Clinical trial NCT02954354
Conditions: Influenza
Keywords: Flu Baloxavir Marboxil Oseltamivir Tamiflu®
Sponsor: Shionogi
Start date: 2016-12-08; Completion date: 2017-04-24
Enrollment: 1436 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The primary objective of this study is to evaluate the efficacy of a single, oral dose of baloxavir marboxil compared with placebo by measuring the time to alleviation of symptoms in patients with uncomplicated influenza virus infection.

Detailed description:

Arms: arm 1: Participants aged 20 to 64 years will receive two or four 20 mg baloxavir marboxil tablets orally on Day 1 and one oseltamivir placebo capsule orally twice a day (BID) on Days 1 to 5. arm 2: Participants aged 20 to 64 years will receive 75 mg oseltamivir twice a day on Days 1 to 5 and two or four baloxavir marboxil placebo tablets on Day 1. arm 3: Participants aged 20 to 64 years will receive two or four baloxavir marboxil placebo tablets on Day 1 and one oseltamivir placebo capsule orally twice a day on Days 1 to 5. arm 4: Participants aged 12 to 19 years will receive two or four baloxavir marboxil 20 mg tablets on Day 1. arm 5: Participants aged 12 to 19 years will receive two or four baloxavir marboxil placebo tablets on Day 1.
Interventions: intervention 1: Baloxavir Marboxil intervention 2: Placebo to Baloxavir Marboxil intervention 3: Oseltamivir intervention 4: Placebo to Oseltamivir
Intervention descriptions: intervention 1: 2 to4 X 20-mg tablets taken orally intervention 2: 2 to4 X 20-mg tablets taken orally intervention 3: 75 mg capsules taken orally intervention 4: Placebo capsules matching oseltamivir 75 mg capsules

Protocol documents:
Prot_000.pdf: 
Shionogi Study Title:  
A Phase 3, Multicenter, Randomized, Double-blind 
Study of a Single Dose of S-033188 Compared with 
Placebo or Oseltamivir 75 mg Twice Daily for 5 
Days in Otherwise Healthy Patients with Influenza 
Shionogi Study Number: 
1601T0831 
ClinicalTrials.gov 
registration No. 
NCT02954354 
Study Document  
Protocol (Version 3 dated 31October 2016)  
 
 
History of Protocol Amendments 
 
Version 1 (Original): 
05 August 2016 
This version of the protocol was not submitted to regulatory authorities  
Version 2 (Amendment 1): 
16 September 2016 
Version 3 (Amendment 2): 
31 October 2016 
The major change in protocol amendment 2 was: 
• Change in the threshold of body weight for 80-mg dose of S-033188 from ≥ 100 kg to 
≥ 80 kg. This change required associated changes throughout the protocol in text, 
tables, and figures.  
 


Clinical Study Protocol: 1601T0831 
Study Title: 
A Phase 3, Multicenter, Randomized, Double-blind Study 
of a Single Dose of S-033188 Compared with Placebo or 
Oseltamivir 75 mg Twice Daily for 5 Days in Otherwise 
Healthy Patients with Influenza
Study Number:
1601T0831
Study Phase:
3
Product Name:
S-033188
IND Number:
126653
Sponsor* for Japan and 
other Asian countries:  
Shionogi & Co., Ltd. 
1-8, Doshomachi 3-chome, Chuo-ku, Osaka 541-0045, 
Japan
Sponsor* for the United 
States:
Shionogi Inc.
300 Campus Drive, Florham Park, NJ 07932 USA
Sponsor* for Australia, 
New Zealand and South 
Africa:
Shionogi Ltd.  
5th floor, 33 Kingsway, London 
WC2B 6UF, United Kingdom
Sponsor Contact: 
  
Issue Date:
Version 1 (Original):
05 August 2016
Version 2 (Amendment 1):
16 September 2016
Version 3 (Amendment 2):
31 October 2016


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*: The study sponsor may be one or more of the above companies. Throughout the 
protocol, the term “sponsor” represents the various legal entities identified in the 
“Sponsor List of the Study Administrative Structure” in the protocol. The above 
companies are referred to as Shionogi.
Confidentiality Statement
This document and the information contained herein or attached hereto (“Confidential 
Material”) are confidential and proprietary to Shionogi. This Confidential Material 
should only be viewed by those individuals or companies that have been given prior 
written authorization to do so by Shionogi (“Authorized Users”). This Confidential 
Material should not be made available in any form to any person or company, other than 
the Authorized Users and their respective employees or associates on a need-to-know 
basis, without the written consent from Shionogi.


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SYNOPSIS
Study Title:
A Phase 3, Multicenter, Randomized, Double-blind Study of a Single Dose of S-033188
Compared with Placebo or Oseltamivir 75 mg Twice Daily for 5 Days in Otherwise 
Healthy Patients with Influenza
Study Number:
1601T0831
Study Phase: 3
Primary Efficacy Objective:
x
To evaluate the efficacy of a single, oral dose of S-033188 compared with placebo 
by measuring the time to alleviation of symptoms in patients with uncomplicated 
influenza virus infection
Secondary Efficacy Objectives:
x
To evaluate the efficacy of a single, oral dose of S-033188 compared with 
oseltamivir 75 mg twice daily (BID) for 5 days by measuring the time to 
alleviation of symptoms in patients aged 20 to 64 years with uncomplicated 
influenza virus infection
x
To evaluate the efficacy of a single, oral dose of S-033188 compared with placebo 
by measuring the secondary endpoints in patients with uncomplicated influenza
virus infection
x
To evaluate the efficacy of a single, oral dose of S-033188 compared with 
oseltamivir 75 mg BID for 5 days by measuring the secondary endpoints in 
patients with uncomplicated influenza virus infection
Other Efficacy Objective: 
x
To evaluate the polymorphic and treatment-emergent amino acid substitutions in 
the polymerase acidic protein (PA) gene and drug susceptibility in patients with 
evaluable virus
Safety Objectives:
x
To compare the safety and tolerability of a single dose of S-033188 with placebo
x
To compare the safety and tolerability of a single dose of S-033188 with
oseltamivir 75 mg BID for 5 days
x
To compare the frequency of adverse events (AEs) in patients with influenza of a
single dose of S-033188 with oseltamivir 75 mg BID for 5 days and with placebo
Pharmacokinetic Objective:
x
To determine the pharmacokinetics (PK) of the active form of S-033188, ie,
S-033447, in patients with uncomplicated influenza virus infection
Health Economic Outcomes Research Objective: 
x
To compare the total quality-of-life change by measuring the EuroQol–
5 Dimensions–5 Levels (EQ-5D-5L) and a work productivity (WP) questionnaire 
in patients treated with S-033188 compared with oseltamivir 75 mg BID for 
5 days and placebo


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Study Design:
This is a randomized, double-blind, multicenter, parallel-group, placebo- and active-
controlled study enrolling approximately 1494 patients diagnosed with influenza.
Approximately 1350 patients aged 20 to 64 years and 144 patients aged 12 to 19 years 
will be enrolled.  Patients in 20 to 64 years age stratum will be randomly assigned in a 
ratio of 2:2:1 to receive a single dose of 40 or 80 mg of S-033188 according to their 
weight category, 75 mg BID of oseltamivir for 5 days, or placebo. With the aim to 
achieve a broadly comparable exposure, patients who weigh < 80 kg at Screening will 
receive 40 mg of S-033188, and patients who weigh ≥80 kg at Screening will receive 
80 mg of S-033188. Patients in 12 to 19 years age stratum will be randomly assigned in a 
ratio of 2:1 to receive a single dose of 40 or 80 mg (depending on weight) S-033188 or
placebo. Detailed study design and schedule are described in Sections 3.1 and 5.2.
Study Population:
Otherwise healthy male and female patients ≥12 and ≤ 64 years old with influenza A
and/or B infection of developing influenza complications within 48 hours of symptom 
onset
Criteria for Inclusion and Exclusion:
Inclusion Criteria:
Patients who fulfill all of the following criteria will be included in the study:
1. Patients who are able to understand the study and comply with all study 
procedures, and willing to provide written informed consent/assent prior to the 
predose examinations appropriately. For adolescent patients, informed 
consent/assent of voluntary participation should be obtained in accordance with 
local requirements (see Section 7.1).
2. Male or female patients aged ≥12 to ≤64 years at the time of signing the 
informed consent/assent form.
3. Patients with a diagnosis of influenza confirmed by all of the following:
a. Fever ≥38ºC (axillary) in the predose examinations or > 4 hours after dosing 
of antipyretics if they were taken
b. At least one of the following general systemic symptoms associated with 
influenza are present with a severity of moderate or greater

Headache

Feverishness or chills

Muscle or joint pain

Fatigue
c.
At least one of the following respiratory symptoms associated with influenza 
are present with a severity of moderate or greater

Cough

Sore throat

Nasal congestion
4. The time interval between the onset of symptoms and the predose examinations
(Screening) is 48 hours or less.  The onset of symptoms is defined as either:
a.
Time of the first increase in body temperature (an increase of at least 1ºC from 
normal body temperature)


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b. Time when the patient experiences at least one general or respiratory symptom
5. Women of childbearing potential (WOCBP) who agree to use a highly effective
method of contraception for 3 months after the first dose of S-033188 or 
oseltamivir (see Section 6.3.1 for approved contraceptive requirements).
Exclusion Criteria:
Patients who meet any of the following criteria will be excluded from the study:
1. Patients with severe influenza virus infection requiring inpatient treatment.
2. Patients aged ≥20 years with known allergy to oseltamivir (Tamiflu®).
3. Patients with any of the following risk factors*:
y
Women who are pregnant or within 2 weeks post-partum
y
Residents of long-term care facilities (eg, welfare facilities for the elderly, 
nursing homes)
y
Chronic respiratory diseases including bronchial asthma
y
Neurological and neurodevelopmental disorders including disorders of the 
brain, spinal cord, peripheral nerve, and muscle (eg, cerebral palsy, epilepsy 
[seizure disorders], stroke, intellectual disability, moderate to severe 
developmental delay, muscular dystrophy, or spinal cord injury)
y
Heart disease (such as congenital heart disease, congestive heart failure, or 
coronary artery disease), excluding hypertension without any other heart-
related symptoms
y
American Indians and Alaskan natives
y
Blood disorders (such as sickle cell disease)
y
Endocrine disorders (including diabetes mellitus)
y
Kidney disorders
y
Liver disorders
y
Metabolic disorders
y
Compromised immune system (including patients receiving 
immunosuppressant therapy, or those with cancer or human 
immunodeficiency virus [HIV] infection)
y
Morbid obesity (body mass index [BMI] ≥40)
* Based on the definitions of people at high risk by the Centers for Disease Control and 
Prevention (CDC). http://www.cdc.gov/flu/about/disease/high_risk.htm
4. Patients unable to swallow tablets or capsules.
5. Patients who have previously received S-033188.
6. Patients weighing < 40 kg
7. Patients who have been exposed to an investigational drug within 30 days prior to 
the predose examinations.
8. Women who are breastfeeding or have a positive pregnancy test in the predose 
examinations.  The following female patients who have documentation of either a
or b below do not need to undergo a pregnancy test in the predose examinations:
a.
Postmenopausal women (defined as cessation of regular menstrual periods for 
2 years or more and confirmed by a follicle-stimulating hormone test)
b. Women who are surgically sterile by hysterectomy, bilateral oophorectomy, or 
tubal ligation


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9. Patients with concurrent infections requiring systemic antimicrobial and/or 
antiviral therapy at the predose examinations.
10. Patients who have received peramivir, laninamivir, oseltamivir, zanamivir, 
rimantadine, umifenovir or amantadine within 30 days prior to the predose 
examinations.
11. Patients who have received an investigational monoclonal antibody for a viral 
disease in the last year.
12. Patients with severe underlying diseases.
13. Patients with current creatinine clearance ≤60 mL/min (≤30 mL/min in Japan).
14. Patients who, in the opinion of the investigator, would be unlikely to comply with 
required study visits, self-assessments, and interventions.
Study Drug, Dose, and Mode of Administration:
Test Drug
x
S-033188 20-mg tablets
Control Drugs
x
Oseltamivir 75-mg capsules
x
Placebo tablet matching S-033188 20-mg tablets
x
Placebo capsule matching oseltamivir 75-mg capsules
All patients will receive the study drug provided for each group according to the result of 
allocation. 
Patients aged ≥20 years
[S-033188 group]
Day 1: Two or four 20-mg S-033188 tablets (depending on weight) will be
administered orally. One oseltamivir placebo capsule will be administered 
orally BID (morning and evening).
Days 2 to 5: One oseltamivir placebo capsule will be administered orally BID 
(morning and evening).
[Oseltamivir group]
Day 1: Two or four S-033188 placebo tablets (depending on weight) will be
administered orally. One 75-mg oseltamivir capsule will be administered 
orally BID (morning and evening).
Days 2 to 5: One 75-mg oseltamivir capsule will be administered orally BID
(morning and evening).
[Placebo group]
Day 1: Two or four S-033188 placebo tablets (depending on weight) will be
administered orally. One oseltamivir placebo capsule will be administered 
orally BID (morning and evening).
Days 2 to 5: One oseltamivir placebo capsule will be administered orally BID 
(morning and evening).


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Patients aged 12 to 19 years
[S-033188 group]
Day 1: Two or four 20-mg S-033188 tablets (depending on weight) will be
administered orally.
[Placebo group]
Day 1: Two or four S-033188 placebo tablets (depending on weight) will be
administered orally.
Duration of Treatment:
Patients aged 20 to 64 years: 5 days
Patients aged 12 to 19 years: 1 day
Prohibited Concomitant Therapy:
The use of the following drugs and over-the-counter drugs with equivalent efficacy to 
them will be prohibited from Visit 1 (Day 1) until Visit 7 (Day 22) or early termination.
a.
Systemic antiviral drugs
b.
Antimicrobial* and antifungal drugs**
c.
Antipyretics/analgesics except acetaminophen
d.
Antitussives/expectorants
e.
Combination cold remedies
f.
Antihistamines**
g.
Corticosteroids**
h.
Immunosuppressants
i.
Herbal medicines or complementary therapies indicated for influenza virus 
infection (eg, Maoutou)
j.
Other investigational drugs
*
Except for the treatment of complications of influenza suspected to be bacterial infection
after Day 1.
** Dermal preparations will be permitted, but application to the eyes, nose or ears, or by 
inhalation will be prohibited.
Efficacy Assessments:
Primary endpoint:
Time to alleviation of symptoms (cough, sore throat, headache, nasal congestion, 
feverishness or chills, muscle or joint pain, and fatigue), defined as the time from the start 
of treatment to the time when all influenza symptoms are rated as absent or mild
Secondary endpoints:
x
Proportion of patients positive for influenza virus titer and proportion of patients 
positive by RT-PCR at each time point
x
Change from baseline in virus titer and in the amount of virus RNA (RT-PCR) at 
each time point
x
Area under the curve adjusted by baseline in virus titer and in the amount of virus 
RNA (RT-PCR)
x
Time to cessation of viral shedding by virus titer and by RT-PCR
x
Proportion of patients whose symptoms has been alleviated at each time point 
x
Time to alleviation of the 4 systemic symptoms (headache, feverishness or chills,
muscle or joint pain, and fatigue)


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x
Time to alleviation of the 3 respiratory symptoms (cough, sore throat and nasal 
congestion)
x
Change from baseline in composite symptom score at each time point
x
Time to resolution of fever
x
Proportion of patients reporting normal temperature at each time point
x
Body temperature at each time point
x
Time to alleviation of individual symptoms
x
Time to return to preinfluenza health status
x
Incidence of influenza-related complications (hospitalization, death, sinusitis, 
bronchitis, otitis media, and radiologically confirmed pneumonia)
x
Intrahousehold infection rate (for Japan only)
Other Assessments:
x
Serum antibody titer
x
Polymorphic and treatment-emergent amino acid substitutions in the PA gene
x
Drug susceptibility in patients with evaluable virus
x
Health economic outcomes

