A Phase I, Single-Centre, Open-Label, Parallel, Two Dose Level Study to Investigate the Pharmacokinetics, Safety, and Tolerability Following a Single Dose of Baloxavir Marboxil in Healthy Chinese Volunteers
Phase: NA
Conditions: Healthy Volunteer
Sponsor: Hoffmann-La Roche

Official Title: 
NCT Number: 
Document Date: 
A Phase I, Single-Center, Open-Label, Parallel, Two Dose Level 
Study to Investigate the Pharmacokinetics, Safety, and Tolerability 
Following a Single Dose of Baloxavir Marboxil in Healthy Chinese 
Volunteers 
NCT03959332 
Protocol Version 2: 1 0-January-2019 

FINAL PROTOCOL APPROVAL
CONFIDENTIAL
The information contained in this document, especially any unpublished data, is the property of 
F. Hoffmann-La Roche Ltd and Shionogi & Co., 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 and Shionogi & Co., Ltd
Protocol YP40902, Version 2
PROTOCOL
TITLE:
A PHASE I, SINGLE-CENTER, OPEN-LABEL, 
PARALLEL, TWO DOSE LEVEL STUDY TO 
INVESTIGATE THE PHARMACOKINETICS, 
SAFETY, AND TOLERABILITY FOLLOWING A 
SINGLE DOSE OF BALOXAVIR MARBOXIL IN 
HEALTHY CHINESE VOLUNTEERS
PROTOCOL NUMBER:
YP40902
VERSION:
2
TEST PRODUCT:
Baloxavir marboxil (RO7191686)
SPONSOR:
F. Hoffmann-La Roche Ltd and Shionogi & Co., Ltd
DATE FINAL:
06 December 2018
DATE AMENDED:
Version 1: 07 August 2018
Version 2:  See electronic date stamp below
 
10-Jan-2019 15:03:20
Title
Approver's Name
Company Signatory
Date and Time (UTC)
 
10-Jan-2019 15:03:20
Title
Approver's Name
Company Signatory
Date and Time (UTC)
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PROTOCOL AMENDMENT – SUMMARY OF CHANGES
Amendment 1: 
This amendment is considered to be substantial based on the criteria set forth in Article 
10(a) of Directive 2001/20/EC of the European Parliament and the Council of the 
European Union.
Overall rational for the amendment
This amendment includes changes in protocol sections to clarify clinical operation 
methods and to give clearer instructions to study centers in accordance with local clinical 
practice.
List of Main Changes in the Amendment:

Table 1 and Table 1 footnote in Section 1.3: Add drug screen action on Day -1 
visit in the table; move weight assessment from Day 1 to Day -1; remove 
hematology, urinalysis, clinical chemistry test on Day 1; remove HBcAg, HbcAb 
related tests and contents, add serological test for syphilis in the footnote ‘l’; 
remove blood samples for pharmacogenomic testing; update information of ECG 
testing in the footnote ‘f’ from “Triplicate 12-lead ECG will be performed at 
specified timepoints” to “Triplicate 12-lead ECG can be performed at specified 
timepoints if deemed necessary by investigator”, also add text “Timepoints for 
ECG evaluation from Day 1 are provided in Table 2”.

Table 2 in Section 1.3: Remove weight, ECG, laboratory tests at pre-dose from 
administration on Day 1 during the in-house period; remove blood samples for 
pharmacogenomic testing.

Section 1.1 and 4.1: Add “PK sampling” to the assessments of participants who 
will visit the study center on Days 6, 8, 10,12, and 15.

Synopsis and Sections 5.1: Update “body mass index is ≥18.5 to 26 kg/m2” to 
“body mass index is ≥18.5 to <26 kg/m2” in the inclusion criteria.

Synopsis and Sections 5.2: Revise “average diastolic blood pressure (40-90 
mmHg)” to “average diastolic blood pressure (60-90 mmHg)” in the exclusion 
criteria. 

Sections 8.2.3: Add information “Triplicate 12-lead ECG can be performed at specified 
timepoints if deemed necessary by investigator”.
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
Sections 8.7: Remove all pharmacogenomics information in the section and 
replace with “Pharmacogenomics assessments are not performed in this study”.

Table 7 in Appendix 4: Remove HBcAb test and add serological test for syphilis.
In addition, minor formatting updates and corrections have been made. Such changes 
are not listed in this amendment.
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TABLE OF CONTENTS
PROTOCOL ACCEPTANCE FORM .................................................................... 2
1.
PROTOCOL SUMMARY............................................................................. 10
1.1
Synopsis................................................................................ 10
1.2
Schematic of Study Design.................................................... 14
1.3
Schedule of Activities ............................................................ 15
2.
INTRODUCTION ........................................................................................ 19
2.1
Study Rationale ..................................................................... 20
2.2
Background ........................................................................... 20
2.3
Benefit/Risk Assessment....................................................... 22
3.
OBJECTIVES AND ENDPOINTS ............................................................... 23
4.
STUDY DESIGN......................................................................................... 23
4.1
Overall Design ....................................................................... 23
4.1.1
Length of the Study ............................................................... 24
4.1.2
Stopping Rules Criteria.......................................................... 24
4.2
Scientific Rationale for Study Design..................................... 25
4.2.1
Rationale for Study Population .............................................. 26
4.3
Dose Justification .................................................................. 26
4.4
End of Study Definition .......................................................... 27
5.
STUDY POPULATION................................................................................ 28
5.1
Inclusion Criteria.................................................................... 28
5.2
Exclusion Criteria................................................................... 28
5.3
Lifestyle Considerations......................................................... 30
5.3.1
Meals and Dietary Restrictions.............................................. 30
5.3.2
Caffeine, Alcohol, and Tobacco............................................. 30
5.3.3
Activity ................................................................................... 30
5.4
Screen Failures ..................................................................... 30
5.5
Recruitment Procedures........................................................ 31
6.
TREATMENTS............................................................................................ 31
6.1
Treatments Administered....................................................... 31
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6.2
Preparation/Handling/Storage/Accountability ........................ 32
6.3
Measures to Minimize Bias: Randomization and 
Blinding.................................................................................. 33
6.3.1
Method of Treatment Assignment.......................................... 33
6.3.2
Blinding.................................................................................. 33
6.4
Treatment Compliance .......................................................... 33
6.5
Concomitant Therapy ............................................................ 33
6.5.1
Permitted Therapy................................................................. 33
6.5.2
Prohibited Therapy ................................................................ 34
6.6
Dosage Modification .............................................................. 34
6.7
Treatment after the End of the Study..................................... 34
7.
DISCONTINUATION OF STUDY DRUG AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL ......................................................... 34
7.1
Discontinuation of Study Drug ............................................... 34
7.2
Participant Discontinuation/Withdrawal from the 
Study ..................................................................................... 34
7.3
Lost to Follow-Up................................................................... 35
8.
STUDY ASSESSMENTS AND PROCEDURES ......................................... 35
8.1
Efficacy Assessments............................................................ 36
8.2
Safety Assessments .............................................................. 36
8.2.1
Physical Examinations........................................................... 36
8.2.2
Vital Signs.............................................................................. 36
8.2.3
Electrocardiograms................................................................ 37
8.2.4
Clinical Safety Laboratory Assessments................................ 37
8.2.5
Medical History and Demographic Data ................................ 38
8.3
Adverse Events and Serious Adverse Events ....................... 39
8.3.1
Time Period and Frequency for Collecting 
Adverse Event and Serious Adverse Event Information .......................... 39
8.3.2
Method of Detecting Adverse Events and Serious 
Adverse Events........................................................................................ 40
8.3.3
Follow-Up of Adverse Events and Serious 
Adverse Events........................................................................................ 40
8.3.3.1
Investigator Follow-Up.......................................................... 40
8.3.3.2
Sponsor Follow-Up............................................................... 40
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8.3.4
Regulatory Reporting Requirements for Serious 
Adverse Events........................................................................................ 40
8.3.4.1
Emergency Medical Contacts............................................... 41
8.3.5
Pregnancy ............................................................................. 41
8.3.6
Non-Serious Adverse Events of Special Interest................... 41
8.3.7
Disease-Related Events and/or Disease-Related 
Outcomes Not Qualifying as AEs or SAEs............................................... 42
8.3.8
Management of Specific Adverse Events .............................. 42
8.4
Treatment of Overdose.......................................................... 42
8.5
Pharmacokinetics .................................................................. 42
8.6
Pharmacodynamics ............................................................... 43
8.7
Genetics/Proteomics ............................................................. 43
8.8
Biomarkers ............................................................................ 43
8.9
Health Economics OR Medical Resource 
Utilization and Health Economics .......................................... 43
8.10
Timing of Study Assessments ............................................... 43
8.10.1
Screening and Pre-treatment Assessments .......................... 43
8.10.2
Assessments during In-house Period.................................... 43
8.10.3
Assessments at Study Completion/Early 
Termination Visit...................................................................................... 44
8.10.4
Post-Dosing and Follow-Up Assessments............................. 44
9.
STATISTICAL CONSIDERATIONS ............................................................ 44
9.1
Statistical Hypotheses ........................................................... 44
9.2
Sample Size Determination ................................................... 44
9.3
Populations for Analyses ....................................................... 44
9.4
Statistical Analyses................................................................ 44
9.4.1
Summaries of Treatment Group Comparability ..................... 44
9.4.2
Efficacy Analyses .................................................................. 44
9.4.3
Safety Analyses..................................................................... 45
9.4.4
Pharmacokinetic Analyses..................................................... 46
9.5
Interim Analyses .................................................................... 47
9.6
Summaries of Conduct of Study............................................ 47
10. REFERENCES ........................................................................................... 48
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11. SUPPORTING DOCUMENTATION AND OPERATIONAL
CONSIDERATIONS.................................................................................... 49
LIST OF TABLES
Table 1
Schedule of Activities.................................................................. 16
Table 2
Detailed Table of Activities.......................................................... 18
Table 3
Objectives and Endpoints ........................................................... 23
Table 4
Summary of Treatment Administered ........................................ 31
Table 5
Safety Statistical Analysis Methods ............................................ 45
Table 6
Adverse Event Severity Grading Scale ...................................... 59
Table 7
Protocol-Required Safety Laboratory Assessments................... 68
Table 8
Highly Effective Contraceptive Methods ..................................... 71
LIST OF FIGURES
Figure 1
Overview of Study Design........................................................... 14
LIST OF APPENDICES
Appendix 1
Regulatory, Ethical, and Study Oversight Considerations.......... 49
Appendix 2
Adverse Events: Definitions and Procedures for Evaluating, 
Follow-up and Reporting............................................................. 56
Appendix 3
Procedures for Recording Adverse Events ................................ 63
Appendix 4
Clinical Laboratory Tests ........................................................... 68
Appendix 5
Contraceptive Guidance and Collection of Pregnancy 
Information.................................................................................. 70
Appendix 6
Protocol Amendment History ..................................................... 74
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviation
Definition
AE
adverse event
AUC0-inf
area under the concentration-time curve from Time 0 to 
infinity
AUC0-last
area under the concentration-time curve from Time 0 to 
last measurable concentration
AUC0-t
area under the plasma concentration-time curve 
between Time 0 and the time t
BUN
blood urea nitrogen
CEN
cap-dependent endonuclease
CL/F
apparent clearance
Cmax
maximum plasma concentration 
eCRF
electronic Case Report Form
IB
Investigator’s Brochure
ICF
Informed Consent Form
IEC
Independent Ethics Committee
NA
neuraminidase
OTC
over-the-counter
PK
pharmacokinetic
SoA
Schedule of Activities
Tmax
time to maximum plasma concentration
T1/2
terminal elimination half-life
ULN
upper limit of normal
Vz/F
apparent volume of distribution based on the terminal 
phase
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1.
PROTOCOL SUMMARY
1.1
SYNOPSIS
PROTOCOL TITLE:
A PHASE I, SINGLE-CENTER, OPEN-LABEL, PARALLEL, TWO 
DOSE LEVEL STUDY TO INVESTIGATE THE 
PHARMACOKINETICS, SAFETY, AND TOLERABILITY 
FOLLOWING A SINGLE DOSE OF BALOXAVIR MARBOXIL IN 
HEALTHY CHINESE VOLUNTEERS
SHORT TITLE:
THE PK, SAFETY, AND TOLERABILITY OF BALOXAVIR 
MARBOXIL IN HEALTHY CHINESE VOLUNTEERS
PROTOCOL NUMBER:
YP40902
VERSION:
2
TEST PRODUCT:
Baloxavir marboxil (R07191686)
PHASE:
I
RATIONALE
The purpose of the study is to evaluate the pharmacokinetics (PK), safety, and 
tolerability after a single oral dose of baloxavir marboxil (40 mg or 80 mg) in healthy 
Chinese participants. As this is a Phase I study in healthy participants, no therapeutic 
benefit is anticipated for these study participants.
OBJECTIVES AND ENDPOINTS
The specific objectives and corresponding endpoints/parameters for the study are 
outlined below.
Objectives
Endpoints/Parameters
Primary

To evaluate the pharmacokinetics
of baloxavir marboxil and 
baloxavir after a single oral dose 
of baloxavir marboxil

Maximum plasma concentration (Cmax)

Time to maximum plasma concentration (Tmax)

Area under the plasma concentration-time curve 
(AUC0-last, AUC0-inf, AUC0-t)

Terminal elimination half-life (t1/2)

Apparent total oral clearance (CL/F)

Apparent volume of distribution based on the 
terminal phase (Vz/F)

Plasma concentration at 24 hours (C24), 
48 hours (C48), and 72 hours (C72)
Secondary

To evaluate the safety and 
tolerability following a single oral 
dose of baloxavir marboxil

Incidence, severity, and frequency of adverse 
events, serious adverse events, vital signs
measurements, and clinical laboratory tests.
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OVERALL DESIGN
Study Design
This Phase I study is an open-label, randomized, parallel-group, two dose level study in 
healthy Chinese participants to evaluate the PK, safety, and tolerability of baloxavir 
marboxil and baloxavir following a single oral administration of baloxavir marboxil.
Treatment Groups and Duration
A total of 32 healthy Chinese participants 16 in each group will be enrolled in the study.
After signing the informed consent, a screening period of up to 28 days is provided to 
complete the study-related assessments.
During the in-house period, on confirming all the eligibility requirements, the participants
will be randomly allocated to one of the two parallel groups, 40 mg or 80 mg of study 
drug (baloxavir marboxil). The participants will be admitted to the study center on Day -1 
and receive study drug on morning of Day 1. Safety assessments and PK sampling will 
be carried out at scheduled timepoints. The study drug will be given after an overnight 
fast of approximately 10 hours followed by a fast of at least 4 hours postdose.
Participants will receive standard meals while in the study center and can be discharged 
at the investigator’s discretion on Day 4 after the 72-hour assessments have been 
completed.
The participants will visit the study center on Days 6, 8, 10, 12, and 15 for PK sampling, 
safety, and other assessments such as vital signs, ECG, and laboratory test etc.
Length of Study
The total duration of the study for each participant will be up to 6 weeks divided as 
follows: 

Screening: Up to 4 weeks

In-house period: Day -1 to morning of Day 4

Post-dosing and follow-up observation: Days 6, 8, 10, 12, and 15.
Participants will be admitted to the study center on Day -1 and will be discharged 
approximately 72 hours after the study drug administration.
End of Study
The end of the study is defined as the date when the last observation of the last 
participant occurs and is expected 141 day after the dose administration of last 
participant, unless the participant withdraws his/her consent or withdraws early due to 
any other reason.
Data Monitoring Committee
No Data Monitoring Committee is involved in the study.
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PARTICIPANT POPULATION
The study population will consist of healthy Chinese participants.
Inclusion Criteria
Participants must meet the following criteria for study entry:

Healthy male or female Chinese participants, aged 20-59 years inclusive at the time 
of screening. The female participants should be of non-childbearing potential.

