalised patients with influenza: an international, randomised, double-blind, 
double-dummy, phase 3 trial. Lancet Respir Med 2017;5(2):135-46.
Muthuri SG, Venkatesan S, Myles PR, et al. Effectiveness of neuraminidase inhibitors in 
reducing mortality in patients admitted to hospital with influenza A H1N1pdm09 
virus infection: a meta-analysis of individual participant data. Lancet Respir Med 
2014;2:395404. 
Paules C, Subbarao K. Influenza. Lancet 2017;390:697708.
Rothberg MB, Haessler SD. Complications of seasonal and pandemic influenza. Crit 
Care Med 2010;38:e917.
Royal College of Physicians. National early warning score (NEWS) 2 Standardising the 
assessment of acute-illness severity in the NHS. London: RCP, 2017.


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Appendix 1
Schedule of Activities
Treatment Perioda
Follow-Up Period
Unsched 
Visit
Day(s)
D1
D2
D3
D4 D5 D6
D7
D8 D9
D10
(2 day) b
Hosp Day 
11+c
Discharged 
D1130 d
EOS
D35
(3 day) d
Visits
Screeninge
Random/
V1
V2
V3
V4 V5
V6
V7
V8
V9
Administrative Procedures
Informed consent and assent 
x
Inclusion/Exclusion criteria
x
Baseline characteristics
x
Medical history
x
Concomitant medication monitoring
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Clinical Procedures
Physical examination f
x f
x
x
x
x
x
x
x
x
x
x
x
xg
x g
x h
Body weight
x
x g
Vital sign measurementsi, j, k
x
x
x
x
x
x
x
x
x
x
x
x
xg
xg
x h
Assessment of consciousness i, j, k
x
x
x
x
x
x
x
x
x
x
x
x
xg
x g
x h
Presence or absence of respiratory 
support i, j, k
x
x
x
x
x
x
x
x
x
x
x
x
xg
x g
xh
Full blood hematology and chemistry l
x m
x
x  g
xg
xg
x h
Blood liver chemistry l
x m
x m
Electrocardiogram n
x
x
Chest X-ray/CT Scano
x
(x)


Appendix 1
Schedule of Activities (cont.)
Baloxavir Marboxil—F. Hoffmann-La Roche Ltd
84/Protocol CP40617, Version 2
Treatment Perioda
Follow-Up Period
Unsched 
Visit
Day(s)
D1
D2
D3
D4 D5 D6
D7
D8 D9
D10
(2 day) b
Hosp Day 
11+c
Discharged 
D1130 d
EOS
D35
(3 day) d
Visits
Screeninge
Random/
V1
V2
V3
V4 V5
V6
V7
V8
V9
Nasopharyngeal swabs for local 
testing (RIDT or RT-PCR )  p
x
Nasopharyngeal swabs for central 
testing (non-influenza respiratory 
virus coinfections; RT-PCR; titer; 
phenotyping and genotyping, drug 
susceptibility test)q
x
x
x
x
x
x
x
x g
xg
x g
xh
Blood for influenza antibody titer
x
x
Pregnancy test r
x
x
xh
Adverse events s
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Ordinal scale recordingt
x
x
x
x
x
x
x
x
x
x
x
x
Study Drug Administration
Baloxavir marboxil/placebo u
x m
x m
x m
SOC NAIv
x
x
Meal intake documentation w
x
x
x
Palatability & acceptability 
assessment z
x
x
x
Pharmacokinetic Assessments
Plasma PK samples for baloxavirw, x, y
x
x
x
x
x
x


Appendix 1
Schedule of Activities (cont.)
Baloxavir Marboxil—F. Hoffmann-La Roche Ltd
85/Protocol CP40617, Version 2
CTcomputed tomography; Dday; EOSend of study; HospHospitalized; NAIneuraminidase inhibitor; PKpharmacokinetics; 
NEWS2National Early Warning Score 2; Random Randomization; RIDT Rapid Influenza Diagnostic Test; RT-PCRreverse transcription
polymerase chain reaction; SOCstandard-of-care; UnschedUnscheduled; Vvisit; VHP Voluntary Harmonization Procedure.
a.
During the treatment period, Visits 17 should be performed for all patients regardless if they remain hospitalized or have been discharged.  On 
non-visit Days 6, 8, and 9, procedures are only to be conducted for patients who remain hospitalized.
b.
A visit window of 2 days applicable for discharged patients only. 
c.
Hospitalized Days 11+:  procedures are to be conducted for patients who remain hospitalized, only.  
d.
The follow-up visit, Visit 8, should occur after hospital discharge, but not before Day 11 or within 5 days before the EOS visit.  Visit 8 should
occur after Visit 7. The EOS visit should occur approximately 28 days after the last dose of study drug.
e.
Randomization should occur as soon as possible, ideally within 12 hours, after screening.
f.
A complete physical examination should be conducted at screening. At post-baseline visits and as clinically indicated, limited, 
symptom-directed physical examinations should be performed. Examinations should occur on a daily basis during the hospitalization and at 
each return visit after discharge.  See Section 4.5.3 for definitions of complete and limited, symptom-directed physical examinations.
g.
Clinical procedures/nasopharyngeal swabs may be undertaken at investigator’s discretion if symptoms and signs persist beyond the treatment 
period or if viral shedding is detected beyond Day 10.
h.
Perform assessments at any unscheduled visits based upon the cause of the visit and the investigator’s discretion.
i.
During the study treatment period (Day 1/Visit 1 to Day 10), all vital sign measurements (i.e., respiratory rate, pulse rate, peripheral oxygen 
saturation, systolic and diastolic blood pressures, and body temperature) and NEWS2-specific assessments (i.e., consciousness and presence 
or absence of respiratory support) should be recorded together four times per day, and spread throughout the day, for the duration of the 
hospitalization and once at each return visit to the clinic following hospital discharge up to Day 10 (Visit 7). During the follow-up period, for 
patients who remain in hospital, vital sign measurements and NEWS2-specific assessments should be conducted once per day.  In patients 
who have been discharged, vital sign measurements and NEWS2-specific assessments are to be recorded at the investigators’ discretion (e.g.,
if symptoms and signs persist during follow-up).
j.
Should be assessed according to NEWS2 parameters (see Appendix 3).  Presence or absence of respiratory support per the NEWS2 
parameter may be air or oxygen; “oxygen” can include other forms of ventilation to maintain oxygen saturations.
k.
The NEWS2 should be calculated by the site at screening only to determine patient eligibility based upon vital sign values and assessments 
related to National Early Warning Score 2 (see Section 4.5.5) recorded during the patient assessment. Should these assessments be conducted 
more than once during the screening period (per site patient care), all data collected closest to but before randomization should be used for 
the NEWS2 score calculation and assessment of patient eligibility.  See Appendix 3 for calculation instructions.
l.
See Section 4.5.7 for tests included in laboratory panels.
m.
Local laboratory liver function test results to be reviewed by the investigator before baloxavir marboxil, or its matching placebo, is administered.  
On Day 1 and Day 4, the assessment is mandatory. On Day 1, the local laboratory full blood chemistry panel required as part of screening can 
be used for this assessment or prior blood results if tests conducted within 24 hours prior to screening. On Day 4, the protocol required local 
laboratory blood liver chemistry panel should be used for this assessment.  On Day 7, the local laboratory blood liver chemistry panel and 
associated review of liver chemistry is only required if the patient will receive baloxavir marboxil or matching placebo on this study day.


Appendix 1
Schedule of Activities (cont.)
Baloxavir Marboxil—F. Hoffmann-La Roche Ltd
86/Protocol CP40617, Version 2
n.
This assessment cannot be conducted by a mobile nurse.
o.
If a chest X-ray has not been taken within the 24 hours prior to screening, it must be performed on Day 1.  If a chest X-ray was performed within 
24 hours prior to screening, no additional chest X-ray needs to be performed.  If the SOC is a chest CT scan, this can be used as alternative to 
the chest X-ray.  The chest X-ray/CT scan must not be performed any later than Day 1.  This assessment cannot not be conducted by a mobile 
nurse.  
p.
Nasopharyngeal swabs for RIDTs or RT-PCR: Rapid influenza test or RT-PCR should be performed at screening or conducted within 24 hours 
prior to screening, and can be undertaken by a local test kit or Sponsor-provided kit.  
q.
Patients who are intubated will have endotracheal samples (aspirates) taken for virological assessment, in addition to two nasopharyngeal 
swabs at each timepoint, including at the screening visit.
r.
All women of childbearing potential will have a pregnancy test at screening (urine or serum).  For those countries under VHP (i.e., Belgium, 
Czech Republic, Estonia, Finland, France, Germany, Hungary, Romania, Spain, and Sweden), as well as the Netherlands, a serum 
pregnancy test is mandated at screening. Urine pregnancy tests (for all women of childbearing potential) will be performed at the end of study 
visit and at unscheduled visits (as required). If a urine pregnancy test is positive, a serum pregnancy test must be performed.
s.
Adverse events should be recorded on a daily basis during the hospitalization and at each return visit after discharge.  
t.
Assessment of patient status using the ordinal scale should be recorded at baseline on Day 1/Visit 1 then again daily every morning (between 
8 am and 12 pm) for patients who remain hospitalized.
u.
Study treatment dosing will occur on Day 1 and Day 4, with a further dose at Day 7 for patients who have not improved at Day 5.  Specific 
criteria must be met for additional dosing at Day 7 include ongoing mechanical ventilation, persistence of fever, severely immunocompromised, 
confirmed/suspected influenza-related complication, or pneumonia. Study treatment will be given in the hospital setting due to the requirement 
for pre-dose liver function monitoring.  In order to maximize the study blind, it is mandated that each site delegates the preparation of 
baloxavir marboxil and placebo granules to dedicated site personnel that are not involved in any other study related assessments or 
procedures.  Dose administration cannot be conducted by a mobile nurse.
v.
The SOC NAI should to be administered to cover the minimum treatment exposure from Day 1 through Day 5, where possible.  This may be 
extended to Day 10 or beyond, at the discretion of the investigator and in accordance with clinical practice (see Section 4.3.2.2 for further 
guidance).
w.
The time of last food intake prior to dosing with study treatment and the fasting period following study treatment should be recorded on Days 1 
and 4, as well as on Day 7 if additional study treatment is administered.
x.
Sparse PK samples:  See Appendix 2.
y.
Sequential PK samples: See Appendix 2. Although sequential PK sampling is optional the protocol aim is to attempt to collect it from a
maximum of 12 patients.
z
Palatability and acceptability assessments are to be conducted for patients that take study treatment as an oral suspension, and are awake 
and compos mentis during administration on Day 1 and Day 4 (as well as Day 7 if an additional dose is required). The time of assessment 
should be completed approximately 1 minute after swallowing the drug solution, and before rinsing the mouth.


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Appendix 2
Schedule of Pharmacokinetic Samples
Visit
Timepoint
Sample 
Type
Sparse PK Sampling (all patients)
Post-randomization/
Visit 1 (Day 1)
0.52 hours, 46 hours, and 1012 hours postdose
plasma
Visit 2 (Day 2)
24 (2) hours postdose
plasma
Visit 4 (Day 4)
pre-dose a
plasma
Visit 5 (Day 5)
24 (2) hours postdose
plasma
Visit 6 (Day 7)
pre-dose (72 hours postdose) b
plasma
Visit 8 (Days 1130 or 
Hospital Day 11+)
Collect one sample during the washout/follow-up period
plasma
Rich (sequential) PK samples (optional in a total of maximum 12 patients)
Post-randomization/V1
(Day 1)
30 (15) min, 2 hours (15 min), 4 hours (30 min), and 
10 (1) hours postdose
plasma
Visit 2 (Day 2)
24 (2) hours postdose
plasma
Visit 4 (Day 4)
pre-dosea, 30 (15) min, 2 hours (15 min), 4 hours
(30 min), and 10 (1) hours postdose
plasma
Visit 5 (Day 5)
24 (2) hours postdose
plasma
Visit 6 (Day 7)
pre-dose (72 hour postdose) b and 4 hours (30 min) c
postdose
plasma
Day 8 
24 (2) hours postdose c
plasma
Visit 8 (Days 1130 or 
Hospital Day 11+)
Collect one sample during the washout/follow-up period
plasma
PKpharmacokinetic.
Note:  All PK samples are for determining plasma levels of baloxavir.
a Collect sample immediately prior (within 3 hours) to dosing on Day 4.
b Collect sample immediately prior (within 3 hours) to dosing on Day 7.  If no dose is given 
on Day 7, take sample as a 72-hour (± 3 hours) after Day 4 dose sample.
c Collect sample only if a dose is administered on Day 7.


Baloxavir Marboxil—F. Hoffmann-La Roche Ltd
88/Protocol CP40617, Version 2
Appendix 3
National Early Warning Score 2 (NEWS2)
Reference
Royal College of Physicians. National early warning score (NEWS) 2 Standardizing the assessment of 
acute-illness severity in the NHS. London: RCP, 2017.
At screening, the NEWS2 should be calculated based upon vital sign values recorded 
during the patient assessment. Should these vital signs assessments be recorded more 
than once during the screening period (per site patient care) all data collected closest to 
but before randomization should be used for the NEWS2 score calculation and 
assessment of patient eligibility.
The oxygen saturation should be scored according to either the SpO2 Scale 1 or 2
presented in the table above. The SpO2 Scale 2 is for patients with a target oxygen 
saturation requirement of 88%92% (e.g., in patients with hypercapnic respiratory failure 
related to advanced lung diseases, such as chronic obstructive pulmonary 
disease [COPD]). This should only be used in patients confirmed to have hypercapnic 
respiratory failure by blood gas analysis on either a prior or their current hospital 
admission.
The decision to use the SpO2 Scale 2 should be made by the treating physician and 
should be recorded in the eCRF. In all other circumstances, the SpO2 Scale 1 should be 
used.


Appendix 3
National Early Warnig Score 2 (NEWS2) (cont.)
Baloxavir Marboxil—F. Hoffmann-La Roche Ltd
89/Protocol CP40617, Version 2
For physiological parameter “Air or Oxygen?”: Any patients requiring the use of oxygen 
or other forms of ventilation to maintain oxygen saturations and support respiration 
should be assigned a score of 2.
The consciousness level should be recorded according to the best clinical condition of 
the patient during the assessment. Patients who are assessed as “Alert” (A) should be 
assigned a score of 0. Patients assessed as “New Confusion” (C), “Responsive to Voice”
(V), “Responsive to Pain” (P), or “Unconscious” should be assigned a score of 3.
Scores should be assigned for respiratory rate, systolic blood pressure, pulse, and 
temperature according to the table above. 
The NEWS2 should be recorded in the eCRF at the screening visit to ensure patients 
meet the eligibility criteria.  In addition to the total NEWS2, the individual components of 
the score should also be recorded in the eCRF. Additional NEWS2 values will be 
calculated electronically throughout the study by the Sponsor based upon entry of vital 
sign parameters by the investigator in the appropriate eCRF.
Example Case Calculation:
A 82-old lady was admitted to an acute medical unit from a residential care home. Her 
taken observations and corresponding NEWS2 score are as follows: 
Physiological Parameter 
Observation
Component Score
Respiratory rate (per min)
26
3
Oxygen saturations (SpO2 %)
95%
1
Supplemental Oxygen 
No
0
Systolic blood pressure (mmHg)
140
0
Pulse Rate (bpm)
109
1
Conscious level
Alert
0
Temperature (oC)
39
1
Total NEWS2 Score
6


Baloxavir Marboxil—F. Hoffmann-La Roche Ltd
90/Protocol CP40617, Version 2
Appendix 4
Management Criteria for Abnormal Liver Function Tests
Management Criteria for Abnormal Liver Function tests have been designed to ensure
patient safety and evaluate liver event etiology (see Guidance for Industry Drug-Induced
Liver Injury: Premarketing Clinical Evaluation, FDA: 2009; available from: 
https://www.fda.gov/downloads/Guidances/UCM174090.pdf).
Abnormal Liver Chemistry Criteria
The investigator or subinvestigator must review study patient laboratories to identify if
any levels meet the following criteria:

AST or ALT 5upper limit of normal (ULN)

AST or ALT 3ULN and total bilirubin (TBL) 2ULN or INR 1.5, if INR is 
measured

AST or ALT 3ULN with signs or symptoms compatible with hepatitis or 
hypersensitivity (e.g., fatigue, nausea, vomiting, right upper quadrant pain or 
tenderness, jaundice, fever, rash, eosinophilia [5%])
Action to be Taken by Investigator
If any abnormal liver chemistry criterion is met, the investigator or subinvestigator must
do the following:

Patients must be instructed to discontinue study medication immediately.