EQ-5D-5L

WP questionnaire 
Safety Assessments:
Frequencies of AEs, serious AEs, vital sign measurements, electrocardiography (ECG),
and clinical laboratory tests 
Pharmacokinetic Assessments:
For the measurement of plasma S-033447 concentrations, blood samples will be collected
at Visit 2 (Day 2) and 4 (Day 5). If circumstances permit, samples will also be collected 
at 0.5 to 4 hours postdose at Visit 1 (Day 1), Visit 3 (Day 3) and Visit 6 (Day 15).
Statistical Methods:
The intention-to-treat infected (ITTI, defined as RT-PCR positive for influenza) set will 
be the primary efficacy analysis population in the study.  The per-protocol set (PPS) will 
be used as supportive evidence of the primary analyses for efficacy. All statistical testing 
will be performed at the two-sided significance level of 0.05 unless stated otherwise.  
Primary efficacy analysis:
Comparison of the primary endpoint between S-033188 and placebo:
In the primary analysis, the time to alleviation of symptoms will be compared between 
the S-033188 group and the placebo group using the stratified generalized Wilcoxon test 
with composite symptoms score at baseline and region as stratification factors.
Furthermore, the Kaplan-Meier curves will be plotted for each treatment group, and the 
median time to alleviation of symptoms and its 95% confidence interval (CI) will be 
calculated. The same analyses in PPS will be performed as a sensitivity analysis.
Secondary efficacy analysis for primary endpoint:
Comparison of the primary endpoint between adult stratum of S-033188 group and 
oseltamivir group:
Among patients aged 20 to 64 years, the time to alleviation of symptoms will be 
compared between the S-033188 group and the oseltamivir group using the stratified 
generalized Wilcoxon test with composite symptoms score at baseline and region as 


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stratification factors. Furthermore, the Kaplan-Meier curves will be plotted for each 
treatment group, and the median time to alleviation of symptoms and its 95% CI will be 
calculated.  
Together with the primary efficacy analysis, this comparison will be conducted in a 
hierarchical manner so as to maintain control of overall Type I error.  For Japan, control 
of overall Type I error is not required for the secondary efficacy analysis of primary 
endpoint. 
Other secondary efficacy analyses: 
The following analytical procedures will be applied to the various secondary efficacy 
variables: stratified generalized Wilcoxon test, analysis of covariance (ANCOVA), van 
Elteren test, Mantel-Haenszel test, and Fisher's exact test.
Safety analyses: 
For AEs and treatment-related AEs, the numbers of events and patients with 
AEs/treatment-related AEs will be counted for each treatment group.  The numbers of 
events and patients with AEs/treatment-related AEs will be counted by system organ 
class (SOC) and preferred term (PT) for each treatment group.
Descriptive statistics (number of patients, mean, standard deviation, minimum, median, 
and maximum) for quantitative data obtained at each time point will be calculated for 
each treatment group for vital sign measurements, ECG, and laboratory values.  For 
qualitative data, the frequency of each category at each time point will be summarized.
Study Duration: 
Study duration in individual patients: 22 days
Planned study duration for the study: 
Date of Original: 05 August 2016
Date of Latest Amendment: 31 October 2016 (Amendment 2)


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TABLE OF CONTENTS
SYNOPSIS.......................................................................................................................... 3 
TABLE OF CONTENTS.................................................................................................. 10 
LIST OF IN-TEXT TABLES ........................................................................................... 15 
LIST OF IN-TEXT FIGURES.......................................................................................... 15 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS................................... 16 
1. 
INTRODUCTION .................................................................................................... 19 
1.1 
Nonclinical Studies ......................................................................................... 20 
1.1.1 
Pharmacology ....................................................................................... 20 
1.1.2 
Safety .................................................................................................... 20 
1.1.3 
Pharmacokinetics .................................................................................. 21 
1.2 
Clinical Summary ........................................................................................... 22 
1.2.1 
Single-ascending Dose Study (Study 1510T0811)............................... 22 
1.2.2 
Relative Bioavailability and Food Effect Study (Study 1512T0813)... 23 
1.2.3 
Drug-drug Interaction Study with Midazolam (Study 1519T0814) ..... 23 
1.2.4 
Drug-drug Interaction Study with Itraconazole (Study 1520T0815).... 24 
1.2.5 
Thorough QT/QTc Study (Study 1527T0816) ..................................... 24 
1.2.6 
A Phase 2 Proof of Concept and Dose Finding Study 
(Study 1518T0821) ............................................................................... 25 
1.3 
Comparator Data............................................................................................. 26 
1.3.1 
Clinical Data of Oseltamivir................................................................. 26 
1.3.1.1 
Oseltamivir Efficacy................................................................... 26 
1.3.1.2 
Oseltamivir Safety ...................................................................... 27 
1.3.1.3 
Clinical Studies........................................................................... 27 
1.3.1.4 
Oseltamivir Dosing ..................................................................... 28 
1.3.1.5 
Oseltamivir Dosing and Renal Impairment ................................ 28 
1.4 
Rationale for the Study ................................................................................... 28 
2. 
STUDY OBJECTIVES............................................................................................. 30 
2.1 
Primary Efficacy Objective............................................................................. 30 
2.2 
Secondary Efficacy Objectives....................................................................... 30 
2.3 
Other Efficacy Objective ................................................................................ 30 
2.4 
Safety Objectives ............................................................................................ 30 
2.5 
Pharmacokinetic Objective ............................................................................. 30 
2.6 
Health Economic Outcomes Research Objective ........................................... 31 
3. 
INVESTIGATIONAL PLAN................................................................................... 32 
3.1 
Overall Study Design and Plan....................................................................... 32 
3.2 
Rationale for Study Design and Control Group.............................................. 33 
3.2.1 
Rationale for Study Design................................................................... 33 


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3.2.2 
Selection of the Dose of S-033188 ....................................................... 33 
3.2.3 
Selection of the Dose of Oseltamivir.................................................... 35 
3.3 
Study Duration................................................................................................ 35 
3.3.1 
Study Duration in Individual Patients................................................... 35 
3.3.2 
Planned Study Duration for the Study .................................................. 35 
3.3.3 
End of Study ......................................................................................... 35 
4. 
STUDY POPULATION SELECTION .................................................................... 36 
4.1 
Study Population............................................................................................. 36 
4.2 
Inclusion Criteria ............................................................................................ 36 
4.3 
Exclusion Criteria ........................................................................................... 37 
4.4 
Screen Failures................................................................................................ 38 
5. 
STUDY TREATMENTS.......................................................................................... 39 
5.1 
Description of Treatments............................................................................... 39 
5.1.1 
Test Drug .............................................................................................. 39 
5.1.2 
Placebo.................................................................................................. 39 
5.1.3 
Active Control....................................................................................... 39 
5.2 
Treatments to be Administered....................................................................... 39 
5.2.1 
Patients Aged 20 to 64 Years................................................................ 39 
5.2.2 
Patients Aged 12 to 19 Years................................................................ 40 
5.3 
Selection and Timing of Dose for Each Patient.............................................. 40 
5.4 
Method of Assigning Patients to Treatment Groups....................................... 40 
5.5 
Blinding........................................................................................................... 41 
5.6 
Packaging and Labeling.................................................................................. 42 
5.7 
Storage and Accountability............................................................................. 42 
5.8 
Investigational Product Retention at Medical Institution ............................... 42 
5.9 
Treatment Compliance.................................................................................... 43 
6. 
RESTRICTIONS ...................................................................................................... 44 
6.1 
Prior Therapy .................................................................................................. 44 
6.2 
Concomitant Therapy during the Study.......................................................... 44 
6.2.1 
Prohibited Concomitant Therapy.......................................................... 44 
6.2.2 
Rescue Therapy (Noninvestigational Medicinal Product).................... 44 
6.3 
Other Restrictions ........................................................................................... 45 
6.3.1 
Contraception........................................................................................ 45 
7. 
STUDY PROCEDURES AND METHODS OF ASSESSMENTS ......................... 46 
7.1 
Informed Consent/Assent................................................................................ 46 
7.2 
Baseline Patient Characteristic and Medical History...................................... 46 
7.2.1 
Baseline Patient Characteristic and Medical History............................ 46 
7.2.2 
Rapid Influenza Diagnostic Test (RIDT).............................................. 47 


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7.2.3 
Meals..................................................................................................... 47 
7.3 
Enrollment in the Study and Dispensing Study Drug..................................... 47 
7.4 
Efficacy Assessments...................................................................................... 47 
7.4.1 
Patient Electronic Diary........................................................................ 47 
7.4.1.1 
Body Temperature Measurement................................................ 48 
7.4.1.2 
Assessment of Severity of Influenza Symptoms ........................ 48 
7.4.1.3 
Assessment of Health.................................................................. 49 
7.4.1.4 
EuroQol-5 Dimensions-5 Levels (EQ-5D-5L) ........................... 49 
7.4.2 
Virology Test ........................................................................................ 49 
7.4.3 
Intrahousehold Infection Rate............................................................... 50 
7.5 
Pharmacokinetics Assessments....................................................................... 50 
7.6 
Safety Assessments......................................................................................... 50 
7.6.1 
Physical Examination............................................................................ 50 
7.6.2 
Vital Sign Measurements...................................................................... 50 
7.6.3 
Electrocardiography.............................................................................. 51 
7.6.4 
Clinical Laboratory Tests...................................................................... 51 
7.6.4.1 
Laboratory Parameters................................................................ 51 
7.6.4.2 
Routine Laboratory Tests............................................................ 51 
7.6.4.3 
Immunological Tests................................................................... 52 
7.6.4.4 
Pregnancy Tests .......................................................................... 52 
7.6.4.5 
Sample Collection, Storage, and Shipping ................................. 52 
7.6.5 
Adverse Events Assessments................................................................ 53 
7.6.5.1 
Performing Adverse Event Assessments .................................... 53 
7.6.5.2 
Timing......................................................................................... 53 
7.6.5.3 
Severity ....................................................................................... 53 
7.6.5.4 
Relationship ................................................................................ 54 
7.6.5.5 
Expectedness............................................................................... 54 
7.6.5.6 
Adverse Event Assessment of Clinical Laboratory and Other 
Safety Parameters........................................................................ 54 
7.6.5.7 
Serious Adverse Events .............................................................. 55 
7.6.5.8 
Liver Function Abnormalities..................................................... 57 
7.6.5.9 
Special Situations - Abuse, Misuse, Overdose, and 
Medication Error......................................................................... 57 
7.6.5.10 
Pregnancy ................................................................................. 57 
7.7 
Other Assessment............................................................................................ 58 
7.7.1 
Serum Antibody Titer Test ................................................................... 58 
7.7.2 
Polymorphic and Treatment-emergent Amino Acid Substitutions....... 58 
7.7.3 
Drug Susceptibility Testing for Test Substances.................................. 58 
7.7.4 
Health Economic Outcomes ................................................................. 58 


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7.7.4.1 
EuroQol-5 Dimensions-5 Levels (EQ-5D-5L) ........................... 58 
7.7.5 
Work Productivity (WP) Questionnaire................................................ 59 
7.8 
Withdrawal of Patients from the Study or Study Drug................................... 59 
7.8.1 
Clinical Progression or Lack of Response............................................ 59 
7.9 
Appropriateness of Measurements.................................................................. 60 
7.9.1 
Primary Efficacy Endpoint ................................................................... 60 
7.9.2 
Secondary Efficacy Endpoints.............................................................. 60 
7.9.3 
Safety Endpoints ................................................................................... 61 
7.9.4 
Plasma Drug Concentrations................................................................. 61 
7.9.5 
Other Endpoints .................................................................................... 61 
7.10 
Allowable Time Window................................................................................ 61 
8. 
STUDY ACTIVITIES .............................................................................................. 63 
8.1 
Poststudy Access to the Study Drug............................................................... 63 
9. 
PLANNED STATISTICAL METHODS ................................................................. 64 
9.1 
General Considerations................................................................................... 64 
9.2 
Determination of Sample Size ........................................................................ 64 
9.3 
Analysis Populations....................................................................................... 66 
9.4 
Handling of Missing Data............................................................................... 66 
9.5 
Patient Disposition.......................................................................................... 66 
9.6 
Demographic and Baseline Characteristics .................................................... 66 
9.7 
Extent of Exposure and Treatment Compliance ............................................. 67 
9.8 
Prior Therapies................................................................................................ 67 
9.9 
Concomitant Therapies ................................................................................... 67 
9.10 
Efficacy Analyses ........................................................................................... 67 
9.10.1 
Primary Efficacy Endpoint ................................................................... 67 
9.10.2 
Secondary Efficacy Endpoints.............................................................. 67 
9.10.3 
Analyses of Efficacy Endpoints............................................................ 69 
9.10.3.1 
Analyses of Primary Endpoint.................................................... 69 
9.10.3.1.1 Primary Analysis......................................................................... 69 
9.10.3.2 
Analyses of Secondary Endpoints .............................................. 70 
9.11 
Safety Analyses............................................................................................... 72 
9.11.1 
Adverse Events ..................................................................................... 72 
9.11.2 
Vital Signs............................................................................................. 72 
9.11.3 
Clinical Laboratory Analysis ................................................................ 72 
9.11.4 
Electrocardiography.............................................................................. 73 
9.12 
Pharmacokinetic Analysis............................................................................... 73 
9.13 
Other Analysis ................................................................................................ 73 
9.13.1 
Serum Influenza Antibody Titer ........................................................... 73 


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9.13.2 
Polymorphic and Treatment-emergent Amino Acid Substitutions in 
the PA Gene .......................................................................................... 73 
9.13.3 
Drug Susceptibility Testing for Test Substances .................................. 73 
9.13.4 
Health Economic Outcomes ................................................................. 74 
9.13.4.1 
EuroQol-5 Dimensions-5 Levels and EuroQol Visual Analog 
Scale ............................................................................................ 74 
9.13.4.2 
Work Productivity (WP) Questionnaire ...................................... 74 
9.13.5 
Intrahousehold infection rate ................................................................ 74 
9.14 
Interim Analysis .............................................................................................. 74 
10. ADMINISTRATIVE CONSIDERATIONS ............................................................. 75 
10.1 
Study Administrative Structure ....................................................................... 75 
10.2 
Institutional Review Board (IRB) Approval ................................................... 77 
10.3 
Ethical Conduct of the Study .......................................................................... 77 
10.4 
Patient Information and Consent/Assent ........................................................ 77 
10.5 
Trial Participation Card ................................................................................... 78 
10.6 
Patient Confidentiality .................................................................................... 78 
10.7 
Study Monitoring ............................................................................................ 78 
10.8 
Case Report Forms and Source Documents .................................................... 78 
10.8.1 
Case Report Forms ................................................................................ 78 
10.8.2 
Source Data and Source Documents ..................................................... 79 
10.8.3 
External Data ........................................................................................ 79 
10.9 
Committees ..................................................................................................... 80 
10.9.1 
Independent Data Monitoring Committee ............................................ 80 
10.10 Termination or Suspension of the Study ......................................................... 80 
10.10.1 Termination or Suspension of the Entire Study .................................... 80 
10.10.2 Termination or Suspension of the Study by Study Center .................... 80 
10.11 Protocol Modifications and Deviations .......................................................... 80 
10.12 Data Management ........................................................................................... 81 
10.13 Retention of Data ............................................................................................ 81 
10.14 Quality Control and Assurance ....................................................................... 81 
10.15 Publication and Disclosure Policy .................................................................. 82 
10.16 Financial Disclosure ........................................................................................ 82 
11. REFERENCE LIST .................................................................................................. 83 
Appendix 1 
Time and Events Schedule .................................................................... 84 
Appendix 2 
 86 
Appendix 3 
Work Productivity (WP) Questionnaire ................................................ 89 
Appendix 4 
Assessment of Health Scale .................................................................. 90 
Appendix 5 
Management and Discontinuation Criteria for Abnormal Liver 
Function Tests ........................................................................................................... 91 