Chinese participants must have Chinese parents and grandparents, all of whom
were born in China.

Healthy status as defined by absence of evidence of any active or chronic disease 
following a detailed medical and surgical history, a complete physical examination
including vital signs, 12-lead ECG, hematology, blood chemistry, viral serology, and 
urinalysis.

Participants whose body weight is ≥50 to <80 kg and body mass index is ≥18.5 to 
<26 kg/m2.

Able to participate and willing to provide written informed consent and to comply with 
the study restrictions.

Female participants must be either surgically sterile (by means of hysterectomy 
and/or bilateral oophorectomy) or postmenopausal for at least 1 year (defined as 
amenorrhea ≥12 consecutive months without another cause, and confirmed by 
follicle-stimulating hormone level > 35 mIU/mL).
Exclusion Criteria
Participants who meet any of the following criteria will be excluded at study entry:

Participants who are considered ineligible for this study by the Principal Investigator 
or subinvestigator due to current or history of significant metabolic, hepatic, renal, 
hematological, pulmonary, cardiovascular, gastrointestinal, urological, endocrine, 
neurological, or psychiatric disorders with clinical manifestations.

Participants with the following laboratory abnormalities at screening and on Day -1:
total bilirubin >1.5 × upper limit of normal (ULN)
AST >1.5 × ULN
ALT >1.5 × ULN
estimated glomerular filtration rate <60 mL/min/1.73 m2 by using Cockcroft-Gualt 
formula.

QTc interval > 450 ms (with Fridericia’s correction)

Participants with vital signs values outside of the reference range for average 
systolic blood pressure (90-140 mmHg), average diastolic blood pressure 
(60-90 mmHg), or average pulse rate (40-90 beats/minute).

Participants with a history of stomach, vagus nerve, or intestinal surgery (except for 
appendectomy).

Participants who have a history of allergic symptoms including food allergy (Note:
Non-active allergic rhinitis will be allowed).
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
Participants who require chronic drug therapy or those who have used drugs (e.g., 
prescription or over-the-counter drugs, herbal and dietary supplements, and 
vitamins) within 3 days prior to screening or within 14 days prior to Day -1.

Participants who have used alcohol-containing, caffeine-containing, grapefruit 
containing, or St. John’s wort-containing products within 72 hours prior to Day -1.

Participants who have used tobacco- or nicotine-containing products within 
24 weeks prior to screening.

Participants who have a history of abuse of drugs and/or alcohol.

Participants who have a positive urine cotinine, drug, and alcohol screen at 
screening and Day -1.

Participants who are positive for serological test for syphilis (Treponema pallidum), 
hepatitis B surface antigen, hepatitis C virus antibody, or HIV antigen/antibody at 
screening.

Participants who have donated >400 mL of blood within 12 weeks or >200 mL of 
blood within 4 weeks prior to screening, or have donated any amount of blood 
between screening and Day -1.

Participants who have been exposed to an investigational drug within 90 days prior 
to the initial screening visit.

Participants who have received baloxavir marboxil previously.

Participants who are considered inappropriate for the study by the Principal 
Investigator or subinvestigator.
NUMBER OF PARTICIPANTS
A total of 32 healthy Chinese participants, 16 participants in each group will be enrolled 
in the study. The number of participants (16 participants for each dose level) is chosen 
based on practical clinical judgement, the PK variability observed, anticipated drop-rate, 
and China’s regulatory requirement. It is considered that 16 study participants in each 
group would provide sufficient data to characterize the PK of baloxavir and baloxavir 
marboxil.
CONCOMITANT MEDICATIONS
The use of drugs (e.g., prescription or over-the-counter (OTC) drugs, herbal and dietary 
supplements, vitamins) is prohibited for 14 days prior to admission (Day -1).
The use of drugs (e.g., prescription or OTC drugs, herbal and dietary supplements, 
vitamins) and procedures without any medication is prohibited from admission (Day -1)
until completion of the post-dosing observation period (Day 15) (or early termination if 
this occurs).
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1.3
SCHEDULE OF ACTIVITIES
The Schedule of the Activities is provided in Table 1.
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b
Breath alcohol, urine cotinine, and urine drug screen of (amphetamines, barbiturates, cocaine, opiates, methadone, cannabinoids, and 
benzodiazepines) will be evaluated.
c
Participants will be randomized to 40 mg or 80 mg baloxavir marboxil in a 1:1 ratio.
d
Complete physical examination will be conducted at screening and brief physical examination will be done at other visits.
e
Vital signs include body temperature, pulse rate, blood pressure, and respiratory rate. Blood pressure and pulse rate should be measured at 
least 5 minutes after the participant rests in a supine position and on the same arm. Assessment of vital signs should be done prior to blood 
collection.
f
Triplicate 12-lead ECG can be performed at specified timepoints if deemed necessary by investigator. At each timepoint at which triplicate 
ECGs are required, three individual ECG tracings should be obtained as closely as possible in succession, but no more than 2 minutes apart.
The full set of triplicates should be completed in less than 4 minutes. Electrocardiogram should be performed prior to any scheduled vital sign 
measurements and blood draws. In some cases, it may be appropriate to repeat abnormal ECGs to rule out improper lead placement as 
contributing to the ECG abnormality. Timepoints for ECG evaluation from Day 1 are provided in Table 2.
g
Hematology test parameters include leucocytes, erythrocytes, hemoglobin, hematocrit, platelets, differential count (neutrophils, eosinophils, 
basophils, monocytes, lymphocytes, other cells).
h
Urinalysis include pH, glucose, protein, and blood (leukocyte). If there is a clinically significant positive result (confirmed by a positive repeated 
sample), urine sample will be sent to the laboratory for microscopy and culture. If there is an explanation for the positive dipstick results (e.g., 
menses), it should be recorded and there is no need to perform microscopy and culture.
i
Clinical chemistry test parameters include sodium, potassium, chloride, bicarbonate, glucose (fasting), urea, creatinine, total protein, serum 
albumin, phosphate, calcium, total and direct bilirubin, alkaline phosphatase, ALT, AST, urate, and LDH.
j
Lipid profile includes total cholesterol and triglycerides; thyroid profile includes Free T4 and TSH; coagulation tests include INR, aPTT, and PT.
k
Blood pregnancy test will be performed at screening and urine pregnancy test will be performed at subsequent visits. If urine pregnancy test is
positive it will be confirmed by blood pregnancy test. If the blood pregnancy test is positive, then the participant must be withdrawn from the 
study.
l
Serology tests for HIV, HBsAg, HCV and syphilis (Treponema pallidum) antibody will be performed.
m
Timepoints for PK samples are provided in Table 2.
n
Adverse events reported from the time of signing consent up to 14 days after the last dose should be documented and recorded in the eCRFs.
Any concomitant medication should also be recorded.
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Table 2
Detailed Table of Activities 
Period
Day
Time from 
administration 
(h)
Randomization
Drug 
Administration
Physical 
Examination
Weight
Vital 
Signs
ECG
Laboratory 
Tests
PK Blood 
Samples
In-House
Day 1
Pre-dose
x
x
x
x
0
x
0.5
x
1
x
x
2
x
x
x
3
x
4
x
x
x
x
5
x
6
x
8
x
12
x
x
x
x
Day 2
24
x
x
x
x
x
36
x
Day 3
48
x
x
x
x
x
Day 4
72
x
x
x
x
x
x
Post-Dosing and 
Follow-up Observation
Day 6
120
x
x
x
x
x
x
Day 8
168
x
x
x
Day 10
216
x
x
x
x
Day 12
264
x
x
x
Day 15
312
x
x
x
x
ECG =electrocardiogram; h = hours; PK = pharmacokinetics.
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2.
INTRODUCTION
Baloxavir marboxil (Xofluza™; baloxavir) is an oral cap-dependent endonuclease (CEN) 
inhibitor that has been developed by Roche and Shionogi. The drug blocks influenza 
virus proliferation by inhibiting the initiation of messenger RNA synthesis.
Influenza virus infection is an acute respiratory infection caused by the influenza virus,
which is transmitted primarily through airborne droplets. It is characterized by a sudden
onset of clinical symptoms such as fever, chills, headache, muscle pains, and loss of
appetite, which start 1 to 4 days after infection; the fever can reach 38ºC to 40ºC within 
24 hours of the onset (Monto et al. 2000; Fields et al. 2007). Other symptoms include 
cough, sore throat, and nasal congestion; cough is very frequent and tends to be 
persistent (Uchida et al. 2006). These characteristics make influenza virus infection a 
potentially severe disease, which should be distinguished from the common cold 
syndrome (Investigator Brochure, 2018).
Influenza viruses are significant human respiratory pathogens that cause both seasonal, 
endemic infections and periodic, unpredictable pandemics (Jeffery K. Taubenberger and 
David M. Morens. 2008). Despite significant advancement in vaccine and virus research, 
influenza continues to be a major public health concern. Each year in the United States, 
influenza viruses are responsible for seasonal epidemics resulting in over 200,000 
hospitalizations and 30,000–50,000 deaths (Vemula et al. 2016). In China, annual 
influenza-associated excess mortality was 18.0 and 11.3 deaths per 100,000 population 
in northern and southern cities, respectively. Although China is experiencing a 
substantial disease burden of influenza, influenza vaccine coverage rate was only 
around 2.0% in 2016. A large majority of the Chinese population are not protected by 
influenza vaccine (Liu et al. 2017). Till date, the following anti-influenza virus drugs have 
been approved (with geographic variability): M2 channel inhibitors, amantadine 
hydrochloride and rimantadine hydrochloride; neuraminidase (NA) inhibitors, oseltamivir 
phosphate, zanamivir hydrate, peramivirhydrate, and laninamivir octanoate hydrate; an 
RNA polymerase inhibitor, favipiravir. The U.S. Centers for Disease Control and 
Prevention have advised that the use of amantadine hydrochloride and rimantadine 
hydrochloride be restricted for the treatment of influenza virus infection (CDC HEALTH 
ALERT, 2006).
The NA inhibitors are mainly prescribed for influenza virus infection; however, they have 
the following limitations: NA inhibitors should be administered within 48 hours of onset; 
oral NA inhibitors need to be administered for 5 days, eliciting concerns for compliance 
with the regimen; use of the inhaler drug is limited by the age of patients who are able to 
inhale the drug; and sufficient evidence is lacking regarding the inhibitory effects on 
exacerbations of influenza such as secondary infections and for therapeutic efficacy in 
patients with severe influenza. Therefore, more convenient and potent anti-influenza 
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virus drugs without limit of use are awaited. In addition, influenza viruses are well-known 
to undergo genomic mutations during replications, which could result in pandemics of
mutated viruses to which many people are not immune or which could make the viruses
resistant to the currently available anti-influenza virus drugs. To prepare for these 
possibilities, the development of new anti-influenza virus drugs with novel mechanisms
of action is anticipated (Investigator Brochure, 2018).
In February 2018, baloxavir marboxil received its first global approval in Japan for the 
treatment of influenza A or B virus infections. The Phase III development for this drug is 
underway in the US, EU, and other countries for this indication (Heo 2018).
To date 11 Phase I studies, one Phase II study, and two Phase III studies have been 
completed and one Phase III study is ongoing. A total of 1346 participants have been 
exposed to at least 1 dose of baloxavir marboxil in the completed studies (Investigator 
Brochure, 2018).
This Phase I clinical study in healthy Chinese participants is designed to evaluate the
pharmacokinetics (PK), safety, and tolerability of baloxavir and baloxavir marboxil
following a single oral dose of baloxavir marboxil.
2.1
STUDY RATIONALE
The objective of the study is to evaluate the PK, safety, and tolerability after a single 
oral dose of baloxavir marboxil (40 mg or 80 mg) in healthy Chinese participants. This is 
a Phase I study in healthy participants, no therapeutic benefit is anticipated for these 
study participants.
The rationale for the study design is provided in Section 4.2.
2.2
BACKGROUND
Baloxavir marboxil is an anti-influenza virus drug with a novel mechanism of action.
Baloxavir marboxil selectively inhibits CEN activity necessary for replication of influenza 
viruses. A broad spectrum of activity against seasonal influenza viruses and alleviating 
effects on the influenza symptoms were shown in nonclinical efficacy studies and the 
clinical studies in patients with influenza including the Phase II proof of concept and 
dose finding study, the Phase III double-blind study in otherwise healthy patients, and 
the Phase III open-label study in otherwise healthy pediatric patients. 
The novel mechanism of action of baloxavir marboxil is anticipated to be effective 
against influenza virus strains resistant to currently marketed drugs.
After oral administration, baloxavir marboxil is extensively converted to its active 
metabolite, baloxavir, predominantly by arylacetamide deacetylase in the gastrointestinal 
lumen, intestinal epithelium, and liver. In the dose range studied (6 mg to 80 mg), the 
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maximum plasma concentration (Cmax) and area under the plasma concentration-time 
curve (AUC) of baloxavir increased generally in a dose-proportional manner. Following a 
single oral administration of baloxavir marboxil, the time to the maximum plasma 
concentration (Tmax) of baloxavir was reached at 4 hours, and the elimination half-life 
was 79.1 hours. Although the absolute bioavailability of baloxavir marboxil/baloxavir has 
not been established, the absorption of the drug was estimated to be good based on the 
total recovery of 80.1% of the administered radioactivity in feces and more than 60% 
was recovered post 48 hours after dosing in the 14C mass balance study. A food-effect 
study involving administration of baloxavir marboxil to healthy volunteers under fasted 
state and with a meal (approximately 400 to 500 kcal including 150 kcal from fat) 
indicated that the Cmax and AUC of baloxavir were decreased by 48% and 36%, 
respectively, under fed conditions. The Tmax was unchanged in the presence of food.
Baloxavir showed serum protein-binding of 92.9% to 93.9%. The drug has multiple 
elimination pathways including UGT1A3 (the major pathway), and CYP3A4 (the minor 
pathway). In addition, the drug has an intestinal/biliary secretion, and a renal excretion 
(in urine, 3.3% of the administered dose was excreted as baloxavir). In vitro and in vivo
human studies have shown that there is no clinically relevant effect of baloxavir marboxil 
and baloxavir on other co-administered medicines. There were no clinically relevant 
effects of other drugs (probenecid, itraconazole, oseltamivir phosphate) on the Cmax and 
AUC of baloxavir.
A population PK analysis revealed that body weight and race were significant covariates 
on the PK of baloxavir. Based on the population modeling, the dose of baloxavir 
marboxil was proposed to be 40 mg for patients weighing < 80 kg and 80 mg for patients 
weighing ≥ 80 kg and investigated in the Phase III studies.
The PK/PD analysis using Phase II and Phase III data showed that at the proposed 
therapeutic doses, the responses of baloxavir using the virus titers change from the 
baseline were at the plateau, i.e., around the maximum effect. 
Safety analysis of all studies indicated that baloxavir marboxil was well-tolerated with 
only mild to moderate and reversible adverse events. The overall safety profile was 
typical of the underlying influenza disease (e.g., diarrhea as the most common adverse 
event). As a result, no adverse drug reactions have been identified in association with 
baloxavir marboxil, either dose or exposure (Investigator Brochure, 2018).
In summary, based on the linear PK, good bioavailability and multiple elimination 
pathways as well as the flat PD and wide therapeutic window, the ethnic sensitivity of 
baloxavir marboxil is likely to be low. Although the exposure between Japanese and 
Caucasian is slightly different (the mechanism is unknown), the proposed dose (40 mg 
for body weight <80 kg and 80 mg for body weight ≥80 kg) was efficacious and safe in 
both Japanese and Caucasian patients documented in the Phase III studies. The 
Sponsor proposes to conduct a single-center, open-label, two parallel arms study. The 
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objective of the study is to evaluate the PK, safety, and tolerability of baloxavir marboxil 
following a single dose of oral administration to healthy Chinese participants.
Participants will be randomized into two parallel groups (n=16 each), 40 mg or 
80 mg under fasting. The PK data in Chinese adults will be compared with the Japanese 
and Caucasian PK data. Given that the disease course of influenza is the same across 
ethnic groups, the Sponsor believes that providing satisfactory PK data in this study will 
be sufficient to support the use of baloxavir marboxil to treat influenza in Chinese 
participants.
A detailed description of the chemistry, pharmacology, efficacy, and safety of baloxavir 
marboxil is provided in the Investigator’s Brochure (IB).
2.3
BENEFIT/RISK ASSESSMENT
Potential benefit
This study is to be conducted in healthy Chinese participants who are not expected to 
gain any individual benefit from participation in this study. The risk to healthy participants, 
however, is justified based on safety knowledge gained from the previous clinical studies 
conducted to justify clinical studies in Chinese patients with influenza virus infection.
The data collected from this study is expected to guide informed dose selection in 
patients from China with influenza virus infection, by bridging the safety and efficacy 
data from global Phase III studies.
Potential risk
The results of safety of baloxavir marboxil were obtained from the 11 Phase I studies, 
one Phase II study, and two Phase III studies. No significant safety concerns were 
identified and therefore, baloxavir marboxil was considered generally safe when 
administered to healthy participants, patients with hepatic and renal impairment, and 
adult patients with influenza virus infection at a single oral dose up to 80 mg, regardless 
of body weight (Investigator Brochure, 2018).
Studies conducted in rats showed no adverse effects on fetal viability, intrauterine 
growth, or external, visceral, and skeletal morphology of live fetuses. The potential risk 
of baloxavir marboxil in pregnant women is unknown. Women of childbearing potential, 
pregnant, and breastfeeding women will not be eligible in this study.
As a risk mitigation strategy, after careful selection of the participants (meeting eligibility 
requirements), close monitoring of standard safety parameters (physical examination,
ECGs, vital signs, laboratory assessments, pregnancy test, concomitant medication 
review, and adverse events) will be conducted during the in-house period and up to the 
follow-up visit occurring 14 days after the administration of baloxavir marboxil. The 
participants will be under observation in the study center for 72 hours post-study drug 
administration to monitor possible drug-related reaction. In addition, reactions related to 
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insertion of indwelling cannula (if used by the study center) will be monitored during the 
study center stay.
More detailed information about the risk-to-benefit profile of baloxavir marboxil is 
provided in the IB.
This study will be performed in compliance with the protocol, International Council for 
Harmonisation, Good Clinical Practice, and applicable regulatory requirements.
3.
OBJECTIVES AND ENDPOINTS
This study will evaluate the PK, safety, and tolerability following a single oral dose of 
baloxavir marboxil in healthy Chinese participants. The objectives and corresponding 
endpoints/parameters are provided in Table 3.
Table 3
Objectives and Endpoints
Objectives
Endpoints/Parameters
Primary