Following the initial observed elevation, every effort should be made to have the
patient return to the clinic within 72 hours (if already discharged from hospital) to 
repeat liver function chemistries and for further hepatic evaluation.

Every effort should be made to have the patients monitored 2 to 3 times per week
until liver function chemistries (i.e., ALT, AST, ALP, TBL) resolve, stabilize per 
investigator judgement, or return to within the normal range or to baseline levels.

Consultation with a specialist, such as a hepatologist, and liver imaging 
(i.e., ultrasound, magnetic resonance imaging [MRI], computerized tomography) 
should be considered for worsening laboratory values or symptoms.


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91/Protocol CP40617, Version 2
Appendix 5
Palatability and Acceptability Assessment of Study Drug
Questionnaire A:  Adolescent (Age 12 to 15 Years) Palatibility and 
Acceptability Assessment of Study Treatment Suspension (Baloxavir Marboxil 
or Placebo)
STUDY CP40617
Site Number:
Visit Number: 
Patient Number: 
Date: 
Date
Month
Year
Instructions:  

Questionnaire A is to be utilized for adolescents aged 1215 years unless they are 
considered to have a sufficient level of understanding to complete Questionnaire 
version B (Adolescents 16 years and above and adults).

The questions below are to be completed approximately 1 minute after swallowing 
the drug solution and before rinsing the mouth.

For Question 1, patients are encouraged to select, from the 5-point visual hedonic 
scale below, the face that best reflects how much he or she liked the taste of the 
ingested study drug solution.

This questionnaire can be given to the patient to complete or the form can be 
completed by study personnel. The patient must provide answers to the questions.  
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
Page 1 of 1


Appendix 5
Palatability and Acceptability Assessment of Study Drug (cont.)
Baloxavir Marboxil—F. Hoffmann-La Roche Ltd
92/Protocol CP40617, Version 2
Questionnaire B:  Adult and Adolescent (Age 16 Years and Above) Palatability 
and Acceptability Assessment of Study Treatment Suspension 
(Baloxavir Marboxil or Placebo)
STUDY CP40617
Site Number:
Visit Number: 
Patient Number: 
Date:
Date
Month
Year
Instructions:  

Questionnaire B is to be utilized for adults and adolescents (age 16 years and above).

The questions below are to be completed approximately 1 minute after swallowing 
the drug solution and before rinsing the mouth. 

This questionnaire can be given to the patient to complete or the form can be 
completed by study personnel. The patient must provide answers to the questions.  
1.
How would you rate the overall taste of the medicine at this moment?
Please tick a box between 1 (very pleasant) and 5 (very unpleasant).





1 (very pleasant)
2
3
4
5 (very unpleasant)
2.
Would you be happy to take the medicine again?

yes

no

not sure/no answer
Page 1 of 1

SAP_001.pdf: 
 
Official Title: 
A Phase III, Randomized, Double-Blind Placebo-Controlled, 
Multicenter Study To Evaluate the Efficacy and Safety of Baloxavir 
Marboxil in Combination With Standard-of-Care Neuraminidase 
Inhibitor in Hospitalized Participants With Severe Influenza 
NCT Number: 
NCT03684044 
Document Date: 
SAP Version 3: 07-May-2020 
 
 




Baloxavir Marboxil —F. Hoffmann-La Roche Ltd
2/Statistical Analysis Plan CP40617
TABLE OF CONTENTS
STATISTICAL ANALYSIS PLAN AMENDMENT RATIONALE............................. 5
1.
BACKGROUND ............................................................................................ 6
2.
STUDY DESIGN........................................................................................... 6
2.1
Description of the Study........................................................... 6
2.2
Protocol Synopsis.................................................................... 7
2.3
Objectives and Endpoints........................................................ 7
2.4
Determination of Sample Size ................................................. 9
2.5
Analysis Timing ..................................................................... 10
2.5.1
Planned Interim Analyses...................................................... 10
3.
STUDY CONDUCT..................................................................................... 11
3.1
Randomization, Stratification and blinding............................. 11
3.2
Safety Data Monitoring .......................................................... 11
3.3
Deviations from Protocol....................................................... 12
4.
STATISTICAL METHODS .......................................................................... 12
4.1
Analysis Populations ............................................................. 12
4.1.1
ITT Population ....................................................................... 12
4.1.2
Modified Intent-to-Treat Infected Population.......................... 12
4.1.3
Pharmacokinetic Population .................................................. 12
4.1.4
Sparse Pharmacokinetic Population...................................... 13
4.1.5
Extensive Pharmacokinetic Population.................................. 13
4.1.6
Safety Population .................................................................. 13
4.2
Analysis of Study Conduct..................................................... 13
4.3
Analysis of Treatment Group Comparability .......................... 13
4.3.1
Baseline Stratification Factors ............................................... 14
4.3.2
Demographics ....................................................................... 14
4.3.3
Disease Characteristics and Influenza History ...................... 14
4.4
Visit Windows ........................................................................ 15
4.5
Efficacy Analysis.................................................................... 16
4.5.1
Primary Efficacy Endpoint...................................................... 17
4.5.1.1
Sensitivity Analysis ................................................................ 19


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3/Statistical Analysis Plan CP40617
4.5.2
Key Secondary Efficacy Endpoints........................................ 19
4.5.2.1
6-Point Ordinal Scale Measured at Day 7.............................. 19
4.5.2.2
Sensitivity Analysis ................................................................ 20
4.5.2.3
Time to Clinical Response..................................................... 20
4.5.3
Other Secondary Efficacy Endpoints ..................................... 24
4.5.4
Subgroup Analyses ............................................................... 29
4.6
Virology Endpoints................................................................. 30
4.6.1
Exploratory Endpoints............................................................ 33
4.6.2
Subgroup Analyses ............................................................... 35
4.7
Safety Analyses..................................................................... 35
4.7.1
Adverse Events ..................................................................... 35
4.7.2
Deaths ................................................................................... 37
4.7.3
Laboratory Data..................................................................... 37
4.7.4
Vital Signs.............................................................................. 37
4.7.5
ECG....................................................................................... 38
4.7.6
Exposure to Study Medication............................................... 38
4.7.7
Exposure to SOC NAI Medication ......................................... 38
4.8
Pharmacokinetic Analyses..................................................... 39
4.8.1
Standard PK Analyses........................................................... 39
4.8.2
Population PK Modelling........................................................ 39
4.9
Exploratory Analyses............................................................. 40
4.9.1
Palatability and Acceptability ................................................. 40
4.9.2
Adolescent Population........................................................... 40
4.10
Missing Data.......................................................................... 40
5.
REFERENCES ........................................................................................... 42
LIST OF TABLES
Table 1
Objectives and Corresponding Endpoints..................................... 8
Table 2
Acceptable Time Windows – Laboratory Parameters ................. 16
Table 3
TTCI Calculations ....................................................................... 17
Table 4
TTCI and Censoring.................................................................... 18
Table 5
Ordinal Scale and Missing Data.................................................. 20
Table 6
TTCR Calculation........................................................................ 22
Table 7
TTCR and Censoring.................................................................. 23
Table 8
Duration of Mechanical Ventilation and Missing Data................. 24


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4/Statistical Analysis Plan CP40617
Table 9
Time to Clinical Failure and Censoring ....................................... 26
Table 10
Time to hospital discharge and Censoring.................................. 27
Table 11
Time to NEWS2 of 2 maintained for 24 hours and 
Censoring.................................................................................... 28
Table 12
Time to Viral Shedding and Censoring ....................................... 30
Table 13
PB1 and PB2 Sequencing........................................................... 34
Table 14
Pre-specified Abnormal Laboratory Criteria ................................ 37
Table 15
Handling for Missing Data........................................................... 40
LIST OF FIGURES
Figure 1
Study Schema............................................................................... 7
LIST OF APPENDICES
Appendix 1
Protocol Synopsis ....................................................................... 43
Appendix 2
Schedule of Activities.................................................................. 50
Appendix 3
Schedule of Pharmacokinetic Samples....................................... 54
Appendix 4
National Early Warning Score 2 (NEWS2).................................. 55
Appendix 5
Palatability and Acceptability Assessment of Study Drug 
Questionnaire.............................................................................. 57
Appendix 6
Immunocompromised Patient Population ................................... 59


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5/Statistical Analysis Plan CP40617
STATISTICAL ANALYSIS PLAN AMENDMENT
RATIONALE
This Statistical Analysis Plan (SAP) has been amended to incorporate the following 
changes:
Endpoint
Update
6-Point Ordinal 
Scale Measured at 
Day 7

Included clarification of the analysis to be conducted, 
including details of exploratory analysis

Included sensitivity analysis to add a score of 1 to the last 
non-missing value (except if last non-missing was death) as 
per protocol.
ECG

Included Section 4.7.5 to present ECG data.
Urinalysis 

Removed urinalysis as this data is not being collected.

Included pregnancy listing.
Definition of 
immunocompromised 
patient population 

Update to appendix 6 criteria which outlines the criteria used 
to define the immunocompromised subgroup analysis of the 
TTCI primary endpoint 
Incidence and 
duration of ICU stay 
and mechanical 
ventilation 

Included additional analysis to include patients who had 
incidence of ICU stay/mechanical ventilation prior to 
randomization and who continued to be in ICU/on 
mechanical ventilation after receiving first treatment.
Additional minor changes have been made to improve clarity and consistency.


Baloxavir Marboxil —F. Hoffmann-La Roche Ltd
6/Statistical Analysis Plan CP40617
1.
BACKGROUND
This Statistical Analysis Plan (SAP) provides details of the planned analyses and 
statistical methods for the clinical efficacy, clinical safety and pharmacokinetic (PK) data 
for Study CP40617, Protocol Version(v) 2.0.
Baloxavir marboxil (also referred to as S-033188, Shionogi Compound Identification
Number) is a pro-drug that is converted to an active form (baloxavir, S-033447) in the
blood, liver, and small intestine through a metabolic process called hydrolysis.
Baloxavir marboxil acts on cap-dependent endonuclease, an enzyme specific to 
influenza viruses, and inhibits viral cap-snatching, thereby suppressing the replication of 
influenza viruses.
2.
STUDY DESIGN
2.1
DESCRIPTION OF THE STUDY
Study CP40617 is a Phase III, randomized, double-blind, placebo-controlled, multicenter 
study to assess the efficacy, safety, and PK of baloxavir marboxil 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 
approximately 366 hospitalized adults and adolescent patients (aged 12 years) with 
influenza.
Patients will be randomized in a 2:1 ratio to receive baloxavir marboxil or matching 
placebo. Study treatment must be given in combination with a SOC NAI according to 
investigator preference (i.e., oseltamivir, zanamivir, or peramivir). 
The study consists of two periods: a 10-day treatment period and a 25-day follow-up 
period. Therefore, the maximum study duration for each patient will be 35 days. 
This study will be conducted at approximately 250 global sites in both Northern and 
Southern hemispheres.
An external independent Data Monitoring Committee (iDMC) will evaluate safety 
according to policies and procedures detailed in an iDMC Charter. Additionally, the 
iDMC will review the primary efficacy data for futility at time of interim analysis.
Figure 1 presents an overview of the study design. A schedule of activities is provided in
Appendix 2
.


Baloxavir Marboxil —F. Hoffmann-La Roche Ltd
7/Statistical Analysis Plan CP40617
Figure 1
Study Schema
NAIneuraminidase inhibitor; SOC standard-of-care.
a All patients will receive at least two doses of baloxavir marboxil or its matching placebo 
(i.e., Days 1 and 4).  A third dose may also be administered on Day 7 if clinical improvement is 
not observed at Day 5 according to protocol defined criteria.
b A SOC NAI should be administered to cover a minimum of treatment exposure from Day 1 to 
Day 5.  This treatment may be extended to Day 10 or beyond, at the discretion of the 
investigator and in accordance with local clinical practice. 
2.2
PROTOCOL SYNOPSIS
The Protocol Synopsis is in Appendix 1 and includes the study objectives, inclusion and 
exclusion criteria, outcome measures, and statistical methods as stated in the Protocol.
2.3
OBJECTIVES AND ENDPOINTS
This study will evaluate the efficacy, safety, and pharmacokinetics of baloxavir marboxil 
in combination with a SOC NAI (i.e., oseltamivir, zanamivir, or peramivir) compared with 
a matching placebo in combination with a SOC NAI in hospitalized patients with 
influenza. Specific objectives and corresponding endpoints for the study are outlined in
Table 1.


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8/Statistical Analysis Plan CP40617
Table 1
Objectives and Corresponding Endpoints
Primary Objective
Corresponding Endpoint
To evaluate the clinical efficacy of 
baloxavir marboxil plus a SOC NAI 
compared with matching placebo 
plus a SOC NAI 
TTCI defined as:

Time to hospital discharge OR

Time to NEWS2 of 2 maintained for 24 hours
Efficacy Objectives
Corresponding Endpoints
To evaluate the clinical efficacy of 
baloxavir marboxil plus a SOC NAI 
compared with matching placebo plus 
a SOC NAI 
Key Secondary Endpoint:
Response rates of the 6-point ordinal scale at Day 7
Time to clinical response based on temperature ranges, 
oxygen saturation, respiratory status, heart rate, and 
hospitalization statusa
Other Secondary Endpoints:
Incidence of mechanical ventilation
Duration of mechanical ventilation
Incidence of ICU stay 
Duration of ICU stay
Time to clinical failure, defined as the time to death, 
mechanical ventilation, or ICU admission, 
corresponding to ordinal scale categories 6, 5, and 4, 
respectively, from baseline
Time to hospital discharge 
Incidence of post-treatment influenza-related 
complicationsb
Mortality rate at Day 7 
Mortality rate at Day 28
Time to NEWS2 of 2 maintained for 24 hours
Virology Objectives
Corresponding Endpoints
To evaluate the virological activity of 
baloxavir marboxil plus a SOC NAI 
compared with matching placebo plus 
a SOC NAI 
Time to cessation of viral shedding by virus titer
Time to cessation of viral shedding by RT-PCR
Change from baseline in influenza virus titer and in the 
amount of virus RNA (RT-PCR) at each timepoint
Proportion of patients with positive influenza virus titer 
and proportion of patients positive by RT-PCR at each 
timepoint
AUC in virus titer and in the amount of virus RNA 
(RT-PCR)
To evaluate the polymorphic and 
treatment-emergent amino acid 
substitutions in the PA, PB1, PB2, 
and NA genes and drug susceptibility 
in patients with evaluable virus
Polymorphic and treatment-emergent amino acid 
substitutions in the PA, PB1, PB2, and NA genes
Drug susceptibility in patients with evaluable virus


Baloxavir Marboxil —F. Hoffmann-La Roche Ltd
9/Statistical Analysis Plan CP40617
Table 1
Objectives and Corresponding Endpoints (cont.)
Safety Objective
Corresponding Endpoints
To evaluate the safety of baloxavir 
marboxil plus a SOC NAI compared 
with matching placebo plus a SOC 
NAI in hospitalized patients with 
influenza
Compare the incidence and severity of AEs and SAEs
Incidence of AEs leading to discontinuation
Proportion of patients with any post-treatment ALT and 
AST above baseline and 3 ULN, 5 ULN, 
10 ULN
Pharmacokinetic Objective
Corresponding Endpoints
To evaluate the single- and 
multiple-dose pharmacokinetics of 
baloxavir 
Plasma concentrations of baloxavir (active metabolite) 
at specified timepoints
After each dose, concentration at predose and 24 hours 
postdose will be summarized 
Non-compartmental PK parameters such as AUC, Cmax
and t1/2 (only for patients undergoing sequential PK 
sampling) 
Exploratory Palatability Objective
Corresponding Endpoint
To evaluate palatability of the oral 
suspension in hospitalized patients 
with influenza
Number and proportion of patients reporting each
palatability and acceptability response at each timepoint
AEadverse event; AUCarea under the concentration-time curve; Cmaxmaximum plasma 
concentration; ICU = intensive care unit; NAIneuraminidase inhibitor; NEWS2National Early 
Warning Score 2; PKpharmacokinetic; RT-PCRreverse transcriptase polymerase chain 
reaction; SAEserious adverse event; SOCstandard-of-care; t½half-life; TTCItime to clinical 
improvement; ULNupper limited normal.
a
Criteria for each parameter noted in Section 6.4.2 of the Clinical Study Protocol (CSP).
b
Incidence of post-treatment influenza-related complications as defined in Section 6.4.3 of the CSP.
2.4
DETERMINATION OF SAMPLE SIZE
The required sample size of the modified intent-to-treat infected (mITTI) population is 
264 patients (176 patients in the baloxavir marboxil group and 88 in the placebo group).  
It is assumed that the reverse transcriptase polymerase chain reaction 
(RT-PCR)positive rate (tested in a central laboratory) will be 75% of the randomized 
population; hence, approximately 366 patients will be randomized to ensure an adequate 
number of patients in the mITTI population and to allow for a 4% dropout rate.  The total 
number of randomized patients may change based on the percentage of patients who 
are RT-PCR positive during the study.
The total mITTI sample size of 264 patients provides at least 80% power using the 
log-rank Chi-Square test to detect a 31-hour difference in the time to clinical 
improvement (TTCI) between treatment groups under the following assumptions: median 
TTCI in the placebo plus NAI group is 94 hours, 840 hours follow-up (35 days), using an 
alpha of 5%, and the minimal detectable difference is 23 hours.  The TTCI in the placebo 
plus NAI group of 94 hours was selected after consideration of the response rates 
observed in a blinded review of TTCI including data from 127 patients. 