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LIST OF IN-TEXT TABLES
Table 5-1 
Study Drug Administration (Patients Aged ≥20 Years) ............ 40 
Table 7-1 
Time Windows of Body Temperature Measurement as a 
Guide........................................................................................... 48 
Table 7-2 
Time Windows of Assessment as a Guide: Assessment of 
Severity of Influenza Symptoms................................................. 49 
Table 7-3 
Time Window of Assessment as a Guide: Assessment of 
Health.......................................................................................... 49 
Table 7-4 
Blood Sample Volumes .............................................................. 51 
Table 7-5 
Routine Laboratory Tests............................................................ 52 
Table 7-6 
Allowable Time Window............................................................ 62 
Table 7-7 
Allowable Time Window for Blood Sample Collection for the 
Measurement of Plasma Drug Concentrations............................ 62 
Table 9-1 
Statistical Power to Compare between S-033188 and 
Oseltamivir.................................................................................. 65 
LIST OF IN-TEXT FIGURES
Figure 3-1 
Study Schematic.......................................................................... 32 
Figure 3-2 
Simulated C24 of S-033447 in Subjects Administered a Single 
Dose of S-033188 (40 or 80 mg, Depending on Body Weight) 
and Observed C24 in the Phase 2 Study...................................... 35 


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
ADL
Activities of Daily Living
AE
adverse event
ALT
alanine aminotransferase
ANCOVA
analysis of covariance
AR
adverse reaction
AST
aspartate aminotransferase
AUC
area under the plasma concentration-time curve
AUC0-72
area under the plasma concentration-time curve from time zero to 
72 hours after dosing
AUC0-inf
area under the plasma concentration-time curve extrapolated from 
time zero to infinity
AUC0-last
area under the plasma concentration-time curve from time zero to the 
time of the last quantifiable concentration after dosing
BA
bioavailability
BCRP
breast cancer resistance protein
BID
twice daily
BLQ
below the limit of quantification
BMI
body mass index
C24
plasma S-033447 concentration 24 hours post-dose
CDC
Centers for Disease Control and Prevention
CEN
cap-dependent endonuclease
CI
confidence interval
Cmax
maximum plasma concentration
CRO
contract research organization
CTCAE
Common Terminology Criteria for Adverse Events
CV%
coefficient of variation
CYP
cytochrome P450
DDI
drug-drug interaction
ECG
electrocardiography
eCRF
electronic case report form
EDC
electronic data capture
eDiary
electronic diary
ePRO
electronic patient-reported outcome
EQ-5D-5L
EuroQol–5 Dimensions–5 Levels
FE
food effect
Feu0-72
fraction of dose excreted in urine from time zero to 72 hours post-
dose


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GCP
Good Clinical Practice
GMP
Good Manufacturing Practice
HBs
hepatitis B virus surface
h-CE
hepatic carboxylesterase
HCV
hepatitis C virus
hERG
human ether à go-go related gene
HIV
human immunodeficiency virus
IC50
half maximal inhibitory concentration
IB
investigator's brochure
IEC
institutional ethics committee
IRB
institutional review board
IRT
interactive response technology
ITTI
intention to treat infected
IUD
intrauterine contraceptive device
LFT
liver function test
MATE
multidrug and toxin extrusion protein
Mean
arithmetic mean
MedDRA
Medical Dictionary for Regulatory Activities
NA
neuraminidase
NOAEL
no observed adverse effect level
NPAE
neuropsychiatric adverse event
OATP
organic anion transporting polypeptide
PA
polymerase acidic protein
PD
pharmacodynamic(s)
P-gp
P-glycoprotein
PK
pharmacokinetic(s)
PPS
Per-protocol set
PT
preferred term
QOL
quality of life
QTcF
QT interval corrected for heart rate by Fridericia's correction
RIDT
rapid influenza diagnostic test
RT-PCR
reverse transcription polymerase chain reaction
SAD
single ascending dose
SAE
serious adverse event
SAP
statistical analysis plan
SD
standard deviation
SmPC
Summary of Product Characteristics
SOC
system organ class


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SUSAR
suspected unexpected serious adverse reaction
t1/2,z
terminal elimination half-life
TEAE
treatment-emergent adverse event
Tmax
time to maximum plasma concentration
UGT
UDP glucuronosyl transferase
ULN
upper limit of normal
VAS
visual analogue scale
WBC
white blood cell
WHO
World Health Organization
WOCBP
women of childbearing potential
WP
work productivity
ΔΔQTcF
placebo-subtracted changes from baseline in the QTcF interval
λz
terminal elimination rate constant


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1.
INTRODUCTION
Influenza 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, and it is especially remarkable in fever reaching 
38ºC to 40ºC within 24 hours of the onset [1, 2]. Other symptoms include cough, sore 
throat, and nasal congestion; cough is very frequent and tends to be persistent. Although 
illness with influenza generally is self-limiting, severe disease with fatal outcome can 
occur in both the otherwise healthy and in those with underlying comorbidities. Fatal 
disease is also more often observed in children and in the elderly, although some 
influenza viruses with novel structures can lead to fatal disease at any age. Influenza is 
also considered to make some chronic health conditions worse, such as asthma and 
congestive heart failure.  The Centers for Disease Control and Prevention (CDC)
classifies people at high risk of developing flu related complications [3]. These 
characteristics make influenza a “potentially severe disease”, which should be 
distinguished from the “common cold syndrome”.
The following anti-influenza virus drugs are currently available (with geographic 
variability): the M2 ion channel inhibitor amantadine; the RNA polymerase inhibitor 
favipiravir; and the neuraminidase (NA) inhibitors oseltamivir, zanamivir, peramivir, and 
laninamivir. Since many cases of seasonal influenza A infection are resistant to 
amantadine, the CDC has recommended against the use of amantadine for the treatment 
and prophylaxis of influenza virus infection [4], and its use is limited in Japan.
Favipiravir is only indicated for the treatment of novel or reemerging influenza virus 
infections with no or poor response to other anti-influenza drugs in Japan and cannot be 
manufactured or marketed unless requested by the Minister of Health, Labour, and 
Welfare. Thus, NA inhibitors are the mainstay of treatment for influenza infections, but 
their oral formulations need to be administered for 5 days, potentially resulting in poor 
patient compliance, and are associated with nausea, vomiting, headaches, and renal and 
psychiatric events. Inhalation formulations can only be used in patients who are able to 
inhale the drug and have been associated with bronchospasm in susceptible individuals.
There is, therefore, an unmet medical need for anti-influenza virus drugs that are well
tolerated and can be easily administered.
In addition, influenza viruses are known to mutate during replication, leading to drug 
resistance, and can evolve by reassortment into a strain to which most people are not 
immune, resulting in a pandemic, or into a strain resistant to existing anti-influenza virus 
drugs, which may be most prevalent in a seasonal epidemic. To protect against these 
situations, the development of an anti-influenza virus drug with a novel mechanism of 
action is needed.
S-033188 is a compound discovered by Shionogi & Co., Ltd. that exerts anti-influenza 
virus activity. S-033188 is a prodrug, which is converted to an active form (S-033447) 
through a metabolic process (hydrolysis). S-033447 acts on cap-dependent endonuclease 
(CEN), an enzyme specific to influenza viruses, and inhibits viral cap-snatching, thereby 
suppressing the growth of influenza viruses. The results from the completed nonclinical 


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and Phase 1 clinical studies are summarized below.
1.1 
Nonclinical Studies 
1.1.1
Pharmacology
1.1.2
Safety
  
,


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1.1.3
Pharmacokinetics


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1.2
Clinical Summary
1.2.1
Single-ascending Dose Study (Study 1510T0811)


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1.2.2 
Relative Bioavailability and Food Effect Study (Study 1512T0813)
  
1.2.3 
Drug-drug Interaction Study with Midazolam (Study 1519T0814)


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1.2.4 
Drug-drug Interaction Study with Itraconazole (Study 1520T0815)
1.2.5 
Thorough QT/QTc Study (Study 1527T0816)


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1.2.6 
A Phase 2 Proof of Concept and Dose Finding Study 
(Study 1518T0821)


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1.3 
Comparator Data 
1.3.1
Clinical Data of Oseltamivir
Oseltamivir Efficacy
1.3.1.1
Oseltamivir (Tamiflu®) is a NA inhibitor indicated for the treatment of uncomplicated acute 
illness due to influenza infection in patients who have been symptomatic for no more than 
2 days (please refer to local prescribing information for regional variations in indications).  
Oseltamivir phosphate is the prodrug of oseltamivir carboxylate, the effective form. 
Oseltamivir phosphate dissociates in the gastrointestinal tract to form oseltamivir, which 
is absorbed and metabolized into oseltamivir carboxylate by hepatic carboxylesterase 


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(h-CE). 
Several large Phase 3 clinical studies have demonstrated that oseltamivir reduced time to 
alleviation of symptoms in otherwise healthy individuals with influenza presenting within 
48 hours of symptom onset [5, 6]. Oseltamivir has also been shown to reduce the 
incidence of symptomatic influenza in contacts of individuals with influenza in 
prophylaxis trials [5]. The efficacy of oseltamivir to reduce complications of influenza is 
less clear with conflicting results across several studies [5, 6, 7, 8]. Oseltamivir has not 
been formally tested beyond 48 hours of symptom onset.
Oseltamivir Safety
1.3.1.2
Neuropsychiatric adverse events (NPAEs) have been reported during administration of 
oseltamivir in patients with influenza, especially in children and adolescents. Close 
monitoring is advised for behavioral changes, and the benefits and risks of continuing 
treatment should be carefully evaluated for each patient. These events may occur in the 
setting of encephalitis or encephalopathy but can occur without obvious severe disease 
and have been associated with fatal outcomes. A causal relationship between oseltamivir 
and these events has never been shown. Similar types and rates of NPAEs have been 
shown to occur in patients with influenza who did not receive oseltamivir.
In adults/adolescents, the most commonly reported adverse reactions (ARs) were nausea 
and vomiting in the treatment studies, and nausea in the prevention studies. The majority 
of these ARs were reported on a single occasion on either the first or second treatment 
day and resolved spontaneously within 1 to 2 days. In children, the most commonly AR 
was vomiting. In the majority of patients, these ARs did not lead to discontinuation of 
oseltamivir.
The following serious ARs have been rarely reported since oseltamivir has been 
marketed: anaphylactic and anaphylactoid reactions, hepatic disorders (fulminant 
hepatitis, hepatic function disorder, and jaundice), angioneurotic edema, Stevens-Johnson 
syndrome and toxic epidermal necrolysis, gastrointestinal bleeding, and neuropsychiatric 
disorders.
Very common ARs listed in the prescribing information and Summary of Product 
Characteristics (SmPC) include headache and nausea. Common ARs include vomiting, 
abdominal pain, dyspepsia, insomnia, pain, dizziness, fatigue, pyrexia, bronchitis, cough, 
sore throat, rhinorrhea, herpes simplex, nasopharyngitis, upper respiratory tract infections, 
and sinusitis. Uncommon ARs include hypersensitivity reactions, altered level of 
consciousness, cardiac arrhythmia, elevated liver enzymes, eczema, dermatitis, rash, and 
urticaria. Rare ARs include visual disturbance, thrombocytopenia, 
anaphylactic/anaphylactoid reactions, agitation, abnormal behavior, anxiety, confusion, 
delusions, delirium, hallucinations, nightmares, and self-injury.
Clinical Studies
1.3.1.3
1.3.1.3.1
Treatment of Influenza Infection in Adults and Adolescents
A total of 1355 patients were included in two Phase 3 multicenter, placebo-controlled 


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trials in naturally acquired influenza conducted in the United States, Europe, etc. (Studies 
WV15670 & WV15671). Time to alleviation of symptoms, the primary efficacy 
endpoint, was significantly reduced by up to 30 hours in the patients received 75 mg of 
oseltamivir twice daily compared with placebo. Significant improvements in the 
secondary efficacy endpoints, such as the median total symptom score AUC and the time 
to return to an afebrile state, were also observed [5, 9].
The Phase 3 study conducted in Japan (Study JV15824) included 316 patients with 
influenza.  As with the Phase 3 studies noted above, significant improvements in the time 
to alleviation of symptoms, the median total symptom score AUC and the time to return 
to an afebrile state were observed in Japanese patients [10].
Oseltamivir Dosing
1.3.1.4
The recommended oral dose of oseltamivir for adolescents/adults ≥13 years of age is 
75 mg BID for 5 days in the United States. For adolescents 12 years of age, the 
recommended oral dose is 75 mg BID for 5 days if the individual weighs > 40 kg.
In Japan, the recommended oral dose for treatment of influenza in adolescent patients 
weighing ≥37.5 kg and adult patients is 75 mg BID for 5 days.
Oseltamivir Dosing and Renal Impairment
1.3.1.5
Oseltamivir 75 mg BID is recommended for individuals with a creatinine clearance of 
> 60 mL/min (≥ 30 mL/min in Japan), and dose adjustment is required for lower 
creatinine clearance. If patients are enrolled in the study and found to have a creatinine 
clearance ≤60 mL/min (≤30 mL/min in Japan), investigators should contact the study 
Medical Monitor to discuss patient management regarding continuation of 
oseltamivir/oseltamivir placebo. Creatinine clearance should be calculated as soon as the 
Screening creatinine result is available by using the following online calculator: 
http://www.mdcalc.com/creatinine-clearance-cockcroft-gault-equation.
1.4
Rationale for the Study
This randomized, double-blind, placebo- and active-controlled study will be conducted to 
investigate the superiority of S-033188 over placebo in efficacy in otherwise healthy 
patients with influenza virus infection receiving 40 or 80 mg of S-033188. The dose to 
be tested in this confirmatory study was selected based on the results of the Phase 2 dose-
finding study, in which the statistically significant efficacy outcome and no notable safety 
concerns were observed in patients who received single 40 mg doses of S-033188 orally.
This study will be conducted with an appropriate study design to confirm the superiority 
of S-033188 to placebo in otherwise healthy patients with influenza virus infection in 
sufficient consideration of the safety of study participants.
Since oseltamivir is to be avoided in adolescents except high risk patients in 
consideration of reports associated with anomalous behavior (per the Japanese label), 
subjects who are 12 to 19 years of age (approximately 15% of overall study population) 
will be randomized to either S-033188, 40 or 80 mg, or placebo only in this study. Thus, 
the superiority of S-033188 to oseltamivir in time to alleviation of symptom will be 


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confirmed only in the patients ≥20 years of age under control of overall Type I error
(except for Japan).  