To evaluate the pharmacokinetics 
(PK) of baloxavir marboxil and 
baloxavir after a single oral dose of 
baloxavir marboxil

Maximum plasma concentration (Cmax)

Time to maximum plasma concentration 
(Tmax)

Area under the plasma concentration-time 
curve (AUC0-last, AUC0-inf, AUC0-t)

Terminal elimination half-life (t1/2)

Apparent total oral clearance (CL/F)

Apparent volume of distribution based on the 
terminal phase (Vz/F)

Plasma concentration at 24 hours (C24), 48 
hours (C48), 72 hours (C72)
Secondary

To evaluate the safety and tolerability 
following a single oral dose of 
baloxavir marboxil

Incidence, severity, and frequency of 
adverse events, serious adverse events, 
vital signs measurements and clinical 
laboratory tests.
4.
STUDY DESIGN
4.1
OVERALL DESIGN
This Phase I study is an open-label, randomized, parallel-group, two dose level study in 
healthy Chinese participants to evaluate the PK, safety, and tolerability of baloxavir 
marboxil and baloxavir following a single oral administration of baloxavir marboxil.
A total of 32 healthy Chinese participants, 16 in each group, will be enrolled in the study.
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An overview of the study design is provided in Section 1.2.
Screening:
After signing the informed consent, the participant will be screened for eligibility through 
medical history and other assessments as indicated in the Schedule of Activities (SoA)
(Section 1.3). A screening period of up to 28 days is provided to complete the 
study-related assessments.
In-house Period:
On confirming all the eligibility requirements, the participants will be randomly allocated 
to one of the two parallel groups, 40 mg or 80 mg of study drug (baloxavir marboxil).
Participants will be admitted to the study center on Day -1. On the morning of Day 1, 
participants will receive a single 40 mg or 80 mg oral dose of the study drug. The study 
drug will be administered after an overnight fast of approximately 10 hours. No breakfast 
will be served in the morning of Day 1. A standard lunch will be provided 4 hours after 
study drug administration. Safety assessments and PK sampling will be done at 
scheduled timepoints. See SoA in Section 1.3. Participants will receive standard meals 
while in the study center and can be discharged at the investigator’s discretion on Day 4 
after the 72-hour assessments have been completed.
Post-Dosing and Follow-up Observation: Participants will visit the study center on Day 6 
for post-dosing assessments and PK sampling. The participants will visit the study center
on Days 8, 10, 12, and 15 for PK sampling, the safety and other assessments as 
specified in SoA.
4.1.1
Length of the Study
The total duration of the study for each participant will be up to 6 weeks divided as 
follows: 

Screening: Up to 4 weeks.

In-house period: Day -1 to morning of Day 4.

Post-dosing and follow-up observation: Day 6, 8, 10, 12, and 15.
Participants will be admitted to the study center on Day -1 and will be discharged 
approximately 72 hours after the study drug administration.
4.1.2
Stopping Rules Criteria
Study Stopping Criteria:
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:
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
The incidence or severity of adverse events in this or other studies indicates a
potential health hazard to the participants.

Participant enrollment is unsatisfactory
The Sponsor will notify the investigator, Ethics Committee, and Health Authorities if the 
study is placed on hold, or if the Sponsor decides to discontinue the study or
development program.
Individual Participant Stopping Criteria
The investigator has the right to withdraw a participant from the study at any time. In 
addition, participants have the right to voluntarily withdraw from the study at any time for 
any reason. Reasons for withdrawal from the study may include, but are not limited to, 
the following:

Participant withdrawal of consent at any time

Any medical condition that the investigator or Sponsor determines may 
jeopardize the participant’s safety if he or she continues in the study.

Investigator or Sponsor determines it is in the best interest of the participant.
Every effort should be made to obtain information on participants who withdraw from the 
study. The primary reason for withdrawal from the study should be documented in the 
electronic Case Report Form (eCRF).
Participants who withdrawn from the study prematurely will be asked to return to the
study center to undergo the assessments specified in the follow-up visit (see
Section 1.3). Participants will not be followed for any reason after consent has been 
withdrawn.
Participants who withdraw or are withdrawn from the study will not be replaced.
The Sponsor reserves the right to discontinue the study for safety or administrative 
reasons at any time while ensuring that early termination does not compromise 
participant’s safety or well-being. If, in the opinion of the Principal Investigator, clinical 
observations suggest it may be unsafe to continue, the Principal Investigator may 
terminate the study after consultation with the Sponsor.
4.2
SCIENTIFIC RATIONALE FOR STUDY DESIGN
The data collected from this study is expected to guide informed dose selection in 
patients from China with influenza virus infection, by bridging the safety and efficacy 
data from global Phase II and Phase III studies.
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4.2.1
Rationale for Study Population
The nonclinical and clinical studies of baloxavir marboxil show that there are no 
significant safety concerns and the study drug is considered generally safe to be 
administered to healthy participants as well as patients with influenza virus infection.
However, the study drug has not been evaluated in clinical studies in the Chinese 
population. Hence healthy Chinese participants will be enrolled to determine the PK, 
safety, and tolerability of baloxavir marboxil following a single oral dose of 40 mg or 
80 mg.
4.3
DOSE JUSTIFICATION
To evaluate the pharmacokinetics in Chinese healthy participants, the two Phase III 
doses 40 mg and 80 mg have been selected for this study. This is considered to be 
adequate to assess the PK of baloxavir marboxil in a Chinese healthy population and to 
compare the results with those from Caucasian and Japanese populations.
In the Phase I single ascending dose and multiple ascending dose placebo-controlled 
study conducted in Japan, baloxavir marboxil was administered to 40 healthy male adult 
subjects. A total of 6 adverse events were reported in 6 of the 40 randomized subjects 
and no serious adverse events were reported. Single oral doses of baloxavir marboxil up 
to 80 mg were found to be safe and well tolerated in healthy adult subjects.
In another Phase I study conducted in Japan to evaluate the relative bioavailability and 
food effect, 20 mg of baloxavir marboxil formulated as either a tablet or suspension was 
administered to 29 healthy subjects (14 subjects in the bioavailability part and 
25 subjects in the food effect part of the study). In the bioavailability part of the study, 
2 of 14 subjects experienced treatment-emergent adverse events of nasopharyngitis and 
blood uric acid increased. In the food effect part of the study, 10 of 15 subjects 
experienced at least 1 treatment-emergent adverse events (ALT increased occurred in 
more than 3 subjects) with a total of 15 treatment-emergent adverse events reported 
overall and no deaths, serious treatment-emergent adverse events or discontinuation 
due to treatment-emergent adverse events were reported in this study. In the Phase I
drug-drug interaction study with CYP3A4 substrate conducted in the United States, a 
single dose of 5 mg of midazolam was administered alone or in combination with a 
single dose of 40 mg of baloxavir marboxil to 12 healthy adult subjects. Three adverse 
events were reported in 2 of the 12 subjects and no deaths or serious adverse events 
were noted. In the Phase I drug-drug interaction study in the United States, a single 
dose of 20 mg of baloxavir marboxil was administered alone or in combination with 
repeated dose of 200 mg of itraconazole to 12 healthy adult subjects.
Ten treatment-emergent adverse events were reported in 6 of 12 enrolled subjects. 
Among them, 3 treatment-emergent adverse events were reported when baloxavir 
marboxil was administered alone and 6 occurred when baloxavir marboxil was co-
administered with itraconazole and no deaths or serious adverse events were observed.
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In the Phase II proof of concept and dose finding study a single dose of 10, 20, or 40 mg 
of baloxavir marboxil was administered to 100 Japanese patients with influenza virus 
infection for each dose. Treatment-related adverse events were reported in 9 of 100 
patients (12 events) in the 10 mg group, 7 of 100 patients (8 events) in the 20 mg group, 
and 6 of 100 patients (7 events) in the 40 mg group compared with 10 of 100 patients 
(14 events) in the placebo group. No deaths or serious adverse events were reported in 
any of the groups. No significant safety concerns were identified and therefore, baloxavir 
marboxil was considered generally safe when administered to the patients with influenza 
virus infection at a single oral dose up to 40 mg.
In the Phase III double-blind study in otherwise healthy patients in the 20 to 64 years of 
age stratum received a single dose of 40 or 80 mg (depending on the patient’s weight) of 
baloxavir marboxil, repeated dose of 75 mg oseltamivir twice daily for 5 days or placebo, 
and patients in the 12 to 19 years of age stratum received a single dose of 40 or 80 mg 
(depending on the patient’s weight) of baloxavir marboxil or placebo. Globally, 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. Two serious adverse events not related 
to the study drug were reported in the baloxavir marboxil group. No deaths were 
reported in all the three groups. Treatment-related adverse events were reported in 27 of 
610 patients (4.4%, 37 events) in the baloxavir marboxil group, 12 of 309 patients (3.9%, 
19 events) in the placebo group, and 43 of 513 patients (8.4%, 53 events) in the
oseltamivir group. In all the three groups, majority of the adverse event were categorized 
as Grade 1 or 2 and their outcome were resolved or resolving.
As described above, no significant safety concerns were identified when compared with 
placebo or oseltamivir, therefore, baloxavir marboxil is considered generally safe when 
administered to patients with influenza at a single oral dose of either 40 or 80 mg 
depending on the patient’s weight.
Further details are provided in the IB.
4.4
END OF STUDY DEFINITION
A participant is considered to have completed the study if he or she has completed all 
assessments and visits of the study including the follow-up visit on Day 15.
The end of the study is defined as the date when the last participant’s, last observation 
occurs and is expected 14±1 day after the dose administration of the last participant, 
unless the participant withdraws his/her consent or withdraws early due to any other 
reason.
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5.
STUDY POPULATION
Healthy Chinese participants in the age of 20-59 years, whose parents and grandparents 
were born in China and who do not have any evidence of active or chronic disease will 
be enrolled in this study.
Prospective approval of protocol deviations from recruitment and enrollment criteria, also 
known as protocol waivers or exemptions, is not permitted.
5.1
INCLUSION CRITERIA
Participants must meet the following criteria for study entry:

Healthy male or female Chinese participants, aged 20-59 years (inclusive) at the 
time of screening. The female participants should be of non-child bearing potential.