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10/Statistical Analysis Plan CP40617
The study power is calculated based on the primary endpoint incorporating a group 
sequential design (GSD) using a beta spending function with non-binding rule, to allow 
for one futility interim, without increasing the overall experiment-wise error rate.
2.5
ANALYSIS TIMING
The primary study analysis will occur when the last patient has either withdrawn or 
completed Day 35 visit, and will be based on cleaned data for all patients up to and 
including this point.
2.5.1
Planned Interim Analyses
After approximately 65% of TTCI events, a formal unblinded non-binding futility interim 
analysis (IA) based on the TTCI will be performed on the mITTI population. Enrollment 
will continue during the IA conduct.
The IA will be conducted by an unblinded external statistical group (independent Data 
Coordinating Centre [iDCC]) and reviewed by the iDMC (also unblinded), while the 
Sponsor will remain blinded until the end of study. Interactions between the iDMC/iDCC 
and Sponsor will be carried out as specified in the iDMC Charter. The iDMC Charter 
details the pre-planned interim analysis and potential recommendations the iDMC can 
make to the Sponsor as a result of the analysis (e.g., stop the study for futility or 
continue the study). 
The futility interim analysis will use a Lan-DeMets Pocock beta spending function. The 
TTCI will be compared between treatment groups using a log-rank test adjusting for the 
stratification factor applied at randomization (i.e. region, National early warning score 2 
[NEWS2] score, and time from symptom onset to study treatment), if the assumption of 
proportional hazards holds. 
If the p-values seen at the interim is above the calculated futility bound (~p0.077), and 
the iDMC members agree, based on their expert opinion, that there is no clinically 
meaningful difference in the TTCI, the trial may be declared futile and recruitment will be 
stopped. The futility bound will be re-calculated based on the final percentage of events 
in the IA.
Should the proportional hazards assumption be violated, the Gehan Wilcoxon test will be 
used to analyze the data. If the p-value is above the calculated futility bound (~p-
value0.077) and the iDMC members agree, based on their expert opinion, that there is 
no clinically meaningful difference in the TTCI, the trial may be declared futile and 
recruitment will be stopped.
As the interim analysis is non-binding, the iDMC may choose to continue the study 
despite the futility boundary being crossed if they determine that there appears to be 
some evidence of a treatment effect from their evaluation of all the available TTCI data.


Baloxavir Marboxil —F. Hoffmann-La Roche Ltd
11/Statistical Analysis Plan CP40617
The expected RT-PCR positive rate of 75% will be continuously monitored prior to the IA 
to ensure this RT-PCR positive rate assumption is correct. The timing of the IA will be 
adjusted accordingly.
The futility interim is non-binding on the Sponsor, and any deviation from the iDMC 
recommendation will be fully documented in the Clinical Study Report (CSR). If the 
study is stopped for futility, all recorded data up to that point will be reported for inclusion 
in a full study report.
3.
STUDY CONDUCT
3.1
RANDOMIZATION, STRATIFICATION AND BLINDING 
Following completion of screening and after all patient eligibility requirements are 
confirmed, patients will undergo randomization in a 2:1 ratio stratified by three regions 
(i.e., North America; Europe, Middle East, and Africa [EMEA]; and rest of world [ROW]), 
NEWS2 score (7, 7), and time from symptom onset to study treatment (48 hours, 
48 hours).
All patients will receive either baloxavir marboxil or its matching placebo. A 
permuted-block randomization method will be used to obtain an approximate 2:1 ratio 
between the active treatment group and the placebo group within each stratum. The 
placebo and active kits are filled and packaged to look identical.
Patients, investigators, and the Sponsor will be blinded to treatment assignment.
At study completion, stratification variables recorded in the Interactive Voice/Web 
Response System (IxRS) will be compared to the stratification variables recorded on the 
electronic Case Report Form (eCRF) to identify any mis-stratifications. These will be 
listed for all patients. If it is found that 10% of mis-stratifications occurred, a sensitivity 
analysis will be carried out on the primary endpoint, using the eCRF stratification 
variables in the model.
3.2
SAFETY DATA MONITORING
An iDMC will evaluate safety during the study on a regular basis. All summaries and 
analyses by treatment group for the iDMC review are prepared by an external iDCC. 
Members of the iDMC are external to the Sponsor and follow a separate iDMC Charter 
that outlines their roles and responsibilities.  Further details can be found in the iDMC 
charter.


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12/Statistical Analysis Plan CP40617
3.3
DEVIATIONS FROM PROTOCOL
Since the finalization of the Protocol v2.0, the following updates have been made to the 
planned analysis:
Planned Interim Analysis
The statistic used to determine futility in the planned interim analysis per Protocol v2.0 
was the hazard ratio: 
–
If the hazard ratio seen at the interim is below the calculated futility bound, the trial 
may be declared futile and recruitment will be stopped.
This has been updated to the pvalue, to ensure consistency between the proportional 
hazards and non-proportional hazards scenarios in the analysis:
–
If the p-value seen at the interim is above the calculated futility bound, the trial may 
be declared futile and recruitment will be stopped.
Clinical Response Definition 
Clinical Response is defined per protocol as: 
–
For patients who achieve four of the five vital sign resolution criteria, both the 
temperature and oxygen saturation response criteria must be maintained for 
24 hours for the clinical response endpoint to be met or hospital discharge, 
whichever occurs first.
This has been updated to:
–
Clinical response is defined as resolution of at least 4 of the 5 vital signs within the
respective resolution criteria, maintained for at least 24 hours, or hospital discharge, 
whichever occurs first.
4.
STATISTICAL METHODS
4.1
ANALYSIS POPULATIONS
4.1.1
ITT Population
The intent-to-treat (ITT) population is defined as all randomized patients, whether or not 
the patient received the assigned treatment. The ITT patients will be analyzed according 
to the treatment assigned at randomization.
4.1.2
Modified Intent-to-Treat Infected Population
Efficacy analyses will be conducted for the mITTI population.  This is defined as all 
patients randomized who received at least one dose of study drug and were centrally 
assessed as RT-PCR positive for influenza at any timepoint, with patients grouped 
according to the treatment assigned at randomization.
4.1.3
Pharmacokinetic Population
The PK population will consist of patients who received any amount of study treatment 
and who provided at least one measurable post-dose concentration at a scheduled visit 


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timepoint. Patients may be excluded from the PK population only if they significantly 
violate the inclusion or exclusion criteria, deviate significantly from the protocol, or if data 
are unavailable or incomplete. Decisions on patient exclusion from the PK population 
will be made prior to database closure by the clinical pharmacologist. Excluded patients 
will be documented, together with the reason for exclusion.
4.1.4
Sparse Pharmacokinetic Population
The sparse PK population comprises all patients in the PK population who did not 
provide informed consent to intensive PK sampling. Decisions on patient exclusion from 
the sparse PK population will be made prior to database closure by the clinical 
pharmacologist. Excluded patients will be documented, together with the reason for 
exclusion. Patients with a dose modification during the course of the treatment will be 
fully documented but will not be excluded from the population PK analysis.
4.1.5
Extensive Pharmacokinetic Population
The extensive PK population comprises all patients in the PK population who provided 
informed consent to intensive PK sampling.
4.1.6
Safety Population
The safety population is defined as patients who received any amount of study treatment. 
Patients will be analyzed according to the treatment received. Patients who were 
randomized to the study but who did not receive any study drug will not be included in 
the safety population.
4.2
ANALYSIS OF STUDY CONDUCT
The number of patients who are randomized (ITT population), who are RT-PCR positive, 
who are treated (safety population), who are included in the mITT population and who 
discontinue or complete the study will be summarized by treatment group.  Reasons for 
premature study withdrawal from treatment and from study will be both summarized.
Major protocol deviations will be listed and evaluated for their potential effects on the 
interpretation of study results.
4.3
ANALYSIS OF TREATMENT GROUP COMPARABILITY
To descriptively assess the comparability of treatment arms at baseline, summary tables 
will be produced for both the safety and mITTI population for clinically important baseline 
demographics and disease characteristics by treatment group. 
These summary tables will include number of patients, mean, standard deviation, 
median, minimum, maximum, first and third quartiles (Q1 and Q3) for continuous 
demographic/disease characteristics and number and percentage of patients for 
categorical characteristics.


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Demographic and baseline disease characteristics will be summarized as described in
the following sections.
4.3.1
Baseline stratification factors
Baseline stratification factors as recorded in the IxRS will be presented as follows:

NEWS2 (7, >7)

Time from symptom onset to study treatment (48 hours, >48 hours)

Regions (i.e., North America; EMEA; and ROW)
4.3.2
Demographics
Frequency tabulations for:

Age:
–
(65, 65 years)
–
(80, 80 years)

Sex (male, female)

Ethnicity (Hispanic or Latino, Not Hispanic or Latino)
–
Race (American Indian or Alaska Native, Asian, Black or African American, Native 
Hawaiian or Other Pacific Islander, White, Unknown)
–
Region (North America; EMEA; and ROW)
–
Female fertility status (Childbearing Potential, Surgically Sterile, Post-menopausal, 
Pre-menarchal)
–
Tobacco use history (never, current, previous)
–
Alcohol use history (never, current, previous)
–
Current substance use (yes, no)
will be presented by treatment group.
Descriptive statistics for age and weight will be presented.
4.3.3
Disease Characteristics and Influenza History

RT-PCR status (positive, negative)

Influenza Subtype

Time from symptom onset to study treatment

Reason for hospitalization (Current Influenza Episode or Other (Prolonged 
Hospitalization)

Seriousness criteria: 
–
Required ventilation or supplemental oxygen to support respiration at baseline
–
Complication requiring hospitalization  


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
Complication by body system category (Cardiac, Central Nervous System 
[CNS], Hepatic, Renal, Respiratory, Gastrointestinal, Metabolic, 
Musculoskeletal, Other)

NEWS2 at baseline 

intensive care unit (ICU) status at baseline 

Chronic Hypoxia History (Yes, No, Unknown)

Co-infections (identified via the non-influenza respiratory bacterial and virus co-
infection panel)

Previous anti-influenza treatments
–
Vaccination history (within last 6 months, within last 12 months)
–
Antiviral treatment within 48 hours prior to screening.  Type of antiviral treatment 
utilized will be presented e.g: Oseltamivir/oseltamivir phosphate, peramivir, 
zanamivir, Laninamivir, Arbidol, Favipiravir, Amantadine, Rimantadine,

Ordinal scale at Day 1 (categories 1 – 6, see Section 4.5.2.1)
Medical history data, including surgery and procedures and ongoing baseline conditions
will be summarized descriptively by treatment group using the safety population. 
Additionally, ongoing baseline conditions present in >5% of patients in any treatment 
arm will be presented.  Descriptive summaries of any previous and concomitant 
treatment will be produced by treatment group for the safety population.
4.4
VISIT WINDOWS
Visit windows will only be applied to scheduled time points for laboratory parameters. 
This will include full blood hematology and chemistry assessments at Day 1 and Day 10, 
and blood liver chemistry assessment before dosing with the study treatment on Day 1, 
Day 4 and Day 7 (if study treatment is planned on Day 7) (Table 2). No other visit 
windows will be used in the study analysis.


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Table 2
Acceptable Time Windows – Laboratory Parameters
Time Point
(Scheduled Time Point)
Acceptable Time Window
Visit 1 (Day 1)
pre-dose Day 1
Visit 4 (Day 4)
Between Day 3 and Day 5 as follows:
-if patient presents on Day 4 this will be classed as Visit 4;
-if patient presents on Day 3 with no Day 4, and no Day 5 this will 
be classed as Visit 4;
-if patient presents on Day 5 with no Day 4, and no Day 3 this will 
be classed as Visit 4;
provided this is the day study treatment was received.
Visit 6 (Day 7)
Between Day 6 and Day 8 as follows:
-if patient presents on Day 7 this will be classed as Visit 6;
-if patient presents on Day 6 with no Day 7, and no Day 8 this will 
be classed as Visit 6;
-if patient presents on Day 8 with no Day 7, and no Day 6 this will 
be classed as Visit 6;
provided this is the day study treatment was received, per protocol 
guidance.
Visit 7 (Day 10)
Between Day 8 and Day 12
Measurements collected within the acceptable time window for each scheduled 
assessment time point, including data obtained at the time of withdrawal, will be used for 
the analyses at each assessment time point.  For all patients with multiple values within
a visit window, the value obtained closest to the target time point (Day 1 and Day 10) will 
be used for the full blood chemistry and haematology evaluations. The value obtained 
prior to the target time (Day 4 and Day 7) will be used for the pre-study treatment blood 
liver chemistry.  The assessment time point having no measurements within the 
corresponding acceptable time window will be considered as missing.
For summaries of data not collected by visit, such as adverse events, medical history 
and concomitant medications, all data up to the end of study will be included.
4.5
EFFICACY ANALYSIS
Efficacy analyses will be conducted for the mITTI population. Hypothesis tests will be 
two-sided at the 5% significance level, unless stated otherwise.
To manage the overall type I error, the primary and key secondary endpoints will be 
tested sequentially. The order of testing will be as follows:

TTCI

Response rates of the 6-point ordinal scale at Day 7

Time to Clinical Response


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If the primary efficacy analysis hypothesis test result is not statistically significant (i.e. 
p0.05), the hypothesis below that result in the hierarchical chain will be considered 
exploratory and no claims of statistical significance will be made. The same rules apply 
to the next endpoint in the chain.
4.5.1
Primary Efficacy Endpoint
The primary efficacy objective for this study is to evaluate the efficacy of baloxavir 
marboxil plus a SOC NAI, compared with matching placebo plus SOC NAI based on the 
following endpoint:

TTCI (defined as time from treatment start to hospital discharge or time to 
NEWS2 2 and maintained for 24 hours, whichever comes first)
TTCI is calculated as per Table 3.
Table 3
TTCI Calculations
TTCI based on
TTCI (hours)
NEWS2 2 for 24 hours
date time of initial NEWS2 assessment ≤2 - start treatment date
time 
NEWS2 2 prior to 
discharge*
date time of initial NEWS2 assessment ≤2 - start treatment date
time
Hospital discharge
date time of hospital discharge - start date time of treatment
*when a patient met the NEWS2 2 and was discharged from hospital during the 24 hour period 
of stability confirmation, the time of achieving TTCI was defined as the initial time at which the 
NEWS2 2 and not the time of hospital discharge.
NEWS2 (National early warning score 2) is the sum of the score of each of the following 
assessments, as described in Appendix 4: respiration rate (per minute), oxygen 
saturation (SpO2%) according to scale 1 or scale 2, supplemental oxygen or room air, 
systolic blood pressure (mmHg), pulse rate (bpm), consciousness level, temperature 
(oC).
Missing data for the calculation of the NEWS2 will not be imputed for the following 
reasons:
1.
TTCI endpoint can be met through hospital discharge.
2.
The physiological components of the NEWS2 can be highly heterogeneous in the 
study patient population and therefore the process of imputation would not be 
relevant.
The TTCI will be compared between the baloxavir marboxil plus SOC NAI and matching 
placebo plus SOC NAI arms using the stratified log-rank test within three regions (i.e. 
North America, EMEA, ROW), NEWS2 score at baseline (7, > 7), and time from 
symptom onset to study treatment (48 hours, > 48 hours) included as the stratification 
factors.  The Kaplan Meier plot, median time to response, 95% CIs, and p-values will be 
presented.