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2.
STUDY OBJECTIVES
2.1
Primary Efficacy Objective
The primary objective of this study is:
x
The primary efficacy objective of this study is to evaluate the efficacy of a single,
oral dose of S-033188 compared with placebo by measuring the time to 
alleviation of symptoms in patients with uncomplicated influenza virus infection.
2.2
Secondary Efficacy Objectives
The secondary efficacy objectives of this study are:
x
To evaluate the efficacy of a single, oral dose of S-033188 compared with 
oseltamivir 75 mg BID for 5 days by measuring the time to alleviation of 
symptoms in patients aged 20 to 64 years with uncomplicated influenza virus 
infection
x
To evaluate the efficacy of a single, oral dose of S-033188 compared with 
placebo by measuring the secondary endpoints in patients with uncomplicated 
influenza virus infection
x
To evaluate the efficacy of a single, oral dose of S-033188 compared with 
oseltamivir 75 mg BID for 5 days by measuring the secondary endpoints in 
patients with uncomplicated influenza virus infection
2.3
Other Efficacy Objective
The other efficacy objective of this study is:
x
To evaluate the polymorphic and treatment-emergent amino acid substitutions in 
the polymerase acidic protein (PA) gene and drug susceptibility in patients with 
evaluable virus 
2.4
Safety Objectives
Safety objectives of this study are:
x
To compare the safety and tolerability of a single dose of S-033188 with placebo
x
To compare the safety and tolerability of a single dose of S-033188 with 
oseltamivir 75 mg BID for 5 days
x
To compare the frequency of AEs in patients with influenza of a single dose of 
S-033188 with oseltamivir 75 mg BID for 5 days and with placebo
2.5
Pharmacokinetic Objective
The PK objective of this study is:
x
To determine the PK of the active form of S-033188, ie, S-033447, in patients 
with uncomplicated influenza virus infection


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2.6
Health Economic Outcomes Research Objective
x
To compare the total quality-of-life change by measuring the 
EuroQol-5 Dimensions–5 Levels (EQ-5D-5L) and a work productivity (WP) 
questionnaire, in patients treated with of S-033188 compared with oseltamivir 
75 mg BID for 5 days and placebo


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3.
INVESTIGATIONAL PLAN
3.1
Overall Study Design and Plan
This study is a randomized, double-blind, multicenter, parallel-group, placebo- and 
active-controlled study designed to evaluate the efficacy and safety of single dose of 
S-033188 in otherwise healthy adult and adolescent patients with influenza virus 
infection.
Prior to the initiation of the study treatment on Day 1, patients will be assessed for 
eligibility for participation in the study.  Patients aged 20 to 64 years who are determined 
to be eligible will be randomly assigned in a ratio of 2:2:1 to receive a single dose of 
S-033188 (either 40 mg or 80 mg according to weight), 75 mg BID of oseltamivir for 
5 days, or placebo.  Patients aged 12 to 19 years who are determined to be eligible will be 
randomly assigned in a ratio of 2:1 to receive a single dose of either 40 or 80 mg of 
S-033188 or placebo. Patients who weigh < 80 kg at Screening will receive 40 mg of 
S-033188, and patients who weigh ≥80 kg at Screening will receive 80 mg of S-033188.
The study drug will be administered orally at the study center on Day 1 (initial dose).
Patients aged 20 to 64 years will receive study drug twice daily for 5 days in total.  For 
patients aged 12 to 19 years, a single dose of study drug will be tested. There is a
maximum of 9 visits including 2 optional visits during a period to assess the efficacy and 
safety: 14 days for efficacy and 22 days for safety. The study schematic is shown in 
Figure 3-1.  The time and events schedule is provided in Appendix 1.
Figure 3-1
Study Schematic
S-033188 group
Patients
aged 20 to 64 years
Oseltamivir group
Placebo group
ј ј
ј ј
ј ј
ј ј
ј ј
S-033188 group
Patients
aged 12 to 19 years
Placebo group
ј 
D1
V1
D2
V2
D3
V3
D4
OpV1
D5
V4
D6
OpV2
D9
V5
D15
V6
D22
V7
Informed consent
I/E criteria
Randomize
End-of-study visit
D = day; I/E = inclusion/exclusion; OpV1 = optional Visit 1; OpV2 = optional Visit 2; V = visit
Up arrows demonstrate the administrations of study drug.
Treatment 
period
Follow-up
period


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This study will be conducted in compliance with this protocol, International Conference 
on Harmonisation-Good Clinical Practices (ICH-GCPs), and all applicable requirements.  
3.2 
Rationale for Study Design and Control Group 
3.2.1
Rationale for Study Design
A multicenter, randomized, double-blind design will be used to evaluate the efficacy of a 
single, oral dose of S-033188 compared with oseltamivir 75 mg BID for 5 days and 
placebo in patients with influenza virus infection.  
3.2.2
Selection of the Dose of S-033188
   


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Figure 3-2 
3.2.3
Selection of the Dose of Oseltamivir
The dose of oseltamivir to be used in this study was set in accordance with the approved 
dosage and administration of oseltamivir (Tamiflu®) capsules for oral use.
3.3 
Study Duration 
3.3.1
Study Duration in Individual Patients 
Study duration in individual patients is 22 days. 
3.3.2
Planned Study Duration for the Study
The planned study duration is from 
3.3.3
End of Study
The End of the Study is defined as the last patient’s last visit.. 


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4.
STUDY POPULATION SELECTION
4.1
Study Population
Patients will be male and female adolescents and adults (age 12 to 64 years) with 
influenza A and/or B virus infection, with typical systemic and respiratory symptoms of 
influenza, whose new symptoms were first noticed ≤48 hours prior to the predose 
examinations.
Approximately 1494 patients will be enrolled. Patients with confirmed influenza with 
symptom onset ≤48 hours who satisfy the following eligibility criteria will be 
randomized. 
4.2
Inclusion Criteria
Patients who fulfill all of the following criteria will be included in the study:
1.
Patients who are able to understand the study and comply with all study procedures, 
and willing to provide written informed consent/assent prior to the predose 
examinations appropriately.  As for adolescent patients, informed consent/assent of 
voluntary participation should be obtained in accordance with local requirements
(see Section 7.1).
2.
Male or female patients aged ≥12 to ≤64 years at the time of signing the informed 
consent/assent form.
3.
Patients with a diagnosis of influenza virus infection confirmed by all of the 
following:
a.
Fever ≥38ºC (axillary) in the predose examinations or > 4 hours after dosing of
antipyretics if they were taken
b.
At least one of the following general systemic symptoms associated with 
influenza are present with a severity of moderate or greater

Headache

Feverishness or chills

Muscle or joint pain

Fatigue
c.
At least one of the following respiratory symptoms associated with influenza are
present with a severity of moderate or greater

Cough

Sore throat

Nasal congestion
4.
The time interval between the onset of symptoms and the predose examinations
(Screening) is 48 hours or less.  The onset of symptoms is defined as either:
a.
Time of the first increase in body temperature (an increase of at least 1ºC from 
normal body temperature)
b.
Time when the patient experiences at least one general or respiratory symptom
5.
Women of childbearing potential (WOCBP) who agree to use a highly effective 
method of contraception for 3 months after the first dose of study drug (see Section 


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6.3.1 for approved contraceptive requirements).
4.3
Exclusion Criteria
Patients who meet any of the following criteria will be excluded from the study:
1.
Patients with severe influenza virus infection requiring inpatient treatment.
2.
Patients aged ≥20 years with known allergy to oseltamivir (Tamiflu®).
3.
Patients with any of the following risk factors*:
a.
Women who are pregnant or within 2 weeks post-partum
b.
Residents of long-term care facilities (eg, welfare facilities for the elderly, 
nursing homes)
c.
Chronic respiratory diseases including bronchial asthma
d.
Neurological and neurodevelopmental disorders including disorders of the brain, 
spinal cord, peripheral nerve, and muscle (eg, cerebral palsy, epilepsy [seizure 
disorders], stroke, intellectual disability, moderate to severe developmental delay, 
muscular dystrophy, or spinal cord injury)
e.
Heart disease (such as congenital heart disease, congestive heart failure, or 
coronary artery disease), excluding hypertension without any other heart-related 
symptoms)
f.
American Indians and Alaskan natives
g.
Blood disorders (such as sickle cell disease)
h.
Endocrine disorders (including diabetes mellitus)
i.
Kidney disorders
j.
Liver disorders
k.
Metabolic disorders
l.
Compromised immune system (including patients receiving immunosuppressant 
therapy, or those with cancer or human immunodeficiency virus [HIV] infection)
m.
Morbid obesity (body mass index [BMI] ≥40)
* Based on the definitions of people at high risk by the Centers for Disease Control and 
Prevention (CDC). http://www.cdc.gov/flu/about/disease/high_risk.htm
4.
Patients unable to swallow tablets or capsules.
5.
Patients who have previously received S-033188.
6.
Patients weighing < 40 kg
7.
Patients who have been exposed to an investigational drug within 30 days prior to the 
predose examinations.
8.
Women who are breastfeeding or have a positive pregnancy test in the predose 
examinations.  The following female patients who have documentation of either a or 
b below do not need to undergo a pregnancy test in the predose examinations:
a.
Postmenopausal (defined as cessation of regular menstrual periods for 2 years or
more and confirmed by a follicle-stimulating hormone test) women
b.
Women who are surgically sterile by hysterectomy, bilateral oophorectomy, or 
tubal ligation
9.
Patients with concurrent infections requiring systemic antimicrobial and/or antiviral
therapy at the predose examinations.


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10. Patients who have received peramivir, laninamivir, oseltamivir, zanamivir, 
rimantadine, umifenovir or amantadine within 30 days prior to the predose 
examinations.
11. Patients who have received an investigational monoclonal antibody for a viral 
disease in the last year.
12. Patients with severe underlying diseases.
13. Patients with current creatinine clearance ≤60 mL/min (≤30 mL/min in Japan).
14. Patients who, in the opinion of the investigator, would be unlikely to comply with 
required study visits, self-assessments, and interventions.
4.4
Screen Failures
Screen failures are defined as patients who consented to participate in the study but were 
not subsequently randomized/administered the study drug. Minimal information will 
include informed consent date, baseline patient characteristics, all of eligibility criteria 
violated, reasons for screen failure, nasopharyngeal/pharyngeal swab influenza RT-PCR 
result, AEs that led to screen failure, and any SAEs and will be entered in the electronic 
case report form (eCRF). Rescreening will be permitted, but patients who do not meet 
the clinical criteria for participation in the study within 48 hours (screen failure) may not
be rescreened.


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5.
STUDY TREATMENTS
5.1
Description of Treatments
5.1.1
Test Drug
x
S-033188 20-mg tablets: White to light yellow, oblong shaped film-coated tablets 
containing 20 mg of S-033188, manufactured by Shionogi & Co., Ltd.
5.1.2
Placebo
x
S-033188 placebo tablets: white to light yellow, oblong-shaped, film-coated placebo 
tablets matching the S-033188 20-mg tablets but without active drug substance
x
Oseltamivir placebo capsules: matching placebo for oseltamivir 75-mg capsules
5.1.3
Active Control
x
Oseltamivir 75-mg capsules: Oseltamivir phosphate (Tamiflu® Roche) capsules.
5.2
Treatments to be Administered
5.2.1
Patients Aged 20 to 64 Years
Patients who are qualified for entry will be randomly assigned in a ratio of 2:2:1 to 
receive S-033188, oseltamivir, or placebo according to the assignment procedures 
specified in Section 5.4. Patients will receive S-033188 or placebo once on Day 1.
Oseltamivir or placebo should be dosed 12 hours apart from Day 1 through Day 5. The 
details of administration are shown in Table 5-1. Study drugs can be taken without 
regard to food (although food may improve tolerability of oseltamivir).
Patients should be instructed that in the case of missed doses of oseltamivir/placebo they 
should take the missed dose as soon as they remember, unless it is 2 hours or less before 
the next dose. They should then continue to take oseltamivir/placebo at the usual times. 
Patients should not take 2 doses at a time to make up for a missed dose.


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Table 5-1
Study Drug Administration (Patients Aged ≥20 Years)
Treatment Group
Day 1
Day 2
Day 3
Day 4
Day 5*
S-033188
Oseltamivir placebo
2 capsules
2 capsules
2 capsules
2 capsules
2 capsules
S-033188 40 mg
(weight < 80 kg)
2 tablets
S-033188 80 mg
(weight ≥ 80 kg)
4 tablets
Oseltamivir
Oseltamivir 75 mg 
2 capsules
2 capsules
2 capsules
2 capsules
2 capsules
S-033188 placebo
(weight < 80 kg)
2 tablets
S-033188 placebo
(weight ≥ 80 kg)
4 tablets
Placebo
Oseltamivir placebo
2 capsules
2 capsules
2 capsules
2 capsules
2 capsules
S-033188 placebo
(weight < 80 kg)
2 tablets
S-033188 placebo
(weight ≥ 80 kg)
4 tablets
*
If only 1 dose of oseltamivir or placebo is taken on Day 1 due to the patient being randomized after 
17:00, dosing will be completed on Day 6. 
5.2.2
Patients Aged 12 to 19 Years
Patients who are qualified for entry will be randomly assigned in a ratio of 2:1 to receive 
S-033188 or placebo according to the assignment procedures specified in Section 5.4.
Patients will receive two or four S-033188 20-mg tablets or two or four matching placebo
tablets (depending on weight at Screening) on Day 1. Study drugs can be taken without
regard to food.
5.3
Selection and Timing of Dose for Each Patient
The patient will be randomly assigned to one of the treatment groups, and the dosage 
assigned will be maintained until the end of the study. The initial single oral dose of 
study medication (S-033188, oseltamivir or placebo) will be taken by patients at the study 
site. Patients who weigh less than 80 kg at Screening will receive 40 mg of S-033188,
and patients who weigh ≥80 kg at Screening will receive 80 mg of S-033188.
5.4
Method of Assigning Patients to Treatment Groups
This study will be primarily conducted in Japan, but other Asian countries and the US are 
also expected to participate. Because of the recommendation in Japan not to use 
oseltamivir in patients aged < 20 years due to previously reported neuropsychiatric AEs
and suicidality in Japan, assignment of patients to treatment groups will be proceeded in 
each of two age strata, ie, 12 to 19 years age stratum and 20 to 64 years age stratum, 
separately. Approximately 15% of the whole population to be enrolled in this study will 


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be patients in 12 to 19 years age stratum.  
Patients in 20 to 64 years age stratum will be randomized on a 2:2:1 basis to S-033188
group, oseltamivir group, or placebo group. Patients in 12 to 19 years age stratum will be 
randomized on a 2:1 basis to either S-033188 group or placebo group. An interactive 
response technology (IRT) will be used to assign patients to numbers for which treatment 
has already been randomly assigned. The randomization will also be stratified by region 
(Japan/Asia, Rest of the world), patients weight (< 80 kg, ≥80 kg) and baseline 
composite symptom score (≤11, ≥12).
5.5
Blinding
The study will be conducted in a double-blind, double-dummy fashion by using placebo 
matching S-033188 and oseltamivir in appearance, labeling, and packaging. An IRT will 
be used for central patient randomization and study drug assignment. IRT will assign 
drug identifiers according to a randomization schedule. Only unblinded staff members of 
contract research organization (CRO) or designee will have the authority to assign the 
drug identifiers. All patients, investigators, study personnel and data analysts will be 
blinded to the treatment assigned at randomization until database lock. The 
randomization schedule will be kept confidential and will not be accessible to anyone 
until unblinding, except for Drug Supply Management staff, IRT clinical coordinators, 
IRT vendor staff, the unblinded statistician and Drug Safety personnel for reporting 
suspected unexpected serious adverse reactions (SUSARs) as required by local 
regulations.
Unblinding by request of an investigator should occur only in the event of an emergency, 
pregnancy of the patient or the patient’s partner, or AEs for which it is necessary to know 
the study treatment to determine an appropriate course of therapy for the patient. Should 
the investigator decide that the treatment assignment of an individual patient needs to be 
disclosed, the investigator or qualified designee is to call the IRT.
Prior to unblinding, and if the situation allows it, the investigator should try to contact the 
sponsor or CRO designee within 24 hours. If this is impractical, the investigator must 
notify the sponsor as soon as possible, without revealing the treatment assignment of the 
unblinded patient. The investigator must document the patient identification, the date and 
time for breaking the blind and must clearly explain the reasons for breaking the code. 
This information must be documented and submitted to the sponsor in a form specified 
by the sponsor. Procedures for emergency unblinding will be detailed in a separate 
document.
Plasma drug concentrations may reveal the treatment assignment and will therefore be 
reported to the sponsor after the database is locked.