Chinese participants must have Chinese parents and grandparents, all of whom
were born in China.

Healthy status as defined by absence of evidence of any active or chronic disease 
following a detailed medical and surgical history, a complete physical examination
including vital signs, 12-lead ECG, hematology, blood chemistry, viral serology, and 
urinalysis.

Participants whose body weight is ≥50 to <80 kg and body mass index is ≥18.5 to 
<26 kg/m2.

Able to participate and willing to provide written informed consent and to comply with 
the study restrictions.

Female participants must be either surgically sterile (by means of hysterectomy 
and/or bilateral oophorectomy) or postmenopausal for at least 1 year (defined as 
amenorrhea ≥12 consecutive months without another cause, and confirmed by 
follicle-stimulating hormone level > 35 mIU/mL).
5.2
EXCLUSION CRITERIA
Participants who meet any of the following criteria will be excluded at study entry:

Participants who are considered ineligible for this study by the Principal Investigator 
or subinvestigator due to current or history of significant metabolic, hepatic, renal, 
hematological, pulmonary, cardiovascular, gastrointestinal, urological, endocrine, 
neurological, or psychiatric disorders with clinical manifestations.

Participants with the following laboratory abnormalities at screening and on Day -1: 
total bilirubin > 1.5 × upper limit of normal (ULN)
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AST > 1.5 × ULN
ALT > 1.5 × ULN
estimated glomerular filtration rate <60 mL/min/1.73 m2 using Cockcroft-Gualt 
formula

QTc interval >450 ms (with Fridericia’s correction)

Participants with vital signs outside of the reference range for average systolic blood 
pressure (90-140 mmHg), average diastolic blood pressure (60-90 mmHg), or 
average pulse rate (40-90 beats/minute).

Participants with a history of stomach, vagus nerve, or intestinal surgery (except for 
appendectomy).

Participants who have a history of allergic symptoms including food allergy (Note:
Non-active allergic rhinitis will be allowed).

Participants who require chronic drug therapy or those who have used drugs (e.g., 
prescription or OTC drugs, herbal and dietary supplements, and vitamins) within 
3 days prior to screening or within 14 days prior to Day -1.

Participants who have used alcohol-containing, caffeine-containing, grapefruit 
containing, or St. John’s wort-containing products within 72 hours prior to Day -1.

Participants who have used tobacco- or nicotine-containing products within
24 weeks prior to screening.

Participants who have a history of abuse of drugs and/or alcohol.

Participants who have a positive urine cotinine, drug, and alcohol screen at 
screening and Day -1.

Participants who are positive for serological test for syphilis (Treponema pallidum), 
hepatitis B surface antigen, hepatitis C virus antibody, or HIV antigen/antibody at 
screening.

Participants who have donated > 400 mL of blood within 12 weeks or > 200 mL of 
blood within 4 weeks prior to screening, or have donated any amount of blood 
between screening and Day -1.

Participants who have been exposed to an investigational drug within 90 days prior 
to the initial screening visit.

Participants who have received baloxavir marboxil previously.
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
Participants who are considered inappropriate for the study by the Principal 
Investigator or subinvestigator.
5.3
LIFESTYLE CONSIDERATIONS
5.3.1
Meals and Dietary Restrictions

Participants are required to fast approximately 10 hours prior to study drug
administration and up to 4 hours postdose.

Participants have to refrain from food items with well-known CYP3A perpetrator 
potential (such as grapefruit [juice], Seville oranges, pomelos, and St. John’s 
wort-containing products) within 72 hours prior to Day -1.
5.3.2
Caffeine, Alcohol, and Tobacco

Participants will have to refrain from alcohol and caffeine-containing products 
within 72 hours prior to Day -1 and during the study.The use of tobacco- or 
nicotine-containing products is not allowed between 24 weeks prior to screening 
and Day -1 and throughout the study.
5.3.3
Activity

Participants must abstain from strenuous exercise for 96 hours before admission 
and before each blood collection for clinical laboratory tests during the follow-up 
period.

Donation of > 400 mL of blood within 12 weeks or > 200 mL of blood within 
4 weeks prior to screening by the participant, or donation of any amount of blood
between screening and Day -1 is prohibited.
5.4
SCREEN FAILURES
Screen failures are defined as participants who consent to participate in the clinical study 
but are not subsequently enrolled to the study treatment.
The investigator will maintain a screening log to record details of all participants 
screened and to confirm eligibility or record reasons for screen failures.
If a participant fails to fulfill eligibility requirement due to a transient and non-clinical
significant condition at screening, the Principal Investigator may repeat the relevant 
screening assessment(s) within the 28-day screening period. If the participant fails a 
second time they will be classed as a screen failure and cannot be re-screened.
Re-screening is allowed for participants who were screened in the study and met 
eligibility requirements but failed to be enrolled within 28 days after the start of screening 
period because the enrollment was suspended. In order to re-screen such a participant, 
all eligibility requirements should be re-evaluated and all applicable screening 
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assessments repeated if done more than 28 days prior to the enrollment (Appendix 1
[Section 1.3]).
5.5
RECRUITMENT PROCEDURES
Participants will be identified for potential recruitment using pre-screening enrollment 
logs, clinical database and Independent Ethics Committees (IEC) approved 
newspaper/radio/social-media advertisements prior to consenting to take part in the
study.
6.
TREATMENTS
Study drug is defined as any investigational treatment(s), marketed product(s), placebo,
or medical device(s) intended to be administered to a participant according to the study 
protocol.
All the study drug (baloxavir marboxil) required for completion of this study will be 
provided by the Sponsor. The study drug will be administered at the study center under 
the supervision of study center’s staff.
6.1
TREATMENTS ADMINISTERED
Baloxavir marboxil is a prodrug of polycyclic pyridone compound that is expected to 
have anti-influenza activity. Table 4 summarizes the treatment administered.
Table 4
Summary of Treatment Administered
Study Drug Name:
Baloxavir marboxil
Dosage Formulation:
Baloxavir marboxil will be provided as a film-coated oral 
tablet in 20 mg strength.
The tablet composition includes lactose monohydrate,
croscarmellose sodium, povidone, microcrystalline 
cellulose, sodium stearyl fumarate, hypromellose, talc,
and titanium oxide.
Unit Dose Strength/Dosage Levels:
Baloxavir marboxil is available as 20 mg tablet
Route of Administration:
Baloxavir marboxil will be administered orally on Day 1 
only.
Dosing Instructions:
Baloxavir marboxil is to be taken orally once with a glass 
of water.
The study drug will be given after an overnight fast of 
approximately 10 hours followed by a fast of at least 
4 hours postdose.
Packaging and Labeling
Study drug will be provided in blister packaging in a 
carton box.
Manufacturer:
Shionogi & Co., Ltd. Settsu plant, Japan
Please see the IB for more details.
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6.2
PREPARATION/HANDLING/STORAGE/ACCOUNTABILITY
Study drug packaging will be overseen by the F. Hoffmann-La Roche Ltd and Shionogi & 
Co., Ltd clinical trial supplies department and bear a label with the identification required 
by local law, the protocol number, drug identification and dosage.
The packaging and labeling of the study drug will be in accordance with F. Hoffmann-La 
Roche Ltd and Shionogi & Co., Ltd standard and local regulations.
The investigational study center will acknowledge receipt of the study drug and confirm 
the shipment condition and content. Any damaged shipments will be replaced.
Upon arrival of the study drug at the study center, the personnel will complete the 
following:

Check the study drug for damage.

Verify proper identity, quantity, integrity of seals and temperature conditions.

Report any deviations or product complaints to the Monitor upon discovery.
The investigator or delegate must confirm appropriate temperature conditions have been 
maintained during transit for all study drug received and any discrepancies are reported 
and resolved before use of the study drug.
Only participants enrolled in the study will receive the study drug and only authorized 
study center staff will supply or administer correct dose of the study drug. All study drugs
must be stored in a secure, environmentally controlled, and monitored (manual or 
automated) area in accordance with the labeled storage conditions with access limited to 
the investigator and authorized study center staff.
The Principal Investigator is responsible for accountability of study drug, reconciliation, 
and record maintenance (i.e., receipt, reconciliation and final disposition records).
Study drugs will either be disposed of at the study center according to the study center’s
institutional standard operating procedure or returned to the Sponsor with the 
appropriate documentation. The study center's method of study drug destruction must be 
agreed upon by the Sponsor. Local or institutional regulations may require immediate 
destruction of used study drug for safety reasons. The study center must obtain written 
authorization from the Sponsor before any drug is destroyed, and the study drug
destruction must be documented on the appropriate form.
Further guidance and information for the final disposition of unused study drug are 
provided in the Pharmacy Manual.
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6.3
MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND 
BLINDING
6.3.1
Method of Treatment Assignment
This is an open-label study. Participants will be randomized to 40 mg or 80 mg baloxavir 
marboxil in a 1:1 ratio. The randomization list will be generated by the Sponsor or its 
designee. The randomized treatment assignment will be allocated from the list 
sequentially to participants in the order in which they are enrolled. The study center will 
record the treatment assignment on the applicable eCRF.
6.3.2
Blinding
This is an open-label study.
6.4
TREATMENT COMPLIANCE
The study drug will be administered in the study center by the authorized study center
staff. The investigator or designee will record the correct dose, date, and time of 
administration on the Drug Accountability Record.
6.5
CONCOMITANT THERAPY
Concomitant therapies are defined as therapies taken after the initiation of the drug. In 
the case that any therapies are used during the study, the investigator or subinvestigator 
will record the following information for all therapies used after the first dose of the study 
drug till end of the study in the eCRF:

Name of used drug or used procedures

Change in dose, as-needed use, and route of administration (if a drug is 
administered)

Duration of treatment

Reason for use
The Medical Monitor should be contacted if there are any questions regarding 
concomitant or prior therapy.
All concomitant medications should be reported to the investigator and recorded on the 
page of concomitant medications eCRF.
6.5.1
Permitted Therapy
Any medication which is considered necessary for participant’s welfare and medications 
for treatment of adverse events are permitted and may be given at the discretion of the 
Principal Investigator.
All therapy and/or medication administered to manage adverse events should be 
recorded on the adverse event and concomitant page of the eCRF.
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6.5.2
Prohibited Therapy
The use of drugs (e.g., prescription or OTC drugs, herbal and dietary supplements, 
vitamins) is prohibited for 14 days prior to admission (Day -1).
The use of drugs (e.g., prescription or OTC drugs, herbal and dietary supplements, 
vitamins) and procedures without any medication is prohibited from admission until 
completion of the post-dosing observation period (or early termination).
6.6
DOSAGE MODIFICATION
There will be no dose modification during the study. Two dose levels of the study drug
will be evaluated. Sixteen participants in each group will receive either the 40 mg or 
80 mg of study drug in parallel.
6.7
TREATMENT AFTER THE END OF THE STUDY
The Sponsor does not intend to provide the study drug or other study interventions to
participants after conclusion of the study or any earlier participant withdrawal.
7.
DISCONTINUATION OF STUDY DRUG AND PARTICIPANT
DISCONTINUATION/WITHDRAWAL
7.1
DISCONTINUATION OF STUDY DRUG
This is a single-dose study therefore there are no criteria for study drug discontinuation 
for a given participant once the study drug has been administered.
7.2
PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE 
STUDY
Participants have the right to voluntarily withdraw from the study at any time for any 
reason.
In addition, the Principal Investigator has the right to withdraw a participant from the 
study for medical conditions that the Principal Investigator or Sponsor determines, may 
jeopardize the participant’s safety if he or she continues in the study.
If possible, information on reason for withdrawal from the study should be obtained. The 
primary reason for withdrawal from the study should be documented on the appropriate 
eCRF. Participants will not be followed for any reason after consent has been withdrawn.
When a participant voluntarily withdraws from the study, or is withdrawn by the Principal 
Investigator, samples collected until the date of withdrawal will be analyzed, unless the 
participant specifically requests for these to be discarded or local laws require their 
immediate destruction. However, if samples have been tested prior to withdrawal, results 
from those tests will remain as part of the overall research data.
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Participants who withdraw from the study for safety reasons will not be replaced.
Participants who withdraw from the study for other reasons will be replaced.
See SoA (Section 1.3) for data to be collected at the time of follow-up visits, and for any 
further evaluations that need to be completed.
7.3
LOST TO FOLLOW-UP
A participant will be considered lost to follow-up if the participant repeatedly fails to
return for scheduled visits and is unable to be contacted by the study center.
The following actions must be taken if a participant fails to return to the study center for a 
required study visit:

The study center must attempt to contact the participant and reschedule the missed 
visit as soon as possible and counsel the participant on the importance of 
maintaining the assigned visit schedule and ascertain whether or not the participant
wishes to and/or should continue in the study.

Before a participant is deemed lost to follow-up, the investigator or designee must 
make every effort to regain contact with the participant. These contact attempts 
should be documented in the participant’s medical record.

Should the participant continue to be unreachable, he or she will be considered to 
have withdrawn from the study.
Discontinuation of study center or of study as a whole are handled as part of Appendix 1.
8.
STUDY ASSESSMENTS AND PROCEDURES

Study procedures and their timepoints are summarized in the SoA (Section 1.3).

Protocol waivers or exemptions are not allowed.