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The log-rank test is most appropriate when the assumption of proportional hazards is 
met.  The proportional hazards assumption will be tested graphically using the log 
cumulative hazard plot by treatment group.  The plots for each treatment group will be 
parallel if the proportional hazard assumption holds.  Should the proportional hazards 
assumption be violated, the Gehan Wilcoxon test will be used to analyze the data.  
The estimand is the difference in distributions between baloxavir marboxil plus SOC NAI 
and matching placebo plus SOC NAI arms in the mITTi for the TTCI using appropriate 
method, as described above. This absolute measure will be assessed over the duration 
of the study (35 days). The median TTCI for each treatment group and difference 
between treatment groups will be presented. Intercurrent events are those that occur 
after treatment initiation and either preclude observation of the variable or affect its 
interpretation.  Intercurrent events, such as patients who are lost to follow-up, die or 
discontinue for any reason prior to achieving a clinical improvement or do not have a 
clinical improvement event, will be accounted for through censoring rules, as described 
in Table 4 below.
Table 4
TTCI and Censoring
Event
Censo
r
Date and Time
Clinical improvement (based on NEWS2 ≤2 for 24 
hours)
No
vital signs assessment where 
NEWS2 ≤2 at start of 24 hour 
period
Clinical improvement (based on NEWS2 ≤2 prior 
to discharge)
No
first vital signs assessment where 
NEWS2 ≤2 prior to discharge
Clinical improvement (based on hospital 
discharge)
- hospital discharge and hospital re-admission 
within 24 hours) and discontinue study on same 
day
Yes
hospital discharge
- hospital discharge and hospital re-admission 
within 24 hours) and continue study
Yes
hospital discharge
- hospital discharge against medical advice (i.e. 
self-discharge)
Yes
hospital discharge
- all other hospital discharge
No
hospital discharge
Death prior to achieving a clinical improvement
Yes
last vital signs assessment prior 
to death
Discontinuation for any reason prior to achieving a 
clinical improvement
Yes
last vital signs assessment prior 
to discontinuation
Lost to follow-up 
Yes
last vital signs assessment
No clinical improvement
Yes
last vital signs assessment
TTCITime to clinical improvement; NEWS2National early warning score


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4.5.1.1
Sensitivity Analysis
The following sensitivity analyses will be conducted:
1.
to examine the effect of subjects who discontinue for any reason prior to achieving a 
clinical response event

patients who are lost to follow-up or who do not have a clinical response event will 
be censored at 35 days.

any imbalance in demographics, disease characteristics and influenza history 
between treatment arms will be assessed in relation to reasons for discontinuation 
to identify any confounding factors. Identified confounding factors will be adjusted 
for in a sensitivity analysis.

considering death as a competitive event, using a competing risk model will be 
conducted if there are a sufficient number of deaths (~10%) or an imbalance 
between groups in deaths and reason attributed. 
2.
to examine the effect of artificial support, defined as receiving non-invasive 
mechanical ventilation, mechanical ventilation, Extracorporeal membrane 
oxygenation (ECMO) and/or inotropic support

patients who met the NEWS2 criteria (2 for 24 hours) and received artificial 
support during this time period will be censored at the vital signs assessment where 
NEWS2 2 at start of 24 hour period.
4.5.2
Key Secondary Efficacy Endpoints
4.5.2.1
6-Point Ordinal Scale Measured at Day 7
For the key secondary endpoint of 6-point ordinal scale, which is recorded after 
randomization on Day 1, and again once daily every morning (between 8 am and 12 pm) 
while hospitalized, the response rate of the scale will be measured at Day 7. The ordinal 
scale categories are as follows:
1.
Discharged (or “ready for discharge”)
2.
Non-ICU hospital ward (or “ready for hospital ward”) not requiring supplemental
oxygen/non-invasive ventilation
3.
Non-ICU hospital ward (or “ready for hospital ward”) requiring supplemental
oxygen/non-invasive ventilation
4.
ICU without mechanical (invasive) ventilation (or “ready for ICU admission”)
5.
Mechanical (invasive) ventilation
6.
Death
Patients who are ready to be discharged (e.g., still hospitalized due to non-medical or 
administrative reasons) will be assigned an ordinal scale of 1. 
Patients in non-ICU hospital ward that are eligible for ICU care based on clinical
presentation but awaiting ICU care will be assigned an ordinal scale of 4.


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Patients in ICU for administrative or non-medical reasons, who are ready for a non-ICU
hospital ward, will be assigned an ordinal scale of 2 (if not requiring supplemental
oxygen/ non-invasive ventilation) or 3 (requiring supplemental oxygen/ non-invasive
ventilation).
The 6-point ordinal scale will be analyzed using the Cochran-Mantel-Haenszel test 
statistic stratified by region (i.e., North America, EMEA, ROW), NEWS2 at baseline 
(7, > 7), and time from symptom onset to study treatment (≤48 hours, > 48 hours) for 
the mITTI population.
For the ordinal endpoint, missing data will be imputed as per the following rules as 
described in Table 5 below:
Table 5
Ordinal Scale and Missing Data
Event
Imputation Rule
Patient Discontinued or Lost to 
follow-up (prior to Day 7)
Impute to last ordinal assessment if either ‘Discharged’ or 
‘Death’
otherwise not imputed
Patient ongoing but Missing 
Day 7
Impute to the higher scale score of the prior and subsequent 
assessment
The proportion of patients with a response in each category will be summarized by 
treatment group and Cochran-Mantel-Haenszel test statistic result presented. 
Additionally, a stacked bar-chart will present the ordinal scale responses over time by 
treatment.
An exploratory analysis using an ordinal outcome logistic regression model will 
conducted.
4.5.2.2
Sensitivity Analysis
To examine the effect of missing ordinal scale data subjects with a missing score at any 
timepoint will have that score imputed to last non-missing score +1.  The proportion of 
patients with a response in each category will be summarized by treatment group and 
Cochran-Mantel-Haenszel test statistic result presented. Additionally, a stacked 
bar-chart will present the ordinal scale responses over time by treatment.
4.5.2.3
Time to Clinical Response
Time to clinical response will be based upon hospital discharge, fever, and oxygen 
saturation, and two or more of the following: improved respiratory status, heart rate, or 
systolic blood pressure (Marty et al. 2017). Time to clinical response is defined as the 
time from start of study treatment until the timepoint where “clinical response”, as 
defined below, is met. 


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Patient should meet conditions A and B, and (2 of C, D and E) OR F below. For patients 
who achieve four of the five vital sign resolution criteria above each of these must be 
maintained for 24 hours for the clinical response endpoint to be met. As for the primary 
endpoint, missing data will not be imputed.
A.
Temperature
6·6°C (97·9°F) if axillary, or
37·2°C (99°F) if oral, or
37·7°C (99·9°F) if rectal, core, temporal or tympanic
- without use of antipyretics within 8 hours (missing antipyretics will be assumed to have 
been taken)
B.
Oxygen Saturation
95% (without supplemental oxygen)*+
*This requirement will be waived for patients with a history of chronic supplemental oxygen requirement who 
had a baseline oxygen saturation <95% with supplemental oxygen, within 12 months of enrolment as 
documented in the patient’s medical records.
+A patient with a history of chronic hypoxia (without supplemental oxygen) can satisfy the normalisation 
criteria for oxygen saturation if the value (without supplemental oxygen) was 2% from patient’s historical 
oxygen saturation baseline as recorded within 12 months before enrolment and documented in the patient’s 
medical records.
C
Respiratory Status:
I.
Return to pre-morbid oxygen requirement (patients with chronic oxygen use), OR
II.
Need for supplemental oxygen (given in any way–ventilator, non-invasive 
ventilation, facemask, face-tent, or nasal cannula) to no need for supplemental 
oxygen, OR
III.
Respiratory rate ≤24 per min (without supplemental oxygen)
D
Heart Rate
100 beats per min 
E
Systolic blood pressure
90 mmHg, without inotropic support given within 2 hours of assessment


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OR
F
Hospital Discharge
TTCR is calculated as per Table 6.
Table 6
TTCR Calculation
TTCR based on
TTCR (hours)
A and B and (2 of C, D 
and E) met for 24 hours
date time of initial vital signs assessment where 4 out of 5 criteria 
initially met and subsequently maintained for 24 hours - start 
treatment date time 
A and B and (2 of C, D 
and E) met prior to 
discharge*
date time of initial vital signs assessment where 4 out of 5 criteria 
initially met and subsequently discharged - start treatment date time
Hospital discharge
date time of hospital discharge - start date time of treatment
TTCRTime to Clinical Response.
*when a patient met vital sign criteria and was discharged from hospital during the 24 hour period 
of stability confirmation, the time of achieving TTCR was defined as the initial time at which 
vital signs were resolved and not the time of hospital discharge.
The time to clinical response will be compared between the baloxavir marboxil plus 
SOC NAI and matching placebo plus SOC NAI arms using the stratified log-rank test 
within three regions (i.e. North America, EMEA, ROW), NEWS2 at baseline (7, > 7), 
and time from symptom onset to study treatment (≤48 hours, > 48 hours) included as 
the stratification factors.  The Kaplan Meier plot, median time to response, 95% CIs, and 
p-values will be presented.
The log-rank test is most appropriate when the assumption of proportional hazards is 
met.  The proportional hazards assumption will be tested graphically using the log 
cumulative hazard plot by treatment group.  The plots for each treatment group will be 
parallel if the proportional hazard assumption holds.  Should the proportional hazards 
assumption be violated the Gehan Wilcoxon test will be used to analyze the data.
The estimand is the difference in distributions between baloxavir marboxil plus SOC NAI 
and matching placebo plus SOC NAI arms in the mITTi for the time to clinical response, 
using appropriate method, as described above. This absolute measure will be assessed 
over the duration of the study (35 days).  The median TTCR for each treatment group 
and difference between treatment groups will be presented.
Intercurrent events are those that occur after treatment initiation and either preclude 
observation of the variable or affect its interpretation.  Intercurrent events, such as
patients who are lost to follow-up, die or discontinue for any reason prior to achieving a 
clinical improvement or do not have a clinical improvement event, will be accounted for 
through censoring rules, as described in Table 7 below.


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Table 7
TTCR and Censoring
Event
Censor
Date and Time
Clinical Response (based on vital signs 
assessments)
No
first vital signs assessment where 
4 out of 5 criteria initially met and 
subsequently maintained for 24 
hours period
Clinical Response (based on vital signs criteria 
met prior to discharge)
No
first vital signs assessment where 
4 out of 5 criteria initially met and 
maintained prior to discharge
Clinical Response (based on hospital discharge)
- hospital discharge to another hospital (i.e. 
hospital admission within 24 hours) and 
discontinue study on same day
Yes
hospital discharge
- hospital discharge to another hospital (i.e. 
hospital admission within 24 hours) and continue 
study
Yes
hospital discharge
- hospital discharge against medical advice
Yes
hospital discharge
- all other hospital discharge
No
hospital discharge
Death prior to achieving a clinical response
Yes
last vital signs assessment prior 
to death
Discontinuation for any reason prior to achieving 
a clinical response
Yes
last vital signs assessment prior 
to discontinuation
Lost to follow-up 
Yes
last vital signs assessment
No clinical response
Yes
last vital signs assessment
4.5.2.3.1
Sensitivity Analysis
The following sensitivity analyses may be conducted if appropriate based on evaluation 
of data:
1. To examine the effect of subjects who discontinue for any reason prior to 
achieving a clinical response event
o
patients who are lost to follow-up or who do not have a clinical response 
event will be censored at 35 days.
2. To examine the effect of antipyretics on achieving clinical response 
o
the restriction of antipyretics use within 8 hours on temperature condition
will be removed
3. To examine the effect of inotropic support on achieving clinical response.
o
the restriction of no inotropic support within 2 hours.


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4.5.3
Other Secondary Efficacy Endpoints
The other secondary efficacy endpoints for this study are as follows:
Incidence of mechanical ventilation
Incidence of mechanical ventilation, as defined as being on non-invasive mechanical 
ventilation, mechanical invasive ventilation or ECMO, will be assessed from the vital 
signs assessment log where the patients need for mechanical ventilation is documented. 
It will be assumed, unless the mechanical ventilation status has changed, that the first 
occurrence is continuous and as such will be counted as one event. This will also be the 
case for each subsequent event. If there is a missing status, and the prior and 
subsequent status are the same, it can be assumed this is the one continuous incidence 
of mechanical ventilation.
The number of incidences of mechanical ventilations between start of treatment and end 
of study, as well as number and percentage of patients, will be presented.
As an additional analysis, patients whose mechanical ventilation had started before 
being randomized into the study, who continued to be on mechanical ventilation after 
receiving first treatment will also be included in the number of incidences of mechanical 
ventilations.  The number and percentage of patients will also be presented.
Duration of mechanical ventilation
Duration of mechanical ventilation, in hours, will be assessed from the vital signs 
assessment log where the patients need for mechanical ventilation is documented. The 
duration of mechanical ventilation will be defined as sum of the duration of each 
mechanical ventilation incidence. The duration of each incidence is defined as the date 
and time of the first occurrence of mechanical ventilation until the next date and time 
where the patient mechanical ventilation status has changed on the vital signs log. It will 
be assumed that, unless the mechanical ventilation status has changed, the first 
occurrence is continuous and as such will be counted as one event. This will also be the 
case for each subsequent event. Duration is calculated for events between start of 
treatment and end of study.  
Patients who are on mechanical ventilation at the last vital signs assessment will use the 
imputation rules defined in Table 8 below for calculation of the duration of last 
mechanical ventilation incidence. Missing and partial vital dates will be imputed based 
on available data, following a conservative approach.
Table 8
Duration of Mechanical Ventilation and Missing Data
Event
Imputation Rule
Patient Discontinued or Lost to 
follow-up
duration of last incidence uses date of discontinuation or 
date lost to follow up as the end date
Patient died
duration of last incidence uses date of death as the end date


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The analysis of duration of mechanical ventilation will be repeated to include patients
whose mechanical ventilation had started before being randomized into the study, who 
continued to be on mechanical ventilation after receiving first treatment.  The duration 
will be calculated as specified above, except it will start from the start date of mechanical 
ventilation.
Incidence of ICU stay
Incidence of ICU will be assessed from the ICU admissions log. It will be assumed that, 
unless a discharge date is available, the first ICU admission is continuous and as such 
will be counted as one event.  This will also be the case for each subsequent event. The 
number of incidences of ICU stay as well as number and percentage of patients with ICU 
stay, between start of treatment and end of study will be presented.
This analysis will be repeated to include patients who were admitted to ICU prior to 
randomization in the study, but remained in ICU after first treatment.  The number of 
incidences of ICU stay, and the number and percentage of patients with ICU stay whilst 
on treatment will be presented.
Duration of ICU stays
Duration of ICU stay will be calculated in hours as the sum of the duration of ICU stay, 
based on the admission and discharge date and time of the ICU admissions log: (ICU 
discharge datetime – ICU admission datetime). 
Patients who are in ICU until end of study will be censored at last available date and 
time. Patients who die will be censored at their date of death.
Partial admission and discharge dates and times will be imputed based on available data, 
following a conservative approach.
This analysis will be repeated to also include patients who were admitted to ICU prior to 
randomization in the study, but remained in ICU after first treatment.  
Time to clinical failure
Time to clinical failure, in hours, is defined as the time from start of treatment to death, 
mechanical ventilation, or ICU admission, corresponding to ordinal scale categories 6, 5, 
and 4, respectively.
For patients who are on mechanical ventilation, or in ICU without mechanical (invasive) 
ventilation at start of treatment the time to clinical failure is calculated as time to 
worsening condition i.e. for patients with ordinal scale of 4 (ICU admission without 
mechanical [invasive] ventilation) at start of treatment worsening is defined as a 
mechanical ventilation or death), for patients with ordinal scale 5 (mechanical ventilation) 
at start of treatment worsening defined as a death.