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5.6
Packaging and Labeling
The study drugs will be supplied in wallet card(s) containing 2 S-033188 active 20-mg 
tablets or its matching placebo with/without the 10 oseltamivir capsules or their matching 
placebo, or only placebo. The wallet card will be labelled with an identification number, 
protocol number, contents, direction for use, storage condition at a minimum, as well as 
other pertinent information according to local regulations. The expiry or use-by date will 
be stored in the IRT or on the label according to local regulations. Study drug should not 
be used after the expiry or use-by date. All packaged and labelled supplies will be 
formally released in accordance with both Good Manufacturing Practice (GMP) and 
Good Clinical Practice (GCP) guidelines.
5.7
Storage and Accountability
The study drug will be stored at room temperature (15°C to 25°C [59°F to 77°F]). The 
temperature of the drug storage area will be recorded every working day.
The sponsor will supply the study drug to the person responsible for study drug handling, 
who is a designee of the head of the study center, under the study contract between the 
sponsor and the study center.  The person responsible for study drug handling will handle 
the study drug according to procedures for method of storage and drug accountability 
record as specified in a separate document.
The investigator or person responsible for study drug handling will ensure that all study 
drugs are stored and dispensed in accordance with local regulations concerning the 
storage and administration of investigational drugs. All drug supplies must be kept in a 
secure locked area with access limited to those authorized by the investigator.
The investigator or pharmacist will maintain accurate records on the information: receipt 
and condition of all study drugs, date of the receipt, when and how much study drug is 
dispensed and used by each patient in the study, and any reasons for departure from the 
protocol-dispensing regimen. The drug accountability records will be available for 
verification by sponsor’s monitor (or designee) at each monitoring visit. At the 
completion of the study, a final reconciliation of all study drugs will be performed. Study 
drug must not be used for any purpose other than the present study. Further details on 
drug procedures and accountability are described in a separate written procedure.
5.8
Investigational Product Retention at Medical Institution
At the end of the study, all unused study drug and used wallet cards will be returned.  The 
site monitor or designee responsible for study drug handling will record accurate amounts 
of used and unused drug supplies. Final reconciliation must be completed by the monitor 
prior to returning.  All used and unused drug supplies in appropriate boxes will be 
returned as per Shionogi’s written instructions with a copy of the overall drug 
accountability record and appropriate return form as described in a separate written 
procedure.


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5.9
Treatment Compliance
The investigator or subinvestigator will administer the first dose of the study drugs and 
perform a mouth check of patients immediately after the drug is taken. The time of 
ingestion (co-administration of S-033188, oseltamivir, and placebo) will be recorded in 
the source documents and the eCRF. Patients must bring their wallet cards and any 
unused drug at all visits up to Visit 5 (Day 9), unless dosing was completed at Visit 4
(Day 5), whether or not the wallet card is empty. The investigator or subinvestigator will 
perform compliance checks of wallet cards to verify that the correct number of doses 
have been taken according to the actual time interval that has elapsed between clinic 
visits. A record of the supplies dispensed and returned will be documented. On the basis 
of compliance checks, if < 100% of the required study drug has been taken by a patient,
the patient will be counseled by the site about the importance of taking study drug as 
directed.


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6.
RESTRICTIONS
6.1
Prior Therapy
Prior therapies are defined as therapies which were taken prior to the initiation of study 
treatment. All prior therapy (prescription drugs, over-the-counter drugs, procedures 
without any medication) taken by a patient within 14 days prior to the initiation of study 
treatment will be recorded in the eCRF and the information will include a name of used 
drug or used procedures, duration of treatment, and reason for use.
6.2
Concomitant Therapy during the Study
Concomitant therapies are defined as therapies taken at or after the initiation of study 
treatment. The investigator or subinvestigator will record the following information for 
all therapies (prescription drugs, over-the-counter drugs, procedures without any 
medication) used during the study (from Visit 1 [Day 1] to Visit 7 [Day 22] or early 
termination) in the eCRF.
●
Name of used drug or used procedures
●
Route of administration
●
Duration of treatment 
●
Reason for use
6.2.1
Prohibited Concomitant Therapy
The use of the following drugs and over-the-counter drugs with equivalent efficacy to 
them will be prohibited from Visit 1 (Day 1) until Visit 7 (Day 22) or early termination.
●
Systemic antiviral drugs
●
Antimicrobial* and antifungal drugs**
●
Antipyretics/analgesics except acetaminophen
●
Antitussives/expectorants
●
Combination cold remedies
●
Antihistamines**
●
Corticosteroids**
●
Immunosuppressants
Herbal medicines or complementary therapies indicated for influenza virus infection 
(eg, Maoutou)
●
Other investigational drugs
* Except for the treatment of complications of influenza suspected to be bacterial infection
after Day 1.
** Dermal preparations will be permitted, but application to the eyes, nose or ears, or by 
inhalation will be prohibited.
6.2.2
Rescue Therapy (Noninvestigational Medicinal Product)
If influenza symptoms, such as fever, headache and muscle pain, are so severe that the 
patient needs rescue therapy between Visits 1 (Day 1) and 7 (Day 22), the use of 
acetaminophen at a dose of 3000 mg/day or less will be permitted only for the relief of 
fever or pain.  The site can supply the acetaminophen tablets or the investigator can 


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prescribe the tablets then reimburse the patient; in either case, the country’s commercial 
pack will be used, and the sponsor or designee will indirectly supply the tablets by 
reimbursing the site. If acetaminophen is used, the patient will record the date and time
of each administration in the patient eDiary. The measurement of body temperature and 
assessment of influenza symptoms by the patient will occur immediately before the use 
of acetaminophen or more than 4 hours after acetaminophen administration.
6.3
Other Restrictions
6.3.1
Contraception
WOCBP should use one of the following highly effective methods of contraception as 
instructed by the investigator or subinvestigator for 3 months after the initiation of the 
study treatment (Visit 1, Day 1).
Highly effective methods of contraception are:
●
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
–
Implantable
●
Intrauterine contraceptive device (IUD)
●
Intrauterine hormone-releasing system (IUS, ie, Mirena®)
●
Bilateral tubal occlusion
●
Vasectomized partner
●
Sexual abstinence (considered a highly effective method only if defined as 
refraining from heterosexual intercourse during the entire period of risk associated 
with the study treatments. The reliability of sexual abstinence will need to be 
evaluated in relation to the duration of the clinical trial and the preferred and usual 
lifestyle of the patient.)


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7.
STUDY PROCEDURES AND METHODS OF ASSESSMENTS
The time and events schedule are referred to Appendix 1.
7.1
Informed Consent/Assent
For adult patients, the investigator or subinvestigator will fully explain the nature of the 
study to a patient using the institutional review board (IRB)/institutional ethics committee 
(IEC)-approved informed consent document. When the patient agrees to participate in 
the study, the patient must voluntarily sign a consent form prior to the initiation of any 
study procedures. A copy of the signed and dated informed consent document will be 
given to the patient. The signed and dated original consent form will be retained by the 
investigator. Informed consent will be obtained from all patients. A patient cannot be 
entered the study until he/she has signed and dated on the consent form.
For adolescent patients, the investigator or subinvestigator will fully explain the nature of 
the study to a patient and parent(s)/legally acceptable representative as required by age or 
local regulations of each patient by using the IRB/IEC-approved informed consent/assent 
document. Informed consent will be obtained from parent(s) or legally acceptable 
representative of each patient. The parent or the legally acceptable representative must 
sign a consent form prior to the initiation of any study procedures. Patients will be 
informed about the nature and duration of the study with written age-appropriate 
information, in language and terms they can understand and must sign an assent form. A
copy of the signed and dated informed consent/assent document will be given to the 
patient and parent(s)/legally acceptable representative. The signed and dated original 
consent/assent form will be retained by the investigator. A patient cannot be entered the 
study until his/her parent(s)/legally acceptable representative has signed and dated the 
consent form. The informed consent/assent should be obtained in accordance with local 
requirements.
The investigator or subinvestigator is responsible for ensuring that the patient 
understands the risks and benefits of participating in the study, including answering any 
questions the patient may have throughout the study and sharing any new information in 
a timely manner that may be relevant to the patient’s willingness to continue his/her 
participation in the study.
7.2
Baseline Patient Characteristic and Medical History
7.2.1
Baseline Patient Characteristic and Medical History
The following baseline patient characteristics will be obtained at Visit 1 (Day 1) if 
allowed per the country’s requirement and entered in the eCRF:
Date of written informed consent by the patient/guardian
Date of birth
Sex
Ethnicity
Race
Current smoking status


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Prior therapy
Presence or absence of influenza vaccination within the last 6 months
Duration of influenza symptoms
Medical history
Medical history will include any previous or concurrent significant medical condition 
such as hospitalization, all concurrent medical conditions, and surgical history within 
12 months.
7.2.2
Rapid Influenza Diagnostic Test (RIDT)
Once a patient has been determined to be eligible based on body temperature and clinical 
symptoms, the investigator or subinvestigator will collect nasopharyngeal (a 
nasopharyngeal swab is preferred, but a pharyngeal swab will be acceptable if a 
nasopharyngeal swab cannot be performed) swabs for influenza A and/or B virus using a 
supplied commercial RIDT kit at the same time as performing the central lab PCR 
nasopharyngeal/pharyngeal swabs. The RIDT results will be recorded in the eCRF. The 
collection of specimens, operation of the kit, and interpretation of test results will be 
performed according to the instructions for use or package insert of the RIDT kit. The 
RIDT will be provided by the sponsor, and this will be the preferred test; however, if a 
site has performed a RIDT prior to consideration for the study, the local RIDT result will 
be entered into the eCRF. The patient will be informed of the RIDT result, and if the 
result is negative, the investigator will explain the low and unpredictable sensitivity of the 
RIDT and will confirm with the patient that they wish to continue in the study. This 
decision will be documented in the ICF addendum, and this will serve as source 
documentation.
7.2.3
Meals
To collect information on meals before and after the initial study treatment
(coadministration of S-033188/placebo and oseltamivir/placebo), whether the patient
takes meals on Day 1 and the time of meal ingestion will be recorded in the eCRF.
7.3
Enrollment in the Study and Dispensing Study Drug
After a patient is determined to be eligible according to the inclusion/exclusion criteria, 
the investigator or subinvestigator will contact the IRT for an identification number or 
send the registration sheet with the required information filled in to the registration center.
If the registration is accepted, the patient will be entered in the study. After the patient is 
entered in the study, the investigator, subinvestigator, or site pharmacist will dispense the 
study drug as specified in Section 5.
7.4
Efficacy Assessments
7.4.1
Patient Electronic Diary
The patient will self-measure/assess the following outcome measures and record the 
results in the patient electronic diary (eDiary).  The patient eDiary will consist of 
electronic data entered by the patient into the electronic patient-reported outcome (ePRO) 
system via a mobile computer or other vendor-provided electronic devices.


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The results of the measurements and assessments will be entered into the eDiary predose 
at Visit 1 (Day 1) once the device has been set up by the investigator or designee. After 
the initiation of the study treatment on Day 1, only the measurements and the assessments 
in the available time period of the day will be conducted. If the study treatment is 
initiated at 18:00 or later on Day 1, the patient will not need to perform Day 1 evening 
assessments.
Prior to the initiation of the study treatment on Day 1, the investigator, subinvestigator, or 
study coordinator will instruct the patient on how to assess the outcome measures and 
then have him/her record the results of the initial assessments. The ePRO system will be 
personally delivered to the patient after enrollment.
Body Temperature Measurement
7.4.1.1
With an electronic thermometer, the patient will self-measure axillary temperature.  The 
sweat should be wiped off the measurement site in advance. The patient will measure, 
and record in the patient eDiary, body temperature predose on Day 1, and then 4 times 
daily (morning, noon, evening and bedtime) until Day 3 and twice daily (morning and 
evening) from Days 4 to 14.  The patient will measure body temperature during the time 
period described in Table 7-1 or at time point as near as possible. After the initiation of 
the study treatment, body temperature measurement will occur before taking 
acetaminophen or more than 4 hours after the last dose of acetaminophen.
The body temperature obtained at the study center prior to informed consent will be 
acceptable as an alternative to the predose value on Day 1 (provided that it is obtained on 
Day 1).
Table 7-1
Time Windows of Body Temperature Measurement as a 
Guide
Assessment period
Time period of a day
Time window as a guide
Day 1 - Day 3
Morning
- 9:59
Noon
10:00 - 14:59
Evening
15:00 - 19:59
Bedtime
20:00 -
Day 4 - Day 14
Morning
- 11:59
Evening
18:00 -
Assessment of Severity of Influenza Symptoms
7.4.1.2
The patient will self-assess 7 symptoms associated with influenza (cough, sore throat, 
headache, nasal congestion, feverishness or chills, muscle or joint pain, and fatigue) on a 
4-point rating scale (0, None; 1, Mild; 2, Moderate; 3, Severe).
The patient will assess, and record on a paper questionnaire, influenza symptoms predose 
on Day 1; then subsequent influenza symptoms will be assessed and recorded in the 
patient eDiary twice daily (morning and evening) until Day 9 and once daily (evening) 
from Days 10 to 14.  Table 7-2 provides the time windows of assessment as a guide.


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Table 7-2
Time Windows of Assessment as a Guide: Assessment 
of Severity of Influenza Symptoms
Assessment period
Time period of a day
Time window as a guide
Day 1 - Day 9
Morning
- 11:59
Evening
18:00 -
Day 10 - Day 14
Evening
18:00 -
Assessment of Health
7.4.1.3
The patient will self-assess his or her health on a scale of 0 (Worst possible health) to 10 
(Normal health [for someone your age and condition]) and record in the patient eDiary,
predose on Day 1 and then once daily (evening) until Day 14. Table 7-3 provides the 
time windows of assessment as a guide.
Table 7-3
Time Window of Assessment as a Guide: Assessment of 
Health
Assessment period
Time period of a day
Time window as a guide
Day 1 - Day 14
Evening
18:00 -
Assessment of health prior to influenza symptoms will be performed predose on Day 1 
and recorded in either the eDiary or a paper diary (see Appendix 4).
EuroQol-5 Dimensions-5 Levels (EQ-5D-5L)
7.4.1.4
The EQ-5D-5L will be recorded in the patient eDiary.  The details of the measurement 
are described in the Section 7.7.4.1.
7.4.2
Virology Test
Two nasopharyngeal/pharyngeal swabs (nasopharyngeal swabs are the preferred method 
of virology collection as they are the most accurate, but pharyngeal swabs will be 
acceptable if nasopharyngeal swabs cannot be performed) will be collected predose at
Visit 1 (Day 1 at the same time as the RIDT), Visit 2 (Day 2), Visit 3 (Day 3), Visit 4
(Day 5) and Visit 5 (Day 9).  If circumstances permit, specimens will also be collected at 
Optional Visit 1 (Day 4) and Optional Visit 2 (Day 6) and Visit 7 (Day 22). If the 
investigator or subinvestigator determines that influenza symptoms are ongoing, 
specimens will also be collected at Visit 6 (Day 15) and Visit 7 (Day 22) (or early 
termination). Specimens will be handled according to Section 7.6.4.5.
The virology testing facility (see Section 10.1) will perform virus typing and subtyping, 
determination of virus titer and viral RNA load according to procedures or a protocol 
specified in a separate document. Access to the virological endpoints will be limited.  
Specific details of who will have access to each endpoint will be specified in a separate 
document.


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7.4.3
Intrahousehold Infection Rate
For sites in Japan only, patient will be interviewed predose at Visit 1 (Day 1) about their
household size, the number of household members infected this season before the patient 
is enrolled the study and their diagnosis date (if the date is within 2 weeks) of influenza.  
From Day 1 to Day 15, the patient will be interviewed about the number of household 
members infected and their diagnosis date of influenza to evaluate the intrahousehold 
infection rate.
7.5
Pharmacokinetics Assessments
For the measurement of plasma S-033447 concentrations, blood samples will be collected
at Visit 2 (Day 2) and Visit 4 (Day 5); if circumstances permit, samples will also be 
collected within the period from 0.5 to 4 hours after the initial dose at Visit 1 (Day 1), 
Visit 3 (Day 3) and Visit 6 (Day 15).
The actual time of each blood sample collection and the time of study drug ingestion will 
be recorded in the eCRF.
At each sample collection, blood will be drawn into a heparin sodium-containing tube, 
followed promptly by centrifugation to separate plasma.  The resulting plasma will be 
stored at −20ºC or below.  Detailed procedures for the sample collection, handling, and 
shipping to the bioanalytical laboratory (see Section 10.1) are specified in a separate 
document.
Plasma concentrations of S-033447 will be analyzed with a validated liquid 
chromatography-tandem mass spectrometry method.
7.6
Safety Assessments
7.6.1
Physical Examination
The full physical examination will be performed at Visit 1 (Day 1) and Visit 7 (Day 22)
(or early termination) according to the normal practice of the clinical study center by the 
investigator or subinvestigator in order to check for any AEs (see Section 7.6.5.1). In 
addition, symptom-focused physical examination will be performed at Visit 2 (Day 2),
Visit 3 (Day 3), optional Visit 1 (Day 4), Visit 4 (Day 5), optional Visit 2 (Day 6), Visit 5
(Day 9) and Visit 6 (Day 15). The patient will also be observed for any influenza-related 
complications (sinusitis, bronchitis, otitis media, and pneumonia) at all visits after Visit 1
(Day 1).
Height in centimeters and body weight in kilograms will be obtained in predose 
examinations on Day 1 and entered in the eCRF, along with BMI.
7.6.2
Vital Sign Measurements
Blood pressure (systolic and diastolic), respiratory rate (breaths per minute) and pulse 
rate will be measured by the investigator, subinvestigator or designee at Visit 1 (Day 1),
Visit 2 (Day 2), Visit 3 (Day 3), optional Visit 1 (Day 4), Visit 4 (Day 5), optional Visit 2
(Day 6), Visit 5 (Day 9), Visit 6 (Day 15) and Visit 7 (Day 22) (or early termination).