Safety concerns should be discussed with the Sponsor immediately upon 
occurrence or awareness to determine if the participant should be administered 
the study drug.

Procedures conducted as part of the participant’s routine clinical management 
(e.g., blood count) and obtained before signing of the Informed Consent Forms 
may be utilized for screening or baseline purposes provided the procedure met 
the protocol-specified criteria and were performed within the time-frame defined 
in the SoA.

Repeat or unscheduled samples may be taken for safety reasons or for technical 
issues with the samples.
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
At time-points when several assessments coincide, the following sequence is 
suggested; at the discretion of the investigator, the order can be adjusted to 
optimize site personnel and participant’s time management.
Urine collection
ECG recordings
Vital signs
PK and safety blood sampling
Study drug administration
8.1
EFFICACY ASSESSMENTS
Not applicable.
8.2
SAFETY ASSESSMENTS
Planned timepoints for all safety assessments are provided in the SoA (Section 1.3).
8.2.1
Physical Examinations

A complete physical examination will include, at a minimum, assessments of the 
cardiovascular, respiratory, gastrointestinal, dermatological, neurological, and 
musculoskeletal system in addition to head, eyes, ears, nose, throat, neck, and 
lymph nodes. Height and weight will be measured and recorded at screening. 
Additionally, weight will be measured on Days -1, 4, and 6. Further examination of 
other body systems may be performed in case of evocative symptoms at the 
investigator’s discretion.

A brief physical examination will include, at a minimum, assessments of the skin, 
lungs, cardiovascular system, and abdomen (liver and spleen).

Investigators should pay special attention to clinical signs related to previous serious 
illnesses.

Any abnormality identified at baseline should be recorded on the General Medical 
History and Baseline Conditions eCRF. Changes from baseline abnormalities 
should be recorded in participant’s notes. New or worsened clinically significant 
abnormalities should be recorded as adverse events on the adverse event eCRF.
8.2.2
Vital Signs

Body temperature, pulse rate, blood pressure, and respiratory rate will be assessed.

Blood pressure and pulse measurements will be assessed in a supine position with a 
completely automated device and will be measured at each timepoint on the same 
arm. Manual techniques will be used only if an automated device is not available.
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
Blood pressure and pulse measurements should be preceded by at least 5 minutes 
of rest for the participant in a quiet setting without distractions (e.g., television, cell 
phones).

Vital signs (to be taken before blood collection for laboratory tests) will consist of one 
pulse and three blood pressure measurements (three consecutive blood pressure 
readings will be recorded at intervals of at least 1 minute). The average of the three
blood pressure readings will be recorded on the eCRF.
8.2.3
Electrocardiograms

12-lead ECGs will be obtained as outlined in the SoA (see Section 1.3) using an 
ECG machine that automatically calculates the pulse rate and measures PR, QRS, 
QT, and QTc intervals. Triplicate 12-lead ECGs can be performed at specified timepoints if 
deemed necessary by investigator.

At each timepoint at which triplicate ECGs are required, three individual ECG 
tracings should be obtained as closely as possible in succession, but no more than 
2 minutes apart. The full set of triplicates should be completed in less than 
4 minutes.

To minimize variability, it is important that participants be in a resting position (for 
approximately 10 minutes) prior to each ECG evaluation. Body position should be 
consistently maintained for each ECG evaluation to prevent changes in heart rate. 
Environmental distractions (e.g., television, radio, conversation) should be avoided 
during the pre-ECG resting period and during ECG recording. Electrocardiogram 
should be performed prior to any scheduled vital sign measurements and blood 
draws. In some cases, it may be appropriate to repeat abnormal ECGs to rule out 
improper lead placement as contributing to the ECG abnormality.

If at a particular postdose timepoint the mean QTcF is > 500 ms and/or 60 ms longer 
than the baseline value, another triplicate ECG must be recorded, ideally within the 
next 5 minutes, and triplicate ECG monitoring should continue until QTcF has 
stabilized on two successive ECGs. The Medical Monitor should be notified.
Standard‑of-care treatment may be instituted per the discretion of the investigator. If 
a PK sample is not scheduled for that timepoint, an unscheduled PK sample should 
be obtained. The investigator should also evaluate the participant for potential 
concurrent risk factors (e.g., electrolyte abnormalities, co-medications known to 
prolong the QT interval, severe bradycardia).

For safety monitoring purposes, the investigator or designee must review, sign, and 
date all ECG tracings. Paper or electronic copies will be kept as part of the 
participant’s source documents at the study center.
8.2.4
Clinical Safety Laboratory Assessments

See Appendix 4 for the list of clinical laboratory tests to be performed and the SoA
(Section 1.3) for the timing and frequency.
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
The investigator must review the laboratory report, document this review, and record 
any clinically relevant changes occurring during the study in the adverse event
Section of the eCRF. The laboratory reports must be filed with the source 
documents. Clinically significant abnormal laboratory findings are those that are not 
associated with the underlying disease, unless judged by the investigator to be more 
severe than expected for the participant’s condition.

All laboratory tests with values considered clinically significantly abnormal during 
participation in the study or within 15 days after the last dose of study drug should be 
repeated until the values return to normal or baseline or are no longer considered 
clinically significant by the investigator or Medical Monitor.
If such values do not return to normal/baseline within a period judged reasonable by 
the investigator, the etiology should be identified and the Sponsor notified.

All protocol-required laboratory assessments, as defined in Appendix 4, must be 
conducted in accordance with the Laboratory Manual and the SoA.

If laboratory values from non-protocol-specified laboratory assessments performed at 
the institution’s local laboratory require a change in participant’s management or are 
considered clinically significant by the investigator (e.g., serious adverse event s or 
adverse events or dose modification), then the results must be recorded in the eCRF.
Normal ranges for the study laboratory parameters must be supplied to the Sponsor 
before the study starts. 

Additional blood or urine samples may be taken at the discretion of the investigator if 
the results of any test fall outside the reference ranges, or clinical symptoms 
necessitate additional testing to monitor participant safety.

Where the clinical significance of abnormal laboratory results is considered uncertain, 
screening laboratory tests may be repeated before randomization to confirm eligibility.

If there is an alternative explanation for a positive urine or blood test for drugs of 
abuse, e.g., previous occasional intake of a medication or food containing for 
example, codeine, benzodiazepines or opiates, the test could be repeated to confirm 
washout.
8.2.5
Medical History and Demographic Data

Medical history includes clinically significant diseases surgeries, cancer history 
(including prior cancer therapies and procedures), reproductive status, smoking 
history, use of alcohol and drugs of abuse and all medications (e.g., prescription 
drugs, OTC drugs, herbal or homeopathic remedies, nutritional supplements) used 
by the participant within 3 days prior to the screening visit or 14 days prior to 
admission.
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
Demographic data will include age, sex, and self‑reported race/ethnicity.
8.3
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS
The definitions of an AE or SAE can be found in Appendix 2. The non-serious adverse 
events of special interest are discussed in Sections 8.3.6.
The investigator and any qualified designees are responsible for ensuring that all AEs 
(including assessment of seriousness, severity and causality; see Appendix 2) are
recorded on the AE page of eCRF and reported to the Sponsor in accordance with 
instructions provided in this section and in Appendix 2.
Procedures used for recording AEs are provided in Appendix 3
8.3.1
Time Period and Frequency for Collecting Adverse Event and 
Serious Adverse Event Information
The method of recording, evaluating, and assessing causality of AEs and SAEs and the 
procedures for completing and transmitting SAE reports are provided in Appendix 2.
Investigators will seek information on AEs at each visit. All AEs, whether reported by the
participant or noted by study center staff, will be recorded in the participant’s medical 
record and on the AE eCRF as follows:
After informed consent has been obtained but prior to initiation of study drug, only 
SAEs caused by a protocol-mandated intervention should be reported. Any other AEs
should not be reported.
After initiation of study drug: all AEs, regardless of relationship to study drug, will be 
reported until 14 days after the last dose of study drug. 
Post-study adverse events and serious adverse events: The investigator is not 
required to actively monitor participants for AEs after the end of the AE reporting period 
(14 days after the last dose of study drug).
However, if the investigator learns of any SAE (including a death) or other AEs of 
concern that are believed to be related to prior treatment with study drug, at any time 
after a participant has been discharged from the study, and the investigator considers 
the event to be reasonably related to the study drug or study participation, the 
investigator must promptly notify the Sponsor. For the procedure of reporting, see
Appendix 2.
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8.3.2
Method of Detecting Adverse Events and Serious Adverse
Events
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended 
and non-leading verbal questioning of the participant is the preferred method to inquire 
about AE occurrence.
A consistent methodology of non-directive questioning should be adopted for eliciting AE 
information at all participant evaluation timepoints.
8.3.3
Follow-Up of Adverse Events and Serious Adverse Events
8.3.3.1
Investigator Follow-Up
The investigator should follow each AE until the event has resolved to baseline grade or 
better, the event is assessed as stable by the investigator, the event is otherwise 
explained, the participant is lost to follow-up (Section 7.3), or the participant withdraws 
consent. Every effort should be made to follow all SAEs considered to be related to 
study drug or study-related procedures until a final outcome can be reported.
During the study period, resolution of AEs (with dates) should be documented on the AE
eCRF and in the participant’s medical record to facilitate source data verification. If, after 
follow-up, return to baseline status or stabilization cannot be established, an explanation 
should be recorded on the AE eCRF.
All pregnancies in the partner of a male participant reported during the study should be 
followed until pregnancy outcome and reported according to the instructions provided in
Section 8.3.5.
8.3.3.2
Sponsor Follow-Up
For SAEs, non-serious adverse events of special interest, and pregnancies, the Sponsor 
or a designee may follow-up by telephone, fax, electronic mail, 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.
8.3.4
Regulatory Reporting Requirements for Serious Adverse 
Events
Prompt notification by the investigator to the Sponsor of a SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the safety 
of a study drug under clinical investigation are met.
The Sponsor has a legal responsibility to notify both the local regulatory authority and 
other regulatory agencies about the safety of a study drug under clinical investigation. 
The Sponsor will comply with country-specific regulatory requirements relating to safety 
reporting to the regulatory authority, IEC, and investigators.
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Investigator safety reports must be prepared for sudden unexpected serious adverse 
reaction according to local regulatory requirements and Sponsor policy and forwarded to 
investigators as necessary.
An investigator who receives an investigator safety report describing a SAE or other 
specific safety information (e.g., summary or listing of SAEs) from the Sponsor will 
review and then, file it along with the IB and will notify the IEC, if appropriate according 
to local requirements.
For immediate and expedited reporting requirements from investigator to Sponsor and 
from Sponsor to Health Authority, investigators, and IEC, see Appendix 2.
8.3.4.1
Emergency Medical Contacts
To ensure the safety of study participants, access to the Medical Monitor is available 
24 hours a day 7-days a week. Medical Monitor’s contact details will be available on a 
separate list generated by the study management team.
8.3.5
Pregnancy
Male participants will be instructed through the ICF to immediately inform the 
investigator if their partner becomes pregnant during the study or within 28 days after the 
last dose of study drug.
Female participants will be instructed to immediately inform the investigator if they 
become pregnant during the study or within 28 days after the administration of baloxavir 
marboxil.
If a pregnancy is reported, the investigator should inform the Sponsor within 24 hours of 
learning of the pregnancy and should follow the pregnancy reporting process as detailed 
in Appendix 5.
Abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) are considered SAEs (Appendix 5).
8.3.6
Non-Serious Adverse Events of Special Interest
Non-serious 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 Appendix 2 for reporting instructions).
Non-serious adverse events of special interest for this study include the following:

Cases of an elevated ALT or AST in combination with either an elevated bilirubin or 
clinical jaundice, as defined in Appendix 3.