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Intercurrent events, such as patients who are lost to follow-up, or discontinue for any 
reason prior to clinical failure or do not have clinical failure, will be accounted for through 
censoring rules, as described in Table 9 below.
Table 9
Time to Clinical Failure and Censoring
Event
Censor
Date and Time
Clinical Failure (death, mechanical ventilation, 
or ICU admission
No
first occurrence of death, 
mechanical ventilation, or ICU 
admission post baseline
Death
No
date of death
Discontinuation but subsequently reported death 
No
date of death
Discontinuation for any reason prior to having 
clinical failure
Yes
censored at last vital signs 
assessment 
Lost to follow-up 
Yes
last available date
No clinical failure
Yes
last available date
Time to hospital discharge
Time to hospital discharge, in hours, is defined as the time from start of treatment to time 
of discharge from hospital. Patients who are lost to follow-up, die or discontinue for any 
reason prior to discharge or who are not discharged will be censored at the time of their 
last assessment or date of death, whichever is applicable, as per rules presented in 
Table 10 below.


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Table 10 Time to hospital discharge and Censoring
Event
Censor
Date and Time
Hospital discharge
No 
hospital discharge
- hospital discharge to another hospital (i.e. hospital 
admission within 24 hours) and discontinue study on same 
day
Yes
hospital discharge
- hospital discharge to another hospital (i.e. hospital 
admission within 24 hours) and continue study
Yes
hospital discharge
- hospital discharge against medical advice (i.e. self-
discharge)
Yes
hospital discharge
- all other hospital discharge
No
hospital discharge
Death prior to hospital discharge
Yes
last vital signs 
assessment prior to 
death
Discontinuation for any reason prior to hospital discharge
Yes
last vital signs 
assessment prior to 
discontinuation
Lost to follow-up 
Yes
last vital signs 
assessment
No hospital discharge
Yes
last vital signs 
assessment
Incidence of influenza-related complications
Influenza-related complications are recorded on specific complication eCRF pages with 
diagnostic questions for the complications of pneumonia, myositis or rhabdomyolysis, 
encephalitis or encephalopathy, myocarditis and/or pericarditis, otitis media, sinusitis, 
exacerbation of COPD/asthma, sepsis, acute lung injury or acute respiratory distress 
syndrome. These eCRF pages will be utilized for these specific events when they are 
reported as adverse events after the initiation of study treatment.  This data will be 
subject to an internal blinded manual medical review of events together with other 
related eCRF data (e.g. serious adverse event forms as applicable and medical history).
The objective of the review is to ensure that sufficient clinical evidence for each 
individual reported complication event has been provided through the recorded CRF 
data to support the diagnosis. 
The number and percentage of patients, as well as the number of events, will be 
presented by treatment group as follows:

all events, 

internally adjudicated events, 

investigator assessed related to influenza events and 

investigator assessed related to influenza and internally adjudicated events will be 
presented. 


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The process by which internal adjudication of influenza related complications will be 
conducted is outlined in a separate charter.
Mortality rate at Day 7
The mortality rate is defined as the number of patients who died on or before Day 7. 
If date of death is not recorded for any patient who has died, the last known date where 
the patient was alive will be used to ascertain if they were alive at Day 7.
Mortality rate at Day 28
The mortality rate is defined as the number of patients who died on or before Day 28. 
If date of death is not recorded for any patient who has died, the last known date where 
the patient was alive will be used to ascertain if they were alive at Day 28.
Time to NEWS2 of ≤2 maintained for 24 hours
Time to NEWS2 of ≤2 maintained for 24 hours is defined as the time from start of 
treatment to the point at which NEWS2 assessment score ≤2 is reached and must be 
maintained for 24 hours. Patients who are lost to follow-up, die or discontinue for any 
reason prior to achieving NEWS2 of ≤2 for 24 hours will be censored at the time of their 
last assessment or date of death, whichever is applicable, as per rules presented in 
Table 11 below.
Table 11 Time to NEWS2 of 2 maintained for 24 hours and Censoring
Event
Censor
Date and Time
NEWS2 ≤2 for 24 hours
No
vital signs assessment where 
NEWS2 ≤2 at start of 24 hour 
period
NEWS2 ≤2 prior to discharge
No
first vital signs assessment where 
NEWS2 ≤2 prior to discharge
Death prior to achieving NEWS2 ≤2 for 24 
hours
Yes
last vital signs assessment prior 
to death
Discontinuation for any reason prior to 
achieving NEWS2 ≤2 for 24 hours
Yes
last vital signs assessment prior 
to discontinuation
Lost to follow-up 
Yes
last vital signs assessment
No NEWS2 ≤2 for 24 hours
Yes
last vital signs assessment
Incidence and rate endpoints will be analyzed using the Cochran Mantel-Haenszel test 
statistic stratified by region (North America, EMEA, ROW), NEWS2 at baseline (≤7, 7) 
and time from symptom onset to study treatment (≤48 hours, > 48 hours).


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Time to event secondary efficacy endpoints will be analyzed using the same method and 
sensitivity analyses (where required) as specified for the primary endpoint
(see Section 4.5.1).  
Mortality rates and duration of ICU stays and ventilation will be analyzed descriptively.
4.5.4
Subgroup Analyses
The TTCI will be compared between the baloxavir marboxil plus SOC NAI and matching 
placebo plus SOC NAI arms for the following subgroups:

region 
–
North America (United States, Canada); 
–
Europe, Middle East, and Africa [EMEA] (Belgium, Bulgaria, Czech Republic, 
Estonia, France, Germany, Hungary, Israel, Netherlands, Romania, Serbia, 
Spain, Sweden, Turkey, Ukraine); 
–
Rest of world [ROW] (Mexico, Japan, South Korea, Brazil, Argentina, Peru,
Australia, New Zealand, Hong Kong, Singapore, China)

baseline age (<65, 65 years) 

baseline age (<80, 80 years) 

baseline NEWS2 score (≤7, >7)

time from symptom onset to study treatment (≤48 hours, >48 hours)

ICU or mechanical (invasive/non-invasive mechanical or ECMO) intervention at 
baseline or any point during the study prior to clinical improvement (Yes, No)

Patients who received anti-influenza drug within 48 hours prior to screening
(including Oseltamivir, Zanamivir, Peramivir, Laninamivir, Arbidol, Favipiravir, 
Amantadine, Rimantadine) (Yes, No)

On-treatment NAI (Oseltamivir, Zanamivir, Peramivir)

Immunocompromised patients (Yes, No) – see Appendix 6

Patients with ongoing comorbidities at baseline
o
Respiratory comorbidities:

Pneumonia (Yes, No). Including any event preferred term with 
“pneumonia”.

Respiratory thoracic and mediastinal disorders System Organ 
Class and/or pneumonia (Yes/ No)

Respiratory influenza complications that required or extended 
hospitalization, defined as required ventilation or supplemental 
oxygen and/or complications of ‘respiratory’ class as assessed by 
the investigator
o
Cardiac comorbidities

Cardiac disorders System Organ Class 


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
Cardiac influenza complications that required or extended 
hospitalization, defined as complications of ‘Cardiac’ class as 
assessed by the investigator

Patients contracting nosocomial influenza (e.g. prolonged hospitalization)

influenza subtype (A, B) at baseline– will be conducted if >10% patients in B

virus subtype (H1, H3) at baseline

presence of co-respiratory infection at baseline (identified via the non-influenza 
respiratory bacterial and virus co-infection panel) (Yes, No)

high and low baseline viral titre e.g. 2 groups split at the median 

high and low viral titre AUC e.g. 2 groups split at the median
Subgroups will be analyzed descriptively. The median TTCI for each subgroup and a 95% 
CI will be presented.
4.6
VIROLOGY ENDPOINTS
The following virology endpoints will be analyzed for the mITTI population:
Time to cessation of viral shedding by virus titer
Time to cessation of viral shedding by virus titer is defined as the time, in hours, between 
the initiation of study treatment and first time when the influenza virus titer is below the 
limit of detection (0.75 log10 TCID50/mL) and will be analyzed using similar methods as 
specified for the primary endpoint (see Section 4.5.1). 
Patients who are lost to follow-up, whose virus titers have not reached the limit by the 
last observation time point, or who die will be censored at their last observation time 
point or date of death, whichever is applicable, as per Table 12 below.
Table 12 Time to Viral Shedding and Censoring
Event
Censor
Date and Time
Death prior to cessation of viral shedding
Yes
last observation prior to death
Discontinuation for any reason prior to 
cessation of viral shedding
Yes
last observation prior to 
discontinuation
Lost to follow-up prior cessation of viral 
shedding
Yes
last observation
Virus titers have not reached the limit by the 
last observation time point
Yes
last observation
One day is converted into 24 hours. Patients with a positive virus titer on Day 1 will be 
included in this analysis.


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Time to cessation of viral shedding by RT-PCR
Time to cessation of viral shedding by RT-PCR, in hours, is defined as the time between
the initiation of study treatment and first time when the virus RNA by RT-PCR is below 
the limit of detection (2.05 for flu A and 2.83 for flu B log10 virus particles/mL) and will be 
analysed using similar methods as specified for the primary endpoint (see Section 4.5.1). 
Patients who are lost to follow-up, whose virus titers have not reached the limit by the 
last observation time point, or who die will be censored at their last observation time 
point or date of death, whichever is applicable, as per Table 12 above. For the patients
with multiple virus types, this endpoint is defined as the time between the initiation of the
study treatment and first time when the virus RNA by RT-PCR is below the limit of
detection for all virus types. One day is converted into 24 hours.
Patients with a positive virus RNA on Day 1 will be included in this analysis.
Change from baseline in influenza virus titer at each timepoint
Change from baseline in influenza virus titer (log10TCID50/mL) is defined as the change 
from baseline in influenza virus titer on Days 2, 3, 4, 5, 7, and 10 and will be analyzed 
using an analysis of covariance (ANCOVA) model with region (North America, EMEA, 
ROW), NEWS2 (≤ 7, > 7), and time from symptom onset to study treatment (≤48 hours, > 
48 hours) as stratification variables, and the baseline value as a covariate. If influenza 
virus titer is less than the lower limit of quantification, the virus titer will be imputed as 
0.749 (log10TCID50/mL).
Only patients with a positive virus titer on Day 1 will be included in this analysis.
Change from baseline in the amount of virus RNA (RT-PCR) at each 
timepoint
Change from baseline in the amount of virus RNA (unit: log10 virus particles/mL) is 
defined as the change from baseline in the amount of virus RNA on Days 2, 3, 4, 5, 7, 
and 10 and will be analyzed using an ANCOVA model with region (North America, 
EMEA, ROW), NEWS2 (≤ 7, > 7), and time from symptom onset to study treatment (≤48 
hours, > 48 hours) as stratification variables, and the baseline value as a covariate.
If the amount of virus RNA is less than the lower limit of quantification, the amount of
virus RNA will be imputed as 2.18 for flu A and 2.93 for flu B (log10 virus particles/mL). If
a patient is infected with multiple virus types, the sum of those amounts of virus RNA will
be used for analysis.
Patients with a positive by RT-PCR on Day 1 will be included in this analysis.
Proportion of patients with positive influenza virus titer
Proportion of patients positive for influenza virus titer will be presented by treatment at
each visit and is defined as the percentage of patients whose influenza virus titer is not
less than the lower limit of quantification (0.75 log10TCID50/mL) or positive among those


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assessed for influenza virus titer on Days 2, 3, 4, 5, 7, and 10. The Cochran-Mantel-
Haenszel test with region (North America, EMEA, ROW), NEWS2 at baseline (≤ 7, > 7), 
and time from symptom onset to study treatment (≤48 hours, > 48 hours) as stratification 
variables, and the baseline value as a covariate will be used to compare proportion of 
patients positive for influenza virus titer between treatments at each scheduled time 
point.
Patients with a positive influenza virus titer on Day 1 will be included in this analysis.
Proportion of patients positive by RT-PCR at each time-point
Proportion of patients positive by RT-PCR will be presented by treatment at each visit is
defined as the percentage of patients with detectable virus RNA (2.05 for flu A and 2.83
for flu B log10 virus particles/mL) among those assessed by RT-PCR on Days 2, 3, 4, 5, 
7, and 10.  The Cochran-Mantel-Haenszel test with region (North America, EMEA, 
ROW), NEWS2 at baseline (≤ 7, > 7), and time from symptom onset to study treatment 
(≤48 hours, > 48 hours) as stratification variables, and the baseline value as a covariate
will be used to compare proportion of patients positive by RT-PCR between treatments 
at each scheduled time point.
Patients with a positive by RT-PCR on Day 1 will be included in this analysis.
Area under the curve in virus titer 
Area under the curve (AUC) in virus titer will be presented by treatment group and will be
calculated using the trapezoidal method. AUC of change from time 0 (t0) to time K (tk) is
given by the formula:

( + 	
)( −	
)



where tk (hours) represents the date of the kth viral titer assessment (k = 0, ..., K) and yk
represents the log10 value of the kth viral titer assessment (TCID50/mL). 24-hours of time will be 
converted into one day. Patients with a positive virus titer on Day 1 will be subjected to this 
analysis. The lower limit of quantification and lower limit of detection is defined as 0.75 log10
TCID50/mL for flu A and 0.75 log10 TCID50/mL for flu B (TCID50/mL). If a patient is infected 
with multiple virus types, the sum of those virus titers will be used for analysis.
Additionally, the AUC in virus titer adjusted for baseline will be presented by treatment 
group and be calculated using the trapezoidal method. AUC of change from time 0 (t0) to 
time K (tk) adjusted for baseline is given by the formula:

 + −
 −( −−
)





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where tk (hours) represents the date of the kth viral titer assessment (k = 0, ..., K) and yk
represents the log10 value of the kth viral titer assessment (TCID50/mL). 24-hours of time will be 
converted into one day. Patients with a positive virus titer on Day 1 will be subjected to this 
analysis. The lower limit of quantification and lower limit of detection is defined as 0.75 log10
TCID50/mL for flu A and 0.75 log10 TCID50/mL for flu B (TCID50/mL). If a patient is infected with 
multiple virus types, the sum of those virus titers will be used for analysis.
Area under the curve in the amount of virus RNA (RT-PCR)
AUC in virus RNA (RT-PCR) will be presented by treatment group and is defined as
AUC of change from baseline in the amount of virus RNA (RT-PCR) from Day 1 to
Day 10. AUC is calculated using the trapezoidal method similar to AUC in virus titer.
Patients with a positive RT-PCR result on Day 1 will be subjected to this analysis. The
lower limit of quantification is defined as 2.18 for flu A and 2.93 for flu B (log10 virus
particles/mL). If a patient is infected with multiple virus types, the sum of those the
amount of virus RNA will be used for analysis.
Exposure and virology will be included in the pop PK report.
4.6.1
Exploratory Endpoints
Polymorphic and treatment-emergent amino acid substitutions in the PA, 
PB1, PB2, and NA genes
Sanger sequencing of PA and NA will be performed for all or neuraminidase treated 
patients, respectively, and with paired (pre and post dose) samples available, at baseline 
and at the last evaluable timepoint (last sample with > 4 log10 viral particles/ml). For 
patients with amino acid substitutions in the PA gene, additional sequencing will be 
performed for all earlier timepoint samples to evaluate the timepoint of emergence of the 
amino acid substitution. In addition, sequencing of PB1 and PB2 genes will be 
performed on samples selected based on the criteria below. The number and proportion 
of patients with the detected amino acid substitutions will be reported for all investigated 
genes.
Sequencing of PB1 and PB2 will be done for:

baseline viruses with reduced susceptibility to baloxavir (fold-change in EC50 > 
10 for type A viruses and > 5 for type B viruses compared to reference virus in 
phenotypic assay).

viruses (baseline and last evaluable time-point) without amino acid substitution 
in PA, but with reduced response to treatment or with virus rebound. 
These will be defined according to the following criteria below in Table 13. If an amino 
acid substitution is detected, an additional intermediate time point sample will be 
sequenced.