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Blood pressure, pulse rate and respiratory rate will be measured after the patient has 
rested in a sitting position for at least 3 minutes.
The investigator or subinvestigator will consider whether any abnormal changes from 
baseline (predose at Visit 1, Day 1) are clinically significant (see Section 7.6.5.6).
Results of blood pressure, pulse rate and respiratory rate measurements will be entered in 
the eCRF.
7.6.3
Electrocardiography
A 12-lead ECG will be performed by the investigator, subinvestigator or designee at 
Visit 1 (Day 1), Visit 2 (Day 2) and Visit 7 (Day 22) (or early termination).  The ECG 
will be performed after the patient has rested for at least 3 minutes.
The investigator or subinvestigator will assess whether the ECG is normal or abnormal 
(see Section 7.6.5.6).  If the ECG is deemed abnormal and clinically significant, the 
investigator or subinvestigator will contact the CRO as per the medical monitoring plan, 
and it will be recorded as an AE in the eCRF. Result of ECG and its interpretation will 
also be entered in the eCRF.
7.6.4
Clinical Laboratory Tests
Laboratory Parameters
7.6.4.1
Patients will remain in a sitting or supine position during blood collection.  Blood and 
urine samples for clinical laboratory tests will be collected, and the date of specimen 
collection will be entered in the eCRF.  The blood sample volumes for clinical laboratory, 
serum antibody titer and immunological tests are shown in Table 7-4.
Table 7-4
Blood Sample Volumes
Parameter
Total blood sample volume 
(per time point)
Hematology tests
2 mL
Blood chemistry tests
3.5 - 5 mL
Hepatitis B virus surface antigen
Hepatitis C virus antibody
HIV antigen/antibody
Serum influenza virus antibody titer
3.5 mL
Routine Laboratory Tests
7.6.4.2
Routine hematology, blood chemistry, and urinalysis parameters (Table 7-5) will be 
measured by the clinical laboratory (see Section 7.6.4.5). Blood and urine samples for 
routine laboratory tests will be collected at Visit 1 (Day 1), Visit 4 (Day 5), Visit 6
(Day 15) and Visit 7 (Day 22) (or early termination).


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Table 7-5
Routine Laboratory Tests
Category
Evaluation items
Hematology tests
Hematocrit, Hemoglobin, Platelet count, Erythrocytes (red blood cells), 
Leukocytes (white blood cells) with differential (eosinophil count, basophil 
count, neutrophil count, monocyte count, lymphocyte count)
Blood chemistry tests
Alanine aminotransferase (ALT), Aspartate aminotransferase (AST), Total 
bilirubin, Direct bilirubin, Indirect bilirubin, Alkaline phosphatase (ALP), 
Gamma glutamyl transpeptidase (GGT), Lactate dehydrogenase (LDH), 
BUN, Creatinine, Uric acid, Calcium (Ca), Chloride (Cl), Potassium (K), 
Sodium (Na), Total protein, Albumin, and C-reactive protein (CRP)
Urinalysis (Qualitative)
Glucose, Occult blood, Protein, and Urobilinogen 
The investigator or subinvestigator will assess whether any abnormal changes from 
baseline (predose at Visit 1, Day 1) are clinically significant (see Section 7.6.5.6).
Immunological Tests
7.6.4.3
Patients with liver disease, including known chronic hepatitis B and untreated hepatitis C 
are excluded from enrollment in this study. Patients with untreated HIV infection are 
also excluded.
The following antigen/antibody tests will be performed for baseline demographic 
information and to inform clinical management if previously undiagnosed conditions are 
reported: hepatitis B virus surface (HBs) antigen, hepatitis C virus (HCV) antibody, and 
HIV antigen/antibody will be measured predose at Visit 1 (Day 1) by the clinical 
laboratory (see Section 7.6.4.5).
Pregnancy Tests
7.6.4.4
Except for postmenopausal women (defined as cessation of regular menstrual periods for 
2 years or more and confirmed by a follicle-stimulating hormone test) and those who are 
surgically sterile by hysterectomy, bilateral oophorectomy, or tubal ligation, all female 
patients will undergo a urine pregnancy test at Visit 1 (Day 1, predose), Visit 4 (Day 5)
and Visit 7 (Day 22) or early termination.
Sample Collection, Storage, and Shipping
7.6.4.5
Blood and urine samples and nasopharyngeal/pharyngeal swabs (nasopharyngeal swabs 
are the preferred method of virology collection as they are the most accurate, but 
pharyngeal swabs will be acceptable if nasopharyngeal swabs cannot be performed) will 
be collected by the investigator, subinvestigator or designee and sent to the clinical
laboratory for processing. Sample collection, handling, labeling, storage, shipping, etc. 
will be performed according to procedures specified in a separate document.
The sponsor may use any residual blood and/or swab samples collected from patients for 
the purposes of this study or for future scientific research. When the sponsor decides to 
perform the test/research, a detailed plan and procedures will be defined. Other than 
further virology testing, any future use of samples will follow appropriate consent from 
patients following review by an independent ethics committee. The results of the 


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test/research will be reported in documents separate from the clinical study report for this 
study.
7.6.5
Adverse Events Assessments
Performing Adverse Event Assessments
7.6.5.1
An AE is defined as any untoward medical occurrence in a patient administered a 
pharmaceutical product (including a study drug) during the course of a clinical 
investigation.  An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease temporally associated with the use of 
a pharmaceutical product, whether or not considered related to the pharmaceutical 
product.  
An elective surgical procedure not associated with a worsening of a known underlying 
medical condition is not considered an AE, and therefore will not be considered an SAE 
despite requiring hospitalization.  However, complications of the procedure will be 
considered an AE and may be considered an SAE if hospitalization is prolonged (or any 
other SAE criteria is met). A hospitalization or prolongation of a hospitalization for 
reasons other than an AE would not be considered an SAE.
AEs will be found by the patient's spontaneous complaint, patient comment cards, or as a 
result of non-leading questions, physical examination, vital signs, or laboratory tests.  
AEs include any occurrences that are new in onset or aggravated in severity or frequency 
from the baseline condition, or abnormal results of diagnostic procedures, including 
laboratory test abnormalities. Medical histories which are reported at the baseline and 
worsen following the exposure to the study drug will be considered as AEs.  Lack of 
efficacy or fluctuation in influenza symptoms will not constitute an AE in this study.
The investigator or subinvestigator is responsible for assessing AEs. AEs should be fully 
investigated and recorded in detail including start date, end date (if outcome is other than 
recovering, not recovered, or unknown), severity, seriousness with its category, 
relationship with the study drug, action taken to manage the AE, and outcome of the AE
in the eCRF.
Timing
7.6.5.2
AEs will be collected from the time of informed consent through Visit 7 (Day 22).  If a 
patient withdraws early from the study, the investigator or subinvestigator will make an 
effort to collect AEs for 21 days after the last dose of the study drug. All AEs will be 
followed until resolution, stabilization, the condition becomes chronic, or 35 days after 
the last study drug administration. Serious treatment-related AEs or AEs related to 
abnormal liver function tests shown in Appendix 5 will be followed until resolution, 
stabilization, the condition becomes chronic, or the patient becomes lost to follow-up.
Severity
7.6.5.3
The severity of an event will be categorized by the investigator or subinvestigator 
according to the following definitions based on the Common Terminology Criteria for
Adverse Events (CTCAE) Version 4.0 [11]:


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Grade 1:
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations 
only; intervention not indicated
Grade 2:
Moderate; minimal, local, or noninvasive intervention indicated; limiting 
age-appropriate instrumental Activities of Daily Living (ADL)*
Grade 3:
Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; 
limiting self-care ADL**
Grade 4:
Life-threatening consequences; urgent intervention indicated
Grade 5:
Death related to AE
*  Instrumental ADLs refer to preparing meals, shopping for groceries or clothes, using the telephone, 
managing money, etc.
** Self-care ADLs refer to bathing, dressing and undressing, feeding self, using the toilet, taking 
medications, and not bedridden.
The highest severity during the period in which the AE occurred will be recorded in the 
eCRF.
Relationship
7.6.5.4
The relationship of an event to the study drug will be determined by the investigator or 
subinvestigator according to the following criteria:
Related:
An AE which can be reasonably explained as having been caused by 
the study drug.  For example, a similar event has been reported 
previously, or increase/decrease of the dose affects the occurrence or 
seriousness of the AE, etc.
Not related:
An AE which cannot be reasonably explained as having been caused 
by the study drug.
Expectedness
7.6.5.5
A treatment-related AE is considered expected if it is listed in the subsection “Expected
Adverse Reactions” under the section “Undesirable Effects” of “SUMMARY OF DATA 
AND GUIDANCE FOR INVESTIGATORS” in the current investigator's brochure (IB) 
for S-033188. The current version of the Prescribing Information for Tamiflu®
(oseltamivir phosphate) capsules/Tamiflu® for oral suspension should also be used for 
oseltamivir expectedness assessments. Expectedness will be assessed by the sponsor.
Adverse Event Assessment of Clinical Laboratory and Other Safety 
7.6.5.6
Parameters
For any abnormal laboratory test results (hematology, blood chemistry, or urinalysis) or 
other safety assessments (eg, physical examination, vital signs, ECG) that vary following 
exposure to the study drug from baseline, the investigator or subinvestigator will 
determine whether these results are clinically significant.  Abnormal laboratory test 
results are defined as value outside the reference range.  For test results which are 
abnormal at baseline and worsen following the initiation of the study, the investigator or 
subinvestigator must also determine whether these results are clinically significant.  Any 
test results which are considered to be clinically significant by the investigator or 


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subinvestigator will be recorded as AEs.  If the abnormal laboratory finding is associated 
with a disease or organ toxicity, the investigator should report only the disease or organ 
toxicity as AEs.
The investigator or subinvestigator will consider test results to be clinically significant in 
the following circumstances:
●
Test result leads to any of the outcomes included in the definition of an SAE (see 
Section 7.6.5.7).
●
Test result leads to a concomitant drug treatment or other therapy.
●
Test result requires additional diagnostic testing or other medical intervention.
●
Test result meets the management and discontinuation criteria for abnormal liver 
function tests (Appendix 5).
Test results meeting the management and discontinuation criteria for abnormal liver 
function tests (Appendix 5) will require evaluation and additional testing, and the results 
will be recorded on the liver function abnormality follow-up form.
Serious Adverse Events
7.6.5.7
7.6.5.7.1
Definition
An SAE is defined by regulation as any AE occurring at any dose that results in any of 
the following outcomes:
Death
Life-threatening condition
Hospitalization or prolongation of existing hospitalization
Persistent or significant disability/incapacity
Congenital anomaly/birth defect
Other medically important condition
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered as SAE when, based upon appropriate medical 
judgment, they may jeopardize the patient and may require medical intervention to 
prevent one of the outcomes listed in this definition.  Examples of such medical events 
include allergic bronchospasm requiring intensive treatment in an emergency room or at 
home, blood dyscrasias or convulsions that do not result in inpatient hospitalization, or 
the development of drug dependency or drug abuse. Test results that meet the following 
criterion are considered as SAE. The investigator or subinvestigator will determine the 
seriousness of AEs.
AST or ALT > 3 × Upper limit of normal (ULN) and total bilirubin > 2 × ULN.
7.6.5.7.2
Reporting Serious Adverse Events
All information regarding SAEs, including the SAE itself, associated medications, and 
SAE narratives, must be entered into electronic data capture (EDC) within 24 hours from 
the point in time when the investigator first becomes aware of the SAE.  If EDC becomes 
unavailable, all SAEs must be reported to the CRO or sponsor in detail utilizing the SAE 


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form.  Upon availability of EDC, this information must then be entered into EDC.  All 
SAEs must be reported regardless of causal relationship to the study drug.  A sample of 
the SAE form can be found in the Site Regulatory Binder.  Follow-up information on the 
SAE may be requested by the sponsor.   
When reporting SAEs, the investigator should record the diagnosis whenever possible.  If 
no diagnosis is available at the time of reporting, individual signs and symptoms can be 
reported. 
In the event of any SAE reported or observed during the study, whether or not 
attributable to the study drug, site personnel must report within 24 hours.  SAEs 
can be reported by fax, phone, e-mail, or via EDC system (if available). 
If follow-up is required or requested, the investigator should enter the new information 
into EDC.  Discharge summaries, consultant reports, autopsy reports, or other relevant 
documents must be evaluated by the investigator and all relevant information must be 
included on the follow-up SAE form.  Copies of these reports may also be requested by 
the sponsor. 
Appropriate remedial measures should be taken by the investigator using his/her best 
medical judgment to treat the SAE.  These measures and the patient’s response to these 
measures should be recorded.  Clinical, laboratory, and diagnostic measures should be 
employed by the investigator as needed to adequately determine the etiology of the event.  
Any SAEs occurring after the AE assessment period specified in Section 7.6.5.2, that are 
considered to be related to study drug by the investigator must be reported to the CRO or 
the sponsor. 
The investigator will be responsible for reporting all SAEs to the IRB or EC through the 
head of the study center in accordance with applicable regulatory requirements.  The 
sponsor will be responsible for reporting SAEs to the regulatory authorities as required 
by the applicable regulatory requirements.