Suspected transmission of an infectious agent by the study drug, as defined below:
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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 participant exposed to a medicinal 
product. This term applies only when a contamination of the study drug is suspected.
8.3.7
Disease-Related Events and/or Disease-Related Outcomes Not 
Qualifying as AEs or SAEs
Not applicable.
8.3.8
Management of Specific Adverse Events
Not applicable.
8.4
TREATMENT OF OVERDOSE
Study drug overdose is the accidental or intentional use of the drug in an amount higher 
than the dose being studied. An overdose or incorrect administration of study drug is not 
an AE unless it results in untoward medical effects (see Sections 5 and 5.2 of 
Appendix 2 for further details).
For this study, any dose of study drug greater than prescribed within a 24-hour time 
period from previous dose will be considered an overdose.
As per IB, there is no specific antidote for the study drug. In the event of overdose, 
general supportive measures should be initiated based on the participant’s signs and 
symptoms.
In the event of an overdose, the investigator should:
1.
Contact the Sponsor’s Medical Monitor immediately.
2.
Closely monitor the participant for AE/SAE and laboratory abnormalities until 
resolved.
3.
Obtain a blood sample for PK analysis within 24 hours from the date of the last dose 
of study drug, if requested by the Medical Monitor (determined on a case-by-case 
basis).
4.
Document the quantity of the excess dose, as well as the duration of the overdose, 
in the eCRF.
8.5
PHARMACOKINETICS
The PK of the study drug is being evaluated in this study. Blood samples for 
determination of plasma PK will be collected during the study at the timepoints specified 
in Table 2. The plasma obtained from the PK blood sample will be stabilized before 
freezing to block ex-vivo pro-drug conversion to baloxavir. Baloxavir marboxil and 
baloxavir will be analyzed by a validated LC-MS/MS assay.
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The remaining plasma samples will be destroyed within 2 years after the date of final
Clinical Study Report. Remaining PK samples may be used for exploratory analyses, if 
required. Details on sampling procedures, sample storage and shipment are given in the 
Laboratory Manual.
8.6
PHARMACODYNAMICS
Pharmacodynamic parameters are not evaluated in this study.
8.7
GENETICS/PROTEOMICS
Pharmacogenomics assessments are not performed in this study.
8.8
BIOMARKERS
Biomarkers are not evaluated in this study.
8.9
HEALTH ECONOMICS OR MEDICAL RESOURCE UTILIZATION 
AND HEALTH ECONOMICS
Health Economics or Medical Resource Utilization and Health Economics parameters 
are not evaluated in this study.
8.10
TIMING OF STUDY ASSESSMENTS
8.10.1
Screening and Pre-treatment Assessments
Written informed consent for participation in the study must be obtained before 
performing any study-specific screening tests or evaluations. Informed Consent Forms 
for enrolled participants and for participants who are not subsequently enrolled will be 
maintained at the study center.
All screening and pre-treatment assessments must be completed and reviewed to 
confirm that participants meet all the eligibility criteria. The investigator will maintain a 
screening log to record details of all participants screened and to confirm eligibility or 
record reasons for screen failure.
An Eligibility Screening Form documenting the investigator’s assessment of each 
screened participant with regard to the protocol’s eligibility requirement is to be 
completed by the investigator and kept at the study center.
Screening and pre-treatment assessments will be performed within -28 to -2 days prior 
to Day 1.
8.10.2
Assessments during In-house Period
Under no circumstances will participants who enroll in this study and have completed 
treatment as specified, be permitted to re-enroll in the study.
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All assessments must be performed as per SoA (see Section 1.3). Assessments 
scheduled on the day of study drug administration should be performed prior to 
administration of study drug, unless otherwise noted in the SoA (e.g., postdose PK 
samples).
8.10.3
Assessments at Study Completion/Early Termination Visit
Participants who discontinue from the study early will be asked to return to the study 
center14 days after the dose of study drug for a follow‑up visit. Assessments conducted 
at Day 15 will be performed at the early termination visit. (See SoA, Section 1.3).
8.10.4
Post-Dosing and Follow-Up Assessments
Post-dosing and follow-up assessments will be conducted on Days 6, 8, 10, 12, and 15 
as specified in SoA (see Section 1.3). After the study completion or early termination 
visit, adverse event AEs should be followed as outlined in Sections 8.3.1 and 8.3.3.
9.
STATISTICAL CONSIDERATIONS
9.1
STATISTICAL HYPOTHESES
Not applicable.
9.2
SAMPLE SIZE DETERMINATION
A total of 32 Chinese participants will be enrolled in this study with 16 participants in 
each group of 40 mg and 80 mg baloxavir marboxil.
The number of participants (16 participants for each dose level) is chosen based on 
practical clinical judgment, the PK variability observed (AUC and Cmax in Caucasian and 
Japanese healthy participants), anticipated drop-rate, and China’s regulatory 
requirements.
9.3
POPULATIONS FOR ANALYSES
The populations for analysis are defined in section 9.4.3 and 9.4.4.
9.4
STATISTICAL ANALYSES
The number of participants, who enroll, discontinue, or complete the study will be
summarized. Reasons for premature study withdrawal will be listed and summarized.
Enrollment and other major protocol deviations will be listed and evaluated for their
potential effects on the interpretation of study results.
9.4.1
Summaries of Treatment Group Comparability
Demographics and baseline characteristics will be summarized with descriptive statistics 
for all randomized participants, presented overall and by dosing regimen.
9.4.2
Efficacy Analyses
This study does not evaluate efficacy analyses.
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9.4.3
Safety Analyses
All participants who received at least 1 dose of the study drug, whether prematurely 
withdrawn from the study or not, will be included in the safety analysis population.
Participants will be grouped by the actual dose regimen they received.
All safety analyses will be based on the safety analysis population.
The safety statistical analysis methods are presented in Table 5.
Table 5
Safety Statistical Analysis Methods
Endpoint
Statistical Analysis Method
Adverse events
The original terms recorded on the eCRF by the 
investigator for adverse events will be coded by 
the Sponsor.
Adverse events will be classified by system organ 
class and preferred terms using MedDRA.
Clinical laboratory tests
All clinical laboratory data will be stored on the 
database in the units in which they were reported.
Laboratory test values will be presented in 
International System of Units (SI unit) by individual 
listings with flagging of abnormal results.
Summary tables of change from baseline over 
time will be displayed for selected parameters. 
Vital signs
Vital signs data will be presented by individual 
listings with flagging of values outside the normal 
ranges and flagging of abnormalities. In addition, 
tabular summaries may be provided, as 
appropriate.
Concomitant medications
The original terms recorded on the participant’s 
eCRF by the investigator for concomitant 
medications will be standardized by the Sponsor 
by assigning preferred terms.
Concomitant medications will be presented in 
summary tables and listings.
CTCAE = Common Terminology Criteria for Adverse Events; eCRF = electronic Case Report 
Form; NCI = National Cancer Institute
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Electrocardiogram data will be presented in by-patient listings. In addition, tabular 
summaries will be used, as appropriate.
9.4.4
Pharmacokinetic Analyses
All participants who have received study drug and who have evaluable PK data with no 
relevant protocol deviations with respect to the primary PK endpoint will be included in 
the PK analysis population.
Analyses will be carried out on the PK analysis population.
Individual plasma concentrations at each sampling timepoint for baloxavir marboxil and 
its major metabolite, baloxavir will be presented by listings and appropriate descriptive 
summary statistics by dose, including arithmetic means, geometric means, medians, 
minimums-maximums, SD, and coefficients of variation. Individual and mean plasma 
concentration versus time data will be plotted by dose on linear as well as semi-
logarithmic scales.
All PK parameters will be presented by individual listings and summary statistics by dose 
including arithmetic means, geometric means, medians, minimums-maximums, SDs, 
and coefficients of variation.
The primary baloxavir marboxil and baloxavir PK study parameters will be the Cmax and 
the area under the concentration-time curve from Time 0 to infinity (AUC0-inf) if it can be 
derived accurately, otherwise a truncated as appropriate. All other PK parameters will be 
regarded as secondary.
Non-compartmental analysis using WinNonlin software will be used to calculate PK 
parameters where appropriate. Non-compartmental analysis will be employed for 
estimation of the following PK parameters:
Tmax: Time to maximum observed plasma concentration
Cmax: Maximum observed plasma concentration
AUC0-inf: Area under the plasma concentration-time curve between Time 0 
extrapolated to infinity
AUC0-last: Area under the plasma concentration-time curve between Time 0 and the 
time of the last quantifiable concentration
AUC0-t: Area under the plasma concentration-time curve between Time 0 and the 
time t. Time t may be chosen as a time point where evaluable concentrations are 
available in at least 90% of participants
t1/2: Terminal elimination half-life 
CL/F: Apparent total oral clearance
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Vz/F: Apparent oral volume of distribution based on the terminal phase
Plasma concentration at 24, 48, and 72 hours postdose.
9.5
INTERIM ANALYSES
No interim analysis is planned for this study.
9.6
SUMMARIES OF CONDUCT OF STUDY
The number of participants who complete the study and the number of participants who 
enroll, discontinue or complete the study will be summarized. Reasons for premature 
study withdrawal will be listed and summarized by dose levels. Protocol deviations will 
be listed and evaluated for their potential impact on interpretation of study results. Study 
drug administration will be summarized by in-house period. Descriptive statistics will be 
used in evaluating the conduct of the study.
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10.
REFERENCES
Centers for Disease Control and Prevention. CDC HEALTH ALERT: CDC
Recommends against the Use of Amantadine and Rimandatine for the Treatment or
Prophylaxis of Influenza in the United States during the 2005-06 Influenza Season.
2006.
Fields BN, Knipe DM, Howley PM. Fields Virology. 5th ed (2). Wolters Kluwer 
Health/Lippincott Williams & Wilkins 2007;p.1691-740.
Heo YA. Baloxavir: First Global Approval. Drugs. 2018;78(6):693-697.
Liu X, Li Y, Zhu Y, et al. Seasonal pattern of influenza activity in a subtropical city, China, 
2010-2015. Sci Rep. 2017;7:17534.
Monto AS, Gravenstein S, Elliott M, et al. Clinical Signs and Symptoms Predicting 
Influenza Infection. Arch Intern Med 2000;160:3243-7.
S-033188 (Baloxavir Marboxil) [Investigator Brochure]. Version 6, 2018 June.
Taubenberger JK and Morens DM. The Pathology of Influenza Virus Infections. Annu 
Rev Pathol. 2008;3:499-522.
Uchida K, Suzuki S, Yanagisawa K. Clinical Practice; Issues Encountered in Real-World 
Settings; Influenza and Other Respiratory Infections. Internal Medicine 2006;98(5):805-9. 
[Article in Japanese].
Vemula SV, Zhao J, Liu J, et al. Current Approaches for Diagnosis of Influenza Virus 
Infections in Humans. Viruses. 2016;8(4):96.
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11.
SUPPORTING DOCUMENTATION AND OPERATIONAL
CONSIDERATIONS
The following section includes standard appendices such as Appendix 1 (for regulatory, 
ethical and study oversight considerations), Appendix 2 (for AE definitions, reporting) 
and Appendix 3 (procedures of recording), and Appendix 5 (contraceptive guidance and 
collection of pregnancy information). Additional study-related appendices are in order of 
appearance in the protocol.
Appendix 1
Regulatory, Ethical, and Study Oversight Considerations
1.
REGULATORY AND ETHICAL CONSIDERATIONS
1.1.
COMPLIANCE WITH LAWS AND REGULATIONS
This study will be conducted in full conformance with the International Council for 
Harmonisation (ICH) E6 guideline for Good Clinical Practice (GCP) and the principles of 
the Declaration of Helsinki, or the laws and regulations of the country in which the 
research is conducted, whichever affords the greater protection to the individual. The 
study will comply with the requirements of the ICH E2A guideline (Clinical Safety Data 
Management: Definitions and Standards for Expedited Reporting). Studies conducted in 
the United States or under a U.S. Investigational New Drug application will comply with 
U.S. FDA regulations and applicable local, state, and federal laws. Studies conducted in 
the EU/EEA will comply with the EU Clinical Trial Directive (2001/20/EC).
1.2.
INSTITUTIONAL ETHICS COMMITTEE
This protocol, the Informed Consent Forms (ICFs), any information to be given to the 
participant (e.g. advertisements, diaries etc), and relevant supporting information must 
be submitted to the Independent Ethics Committee (IEC) by the Principal Investigator 
and reviewed and approved by the IEC before the study is initiated. In addition, any 
participant recruitment materials must be approved by the IEC.
The Principal Investigator is responsible for providing written summaries of the status of 
the study to the IEC annually or more frequently in accordance with the requirements, 
policies, and procedures established by the IEC. Investigators are also responsible for 
promptly informing the IEC of any protocol amendments (Section 2.3.1 of this Appendix).
The investigator should follow the requirements for reporting all adverse events to the 
Sponsor. Investigators may receive written investigational new drug 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 IEC, and 
archived in the study centers study file.
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1.3.
INFORMED CONSENT
The Sponsor’s Master ICF in local language will be provided to each study center.
Participants must be informed that their participation is voluntary. Participants or their 
legally authorized representative will be required to sign a statement of informed consent 
that meets the requirements of, local regulations, ICH guidelines, where applicable, and 
the IEC or study center. The Sponsor or its designee must review and approve any 
proposed deviations from the Sponsor's sample ICFs or any alternate Consent Forms 
proposed by the study center (collectively, the “Consent Forms”) before IEC submission.
The final IEC‑approved Consent Forms must be provided to the Sponsor for Health 
Authority submission purposes according to local requirements. Participants must be re-
consented to the most current version of the ICF(s) during their participation in the study.
A copy of the ICF(s) signed by all parties must be provided to the participant or the 
participant’s legally authorized representative.
The Consent Forms must be signed and dated by the participant or the participant’s 
legally authorized representative before his or her participation in the study. The case 
history or clinical records for each participant 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 
participant to take part. The final revised IEC approved Consent Forms must be provided 
to the Sponsor for Health Authority submission purposes if required as per local 
regulations.
Participants 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 IEC policy) during their participation in the study. For any updated or revised 
Consent Forms, the case history or clinical records for each participant shall document 
the informed consent process and that written informed consent was obtained using the 
updated/revised Consent Forms for continued participation in the study.
A copy of each signed Consent Form must be provided to the participant or the 
participant’s legally authorized representative. All signed and dated Consent Forms must 
remain in each participant’s study file or in the study center file and must be available for 
verification by study monitors at any time.
Re-screening is allowed for participants who were screened in the study and met study 
eligibility requirements but failed to be enrolled within 28 days after the start of screening 
period because the enrollment was suspended. These participants will have to sign 
another ICF, if the re-screening occurs within 28 days from the previous ICF signature 
date.
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1.4.
CONFIDENTIALITY
Participants will be assigned a unique identifier by the Sponsor. Any participant records 
or datasets that are transferred to the Sponsor will contain the identifier only; participant 
names or any information which would make the participant identifiable will not be 
transferred. 
The participant must be informed that his/her personal study-related data will be used by 
the Sponsor in accordance with local data protection law. The level of disclosure must 
also be explained to the participant. 
Medical information may be given to a participant’s personal physician or other 
appropriate medical personnel responsible for the participant’s welfare, for treatment 
purposes.
The participant must be informed that his or her medical records may be examined by 
Clinical Quality Assurance auditors or other authorized personnel appointed by the 
Sponsor, by appropriate IEC members, and by inspectors from regulatory authorities.
1.5.
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 one year after completion of the study (i.e., LPLV).
2.
DATA HANDLING AND RECORD
2.1.
DATA COLLECTION AND MANAGEMENT RESPONSIBILITIES
2.1.1.
Data Quality Assurance
All participant data relating to the study will be recorded on printed or electronic Case 
Report Form (eCRF) unless transmitted to the Sponsor or designee electronically (e.g., 
laboratory data). The Principal Investigator is responsible for verifying that data entries 
are accurate and correct by physically or electronically signing the Case Report Form.
The Principal Investigator must maintain accurate documentation (source data) that 
supports the information entered in the eCRF.
The Principal Investigator must permit study-related monitoring, audits, IEC review, and 
regulatory agency inspections and provide direct access to source data documents.
The Sponsor or designee is responsible for the data management of this study including 
quality checking of the data.
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Study monitors will perform ongoing source data verification to confirm that data entered 
into the eCRF by authorized study center personnel are accurate, complete, and 
verifiable from source documents; that the safety and rights of participants are being 
protected; and that the study is being conducted in accordance with the currently 
approved protocol and any other study agreements, ICH GCP, and all applicable 
regulatory requirements.
2.1.2
Source Data Records
Source documents (paper or electronic) are those in which participant 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, clinical outcome assessments 
(COAs) (paper or electronic COA), 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, participant files, and records kept at pharmacies, 
laboratories, and medico‑technical departments involved in a clinical trial.
Before study initiation, data to be entered directly into the eCRFs (i.e., no prior written or 
electronic record of the data) and considered source data must be defined in the Trial 
Monitoring Plan.
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 below.
To facilitate source data verification, the investigators and institutions must provide the 
Sponsor direct access to applicable source documents and reports for trial‑related 
monitoring, Sponsor audits, and IEC review. The investigational study center must also 
allow inspection by applicable Health Authorities.
2.1.3
Use of Computerized Systems
When clinical observations are entered directly into an investigational 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.
2.2.
RETENTION OF RECORDS
Records and documents, including signed ICF, pertaining to the conduct of this study 
must be retained by the Principal Investigator for at least 15 years after study completion 
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unless local regulations or institutional policies require a longer retention period. No 
records may be destroyed during the retention period without the written approval of the 
Sponsor. No records may be transferred to another location or party without written 
notification to the Sponsor.
2.3.
STUDY RECORDS
The Principal Investigator must maintain adequate and accurate records to enable the 
conduct of the study to be fully reconstructed, including but not limited to the protocol, 
protocol amendments, ICFs, and documentation of IEC and governmental approval. 
Roche shall also submit an Annual Safety Report once a year to the IEC and CAs 
according to local regulatory requirements and timelines of each country participating in 
the study.
2.3.1.
Protocol Amendments
Any substantial protocol amendments will be prepared by the Sponsor. Substantial 
protocol amendments will be submitted to the IEC and to regulatory authorities in 
accordance with local regulatory requirements.
Approval must be obtained from the IEC and regulatory authorities (as locally required) 
before implementation of any changes, except for changes necessary to eliminate an 
immediate hazard to participants or any non-substantial changes, as defined by 
regulatory requirements.
2.3.2.
Publication Policy
The results of this study may be published or presented at scientific meetings. If this is 
foreseen, the Principal Investigator agrees to submit all manuscripts or abstracts to the 
Sponsor for approval prior to submission. 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 Principal Investigator.
The Sponsor will comply with the requirements for publication of study results. 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.
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 Principal 
Investigator and the appropriate Sponsor personnel.
Authorship will be determined by mutual agreement and in line with International 
Committee of Medical Journal Editors authorship requirements.
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Any inventions and resulting patents, improvements, and/or know-how originating from 
the use of data from this study will become and remain the exclusive and unburdened 
property of the Sponsor, except where agreed otherwise.
2.3.3.
Dissemination of Clinical Study Data
The results of the study should be reported within 1 year from the end of the clinical 
study. Irrespective of the outcome, the Sponsor will submit to the regulatory authorities a 
summary of the results of the clinical study within 1 year from the end of the clinical 
study. It shall be accompanied by a summary written in a manner that is understandable 
to laypersons.
2.3.4.
Study Center Inspections
Study center visits will be conducted by the Sponsor or an authorized representative for 
inspection of study data, participants’ medical records, and eCRFs. The Principal 
Investigator will permit national and local Health Authorities, Sponsor monitors, 
representatives, and collaborators, and the IECs to inspect facilities and records relevant 
to this study.
3.
ADMINISTRATIVE STRUCTURE
3.1.
INDEPENDENT REVIEW COMMITTEE (IRC)
Not applicable.
3.2.
INDEPENDENT DATA MONITORING COMMITTEE (IDMC)
Not applicable.
3.3.
INTERNAL MONITORING COMMITTEE (IMC)
Not applicable.
3.4.
CLINICAL EVENTS COMMITTEE (CEC)
Not applicable.
4.
STUDY AND STUDY CENTER CLOSURE
The Sponsor or designee has the right to close the study center or 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 participants.