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Respiratory coinfections (Biofire)
All baseline samples will be tested for respiratory pathogens using the qualitative PCR-
based FDA cleared BioFire FilmArray® Respiratory Panel 2 assay. This assay detects 
17 respiratory viral or bacterial pathogens in addition to influenza A and B. Frequency 
and proportions for each co-infection will be presented.
Influenza antibody titer
A hemagglutination inhibition assay for the detection of influenza virus A and B specific 
antibodies will be performed from blood samples at baseline and at end of the study and 
the antibody titer will be determined. The lower limit of quantification is defined as a 
hemagglutination inhibition titer of 10. Summaries of findings will be presented.
4.6.2
Subgroup Analyses
Subgroup analysis of the following virology endpoints, based on virus type and subtype, 
will be conducted by treatment group:

Time to cessation of viral shedding by RT-PCR

Time to cessation of viral shedding by virus titer
For the baloxavir treatment group only, an additional subgroup analysis comparing the 
patients with or without the presence of virus with an I38x substitution will be conducted 
for the following:

Time to cessation of viral shedding by RT-PCR

Time to cessation of viral shedding by virus titer

Number and % of patients having 2 doses of baloxavir; number of patients having 
3 doses of baloxavir
Subgroup analyses will be produced where appropriate and where the number of 
patients in each subgroup is sufficient. 
4.7
SAFETY ANALYSES
The safety analysis population will be used for all safety analyses. Patients will be 
analyzed according to the treatment they actually received.
4.7.1
Adverse Events
AEs will be classified by system organ class and preferred term using the latest version 
of Medical Dictionary for Regulatory Activities (MedDRA) and adverse event severity will 
be graded according to National Cancer Institute Common Terminology Criteria for 
Adverse Events (NCI CTCAE) v5.0. Of reported AEs on the eCRF, AEs reported after 
the initial dose of study drug will be used for safety analyses.
In summaries by SOC and PT, AEs will be sorted by overall decreasing frequency within 
each SOC and PT. 


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All Adverse Events
Only treatment-emergent AEs will be summarized. Treatment-emergent events are 
defined as those AEs with observed or imputed onset date on or after the start date of 
trial treatment. Only where the most extreme intensity is greater than the initial intensity 
(or if most extreme intensity is not missing and initial intensity is missing) will events with 
an onset date prior to the start of study treatment be considered treatment-emergent. An 
AE with a completely missing start date will be assumed to be treatment-emergent 
unless the AE has a complete non-imputed end date that is prior to study day 1.
All Adverse events will be coded and tabulated by system organ class and/or preferred 
term. In tabulations, preferred terms and their associated system organ class will be 
presented in order of descending frequency summed across the treatment arms. 
Adverse events will also be tabulated by severity and relationship to study medication as 
indicated by the investigator. 
The following will also be summarized by treatment arm and listings produced where 
required:

Serious AEs

AEs leading to withdrawal from study

AEs leading to death

AEs leading to a withdrawal of study drug 

AEs occurring in ≥5% of patients in at least one treatment group

AEs occurring in ≥1% of patients in at least one treatment group

AEs by background NAI treatment 

AEs by outcome

AEs by time of onset

AEs by CTCAE Grade

AE related to Study Medication or SOC NAI

AE related to Study Medication
Adverse Events of Special Interest
All adverse events of special interest (AESI) will be presented by treatment group. AESI 
include but are not limited to the following: 

Case of an elevated ALT or AST in combination with either an elevated bilirubin or 
clinical jaundice, as defined in protocol

Suspected transmission of an infectious agent by the study drug
Adverse Events by Dosage 
Overall summary of adverse event will be presented by baloxavir dosage (2 dose, 
3 dose)


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4.7.2
Deaths
Details of any deaths will be presented in the form of an individual patient listing, as well 
as a frequency table by treatment.
4.7.3
Laboratory Data
All laboratory data will be converted to SI units. The International Standard for the
Handling and Reporting of Laboratory Data COG 3007 (Version 4.0) will be used to
implement reference ranges and marked abnormalities for laboratory data where
possible.
For each of the haematological and biochemical test parameters, summary statistics of 
observed and change from baseline values at Day 10 will be presented by treatment 
group. Baseline is defined as the last assessment prior to treatment on Day 1.
A listing will present all lab assessments data for patients who had any significant 
change from baseline.
Summaries of the number of patients by CTC grade at each assessment will also be 
presented. For laboratory parameters, observations on Day 1 will be classed as 
baseline.
Additionally, summary statistics of observed and change from baseline values of liver 
function tests (Total Bilirubin, Alkaline phosphatase [ALP], Alanine aminotransferase 
[ALT] and aspartate aminotransferase [AST]), which are collected on Day 1, Day 4, 
Day 7 (if 3rd dose of baloxavir received) and Day 10, will be presented by treatment 
group for each scheduled time point, as well as box and whisker plots at each time point.
The number and proportion of patients who meet the pre-specified criteria shown in 
Table 14 will be presented by treatment group during the study.
Table 14 Pre-specified Abnormal Laboratory Criteria
AST (U/L) or ALT (U/L) and Total bilirubin (mg/dL)
AST(U/L) or ALT (U/L) 3 ULN
AST(U/L) or ALT (U/L) 5 ULN
AST (U/L) or ALT (U/L) 3 ULN and Total bilirubin (mg/dL) 2 ULN
ALTAlanine aminotransferase; ASTaspartate aminotransferase; ULN = upper limit of normal.
A listing of all pregnancies will be presented. 
4.7.4
Vital Signs
Summary statistics for all observed vital signs (diastolic blood pressures, systolic blood 
pressures, peripheral oxygen saturation, respiratory rate, pulse rate and body 
temperature) and the change from baseline to last observation on Day 10, and to 
patients last observation, will be presented by treatment group.


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Baseline is defined as the last assessment prior to treatment.
Additionally, a graphical representation of vital signs data over time will be presented.
4.7.5
ECG
The number and proportion of patients having ECG, as well as the result (Normal, 
Abnormal, Abnormal, not clinically significant, Abnormal, clinically significant, Unable to 
evaluate), will be presented by treatment group.
4.7.6
Exposure to Study Medication
The duration of treatment exposure will be summarized with descriptive statistics by 
treatment group for the safety population.
The duration of treatment exposure [days] is defined as the dosing period during which a 
patient takes medication as follows:
{(final dose date) – (initial dose date) + 1}
Compliance will be calculated based on the actual and expected doses, as recorded on 
the eCRF, as follows: 
{(actual dose of treatment / expected dose of treatment)*100}
The treatment compliance rate will be summarized with descriptive statistics by the 
treatment group for the safety population. The frequency and percentage of patients 
with compliance <80% and ≥80% will be presented.
The number of patients with a missed or incorrect dose will be presented by treatment
group.
In addition, the patients who did not receive the expected dose, together with reason for 
this, will be listed.
4.7.7
Exposure to SOC NAI Medication
The duration of exposure, number of doses received and compliance with expected 
dosing will be presented for each SOC NAI of Oseltamivir, Peramivir and Zanamivir.
The duration of NAI treatment exposure [days] is defined as the dosing period during 
which a patient takes medication as follows:
{(final NAI dose date) – (initial NAI dose date) + 1}
Compliance will be calculated based on the actual and expected doses as follows: 
{(actual treatment received / expected treatment)*100}


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The treatment compliance rate for both treatments will be summarized with descriptive 
statistics by the treatment group for the safety population. The frequency and 
percentage of patients with compliance <80% and ≥80% will be presented.
4.8
PHARMACOKINETIC ANALYSES
4.8.1
Standard PK Analyses
The PK population, as described in section 4.1.3, will be used for all analyses. 
For all patients, individual baloxavir concentration data will be listed by day and by
timepoint postdose. Plasma levels of baloxavir will be summarized (i.e., mean, standard
deviation, coefficient of variation, median, minimum, and maximum) by day and
timepoint post dose. Individual and mean plasma baloxavir concentrations versus time
data will be plotted (i.e., a separate figure panel for each of the three doses). In addition,
for patients who provided sparse PK data, the distribution of plasma baloxavir
concentrations will also be presented by means of a boxplot (i.e., a separate figure for
each dose, X-axis category time postdose).
Non-compartmental PK parameters (e.g., AUC, time to maximum concentration, Cmax,
half-life) will only be derived for patients who underwent the non-sparse (sequential) PK
sampling regimen (Appendix 3) and who provided sufficient data to allow estimation of
such parameters. The following non-compartmental PK parameters will be derived for
each individual after the first and second dose: AUC0-72h, Cmax, C24, and terminal half-life 
(as appropriate for data collected).  AUCinf and clearance at steady state will be reported 
after the first dose, only. Drug accumulation will be assessed based on the AUC0-72h ratio 
between the second and first baloxavir marboxil dose.  Estimates for these parameters 
will be tabulated and summarized (i.e., mean, standard deviation, coefficient of variation, 
median, minimum, and maximum). Inter-patient variability will be evaluated based on 
the summary statistics of the individual PK parameter estimates.
All tables, listings, and figures derived from PK data (concentrations or parameters)
obtained from patients who underwent the sequential PK sampling (Appendix 3) will be
presented separately (i.e., not pooled with data from patients who underwent sparse PK
sampling).
4.8.2
Population PK Modelling
Non-linear mixed effect modelling will be used to characterize the population 
pharmacokinetics of baloxavir in the target population. The population typical PK model 
parameters (e.g., apparent clearance [CL/F], apparent volume of distribution for the 
central compartment [Vc/F]), and their covariates will be estimated. Individual PK 
parameters may also be calculated using post hoc Bayesian estimation for each patient, 
and plotted against significant covariates identified (e.g., body weight, age). The derived 
PK parameters will be tabulated and summarized (i.e., by mean, standard deviation, 
coefficient of variation, median, and minimum and maximum). PK exposure and 


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response (e.g., virus titers) relationships will be explored. The population PK model 
outcomes will be reported in a stand-alone report outside of the clinical report.
4.9
EXPLORATORY ANALYSES
4.9.1
Palatability and Acceptability
The palatability and acceptability endpoint for patients who receive the study treatment 
(baloxavir marboxil or matching placebo) as oral suspension on Days 1, 4, and 7 (if 
additional study treatment is administered on Day 7) will be summarized descriptively.
The number and proportion of patients within each response category for the palatability 
and acceptability questions from the questionnaire (Appendix 5) will be presented for the 
following:

Overall taste on a scale of 1 to 5

Whether the patient would be happy to take the medicine again (yes, no, not 
sure/no answer)
No formal statistical analyses will be performed.
4.9.2
Adolescent Population
The following endpoints will be presented descriptively, including only patients <18 years 
of age:

Time to Clinical Improvement

Response Rate of 6-point ordinal scale at Day 7

Time to clinical response

Time to cessation of viral shedding by virus titer

Time to cessation of viral shedding by RNA-PCR
4.10
MISSING DATA
In safety analyses, all deaths are included, from all sources, regardless of completeness 
of death date; patients who died with only a partial death date available will be included.  
Partial dates for AEs, concomitant medications, laboratory assessments, and medical 
history will be imputed following a conservative approach.
In efficacy analyses, missing data will be handled according to rules in Table 15 below:
Table 15 Handling for Missing Data
Endpoint
Imputation Rules
Time to Clinical 
Improvement
(TTCI)
No imputation of missing data in calculation of NEWS2 for the 
following reasons:
TTCI endpoint can be met through hospital discharge.
The physiological components of the NEWS2 can be highly 
heterogeneous in the study patient population and therefore the 


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Endpoint
Imputation Rules
process of imputation would not be relevant.
Missing data due to death, discontinuation or lost to follow up 
will be censored based on rules in Table 3.
6-Point Ordinal Scale 
Measured at Day 7
No imputation of missing data for patients who ‘Discontinued’ or 
are ‘Lost to follow-up’ (prior to Day 7), with the exception of 
patients whose last assessment was ‘Death’ or ‘Discharge’, in 
which case the last assessment will be used.
For patients who are ongoing with missing data at Day 7 this will 
be imputed to the higher scale score of the prior and subsequent 
assessment
Time to Clinical Response
(TTCR)
No imputation of missing data in calculation of Clinical 
Response for same reason as TTCI.
Missing data due to death, discontinuation or lost to follow up 
will be censored based on rules in Table 5.
Incidence of Mechanical 
Ventilation
This will also be the case for each subsequent event. If there is 
a missing mechanical ventilation status, and the prior and 
subsequent status are the same, it can be assumed this is the 
one continuous incidence of mechanical ventilation.
Alternatively, these will be counted as separate incidences.
Duration of Mechanical 
Ventilation
For patient who Discontinued or Lost to follow-up duration of last 
incidence uses date of discontinuation or date lost to follow up 
as the end date
For patient who died duration of last incidence uses date of 
death as the end date
Time to clinical failure
There will be no imputation for this endpoint.
Mortality rate at Day 7
If date of death is not recorded for any patient who has died, the 
last known date where the patient was alive will be used to 
ascertain if they were alive at Day 7
Mortality rate at Day 28
If date of death is not recorded for any patient who has died, the 
last known date where the patient was alive will be used to 
ascertain if they were alive at Day 28
Time to NEWS2 of 2 
maintained for 24 hours
Patients who are lost to follow-up, die or discontinue for any 
reason prior to achieving NEWS2 of ≤2 for 24 hours will be 
censored at the time of their last assessment or date of death, 
whichever is applicable, as per rules presented in Table 11


Baloxavir Marboxil —F. Hoffmann-La Roche Ltd
42/Statistical Analysis Plan CP40617
5.
REFERENCES
Marty FM, Vidal-Puigserver J, Clark C, et al. Intravenous zanamivir or oral oseltamivir for 
hospitalised patients with influenza: an international, randomised, double-blind, 
double-dummy, phase 3 trial. The Lancet Respiratory Medicine. 2017;5(2):135-46.


Baloxavir Marboxil —F. Hoffmann-La Roche Ltd
43/Statistical Analysis Plan CP40617
Appendix 1
Protocol Synopsis
TITLE:
A PHASE III, RANDOMIZED, DOUBLE-BLIND 
PLACEBO-CONTROLLED, MULTICENTER STUDY TO EVALUATE 
THE EFFICACY AND SAFETY OF BALOXAVIR MARBOXIL IN 
COMBINATION WITH STANDARD-OF-CARE NEURAMINIDASE 
INHIBITOR IN HOSPITALIZED PATIENTS WITH SEVERE 
INFLUENZA
PROTOCOL NUMBER:
CP40617
VERSION NUMBER:
2
EUDRACT NUMBER:
2018-001416-30
IND NUMBER:
126653
TEST PRODUCT:
Baloxavir marboxil (RO7191686)
PHASE:
III
INDICATION:
Influenza
SPONSOR:
F. Hoffmann-La Roche Ltd
Objectives and Endpoints
This study will evaluate the efficacy, safety, and pharmacokinetics of baloxavir marboxil 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 patients with influenza.  Specific objectives and corresponding endpoints for the 
study are outlined below.
In this protocol, "study treatment" refers to baloxavir marboxil or its matching placebo.  Study 
treatment is given in combination with a SOC NAI.
Primary Objective
Corresponding Endpoint
To evaluate the clinical efficacy of 
baloxavir marboxil plus a SOC NAI 
compared with matching placebo plus a 
SOC NAI 
TTCI defined as:
Time to hospital discharge OR
Time to NEWS2 of 2 maintained for 24 hours
Efficacy Objectives
Corresponding Endpoints
To evaluate the clinical efficacy of 
baloxavir marboxil plus a SOC NAI 
compared with matching placebo plus a 
SOC NAI 
Key Secondary Endpoints:
Response rates of the 6-point ordinal scale at Day 7
Time to clinical response based on temperature 
ranges, oxygen saturation, respiratory status, heart 
rate, and hospitalization status a
Other Secondary Endpoints:
Incidence of mechanical ventilation
Duration of mechanical ventilation
Incidence of ICU stay 