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Liver Function Abnormalities
7.6.5.8
When liver function abnormalities meet any of the following criteria the investigator 
must report these abnormalities to the sponsor within 24 hours:
x
AST or ALT > 3 × upper limit of normal (ULN) and total bilirubin (TBL) > 2 ×
ULN
x
AST or ALT > 3 × ULN and prothrombin time international normalized ratio 
(PT-INR) > 1. 5 
In addition, liver function abnormalities meeting any of the following criteria need to be 
managed according to Appendix 5:
x
AST or ALT > 5 × ULN
x
AST or ALT > 3 × ULN with signs and symptoms compatible with hepatitis or 
hypersensitivity
Special Situations - Abuse, Misuse, Overdose, and Medication Error
7.6.5.9
Abuse, misuse, overdose, or medication error of the study drug (as defined below) must 
be reported to the CRO or sponsor via fax or email by the investigator using a Special 
Situations Report Form as soon as possible. If there are associated SAE, investigator will 
report an SAE as well.
x
Abuse - persistent or sporadic, intentional excessive use of an investigational 
product(s), which is accompanied by harmful physical or psychological effects.
x
Misuse - Intentional and inappropriate use of an investigational product(s) other 
than as directed or indicated at any dose.
x
Overdose - Intentional or unintentional intake of a dose of investigational 
product(s) higher than the assigned dose in the protocol. 
x
Medication Error - any unintended error in the prescribing, dispensing or 
administration of an investigational product(s). Cases of patients missing doses of 
investigational product(s) are not considered reportable as medication errors.
Pregnancy
7.6.5.10
Female patients should be instructed to immediately contact the investigator or 
subinvestigator if they become pregnant during the study.  In addition, the investigator or 
subinvestigator must attempt to collect pregnancy information on any female partners of 
male study patients who become pregnant while he is enrolled in the study.  Pregnancy 
information must be reported to the CRO or sponsor as described below.
All pregnancies that occur during the study must be reported within 24 hours of 
becoming aware of the pregnancy, and the Pregnancy Form will be faxed or emailed to 
the CRO or sponsor by the investigator. Pregnancy complications and elective 
terminations due to medical reasons must also be reported as an AE or SAE as 
appropriate.  Spontaneous abortions must be reported as an SAE.  The outcome of the 
pregnancy should be followed and must also be reported using the Pregnancy Form to the 


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CRO or sponsor via fax or email. All pregnancies that are confirmed after the end of the 
study but within 3 months of last study drug dose should be reported to the CRO or 
sponsor and followed to completion by the study center. The outcome of the pregnancy 
(ie, birth, miscarriage, abortion) should be reported to the CRO or sponsor as described 
above. 
7.7
Other Assessment
7.7.1
Serum Antibody Titer Test
Blood samples will be collected predose at Visit 1 (Day 1) and Visit 7 (Day 22).  
Specimens will be handled according to Section 7.6.4.5.
The clinical laboratory will measure serum antibody titers for the influenza A and B 
viruses. 
7.7.2 
Polymorphic and Treatment-emergent Amino Acid Substitutions 
As a part of the virology test, PA gene sequencing of virus will be performed to evaluate 
the incidence and characteristics of polymorphic and treatment-emergent amino acid 
substitutions in patients with evaluable virus.  This sequencing will be performed using 
specimens obtained from all patients in the S-033188 treatment group and 100 patients in 
the placebo group.  The virology testing facility (see Section 10.1) will perform the gene 
sequencing according to procedures or a protocol specified in a separate document.
Access to the gene sequencing data will be limited.  Specific details of who will have 
access to each endpoint will be specified in a separate document.
7.7.3
Drug Susceptibility Testing for Test Substances
As a part of the virology test, the ViroSpot™assay and the NA-star® assay will be 
performed to evaluate the drug susceptibility for S-033188 and oseltamivir acid using 
evaluable virus at baseline sample in patients. The virology testing facility (see Section
10.1) will perform the drug susceptibility testing according to procedures or a protocol 
specified in a separate document.
7.7.4
Health Economic Outcomes
 
EuroQol-5 Dimensions-5 Levels (EQ-5D-5L)
7.7.4.1
The EQ-5D-5L will be recorded electronically predose on Day 1, and then twice daily 
(morning and evening) until Day 9, and once daily (evening) from Days 10 to 14.  Finally, 
EQ-5D-5L will be measured at Visit 7 (Day 22) to estimate a baseline quality-of-life
(QOL) measure. The questionnaire will be completed at Visit 7 (Day 22) or at the 
earliest clinic visit following alleviation of symptoms.
EQ-5D-5L is a standardized measure of health status developed by the EuroQol Group in 
order to provide a simple, generic measure of health for clinical and economic appraisal.
The EQ-5D-5L questionnaire consists of 2 pages: the EQ-5D-5L descriptive system and 
the EQ visual analogue scale (VAS).  The descriptive system comprises 5 dimensions 
(mobility, self-care, usual activities, pain/discomfort, and anxiety/depression), each of 


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which is divided into 5 levels.  The EQ VAS records the patient’s self-rated health on a 
20-cm vertical visual analogue with “the best health you can imagine” as 100 and “the 
worst health you can imagine” as 0.  
The date of assessment, EQ-5D-5L descriptive system score, and EQ VAS score will be 
recorded in the eDiary.
7.7.5
Work Productivity (WP) Questionnaire
The WP questionnaire will be completed at Visit 7 (Day 22), or at the earliest clinic visit 
following alleviation of symptoms. The WP questionnaire consists of 4 questions 
regarding employment, number hours worked, productivity while at work, and
requirement for personal assistance. WP questionnaire is included in Appendix 3.
The WP questionnaire will be completed on paper.
7.8
Withdrawal of Patients from the Study or Study Drug
The investigator will make every reasonable attempt to complete the study for each 
enrolled patient.  A patient may withdraw for any reason. The investigator will advise 
the sponsor about the withdrawal of any patient by the IRT.
The investigator will withdraw a patient from the study or the study drug treatment for 
any of the following reasons:
●
A serious or intolerable AE occurs and the investigator considers that the patient
should be withdrawn because of the AE.
●
The patient requests to be withdrawn from the study.
●
The patient becomes lost to follow-up.
●
The investigator determines that the patient should be withdrawn based on the 
management and discontinuation criteria for abnormal liver function tests 
(Appendix 5).
●
The investigator determines that the patient should be withdrawn because of other 
reasons.
In the event of a patient’s withdrawal, the investigator will promptly notify the sponsor 
and will make every effort to complete the early termination assessments. All patients
withdrawn due to AEs will be followed until resolution of the AEs, until the unresolved 
AEs are judged by the investigator to have stabilized, or the patient becomes lost to 
follow-up. The date of completion (for patients who completed the study), date of 
discontinuation (for patients who discontinued from the study prematurely), period of 
discontinuation, and reason for discontinuation will be entered in the eCRF. Completion 
of the study for each patient is defined as the case that the patient completed the follow-
up period.
7.8.1
Clinical Progression or Lack of Response
In cases where on clinical review, patients appear to be deteriorating clinically or have 
not responded to the study drug, the investigator should consider the possibility of 


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secondary infections, decompensation of underlying conditions, or progression of 
influenza. Patients should be assessed, and investigations should be performed as 
clinically indicated.
In the event an investigator considers that the influenza has not responded and wishes to 
treat with open-label oseltamivir (not provided by the sponsor), the patient should stop all 
blinded study drugs. Since unblinding of the study drugs would not alter the 
management of the patients, unblinding in this situation is discouraged, and the patients 
should remain in the study for follow-up as described in Section 7.8. Such cases should 
be discussed urgently with the sponsor or sponsor’s designated Medical Monitors.
7.9
Appropriateness of Measurements
7.9.1
Primary Efficacy Endpoint
Time to alleviation of symptoms is defined as the time to alleviation of 7 influenza 
symptoms (cough, sore throat, headache, nasal congestion, feverishness or chills, muscle 
or joint pain, and fatigue).  Time to alleviation of symptoms has been commonly used as 
a measure of the efficacy of anti-influenza virus drugs, thereby enabling a comparison 
with the results from clinical studies of currently available medications.  This justifies the 
selection of time to alleviation of symptoms as the primary endpoint of this study.
7.9.2
Secondary Efficacy Endpoints
Available nonclinical data suggest that a single oral dose of S-033188 can provide rapid 
relief of influenza symptoms.  In addition, influenza symptoms were relieved 
significantly earlier in patients who received a 40 mg single oral dose of S-033188
compared to placebo in the Phase 2 proof-of-concept and dose-finding study (Study 
1518T0821).  Thus, the benefits of S-033188 can be evaluated based on the change in the 
total score of influenza symptoms at 24 hours post-dose, which is a measure of the speed 
of symptomatic improvement.
The time to cessation of viral shedding by virus titer and by reverse transcription 
polymerase chain reaction (RT-PCR) will provide data to indicate when both culturable 
viable virus and viral elements have become undetectable by viral titer and PCR, 
respectively. This permits an evaluation of ‘viral shedding’ that is analogous to 
infectivity, where an index case (the patient) is producing virus in nasal secretions and 
can infect close contacts. 
In addition, the efficacy of S-033188 can be examined in detail by assessing the changes 
over time in the scores of symptoms and time to resolution of fever, and the benefits of 
S-033188 in improving QOL can be examined by assessing time to resumption of normal 
activity.
An assessment of the intrahousehold infection rate will provide useful information on the 
transmissibility of influenza infection after treatment with S-033188. This assessment 
will conducted only in Japan.


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7.9.3
Safety Endpoints
Monitoring patients for AEs and treatment-related AEs will provide important 
information to examine the safety of S-033188.
7.9.4
Plasma Drug Concentrations
Assessing the PK of S-033447 in patients will provide important information for the 
future clinical use of S-033188.
7.9.5
Other Endpoints
The benefits of S-033188 in improving QOL can be examined by assessing the time to 
return to preinfluenza health status and the change in the score of the QOL questionnaire 
EQ-5D-5L.
An understanding of potential amino-acid substitutions in S-033188-exposed patients will 
be gained by exploring polymorphic and treatment-emergent amino acid substitutions in
the PA gene in S-033188-exposed patients at baseline and at the last evaluable time point,
with sequencing of approximately 100 placebo-exposed patients performed as a control.
7.10
Allowable Time Window
Measurements will be performed according to the schedule as shown in Appendix 1.  The 
time window shown in Table 7-6 may be accepted for parameters other than blood 
sample collection for the measurement of plasma drug concentrations.  Blood samples for 
the measurement of plasma drug concentrations will be collected within the time window 
shown in Table 7-7. Data obtained outside of this time window will be handled as 
missing data for the Visit, except for plasma drug concentration data.


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Table 7-6
Allowable Time Window
Visit (Day)
Allowable time window a
Predose at Visit 1 (Day 1)
Predose on Day 1
Post-dose at Visit 1 (Day 1)
QOL assessment with EQ-5D-5L questionnaire:
by 0.5 hour post-dose on Day 1
Other measurements:
0.5 to 4 hours post-dose on Day 1
Visit 2 (Day 2)
Day 2
Visit 3 (Day 3)
Day 3 - Day 4
Optional-Visit 1 (Day 4)
Day 4
Visit 4 (Day 5)
Day 5 - Day 6
Optional-Visit 2 (Day 6)
Day 6
Visit 5 (Day 9)
Day 7 - Day 11
Visit 6 (Day 15)
Day 12 - Day 18
Visit 7 (Day 22)
Day 19 - Day 25
Early termination
Date of early termination + 3 days
a
Except for blood sample collection for the measurement of plasma drug concentrations.
Table 7-7
Allowable Time Window for Blood Sample Collection for 
the Measurement of Plasma Drug Concentrations
Measurement
Visit (Day)
Allowable time window
Blood sample collection for the measurement 
of plasma drug concentrations
Visit 1a (Day 1)
0.5 to 4 hours post-dose (Day 1)
Visit 2 (Day 2)
Day 2
Visit 3a (Day 3)
Day 3 - Day 4
Visit 4 (Day 5)
Day 5 - Day 6
Visit 6a (Day 15)
Day 12 - Day 18
a
To be performed if circumstances permit.


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8.
STUDY ACTIVITIES
The overall schedule of events for the study is presented in Appendix 1.
8.1
Poststudy Access to the Study Drug 
There will be no availability of study drug once the patient has completed the study.


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9.
PLANNED STATISTICAL METHODS
9.1
General Considerations
The statistical analysis and PK analysis will be performed by the sponsor or designee.  
The detailed statistical analysis methods will be specified in a statistical analysis plan 
(SAP) and PK analysis plan according to this section of the study protocol.  If analyses 
deviated from those outlined in the protocol, the reason for deviation from the protocol 
must be described in the SAP and PK analysis plan.  The SAP and PK analysis plan will 
be finalized before scheduled unblinding.
Unless otherwise noted, continuous variables will be summarized by using the number of 
non-missing observations, arithmetic mean, standard deviation, median, minimum, and 
maximum values as descriptive statistics; categorical variables will be summarized by 
using the frequency count and the percentage of patients in each category as descriptive 
statistics.
All statistical tests will be performed at the 0.05 significance level using two-sided tests, 
except where otherwise noted. The primary endpoint will first be compared between the 
S-033188 and placebo groups for patients (primary analysis). Together with the primary 
efficacy analysis, comparison between the S-033188 group and the oseltamivir group 
(secondary analysis) will be conducted in a hierarchical manner so as to maintain control 
of overall Type I error. For Japan, control of overall Type I error is not required for the 
secondary efficacy analysis of primary endpoint.
All patient study data will be presented in listings.  In general, all tables will be presented 
by treatment group.  Individual patient data will be presented by treatment group and by 
patient.  All analyses and tabulations will be performed by using both the SAS 
Version 9.2 or higher and WinNonlin Version 6.2.1 or higher.
9.2
Determination of Sample Size
The required sample size of the intention to treat infected (ITTI) population will be 968
(93 patients in 12 to 19 years age stratum and 875 patients in 20 to 64 years age stratum).
It is assumed that the RT-PCR positive rate will be 65%. Therefore, 1494 patients
(144 patients in 12 to 19 years age stratum and 1350 patients in 20 to 64 years age 
stratum) will be randomized to ensure an adequate number of patents in the ITTI 
population. The number of randomized patients may change based on the percentage of 
patients who are RT-PCR positive during the study.
Rationale for the target sample size:
The primary analysis will be to compare time to alleviation of symptoms between the 
S-033188 group and the placebo group (both age strata combined).
The median times to alleviation of symptoms in the three placebo-controlled clinical 
trials of oseltamivir were 116.5, 103.3 and 93.3 hours in the placebo group, respectively
[5, 9, 10]. Taking this into account, it was assumed that the median time to alleviation of 
symptoms in the placebo group will be 100 hours.


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In the Phase 2 study for the otherwise healthy patients with influenza virus infection, the 
median time to alleviation of symptoms was 49.5 hours (95% CI: 44.5, 64.4) in the 
40-mg group versus 77.7 hours (95% CI: 67.6, 88.7) in the placebo group. The 
difference in the median time between 40-mg and placebo was 28.2 hours.
Based on the difference in the Phase 2 study, the difference between the S-033188 group 
and the placebo group is assumed to be 28 hours (72 hours in the S-033188 group,
100 hours in the placebo group).  If the ratio of the median time to alleviation between 
the S-033188 group and the placebo group remains the same (ie, 0.64: 49.5/77.7) in the 
proposed study, the difference can further be assumed to be 36 hours (64 hours in the 
S-033188 group, 100 hours in the placebo group).
The required sample size has been calculated based on the conservative assumption of a 
28 hour difference in the median time to alleviation of symptoms between the S-033188
group and the placebo group to ensure at least a 90% power in the efficacy evaluation and 
to accumulate a larger safety database [12].
Patients will be randomized on a 2:1 basis to either S-033188 or placebo and a follow-up
period will be 336 hours (14 days). Assuming that time to alleviation follows an 
exponential distribution, the study requires 618 patients as the ITTI population, for the 
S-033188 group and the placebo group in total, in order for the stratified generalized 
Wilcoxon test to have 90% or more power with a two-sided significance level of 0.05.
Assuming that the percentage of the number of patients in 12 to 19 years age stratum is
15%, the required breakdown will be 62 patients for the S-033188 group and 31 patients
for the placebo group in 12 to 19 years age stratum, 350 patients for the S-033188 group 
and 175 patients for the placebo group in 20 to 64 years age stratum.
Comparison vs oseltamivir: Using a 1:1 randomization ratio between the S-033188 and 
oseltamivir, ITTI population of oseltamivir will be 350 patients to compare time to 
alleviation of symptoms between the S-033188 and the oseltamivir in 20 to 64 years age 
stratum. Table 9-1 shows the statistical power to compare between the S-033188 group 
and the oseltamivir group under several sets of difference in time to alleviation of 
symptoms. 
Table 9-1
Statistical Power to Compare between S-033188 and 
Oseltamivir
Median time to alleviation of symptoms
(S-033188 group, oseltamivir group)
Statistical power for comparison between 
the S-033188 group and the oseltamivir group
by stratified generalized Wilcoxon test
(72 hours, 84 hours)
42.1%
(70 hours, 84 hours)
54.8%
(68 hours, 84 hours)
67.4%
(66 hours, 84 hours)
78.5%
(64 hours, 84 hours)
87.2%


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9.3
Analysis Populations
The following analysis populations will be analyzed for this study based on enrolled 
patients with GCP compliance:
The ITTI population includes all patients who receive the study drug with a confirmed 
diagnosis of influenza virus infection.  Confirmation of influenza virus infection will 
be based on the results of RT-PCR.  The population will be analyzed according to the 
treatment to which the patients were randomized.
The safety population includes all randomized patients who receive at least one dose of 
the study drug.  The population will be analyzed according to the treatment that the 
patients actually received, rather than the treatment to which the patients were 
randomized.
The per-protocol set (PPS) includes all randomized patients who are included in the 
ITTI population and do not meet any of the following conditions:

Patients with any protocol inclusion or exclusion violations

Patients with study procedure violations

Patients with inadequate follow-up
The PK concentration population includes all patients who receive at least one dose of 
S-033188 and have at least one evaluable PK assay result of S-033447.  This 
population will be used for the concentration listing.
The PK parameter population includes all patients with at least one PK parameter of 
S-033447 estimated.  This population will be used for PK parameter listing and 
summary, and for the plotting and summary of the concentration-time data.
9.4
Handling of Missing Data
Missing data will not be replaced for the primary analyses. A sensitivity analysis will 
follow a predefined rule for missing data.
9.5
Patient Disposition
Among the patients randomized to each treatment group, the number and percentage of 
patients who complete the study and the number and percentage of patients who 
prematurely discontinue the study will be summarized by treatment group.   In addition, 
reasons leading to study discontinuation will be summarized for each treatment group.
The number and percentage of patients for the randomized patients included in the ITTI, 
safety and PPS populations will also be presented
9.6
Demographic and Baseline Characteristics
Demographic and baseline characteristics for the ITTI population will be summarized 
with descriptive statistics by treatment group.  