Participant enrollment is unsatisfactory.
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The Sponsor will notify the Principal Investigator and Health Authorities if the study is 
placed on hold, or if the Sponsor decides to discontinue the study or development 
program.
Study center will be closed upon study completion. A study center is considered closed 
when all required documents and study supplies have been collected and a study center
closure visit has been performed.
The Principal Investigator may initiate study center closure at any time, provided there is 
reasonable cause and sufficient notice is given in advance of the intended termination.
Reasons for the early closure of a study center by the Sponsor or Principal Investigator 
may include but are not limited to:

Failure of the Principal Investigator to comply with the protocol, the requirements of 
the IEC or local Health Authorities, the Sponsor's procedures, or GCP guidelines.

Inadequate recruitment of participants by the Principal Investigator.

Discontinuation of further study drug development.
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Appendix 2
Adverse Events: Definitions and Procedures for Evaluating, 
Follow-up and Reporting
1.
DEFINITION OF ADVERSE EVENTS
According to the E2A International Council for Harmonisation guideline for Good Clinical 
Practices, an adverse event is any untoward medical occurrence in a patient or clinical 
investigation participant administered a pharmaceutical product and which does not 
necessarily have to have a causal relationship with this treatment.
An adverse event can therefore be:

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.
Events Meeting the Adverse Event Definition:

Any deterioration in a laboratory value (hematology, clinical chemistry, or urinalysis) 
or other clinical test (e.g., ECG, X-ray) that is associated with symptoms or leads to 
a change in study drug or concomitant treatment or discontinuation from study drug.

Exacerbation of a chronic or intermittent preexisting condition, including either an 
increase in frequency and/or intensity of the condition.

New conditions detected or diagnosed after study drug administration even though it 
may have been present before the start of the study.

Adverse events that are related to a protocol-mandated intervention, including those 
that occur prior to assignment of study drug (e.g., screening invasive procedures 
such as biopsies).
Events NOT Meeting the Adverse Event Definition:

Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments which are associated with the underlying disease, unless judged by 
the investigator to be more severe than expected for the participant’s condition.

The disease/disorder being studied or expected progression, signs, or symptoms of 
the disease/disorder being studied, unless more severe than expected for the 
participant’s condition.

Medical or surgical procedure (e.g., endoscopy, appendectomy): the condition that
leads to the procedure is an adverse event.

Situations where an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).

Anticipated day-to-day fluctuations of preexisting disease(s) or condition(s) present 
or detected at the start of the study that do not worsen.
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2.
DEFINITION OF SERIOUS ADVERSE EVENTS
If an event is not an AE per definition above, then it cannot be a serious adverse event 
(SAE) even if serious conditions are met (e.g., hospitalization for signs/symptoms of the 
disease under study, death due to progression of disease).
A serious adverse event is defined as any untoward medical occurrence that at any dose:

Results in death.

Is life-threatening.
The term "life-threatening" in the definition of "serious" refers to an event in which 
the participant was at risk of death at the time of the event; it does not refer to an 
event which hypothetically might have caused death if it was more severe.

Requires inpatient hospitalization or prolongation of existing hospitalization
(see Appendix 3).
In general, hospitalization signifies that the participant has been detained (usually 
involving at least an overnight stay) at the hospital or emergency ward for 
observation and/or treatment that would not have been appropriate in the 
physician’s office or outpatient setting. Complications that occur during 
hospitalization are adverse events. If a complication prolongs hospitalization or 
fulfills any other serious criteria, the event is serious. When in doubt as to whether 
“hospitalization” occurred or was necessary, the adverse event should be 
considered serious.
Hospitalization for elective treatment of a preexisting condition that did not worsen 
from baseline is not considered an adverse event.

Results in persistent or significant disability/incapacity
Disability means substantial disruption of the participant’s ability to conduct normal 
life functions.
This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (e.g., sprained ankle) which may interfere with or prevent 
everyday life functions but do not constitute a substantial disruption.

Is a congenital anomaly/birth defect

Other significant events:
Medical or scientific judgment should be exercised in deciding whether serious 
adverse event reporting is appropriate in other situations such as important medical 
events that may not be immediately life-threatening or result in death or 
hospitalization but may jeopardize the participant or may require medical or surgical 
intervention to prevent one of the other outcomes listed in the above definition.
These events should usually be considered serious.
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Examples of such events include invasive or malignant cancers, intensive treatment 
in an emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug dependency 
or drug abuse.
3.
RECORDING OF ADVERSE EVENT AND/OR SERIOUS 
ADVERSE EVENT
When an adverse event/serious adverse event occurs, it is the responsibility of the 
investigator to review all documentation (e.g., hospital progress notes, laboratory reports, 
and diagnostics reports) related to the event.
The investigator will then record all relevant adverse event/serious adverse event
information in the electronic Case Report Form (eCRF).
It is not acceptable for the investigator to send photocopies of the participant’s medical 
records to Medical Monitor in lieu of completion of the eCRF.
There may be instances when copies of medical records for certain cases are requested 
by Sponsor or designee. In this case, all participant identifiers, with the exception of the 
participant number, will be redacted on the copies of the medical records before 
submission to Sponsor or designee.
The Principal Investigator will attempt to establish a diagnosis of the event based on 
signs, symptoms, and/or other clinical information. Whenever possible, the diagnosis 
(not the individual signs/symptoms) will be documented as the adverse event/serious 
adverse event.
3.1.
ASSESSMENT OF SEVERITY
The investigator will make an assessment of severity for each adverse event and serious 
adverse event reported during the study and assign it to one of the categories provided 
in Table 6 (as a guidance for assessing adverse event severity).
The terms “severe” and “serious” are not synonymous. Severity refers to the intensity of 
an adverse event (rated as mild, moderate, or severe, or according to a predefined 
grading criteria [e.g., National Cancer Institute Common Terminology Criteria for 
Adverse Events criteria]); 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).
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Table 6
Adverse Event Severity Grading Scale
Severity
Description
Mild
Discomfort noticed, but no disruption of normal daily activity
Moderate
Discomfort sufficient to reduce or affect normal daily activity
Severe
Incapacitating with inability to work or to perform normal daily activity
Note: Regardless of severity, some events may also meet seriousness criteria. Refer to 
definition of a serious adverse event.
3.2.
ASSESSMENT OF CAUSALITY
Investigators should use their knowledge of the participant, the circumstances 
surrounding the event, and an evaluation of any potential alternative causes to 
determine whether or not 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.

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 participant or use of concomitant medications known 
to increase the occurrence of the event.

Presence of non-treatment-related factors that are known to be associated with the 
occurrence of the event.
For participant receiving combination therapy, causality will be assessed individually for 
each protocol-mandated therapy.
4.
FOLLOW-UP OF AES AND SAES
The Principal Investigator is obligated to perform or arrange for the conduct of 
supplemental measurements and/or evaluations as medically indicated or as requested 
by Sponsor or designee to elucidate the nature and/or causality of the adverse event or 
serious adverse event as fully as possible. This may include additional laboratory tests 
or investigations, histopathological examinations, or consultation with other health care 
professionals.
If a participant dies during participation in the study or during a recognized follow-up 
period, the Principal Investigator will provide the Sponsor or designee with a copy of any 
post-mortem findings including histopathology. New or updated information will be 
recorded in the originally completed eCRF.
The investigator will submit any updated serious adverse event data to the Sponsor 
within 24 hours of receipt of the information.
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5.
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

Non-serious adverse events of special interest

Pregnancies (see Section 8.3.5)

Accidental overdoses or medication errors (see Appendix 2, Section 5.2 for details 
on reporting requirements)
The investigator must report new significant follow-up information for these events to the 
Sponsor immediately (i.e., no more than 24 hours after becoming aware of the 
information). New significant information includes the following:

New signs or symptoms or a change in the diagnosis.

Significant new diagnostic test results.

Change in causality based on new information.

Change in the event’s outcome, including recovery.

Additional narrative information on the clinical course of the event.
Investigators must also comply with local requirements for reporting serious adverse 
events to the local Health Authority and IEC.
5.1
REPORTING REQUIREMENTS OF SERIOUS ADVERSE 
EVENTS AND NON-SERIOUS ADVERSE EVENTS OF SPECIAL 
INTEREST
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 Serious Adverse Event/Adverse Event of Special Interest Reporting Form provided 
to investigators should be completed and submitted to the Serious Adverse Event 
Responsible immediately (i.e., no more than 24 hours after learning of the event).
Events that Occur after Study Drug Initiation
For reports of serious adverse events and non-serious adverse events of special interest 
(Section 8.3.6) that occur after initiation of study drug (Section 8.3.1), investigators 
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should record all case details that can be gathered immediately (i.e., within 24 hours 
after learning of the event) on the appropriate Adverse Event of Special Interest/ Serious 
Adverse Event eCRF form and submit the report via the electronic data capture (EDC) 
system. A report will be generated and sent to the Sponsor’s Safety Risk Management 
department.
In the event that the EDC system is unavailable, the Serious Adverse Event/Adverse 
Event of Special Interest Reporting Form provided to investigators should be completed 
and submitted to the Serious Adverse Event Responsible immediately (i.e., no more 
than 24 hours after learning of the event).
Once the EDC system is available, all information will need to be entered and submitted 
via the EDC system.
Reporting of Post-Study Adverse Events and Serious Adverse Events
If the investigator becomes aware of any other serious adverse event occurring after the 
end of the adverse event reporting period, if the event is believed to be related to prior to 
the study drug, then the event should be reported directly to the Sponsor or its designee, 
either by faxing or by scanning and emailing the Serious Adverse Event Reporting Form 
using the fax number or e-mail address provided to the investigators.
5.2
REPORTING REQUIREMENTS FOR CASES OF ACCIDENTAL 
OVERDOSE OR MEDICATION ERROR 

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. All special situations associated with baloxavir marboxil, regardless of whether 
they result in an adverse event, should be recorded on the Adverse Event eCRF and
reported to the Sponsor immediately (i.e., no more than 24 hours after learning of the 
event). Special situations should be recorded as described below:

Accidental overdose: Enter the drug name and "accidental overdose" as the event 
term. Check the "Accidental overdose" and "Medication error" boxes.

Medication error that does not qualify as an overdose: Enter the name of the drug 
administered and a description of the error (e.g., wrong dose administered, wrong 
dosing schedule, incorrect route of administration, wrong drug, expired drug 
administered) as the event term. Check the "Medication error" box.
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
Medication error that qualifies as an overdose: Enter the drug name and "accidental 
overdose" as the event term. Check the "Accidental overdose" and "Medication 
error" boxes. Enter a description of the error in the additional case details.