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Duration of ICU stay
Time to clinical failure, defined as the time to death, 
mechanical ventilation, or ICU admission, 
corresponding to ordinal scale categories 6, 5, and 4, 
respectively, from baseline
Time to hospital discharge 
Incidence of post-treatment influenza-related 
complications b
Mortality rate at Day 7 
Mortality rate at Day 28
Time to NEWS2 of 2 maintained for 24 hours
Virology Objectives
Corresponding Endpoints
To evaluate the virological activity of 
baloxavir marboxil plus a SOC NAI 
compared with matching placebo plus a 
SOC NAI 
Time to cessation of viral shedding by virus titer
Time to cessation of viral shedding by RT-PCR
Change from baseline in influenza virus titer and in 
the amount of virus RNA (RT-PCR) at each 
timepoint
Proportion of patients with positive influenza virus 
titer and proportion of patients positive by RT-PCR 
at each timepoint
AUC in virus titer and in the amount of virus RNA 
(RT-PCR)
To evaluate the polymorphic and 
treatment-emergent amino acid 
substitutions in the PA, PB1, PB2, and 
NA genes and drug susceptibility in 
patients with evaluable virus
Polymorphic and treatment-emergent amino acid 
substitutions in the PA, PB1, PB2, and NA genes
Drug susceptibility in patients with evaluable virus
Safety Objective (cont.)
Corresponding Endpoints (cont.)
To evaluate the safety of baloxavir 
marboxil plus a SOC NAI compared with 
matching placebo plus a SOC NAI in 
hospitalized patients with influenza
Compare the incidence and severity of AEs and 
SAEs
Incidence of AEs leading to discontinuation
Proportion of patients with any post-treatment ALT 
and AST above baseline and 3ULN, 5ULN, 
10ULN
Pharmacokinetic Objective
Corresponding Endpoints
To evaluate the single- and multiple-dose 
pharmacokinetics of baloxavir 
Plasma concentrations of baloxavir (active 
metabolite) at specified timepoints
After each dose, concentration at predose and 
24 hours postdose will be summarized 
Non-compartmental PK parameters such as AUC, 
Cmax and t1/2 (only for patients undergoing sequential 
PK sampling) 
Exploratory Palatability and 
Acceptability Objective
Corresponding Endpoint

To describe the palatability and 
acceptability of the oral suspension 
in hospitalized patients with 
influenza

Number and proportion of patients reporting 
each palatability and acceptability response at 
each timepoint


Baloxavir Marboxil —F. Hoffmann-La Roche Ltd
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AE adverse event; AUC area under the concentrationtime curve; Cmaxmaximum plasma concentration; 
COPD chronic obstructive pulmonary disease;  ICU intensive care unit; NAI neuraminidase inhibitor; 
NEWS2 National Early Warning Score 2; PK pharmacokinetic; RT-PCR reverse transcriptase 
polymerase chain reaction; SAE serious adverse event; SOC standard-of-care; TTCI time to clinical 
improvement; t1/2half-life; ULN upper limited normal
a
Criteria for each parameter (i.e., temperature, oxygen saturation, respiratory status, heart rate, 
systolic blood pressure, and hospital discharge) as defined in the protocol.
b
Incidence of post-treatment influenza-related complications as defined as pneumonia, myositis or
rhabdomyolysis, encephalitis or encephalopathy, myocarditis and/or pericarditis, otitis media, sinusitis, 
exacerbation of COPD/asthma, sepsis, acute lung injury, or acute respiratory distress syndrome.
Study Design
Description of Study
This is a Phase III, randomized, double-blind, placebo-controlled, multicenter study to assess 
the efficacy, safety, and pharmacokinetics of baloxavir marboxil in combination with a SOC NAI 
(i.e., oseltamivir, zanamivir, or peramivir), compared with a matching placebo in combination 
with a SOC NAI in approximately 366 hospitalized adults and adolescent patients (aged 
12 years) with influenza.
Patients will be randomized as soon as possible after screening (ideally within 12 hours),
providing they are within 96 hours of symptom onset and hospitalized (includes assessment in 
emergency centers pending admission to a hospital ward).  Patients will be assigned in a 
2:1 ratio to receive baloxavir marboxil or matching placebo.  Study treatment must be given in 
combination with a SOC NAI according to investigator preference (i.e., oseltamivir, zanamivir, or 
peramivir).  Re-screening of patients who fail to meet the inclusion and exclusion criteria will be 
permitted only once, providing the time from symptom onset to randomization is still within 96 
hours.
Baloxavir marboxil will be administered as a 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 also on Day 7 if clinical 
improvement has not occurred at Day 5, per protocol defined criteria.  Treatment with a SOC 
NAI (i.e., oseltamivir, zanamivir, or peramivir) should be administered in accordance with local 
clinical practice.  To fully explore the utility of the combination with baloxavir marboxil, or 
matching placebo, the dosing regimen of the SOC NAI should aim to ensure that anti-viral 
activity is maintained from Day 1 to Day 5.  The SOC NAI treatment may be extended to Day 10 
or beyond at the discretion of the investigator and in accordance with local clinical practice.  The 
study consists of two periods:  a 10-day treatment period and a 25-day follow-up period.  
Therefore, the maximum study duration for each patient will be 35 days.
The study assessments to be conducted include the following:  physical examination, vital signs, 
assessment of consciousness, presence, or absence of respiratory support, adverse events, 
concomitant therapies, clinical laboratory tests, nasopharyngeal swabs, and the palatability 
and acceptability questionnaire.  
An external independent Data Monitoring Committee (iDMC) will evaluate safety according to 
policies and procedures detailed in an iDMC Charter.
Number of Patients
Approximately 366 hospitalized adults and adolescent patients (aged 12 years) are planned 
for enrollment at approximately 250 global sites in both Northern and Southern hemispheres.
Target Population
Inclusion Criteria
Patients must meet the following criteria for study entry:

Adult patients:  Signed informed consent by any patient capable of giving consent, or, 
where the patient is not capable of giving consent, by his or her legal/authorized 
representative


Baloxavir Marboxil —F. Hoffmann-La Roche Ltd
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
Adolescent patients not able to legally consent: written informed consent for study 
participation is obtained from patient’s parents or legal guardian, with assent as 
appropriate by the patient, depending on the patient’s level of understanding and capability 
to provide assent. 

Age 12 years at the time of signing the Informed Consent Form/Assent Form

Ability to comply with the study protocol, in the investigator’s judgment

Patients who require hospitalization for severe influenza or acquire influenza during 
hospitalization, the severity of which requires an extension of hospitalization

Diagnosis of influenza A and/or B by a positive Rapid Influenza Diagnostic Test (RIDT) or 
reverse transcriptase-polymerase chain reaction (RT-PCR) 
Positive results from local tests are acceptable if conducted within the 24 hours prior to 
screening.
A patient with a negative RIDT may be enrolled if influenza is suspected based on local 
surveillance data or if the patient reports contact with a known case of influenza within 
the prior 7 days and all other inclusion criteria are met

The time interval between the onset of symptoms and randomization is within 96 hours
The onset of symptoms is defined as the time when the patient experiences at least 
one new general symptom (e.g., headache, feverishness or chills, muscle or joint pain, 
fatigue), respiratory symptom (e.g., cough, sore throat, nasal congestion), or fever.

A score of 4 based on the National Early Warning Score 2 (NEWS2)

Patients will require objective criteria of seriousness defined by at least one of the following 
criteria: 

Requires ventilation or supplemental oxygen to support respiration

Has a complication related to influenza that requires hospitalization (e.g., pneumonia, 
CNS involvement, myositis, rhabdomyolysis, acute exacerbation of chronic kidney 
disease, asthma or chronic obstructive pulmonary disease [COPD], severe dehydration, 
myocarditis, pericarditis, exacerbation of ischemic heart disease)

For women of childbearing potential:  Agreement to remain abstinent (refrain from 
heterosexual intercourse)
Women must remain abstinent or use contraceptive methods with a failure rate of 1% 
per year during the treatment period and for 28 days after the last dose of study 
treatment.  Hormonal contraceptive methods must be supplemented by a barrier 
method.
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 has not undergone surgical sterilization 
(removal of ovaries and/or uterus).
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.
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.
Exclusion Criteria
Patients who meet any of the following criteria will be excluded from study entry:

Patients who have received more than 48 hours of antiviral treatment for the current 
influenza infection prior to screening

Patients who have received baloxavir marboxil for the current influenza infection

Known contraindication to neuraminidase inhibitors

Patients hospitalized for exclusively social reasons (e.g., lack of caregivers at home)


Baloxavir Marboxil —F. Hoffmann-La Roche Ltd
47/Statistical Analysis Plan CP40617

Patients expected to die or be discharged within 48 hours, according to the investigator’s 
judgement

Patients weighing 40 kg

Patients with known severe renal impairment (estimated glomerular filtration rate 
30 mL/min/1.73 m2) or receiving continuous renal replacement therapy, hemodialysis, 
peritoneal dialysis

Patients with any of the following laboratory abnormalities detected within 24 hours prior to 
or during screening (according to local laboratory reference ranges: 

ALT or AST level 5 times the upper limit of normal (ULN) 
OR

ALT or AST 3 times the ULN and total bilirubin level 2 times the ULN 

Pregnant or breastfeeding, or positive pregnancy test in a predose examination, or 
intending to become pregnant during the study or within 28 days after the last dose of study 
treatment

Exposure to an investigational drug within 5 half-lives or 30 days (whichever is longer) of 
randomization 

Any serious medical condition or abnormality in clinical laboratory tests that, in the 
investigator’s judgment, precludes the patient’s safe participation in and completion of the 
study

Known hypersensitivity to baloxavir marboxil or the drug product excipients
End of Study
The end of this study is defined as the date when the last patient, last visit (LPLV) occurs or the 
date at which the last data point required for statistical analysis or safety follow-up is received
from the last patient, whichever occurs later.  The LPLV is expected to occur 35 days after the 
last patient is enrolled. 
Length of Study
The total length of the study, from screening of the first patient to the LPLV, is expected to be 
approximately 2.5 years.
Investigational Medicinal Products
The investigational medicinal products (IMPs) for this study are baloxavir marboxil and its 
matching placebo as the comparator.
Test Product (Investigational Drug)
Baloxavir marboxil or its matching placebo will be administered orally according to body weight 
(40 mg for patients weighing 40 to 80 kg; 80 mg for patients weighing 80 kg), either in tablet 
form or granules for oral suspension for patients unable to swallow or with a nasogastric tube in 
situ (e.g., in intubated patients).  Dosing will occur on Day 1 and Day 4, with a further dose at 
Day 7 for patients who have not improved according to at least 1 of the following specific 
criteria at Day 5:  ongoing mechanical ventilation, persistent fever, severely 
immunocompromised, pneumonia, or confirmed/suspected influenza-related complication.
Non-Investigational Medicinal Product
Standard-of-Care Neuraminidase Inhibitor
The protocol-defined SOC NAIs are oseltamivir, zanamivir, or peramivir.
An open-label SOC NAI should be administered according to local clinical practice (i.e., 
oseltamivir, peramivir, or zanamivir) to ensure anti-viral activity is maintained from Day 1 
through Day 5.  The SOC NAI treatment may be extended to Day 10 or beyond at the discretion 
of the investigator and in accordance with local clinical practice.  Special attention is required for 
dosing in patients with renal impairment, as dose adjustment may be needed.


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Statistical Methods
Primary Analysis
The primary efficacy objective for this study is to evaluate the efficacy of baloxavir marboxil plus 
a SOC NAI, compared with matching placebo plus SOC NAI on the basis of the following 
endpoint:

Time to clinical improvement (TTCI; defined as time to hospital discharge or time to NEWS2 
of 2 and maintained for 24 hours, whichever comes first)
The median TTCI will be compared between the baloxavir marboxil plus SOC NAI and matching 
placebo plus SOC NAI arms using the stratified log-rank test within three regions (i.e., North 
America; Europe, Middle East, and Africa [EMEA]; rest of world [ROW]), NEWS2 (7, 7), and 
time from symptom onset to study treatment (48 hours, 48 hours) included as the 
stratification factors.  The Kaplan-Meier plot, median time to response, and their 95% CI, and a
p-value will be presented.
The log-rank test requires the assumption of proportional hazards to be met.  The proportional 
hazards assumption will be tested graphically using the log cumulative hazard plot by treatment 
group.  The plots for each treatment group will be parallel if the proportional hazard assumption 
holds.  Using a Cox model, the slope of a linear regression will also be tested and a plot of 
scaled Schoenfeld residuals against the Kaplan-Meier estimator will be investigated.  Should 
the proportional hazards assumption be violated, the Gehan-Wilcoxon test will be used to 
analyze the data as the logrank test can be under powered in this situation. All investigations 
will be detailed in the statistical section of the CSR.  
The estimand is the median change in TTCI.  This absolute measure will be assessed over the 
duration of the study (35 days).  Intercurrent events are those that occur after treatment 
initiation and either preclude observation of the variable or affect its interpretation.  Intercurrent 
events will be accounted for through censoring rules.  Patients who are lost to follow-up, who do 
not have a clinical response event, who die or discontinue for any reason prior to achieving a 
clinical response event will be censored at their last contact date or date of death, whichever is 
applicable.  No dose reductions or treatment cross-overs are anticipated.  
The primary efficacy analysis population will be characterized through the inclusion/exclusion 
criteria and will be the modified intent-to-treat (influenza-)infected (mITTI) population, which 
consists of all patients who were randomized to treatment, received a dose of study drug, and 
were RT-PCR positive for influenza (centrally assessed) at any timepoint.
A sensitivity analysis will be conducted where patients who are lost to follow-up or who do not 
have a clinical response event will be assumed to have had an event at 28 days.  A sensitivity
analysis for patients who discontinue for any reason prior to achieving a clinical response 
event will be performed to investigate potential confounding factors. A sensitivity analysis, 
considering death as a competitive event, using a competing risk model will be conducted if 
there are a sufficient number of deaths or an imbalance between groups in deaths and reason 
attributed.  These and any further sensitivity analyses will be fully detailed in the SAP. 
Missing data handling rules for the components of the NEWS2 score will be specified in the 
SAP.
Determination of Sample Size
Two new factors influenced the revised sample size:  1) the revised assumption for the placebo 
plus NAI control-arm TTCI following blinded data review and 2) the faster than anticipated 
enrollment rate.  Integration of these two factors informed a sample size readjustment to 
approximately 366 randomized patients.  Assuming that the RT-PCRpositive rate (tested in 
a central laboratory) will be 75% of the randomized population and a dropout rate of 4% the 
mITTI population will be 264 patients (i.e., 176 patients in the baloxavir marboxil group and 
88 in the placebo group).  
The total number of randomized patients may change based on the percentage of patients who 
are RT-PCR positive during the study.
The total mITTI sample size of 264 patients provides at least 80% power using the Logrank 
Chi-Square test to detect a 31-hour difference in TTCI between treatment groups under the 
following assumptions:  median TTCI in the placebo plus NAI group is 94 hours, 840 hours 


Baloxavir Marboxil —F. Hoffmann-La Roche Ltd
49/Statistical Analysis Plan CP40617
follow-up (35 days) using 5% alpha. The minimal detectable difference is expected to be 
around 23 hours.  The alteration of the TTCI in the placebo plus NAI group to 94 hours was 
selected after consideration of the response rates observed in a blinded review of TTCI 
including data from 127 patients.
The increased sample size has the consequential benefit of a larger population for safety 
analysis of the combination and multiple dose regimen specifically tested in this study for the 
severely ill hospitalized patient group.
The study power is calculated based on the primary endpoint incorporating a group sequential 
design (GSD) using a beta spending function with non-binding rule, to allow for one futility 
interim, without increasing the overall experiment-wise error rate.
Interim Analyses
After approximately 65% of TTCI events, a formal unblinded non-binding futility interim 
analysis based on the TTCI will be performed.  The futility interim analysis will use a Lan-
DeMets Pocock beta spending function.  If the hazard ratio seen at the interim is below the 
calculated futility bound, the trial may be declared futile and recruitment will be stopped. 
The futility interim is non-binding on the Sponsor, and any deviation from the iDMC 
recommendation will be fully documented in the CSR.  If the study is stopped for futility, at 
that point the study results will be reported.  Full operating characteristics of the IA will be 
detailed in the SAP.
The interim analysis will be conducted by an unblinded external statistical group (independent 
Data Coordinating Centre, iDCC) and reviewed by the iDMC (also unblinded), whilst the 
Sponsor will remain blinded until the end of study.  Interactions between the iDMC/iDCC and 
Sponsor will be carried out as specified in the iDMC Charter. 
The iDMC Charter will be updated to document this pre-planned interim analysis and
potential recommendations the iDMC can make to the Sponsor as a result of the analysis (e.g., 
stop the study for futility or continue the study), and the iDMC Charter will also be made 
available to relevant health authorities.