Intercepted medication error: Enter the drug name and "intercepted medication 
error" as the event term. Check the "Medication error" box. Enter a description of the 
error in the additional case details.
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.
6.
EXPEDITED REPORTING TO HEALTH AUTHORITIES, 
INVESTIGATORS, INSTITUTIONAL ETHICS COMMITTEES
The Sponsor will promptly evaluate all serious adverse events and non-serious adverse 
event of special interest against cumulative product experience to identify and 
expeditiously communicate possible new safety findings to investigators, IECs, 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 IB
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.
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Appendix 3
Procedures for Recording Adverse Events
Investigators should use correct medical terminology/concepts when recording adverse 
events on the Adverse Event electronic Case Report Form (eCRF). Avoid colloquialisms 
and abbreviations.
Only one adverse event term should be recorded in the event field on the Adverse Event 
eCRF.
1.
DIAGNOSIS VERSUS SIGNS AND SYMPTOMS
1.1.
INFUSION/INJECTION-RELATED REACTIONS
Not applicable.
1.2.
OTHER ADVERSE EVENTS
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.
2.
ADVERSE EVENTS OCCURRING SECONDARY TO OTHER 
EVENTS
In general, adverse events occurring 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. However, medically significant adverse events 
occurring secondary to an initiating event that are separated in time should be recorded 
as independent events 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 subsequent fracture, all three events should be 
reported separately on the eCRF.
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All adverse events should be recorded separately on the Adverse Event eCRF if it is 
unclear as to whether the events are associated.
3.
PERSISTENT OR RECURRENT ADVERSE EVENTS
A persistent adverse event is one that extends continuously, without resolution, between 
participant evaluation timepoints. Such events should only be recorded once on the 
Adverse Event eCRF. The initial severity of the event should be recorded, and the 
severity should be updated to reflect the most extreme severity any time the event 
worsens. If the event becomes serious, the Adverse Event eCRF should be updated to 
reflect this.
A recurrent adverse event is one that resolves between participant evaluation timepoints 
and subsequently recurs. Each recurrence of an adverse event should be recorded 
separately on the Adverse Event eCRF.
4.
ABNORMAL LABORATORY VALUES
Not every laboratory abnormality qualifies as an adverse event. A laboratory test result 
should be reported as an adverse event if it meets any of the following criteria:

Accompanied by clinical symptoms.

Results in a change in study drug (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.

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., alkaline phosphatase and bilirubin five times the upper limit of normal (ULN)
associated with cholecystitis), only the diagnosis (i.e., cholecystitis) 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 if 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 not be repeatedly recorded on the Adverse Event eCRF, unless the etiology 
changes. The initial severity of the event should be recorded, and the severity or 
seriousness should be updated any time the event worsens.
5.
ABNORMAL VITAL SIGN VALUES
Not every vital sign abnormality qualifies as an adverse event. A vital sign result should 
be reported as an adverse event if it meets any of the following criteria:

Accompanied by clinical symptoms.

Results in a change in study drug (e.g., dosage modification, treatment interruption, 
or treatment discontinuation).

Results in a medical intervention or a change in concomitant therapy.

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 not be repeatedly recorded on the Adverse Event eCRF, unless the etiology 
changes. The initial severity of the event should be recorded, and the severity or 
seriousness should be updated any time the event worsens.
6.
ABNORMAL LIVER FUNCTION TESTS
Drug-induced liver injury has been the most frequent single cause of safety-related drug 
marketing withdrawals or limitation of use, as well as discontinuation of clinical 
development programs. Hence, detection and reporting of liver function abnormalities 
that might herald a signal of severe drug-induced liver injury are conducted for any 
product in clinical development, irrespective of its expected liability for this risk. 
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. 
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.
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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 4 of this 
Appendix) 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 a non-serious adverse event 
of special interest (see Section 5.1 of Appendix 2).
7.
DEATHS
All deaths that occur during the protocol-specified adverse event reporting period (see 
Section 5 of Appendix 2), regardless of relationship to the study drug, must be recorded 
on the Adverse Event eCRF and immediately reported to the Sponsor. This includes 
death attributed to progression of Condition being Studied.
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").
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”).
9.
LACK OF EFFICACY OR WORSENING OF CONDITION BEING 
STUDIED
Not applicable.
10.
HOSPITALIZATION OR PROLONGED HOSPITALIZATION
Any adverse event that results in hospitalization or prolonged hospitalization should be 
documented and reported as a serious adverse event (per the definition of serious 
adverse event in Appendix 2), except as outlined below.
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An event that leads to hospitalization under the following circumstances should not be 
reported as an adverse event or a serious adverse event:

Hospitalization for respite care

Planned hospitalization required by the protocol (hospitalization from Day -1 to 
Day 4 for study drug administration).

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 participant has not suffered an adverse event.
An event that leads to hospitalization under the following circumstances is not 
considered to be a serious adverse event, but should be reported as an adverse event 
instead:

Hospitalization for an adverse event that would ordinarily have been treated in an 
outpatient setting had an outpatient clinic been available.
11
PATIENT-REPORTED OUTCOME DATA (CLINICAL OUTCOME 
ASSESSMENT DATA REPORTED DIRECTLY BY PATIENT)
Not applicable.
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Appendix 4
Clinical Laboratory Tests
The tests detailed in Table 7 will be performed by the local laboratory 
Protocol-specific eligibility requirements of participants are detailed in Sections 5.1
and 5.2, respectively, of the protocol.
Additional tests may be performed at any time during the study as determined necessary 
by the Principal Investigator or required by local regulations.
Table 7
Protocol-Required Safety Laboratory Assessments
All study-required laboratory assessments will be performed by a local laboratory:
Laboratory Assessments
Parameters
Hematology

Leucocytes, erythrocytes, hemoglobin, hematocrit, 
platelets, differential count (neutrophils, eosinophils, 
basophils, monocytes, lymphocytes, other cells).
Clinical Chemistry

Sodium, potassium, chloride, bicarbonate, glucose 
(fasting), urea, creatinine, total protein, serum albumin, 
phosphate, calcium, total and direct bilirubin, alkaline 
phosphatase, ALT, AST, urate, LDH.
Coagulation

INR, aPTT, PT.
Viral Serology

HIV, HBsAg, HCV and syphilis (Treponema pallidum)
antibody.
Lipids

Total Cholesterol, triglycerides
Thyroid Hormones

Free T4, TSH.
Pregnancy Test

All women of childbearing potential (including those who 
have had a tubal occlusion) will have a blood pregnancy 
test 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 
blood pregnancy test.}

{Serum or urine} human chorionic gonadotropin (hCG)
pregnancy test (as-needed for women of childbearing 
potential).
Urinalysis

Specific gravity

Dipstick: pH, glucose, protein, blood, leukocyte 
If there is a clinically significant positive result (confirmed 
by a positive repeated sample), urine will be sent to the 
laboratory for microscopy and culture. If there is an 
explanation for the positive dipstick results (e.g., 
menses), it should be recorded and there is no need to 
perform microscopy and culture.

Microscopic examination (sediment, RBCs, WBCs, 
casts, crystals, epithelial cells, bacteria), if blood or 
protein is abnormal.
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Other Screening Tests

Breath alcohol, urine test for cotinine, and urine drug 
screen (amphetamines, barbiturates, cocaine, opiates, 
methadone, cannabinoids and benzodiazepines).
ALP = alkaline phosphatase, eGFR = estimated glomerular filtration rate, FSH = follicle-
stimulating hormone, GGT = gamma-glutamyl transferase, HBsAg = hepatitis B surface antigen, 
HCV = hepatitis C virus, TSH = thyroid stimulating hormone.
The results of each test must be entered into the eCRF.
Investigators must document their review of each laboratory safety report.
Additional Statistical Considerations for Clinical Laboratory Data

Standard Reference Ranges and Transformation of Data
Roche and Shionogi & Co., Ltd standard reference ranges, rather than the reference 
ranges of the Principal Investigator, will be used for all parameters. For most 
parameters, the measured laboratory test result will be assessed directly using the 
Roche and Shionogi & Co., Ltd standard reference range. Certain laboratory parameters 
will be transformed to Roche and Shionogi & Co., Ltd’s standard reference ranges.
A transformation will be performed on certain laboratory tests that lack sufficiently 
common procedures and have a wide range of investigator ranges, e.g., enzyme tests 
that include AST, ALT, and alkaline phosphatase and total bilirubin. Since the standard 
reference ranges for these parameters have a lower limit of zero, only the upper limits of 
the ranges will be used in transforming the data.

Definition of Laboratory Abnormalities
For all laboratory parameters included, there exists a Roche predefined standard 
reference range. Laboratory values falling outside this standard reference range will be 
labeled “H” for high or “L” for low in participant listings of laboratory data.
In addition to the standard reference range, a marked reference range has been 
predefined by Roche for each laboratory parameter. The marked reference range is 
broader than the standard reference range. Values falling outside the marked reference 
range that also represent a defined change from baseline will be considered marked 
laboratory abnormalities (i.e., potentially clinically relevant). If a baseline value is not 
available for a participant, the midpoint of the standard reference range will be used as 
the participant’s baseline value for the purposes of determining marked laboratory 
abnormalities. Marked laboratory abnormalities will be labeled in the participant listings 
as “HH” for very high or “LL” for very low.
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Appendix 5
Contraceptive Guidance and Collection of Pregnancy 
Information
1.
DEFINITIONS

Woman of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming postmenopausal
unless permanently sterile.

Women in the following categories are considered to be Woman of Non-
Childbearing Potential 
a)
Pre-menarchal
b)
Pre-menopausal female with one of the following:
–
Documented hysterectomy.
–
Documented bilateral salpingectomy.
–
Documented bilateral oophorectomy.
Note: Documentation can come from the study center’s personnel’s review of 
participant’s medical records, medical examination, or medical history interview.
c)
Post-menopausal female
–
A postmenopausal state is defined as no menses for 12 months without an 
alternative medical cause other than menopause. A high follicle-stimulating 
hormone (FSH) level in the postmenopausal range may be used to confirm a 
postmenopausal state in women not using hormonal contraception or hormonal 
replacement therapy (HRT). However, in the absence of 12 months of amenorrhea, 
a single follicle-stimulating hormone measurement is insufficient.
–
Females on HRT and whose menopausal status is in doubt will be required to use 
one of the non-hormonal highly effective contraception methods if they wish to 
continue their HRT during the study. Otherwise, they must discontinue HRT to allow 
confirmation of postmenopausal status before study enrollment.
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2.
CONTRACEPTION GUIDANCE

Female partners of male participants
Female partners of male participant must use a highly effective method of contraception 
consistently and correctly as described in Table 8 below.
Table 8Highly Effective Contraceptive Methods
Highly Effective Contraceptive Methods That Are User-Dependent a
(Failure rate of 1% per year when used consistently and correctly)
Combined (estrogen- and progestogen-containing) hormonal contraception associated with 
inhibition of ovulation

Oral

Intravaginal

Transdermal
Progestogen-only hormonal contraception associated with inhibition of ovulation

Oral

Injectable
Highly Effective Methods That Are User-Independenta
Implantable progestogen-only hormonal contraception associated with inhibition of ovulation

Intrauterine device 

Intrauterine hormone-releasing system 

Bilateral tubal occlusion
Vasectomized partner
A vasectomy is a highly effective contraception method provided that the vasectomized partner 
is the sole male sexual partner of the women of childbearing potential P and the absence of 
sperm has been confirmed. If not, an additional highly effective method of contraception should 
be used.
Sexual abstinence
Sexual abstinence is considered a highly effective method only if defined as refraining from 
heterosexual intercourse during the entire period of risk associated with the study drug. The 
reliability of sexual abstinence needs to be evaluated in relation to the duration of the study and 
the preferred and usual lifestyle of the participant.
a) Typical use failure rates may differ from those when used consistently and correctly. Use 
should be consistent with local regulations regarding the use of contraceptive methods for 
participants participating in clinical studies.
3.
PREGNANCY TESTING
As women of child bearing potential are not enrolled in the study, pregnancy testing will 
not be done.
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4.
COLLECTION OF PREGNANCY INFORMATION

Male participants with partners who become pregnant
The investigator will attempt to collect pregnancy information on any male participant’s 
female partner who becomes pregnant while the male participant is in this study (see 
Section 8.3.5). This applies only to male participants who receive the study drug.
Attempts should be made to collect and report details of the course and outcome of any 
pregnancy in the partner of a male participant exposed to the study drug. The
investigator will record pregnancy information on the Clinical Trial Pregnancy Reporting 
Form and submit it to the Sponsor within 24 hours of learning of the partner’s pregnancy. 
When permitted by the study center, 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
update the Clinical Trial Pregnancy Reporting Form with additional information on the 
course and outcome of the pregnancy when available. An investigator who is contacted 
by the male participant 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. The female partner will be 
followed to determine the outcome of the pregnancy. Information on the status of the 
mother and child will be forwarded to the Sponsor. Monitoring of the participant’s partner 
should continue until conclusion of the pregnancy. Any termination of the pregnancy will 
be reported regardless of fetal status (presence or absence of anomalies) or indication 
for procedure.

Female participants who become pregnant
This section is not applicable as WOCBP are not enrolled in the study.

The investigator will collect pregnancy information on any female participant, who 
becomes pregnant while participating in this study (see Section 8.3.5). Information 
will be recorded on the appropriate form and submitted to the Sponsor within 
24 hours of learning of a participant's pregnancy. The participant will be followed to 
determine the outcome of the pregnancy. The investigator will collect follow‑up 
information on the participant and the neonate, which will be forwarded to the 
Sponsor. Monitoring of the participant should continue until conclusion of the 
pregnancy. Any termination of pregnancy will be reported, regardless of fetal status 
(presence or absence of anomalies) or indication for procedure.

While pregnancy itself is not considered to be an adverse event or serious adverse 
event, and should not be recorded on the adverse event electronic Case Report 
Form (eCRF), any pregnancy complication will be reported as an adverse event or 
serious adverse event. A spontaneous abortion is always considered to be a serious 
adverse event and will be reported as such. Any post-study pregnancy related 
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serious adverse event considered reasonably related to the study drug by the 
investigator, will be reported to the Sponsor as described in Appendix 2. While the 
investigator is not obligated to actively seek this information in former study 
participants, he/she may learn of a serious adverse event through spontaneous 
reporting.
5
ABORTIONS
Any spontaneous abortion in the female partner of male participant should be classified
as a serious adverse event (as the Sponsor considers spontaneous abortions to be 
medically significant events), 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 of Appendix 2).
Any induced abortion due to maternal toxicity and/or embryo-fetal toxicity should also be 
classified as 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 of Appendix 2).
Elective abortion not associated with toxicity (e.g., induced abortion for personal reasons) 
does not require expedited reporting but should be reported as outcome of pregnancy on 
the Clinical Trial Pregnancy Reporting Form.
6
CONGENITAL ANOMALIES/BIRTH DEFECTS
Any congenital anomaly/birth defect in a child born to a female partner of a male 
participant exposed to the 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 of Appendix 2.
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Appendix 6
Protocol Amendment History
Document History
Documents
Dates
Substantial
Region
Version 2 (Amendment 1)
06 December 2018
Yes
China
Version 1 (Original Protocol)
07 August 2018
-
-
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