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Appendix 2 Schedule of Activities
Treatment Perioda
Follow-Up Period
Unsched 
Visit
Day(s)
D1
D2
D3
D4 D5 D6
D7
D8 D9
D10
(2 day) b
Hosp Day 
11+c
Discharged 
D1130 d
EOS
D35
(3 day)d
Visits
Screeninge
Random/
V1
V2
V3
V4 V5
V6
V7
V8
V9
Administrative Procedures
Informed consent and assent 
x
Inclusion/Exclusion criteria
x
Baseline characteristics
x
Medical history
x
Concomitant medication monitoring
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Clinical Procedures
Physical examination f
x f
x
x
x
x
x
x
x
x
x
x
x
xg
xg
x h
Body weight
x
xg, aa
Vital sign measurementsi, j, k
x
x
x
x
x
x
x
x
x
x
x
x
xg
xg
x h
Assessment of consciousness i, j, k
x
x
x
x
x
x
x
x
x
x
x
x
xg
xg
x h
Presence or absence of respiratory 
support i, j, k
x
x
x
x
x
x
x
x
x
x
x
x
xg
xg
xh
Full blood hematology and chemistry l
x m
x
x  g
xg
xg
x h
Blood liver chemistry l
x m
x m
Electrocardiogram n
x
x
Chest X-ray/CT Scano
x
(x)


Baloxavir Marboxil —F. Hoffmann-La Roche Ltd
51/Statistical Analysis Plan CP40617
Appendix 2 Schedule of Activities (cont.)
Treatment Perioda
Follow-Up Period
Unsche
d Visit
Day(s)
D1
D2
D
3
D
4
D
5
D
6
D
7
D
8
D
9
D10
(2 
day) b
Hosp 
Day 11+
c
Discharg
ed 
D1130 d
EOS
D35
(3 
day)d
Visits
Screening
e
Rando
m/V1
V2
V
3
V
4
V
5
V
6
V7
V8
V9
Nasopharyngeal swabs for local 
testing (RIDT or RT-PCR )  p
x
Nasopharyngeal swabs for central 
testing (non-influenza respiratory 
virus coinfections; RT-PCR; titer; 
phenotyping and genotyping, drug 
susceptibility test)q
x
x
x
x
x
x
x
x g
xg
xg
xh
Blood for influenza antibody titer
x
x
Pregnancy test r
x
x
xh
Adverse events s
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Ordinal scale recordingt
x
x
x
x
x
x
x
x
x
x
x
x
Study Drug Administration
Baloxavir marboxil/placebo u
x m
x m
x m
SOC NAIv
X
x
Meal intake documentation w
x
x
x
Palatability & acceptability 
assessment z
x
x
x
Pharmacokinetic Assessments
Plasma PK samples for baloxavirw, x, y
x
x
x
x
x
x


Baloxavir Marboxil —F. Hoffmann-La Roche Ltd
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Appendix 2 Schedule of Activities (cont.)
CT computed tomography; D day; EOS end of study; Hosp Hospitalized; NAI neuraminidase inhibitor; PK pharmacokinetics; NEWS2 National Early 
Warning Score 2; Random Randomization; RIDT Rapid Influenza Diagnostic Test; RT-PCR reverse transcription polymerase chain reaction; SOC standard-
of-care; Unsched Unscheduled; V visit; VHP Voluntary Harmonization Procedure.
a.
During the treatment period, Visits 17 should be performed for all patients regardless if they remain hospitalized or have been discharged.  On non-visit Days 
6, 8, and 9, procedures are only to be conducted for patients who remain hospitalized.
b.
A visit window of 2 days applicable for discharged patients only. 
c.
Hospitalized Days 11+:  procedures are to be conducted for patients who remain hospitalized, only.  
d.
The follow-up visit, Visit 8, should occur after hospital discharge, but not before Day 11 or within 5 days before the EOS visit.  Visit 8 should occur after Visit 7.  
The EOS visit should occur approximately 28 days after the last dose of study drug.
e.
Randomization should occur as soon as possible, ideally within 12 hours, after screening.
f.
A complete physical examination should be conducted at screening.  At post-baseline visits and as clinically indicated, limited, symptom-directed physical 
examinations should be performed.  Examinations should occur on a daily basis during the hospitalization and at each return visit after discharge.  See Section 
Protocol 4.5.3 for definitions of complete and limited, symptom-directed physical examinations.
g.
Clinical procedures/nasopharyngeal swabs may be undertaken at investigator’s discretion if symptoms and signs persist beyond the treatment period or if viral 
shedding is detected beyond Day 10.
h.
Perform assessments at any unscheduled visits based upon the cause of the visit and the investigator’s discretion.
i.
During the study treatment period (Day 1/Visit 1 to Day 10), all vital sign measurements (i.e., respiratory rate, pulse rate, peripheral oxygen saturation, systolic 
and diastolic blood pressures, and body temperature) and NEWS2-specific assessments (i.e., consciousness and presence or absence of respiratory support) 
should be recorded together four times per day, and spread throughout the day, for the duration of the hospitalization and once at each return visit to the clinic 
following hospital discharge up to Day 10 (Visit 7). During the follow-up period, for patients who remain in hospital, vital sign measurements and NEWS2-
specific assessments should be conducted once per day.  In patients who have been discharged, vital sign measurements and NEWS2-specific assessments 
are to be recorded at the investigators’ discretion (e.g., if symptoms and signs persist during follow-up).
j.
Should be assessed according to NEWS2 parameters (see Protocol Appendix 3).  Presence or absence of respiratory support per the NEWS2 parameter may 
be air or oxygen; “oxygen” can include other forms of ventilation to maintain oxygen saturations.
k.
The NEWS2 should be calculated by the site at screening only to determine patient eligibility based upon vital sign values and assessments related to National 
Early Warning Score 2 (see Section Protocol 4.5.5) recorded during the patient assessment.  Should these assessments be conducted more than once during 
the screening period (per site patient care), all data collected closest to but before randomization should be used for the NEWS2 score calculation and 
assessment of patient eligibility. See Protocol Appendix 3 for calculation instructions.
l.
See Protocol Section 4.5.7 for tests included in laboratory panels.
m.
Local laboratory liver function test results to be reviewed by the investigator before baloxavir marboxil, or its matching placebo, is administered.  On Day 1 and 
Day 4, the assessment is mandatory.  On Day 1, the local laboratory full blood chemistry panel required as part of screening can be used for this assessment 
or prior blood results if tests conducted within 24 hours prior to screening.  On Day 4, the protocol required local laboratory blood liver chemistry panel should 
be used for this assessment.  On Day 7, the local laboratory blood liver chemistry panel and associated review of liver chemistry is only required if the patient 
will receive baloxavir marboxil or matching placebo on this study day.


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Appendix 2 Schedule of Activities (cont.)
n.
This assessment cannot be conducted by a mobile nurse.
o.
If a chest X-ray has not been taken within the 24 hours prior to screening, it must be performed on Day 1.  If a chest X-ray was performed within 24 hours prior 
to screening, no additional chest X-ray needs to be performed.  If the SOC is a chest CT scan, this can be used as alternative to the chest X-ray.  The chest X-
ray/CT scan must not be performed any later than Day 1.  This assessment cannot not be conducted by a mobile nurse.  
p.
Nasopharyngeal swabs for RIDTs or RT-PCR:  Rapid influenza test or RT-PCR should be performed at screening or conducted within 24 hours prior to 
screening, and can be undertaken by a local test kit or Sponsor-provided kit.  
q.
Patients who are intubated will have endotracheal samples (aspirates) taken for virological assessment, in addition to two nasopharyngeal swabs at each 
timepoint, including at the screening visit.
r.
All women of childbearing potential will have a pregnancy test at screening (urine or serum).  For those countries under VHP (i.e., Belgium, Czech Republic, 
Estonia, Finland, France, Germany, Hungary, Romania, Spain, and Sweden), as well as the Netherlands, a serum pregnancy test is mandated at screening.  
Urine pregnancy tests (for all women of childbearing potential) will be performed at the end of study visit and at unscheduled visits (as required).  If a urine 
pregnancy test is positive, a serum pregnancy test must be performed.
s.
Adverse events should be recorded on a daily basis during the hospitalization and at each return visit after discharge.  
t.
Assessment of patient status using the ordinal scale should be recorded at baseline on Day 1/Visit 1 then again daily every morning (between 8 am and 12 pm) 
for patients who remain hospitalized.
u.
Study treatment dosing will occur on Day 1 and Day 4, with a further dose at Day 7 for patients who have not improved at Day 5.  Specific criteria must be met 
for additional dosing at Day 7 include ongoing mechanical ventilation, persistence of fever, severely immunocompromised, confirmed/suspected influenza-
related complication, or pneumonia.  Study treatment will be given in the hospital setting due to the requirement for pre-dose liver function monitoring.  In order 
to maximize the study blind, it is mandated that each site delegates the preparation of baloxavir marboxil and placebo granules to dedicated site personnel that 
are not involved in any other study related assessments or procedures. Dose administration cannot be conducted by a mobile nurse.
v.
The SOC NAI should to be administered to cover the minimum treatment exposure from Day 1 through Day 5, where possible.  This may be extended to 
Day 10 or beyond, at the discretion of the investigator and in accordance with clinical practice (see Protocol Section 4.3.2.2 for further guidance).
w.
The time of last food intake prior to dosing with study treatment and the fasting period following study treatment should be recorded on Days 1 and 4, as well as 
on Day 7 if additional study treatment is administered.
x.
Sparse PK samples:  See Protocol Appendix 3.
y.
Sequential PK samples: See Protocol Appendix 3.  Although sequential PK sampling is optional the protocol aim is to attempt to collect it from a maximum of 12 
patients.
z.
Palatability and acceptability assessments are to be conducted for patients that take study treatment as an oral suspension, and are awake and compos mentis 
during administration on Day 1 and Day 4 (as well as Day 7 if an additional dose is required).  The time of assessment should be completed approximately 1 
minute after swallowing the drug solution, and before rinsing the mouth. 
aa.
Bodyweight measurement in the ‘Follow-Up Period: Discharged D11-30' column was a medical editing error. Bodyweight is only measured at Screening and 
not at any other timepoint during the study.


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Appendix 3 Schedule of Pharmacokinetic Samples


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Appendix 4 National Early Warning Score 2 (NEWS2)
Reference
Royal College of Physicians. National early warning score (NEWS) 2 Standardizing the assessment of 
acute-illness severity in the NHS. London: RCP, 2017.
At screening, the NEWS2 should be calculated based upon vital sign values recorded 
during the patient assessment. Should these vital signs assessments be recorded more 
than once during the screening period (per site patient care) all data collected closest to 
but before randomization should be used for the NEWS2 score calculation and 
assessment of patient eligibility.
The oxygen saturation should be scored according to either the SpO2 Scale 1 or 2 
presented in the table above.  The SpO2 Scale 2 is for patients with a target oxygen 
saturation requirement of 88%92% (e.g., in patients with hypercapnic respiratory failure 
related to advanced lung diseases, such as chronic obstructive pulmonary 
disease [COPD]).  This should only be used in patients confirmed to have hypercapnic 
respiratory failure by blood gas analysis on either a prior or their current hospital 
admission.


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The decision to use the SpO2 Scale 2 should be made by the treating physician and 
should be recorded in the eCRF.  In all other circumstances, the SpO2 Scale 1 should be 
used.
For physiological parameter “Air or Oxygen?”:  Any patients requiring the use of oxygen 
or other forms of ventilation to maintain oxygen saturations and support respiration 
should be assigned a score of 2.
The consciousness level should be recorded according to the best clinical condition of 
the patient during the assessment.  Patients who are assessed as “Alert” (A) should be 
assigned a score of 0.  Patients assessed as “New Confusion” (C), “Responsive to Voice” 
(V), “Responsive to Pain” (P), or “Unconscious” should be assigned a score of 3.
Scores should be assigned for respiratory rate, systolic blood pressure, pulse, and 
temperature according to the table above. 
The NEWS2 should be recorded in the eCRF at the screening visit to ensure patients 
meet the eligibility criteria.  In addition to the total NEWS2, the individual components of 
the score should also be recorded in the eCRF.  Additional NEWS2 values will be 
calculated electronically throughout the study by the Sponsor based upon entry of vital 
sign parameters by the investigator in the appropriate eCRF.
Example Case Calculation:
A 82-old lady was admitted to an acute medical unit from a residential care home.  Her 
taken observations and corresponding NEWS2 score are as follows: 
Physiological Parameter 
Observation
Component Score
Respiratory rate (per min)
26
3
Oxygen saturations (SpO2 %)
95%
1
Supplemental Oxygen 
No
0
Systolic blood pressure (mmHg)
140
0
Pulse Rate (bpm)
109
1
Conscious level
Alert
0
Temperature (oC)
39
1
Total NEWS2 Score
6


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Appendix 5 Palatability and Acceptability Assessment of Study 
Drug Questionnaire
Questionnaire A:  Adolescent (Age 12 to 15 Years) Palatibility and Acceptability 
Assessment of Study Treatment Suspension (Baloxavir Marboxil or Placebo)
STUDY CP40617
Site Number:
Visit Number: 
Patient Number: 
Date: 
Date
Month
Year
Instructions:  

Questionnaire A is to be utilized for adolescents aged 1215 years unless they are 
considered to have a sufficient level of understanding to complete Questionnaire 
version B (Adolescents 16 years and above and adults).

The questions below are to be completed approximately 1 minute after swallowing 
the drug solution and before rinsing the mouth.

For Question 1, patients are encouraged to select, from the 5-point visual hedonic 
scale below, the face that best reflects how much he or she liked the taste of the 
ingested study drug solution.

This questionnaire can be given to the patient to complete or the form can be 
completed by study personnel.  The patient must provide answers to the questions.  
How was the taste of the medicine? 





Like very much
Like a little
Not sure
Dislike a little
Dislike very much
Would you be happy to take the medicine again?

yes

no

not sure/no answer


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Appendix 5 Palatability and Acceptability Assessment of Study 
Drug Questionnaire (cont.)
Questionnaire B:  Adult and Adolescent (Age 16 Years and Above) Palatability and 
Acceptability Assessment of Study Treatment Suspension 
(Baloxavir Marboxil or Placebo)
STUDY CP40617
Site Number:
Visit Number: 
Patient Number: 
Date:
Date
Month
Year
Instructions:  

Questionnaire B is to be utilized for adults and adolescents (age 16 years and 
above).

The questions below are to be completed approximately 1 minute after swallowing 
the drug solution and before rinsing the mouth. 

This questionnaire can be given to the patient to complete or the form can be 
completed by study personnel.  The patient must provide answers to the questions.  
1.
How would you rate the overall taste of the medicine at this moment?
Please tick a box between 1 (very pleasant) and 5 (very unpleasant).





1 (very pleasant)
2
3
4
5 (very unpleasant)
2.
Would you be happy to take the medicine again?

yes

no

not sure/no answer


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Appendix 6 Immunocompromised Patient Population
An immunocompromised patient population has been previously defined from the Roche 
NV20234 study evaluating conventional and double dose oseltamivir in the treatment of 
immunocompromised patients with influenza (ClinicalTrials.gov Identifier: 
NCT00545532). Similar criteria will be used to define the immunocompromised sub-
group analysis of the TTCI primary endpoint in the current study, which is detailed below:
1. Primary Immunodeficiency
OR
2. Secondary immunodeficiency, defined as:
a. Solid Organ Transplant with ongoing immunosuppression* OR
b. Allogenic haematological stem cell transplant with ongoing 
immunosuppression* OR
c.
HIV with a most recent CD4 <500/mm3 within the last 6 months (if 
available) and considered to be immunocompromised in the investigator’s 
opinion OR
d. Haematological malignancy that is ongoing OR
e. Investigator confirmed OR
f.
Systemic (e.g., enteric, subcutaneous, intramuscular or intravenous) 
immunosuppressive therapy*, irrespective of medical indication, that were 
started at least 12 weeks prior to#, and ongoing at the first time of study 
drug. 
*Ongoing immunosuppression and immunosuppressive therapy will be assessed via 
the following drug classes:

Steroids

Cytotoxic agents e.g. alkylating agents, anti-metabolites, anti-tumour 
antibiotics, anti-mitotic agents, molecularly targeted agents

Proteasome inhibitors

Calcineurin inhibitors

mTOR inhibitors

Immunosuppressive antibodies

Monoclonal antibodies e.g. inhibitors of pro inflammatory cytokines, T-cell 
inhibitors, B-cell inhibitors

Immunosuppressants
     #If the start date of immunosuppressive therapy is unknown, the medication has been 
assumed to be greater than 12 weeks prior to study drug. For cyclical 
immunosuppressive therapy, any treatment course initiated within 12 weeks prior to 
study drug will also be included.
Clinical Science will complete a manual review of patient level data to ensure that all 
patients that meet the immunocompromised criteria are included in the characterization 
of the immunocompromised subgroup.