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9.7
Extent of Exposure and Treatment Compliance
For ITTI and safety populations, whether each patient receives the study drug or not will 
be presented in a listing. The number of days when the study drug is taken and the 
percent compliance will be summarized with descriptive statistics by the treatment group 
for the safety population.  
9.8
Prior Therapies
Prior therapies for drugs will be coded using the World Health Organization (WHO) 
Drug Dictionary.  In the ITTI population and the safety population, the number of 
patients using each prior drug will be counted by treatment group.  The number of 
patients using each prior therapy will also be counted. Patients who have received prior 
therapy(ies) will be listed for the safety population.
9.9
Concomitant Therapies
Concomitant therapies for drugs will be coded using the WHO Drug Dictionary.  In the 
ITTI population and the safety population, the number of patients using each concomitant 
drug will be counted by treatment group.  The number of patients using each concomitant 
therapy will also be counted. Patients who have received concomitant therapy(ies) will 
be listed for the safety population.
9.10
Efficacy Analyses
9.10.1
Primary Efficacy Endpoint
The primary efficacy endpoint is time to alleviation of symptoms.
Time to alleviation of symptoms is defined as the time between the initiation of the study 
treatment and the alleviation of influenza symptoms.  The alleviation of influenza
symptoms is defined as the time when all of 7 influenza symptoms (cough, sore throat, 
headache, nasal congestion, feverishness or chills, muscle or joint pain, and fatigue) have 
been assessed by the patient as 0 (None) or 1 (Mild) in the patient eDiary, for a duration 
of at least 21.5 hours (24 hours −10%).
9.10.2
Secondary Efficacy Endpoints
The secondary efficacy endpoints include the following variables.
1. Proportion of patients positive for influenza virus titer and proportion of patients 
positive by RT-PCR at each time point
Defined as the percentage of patients whose virus titer is not less than the lower 
limit of quantification among those assessed for virus titer, and the percentage of 
patients with detectable virus RNA among those assessed by RT-PCR, 
respectively.
2. Change from baseline in virus titer and in the amount of virus RNA (RT-PCR) at 
each time point
Defined as the change from baseline in virus titer and the change from baseline in 


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the amount of virus RNA, respectively. Baseline is defined as the last value 
obtained before Visit 1 (predose).
3. Area under the curve adjusted by baseline in virus titer and in the amount of virus 
RNA (RT-PCR)
Defined as AUC of change from baseline in virus titer and AUC of change from 
baseline in the amount of virus RNA, respectively. AUC is calculated using the 
trapezoidal method.
4. Time to cessation of viral shedding by virus titer and by RT-PCR
Defined as the time between the initiation of the study treatment and first time 
when the virus titer is BLQ, and the time between the initiation of the study 
treatment and first time when virus RNA by RT-PCR is BLQ, respectively.
5. Proportion of patients whose symptoms has been alleviated at each time point
Defined as the percentage of patients whose symptoms are alleviated at each time
point.
6. Time to alleviation of the 4 systemic symptoms
Defined as the time between the initiation of the study treatment and the 
alleviation of the 4 systemic symptoms (headache, feverishness or chills, muscle 
or joint pain, and fatigue).
7. Time to alleviation of the 3 respiratory symptoms
Defined as the time between the initiation of the study treatment and the 
alleviation of the 3 respiratory symptoms (cough, sore throat and nasal 
congestion).
8. Change from baseline in composite symptom score at each time point
Defined as the change from baseline in the total score of 7 influenza symptoms 
(cough, sore throat, headache, nasal congestion, feverishness or chills, muscle or 
joint pain, and fatigue) as assessed by the patient in the patient eDiary.  “None”,
“Mild”, “Moderate” and “Severe” will be scored as 0, 1, 2 and 3, respectively.
Baseline is defined as the last value obtained before Visit 1 (predose).
9. Time to resolution of fever
Defined as the time between the initiation of the study treatment and the 
resolution of fever.  The resolution of fever is defined as the time when the 
patient’s self-measured axillary temperature becomes less than 37ºC and is 
maintained at less than 37ºC for a duration of at least 12 hours.
10. Proportion of patients reporting normal temperature at each time point
Defined as the percentage of patients whose axillary temperature drops to less 
than 37ºC after the initiation of the study treatment in the analysis population.
11. Body temperature at each time point
Defined as measured axillary temperature.


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12. Time to alleviation of individual symptoms
Defined as the time between the initiation of the study treatment and the 
alleviation of individual symptom. The alleviation of a symptom is defined as the 
time when the symptom is assessed as 0 (None) or 1 (Mild), for duration of at 
least 21.5 hours (24 hours −10%).
13. Time to return to preinfluenza health status
Patients will be asked to record their preinfluenza health status between 0 (worst 
possible health) and 10 (normal health [for someone your age and your health 
condition]). Then the same information will be taken as part of the eDiary. Return 
to preinfluenza health status is defined as time from the initiation of the study 
treatment to time to the same number on scale for preinfluenza health status.
14. Incidence of influenza-related complications
Defined as the percentage of patients in the analysis population who experience 
each influenza-related complication (hospitalization, death, sinusitis, otitis media, 
bronchitis, and radiologically confirmed pneumonia) as an AE after the initiation 
of the study treatment. A specific complication eCRF with diagnostic criteria for 
the complications of sinusitis, otitis media, bronchitis and pneumonia will be 
provided.
9.10.3
Analyses of Efficacy Endpoints
The ITTI will be the primary population for all efficacy analyses. The PPS will be used 
for sensitivity analysis of the primary efficacy endpoint. The analysis of each efficacy 
endpoint will consist of comparison between S-033188 and placebo using data of the two 
age strata combined (ie, 12 to 64 years age), and comparison between S-033188 and 
oseltamivir using data of 20 to 64 years age stratum.
Analyses of Primary Endpoint
9.10.3.1
9.10.3.1.1Primary Analysis
Comparison of time to alleviation of symptoms (S-033188 group vs placebo group):
Time to alleviation of symptoms will be compared between the S-033188 group and the 
placebo group using the stratified generalized Wilcoxon test with composite symptoms
score at baseline (≤11 or ≥12) and region (Japan/Asia or Rest of the world) as
stratification factors.
The same analysis in PPS will be performed as a sensitivity analysis.
9.10.3.1.2
Secondary Analysis
Comparison of time to alleviation of symptoms (20 to 64 years age stratum of S-033188
group vs oseltamivir group):
Among patients aged 20 to 64 years, time to alleviation of symptoms will be compared 
between the S-033188 group and the oseltamivir group using the stratified generalized 
Wilcoxon test with composite symptoms score at baseline and region as stratification


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factors.
Together with the primary efficacy analysis, this comparison will be conducted in a 
hierarchical manner so as to maintain control of overall Type I error. For Japan, control 
of overall Type I error is not required for the secondary efficacy analysis of primary 
endpoint.
The same analysis in PPS will be performed as a sensitivity analysis.
9.10.3.1.3
Other Analyses
The Kaplan-Meier curves will be plotted for each treatment group, and the median time 
to alleviation of symptoms and its 95% CI will be calculated. In addition, the group 
difference in median of the time to alleviation of symptoms and its 95% CI will be also 
calculated.
The same analysis in PPS will be performed as a sensitivity analysis.
Analyses of Secondary Endpoints
9.10.3.2
The following secondary efficacy endpoints will be compared between the S-033188
group and the placebo group, and between the S-033188 group and the oseltamivir group
(in adults):
1. Proportion of patients positive for influenza virus titer and proportion of patients 
positive by RT-PCR at each time point
Only patients whose virus titer/RT-PCR predose at Visit 1 are greater than or 
equal to the lower limit of quantification will be included in the analyses. Mantel-
Haenszel test will be used by each visit to compare the proportion of patients 
positive for virus titer/RT-PCR between two groups, where composite symptoms
score at baseline and region are stratification factors.
2. Change from baseline in virus titer and in the amount of virus RNA (RT-PCR) at 
each time point
Only patients whose virus titer predose at Visit 1 are greater than or equal to the 
lower limit of quantification will be included in the analyses. Van Elteren test
will be used by each visit to compare the change from baseline in influenza virus 
titer between two groups, where composite symptoms score at baseline and region 
will be used as stratification factors. For only patients whose virus RNA predose 
at Visit 1 are detected, similar analysis will be conducted for the change from 
baseline in the amount of virus RNA.
3. Area under the curve adjusted by baseline in virus titer and in the amount of virus 
RNA
Only patients whose virus titer predose at Visit 1 are greater than or equal to the 
lower limit of quantification will be included in the analyses. Van Elteren test
will be used to compare AUC of virus titer adjusted by baseline between two 
groups, where composite symptoms score at baseline and region will be used as 


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stratification factors. For only patients whose virus RNA predose at Visit 1 are 
detected, similar analysis will be conducted for AUC of the amount of RNA 
adjusted by baseline.
4. Time to cessation of viral shedding by virus titer and by RT-PCR
Only patients whose virus titer/RT-PCR predose at Visit 1 are greater than or 
equal to the lower limit of quantification will be included in the analyses.The 
stratified generalized Wilcoxon test will be used, where composite symptoms
score at baseline and region are stratification factors.
5. Proportion of patients whose symptoms has been alleviated at each time point 
Mantel-Haenszel test will be used by time point to compare success proportion of 
resolution of patients whose symptoms alleviated between two groups, where 
composite symptoms score at baseline and region are stratification factors.
6. Time to alleviation of the 4 systemic symptoms
The stratified generalized Wilcoxon test will be used, where composite symptoms
score at baseline and region are stratification factors.
7. Time to alleviation of the 3 respiratory symptoms
The stratified generalized Wilcoxon test will be used, where composite symptoms
score at baseline and region are stratification factors.
8. Change from baseline in composite symptoms score at each time point
Analysis of covariance (ANCOVA) will be used by time point to compare the 
change from baseline in the composite symptoms score between two groups, 
where composite symptoms score at baseline and region will be used as covariates. 
9. Time to resolution of fever
The stratified generalized Wilcoxon test will be used, where composite symptoms
score at baseline and region are stratification factors.
10. Proportion of patients reporting normal temperature at each time point
Mantel-Haenszel test will be used by time point to compare success proportion of 
resolution of fever between two groups, where composite symptoms score at 
baseline and region are stratification factors.
11. Body temperature at each time point
ANCOVA will be used by time point to compare body temperature between two 
groups, where composite symptoms score at baseline and region will be used as 
covariates.
12. Time to alleviation of individual symptoms
The stratified generalized Wilcoxon test will be used, where composite symptoms
score at baseline and region are stratification factors. Patients whose symptoms at 
baseline are assessed as 0 (None) or 1 (Mild) will be excluded from the analysis.
13. Time to return to preinfluenza health status


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The stratified generalized Wilcoxon test will be used, where composite symptoms
score at baseline and region are stratification factors.
14. Incidence of influenza-related complications (hospitalization, death, sinusitis, 
bronchitis, otitis media, and radiologically confirmed pneumonia)
Fisher's exact test will be used to compare incidence of hospitalization, death, 
sinusitis, otitis media, bronchitis, and radiologically confirmed pneumonia 
between two groups.
9.11
Safety Analyses
The safety population will be used for safety analyses.
9.11.1
Adverse Events
AEs will be classified by system organ class and preferred term using Medical Dictionary 
for Regulatory Activities (MedDRA).  Of reported AEs on the eCRF, AEs reported after 
the initial dose of randomized study drug will be used for safety analyses. 
The number of patients who experience at least 1 AE, deaths, other SAEs, and AEs 
leading to withdrawal will be counted for each treatment group. The incidences and their 
95% CI will be calculated by using the Clopper-Pearson method.  The number of those 
AEs, which are counted by cases reported, will also be presented. Treatment-related AEs 
will be summarized in the same manner as AEs described above.
The number and percentage of patients who experience AEs by MedDRA system organ 
class and preferred term will be presented for each treatment group.  The summary for 
action taken with the study drug, timing of onset, severity, and outcome will be presented 
by system organ class and preferred term.
All AEs, including those occurring prior to the initiation of the study treatment, will be 
listed.
9.11.2
Vital Signs
For each of the vital signs, summary statistics of observation and the change from 
baseline will be presented by treatment group for each scheduled time point. Baseline is 
defined as the last value obtained before the initiation of the study treatment.
9.11.3
Clinical Laboratory Analysis 
For each of laboratory tests, summary statistics of observation and the change from 
baseline will be presented by treatment group for each scheduled time point. Baseline is 
defined as the last value obtained before the initiation of the study treatment.
Qualitative laboratory test data at baseline and at scheduled time point will be classified 
according to test category, and the frequency of each pair will be presented in a two-
dimensional contingency table by treatment group.


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9.11.4
Electrocardiography
ECG will be performed to assess the presence of acute conditions that may exclude 
patients or conditions in the opinion of the investigator or that may be considered AEs 
during the study. The frequency of ECG findings will be summarized by treatment group.
9.12
Pharmacokinetic Analysis
Plasma S-033447 concentration data will be plotted against the actual sampling time to 
determine the PK of S-033447.  Plasma S-033447 concentration 24 hours (acceptable 
time window: 20 to 28 hours) post-dose (C24) will be listed and summarized with the 
number of non-missing observations (N), arithmetic mean (Mean), standard deviation 
(SD) and coefficient of variation (CV%, calculated by SD/Mean × 100), geometric mean 
(Geometric Mean) and coefficient of variation for geometric mean (CV% Geometric 
Mean, calculated by [exp (sd2)−1]1/2 × 100, where sd is the standard deviation for natural 
log [ln]-transformed data), median, minimum and maximum values. C24 will be plotted 
against body weight.
Specification of PK parameters for analysis, statistical level of significance to be used, 
procedures for accounting for missing, unused or spurious data, procedures for reporting 
deviations from the original statistical plan, and selection of patients to be included in the 
analyses population(s) will be presented in the PK analysis plan or PK analysis report as 
appropriate.
PK parameters reported will be detailed in the PK analysis plan. Other parameters may 
be added if deemed appropriate.
If needed, the relationships between C24 and efficacy endpoints may be assessed across 
dose groups.  The PK/Pharmacodynamic (PD) analysis for each efficacy endpoint will 
include all patients who have the value of C24 and each evaluable PD assay result.
9.13
Other Analysis
9.13.1
Serum Influenza Antibody Titer
Serum antibody titers measured at Visit 1 (Day 1) and Visit 7 (Day 22) will be 
categorized, and the frequency of each category will be tabulated by treatment group. 
The ratio of value at Visit 7 to that at Visit 1 will be categorized, and the frequency of 
each category will be tabulated by treatment group. For the ratio (Visit 7/Visit 1), the 
geometric mean value will also be calculated, and S-033188 group will be compared with 
the placebo group regarding the geometric mean ratio, using the Wilcoxon rank sum test.
9.13.2
Polymorphic and Treatment-emergent Amino Acid Substitutions in 
the PA Gene
This analysis will be conducted for the patients in S-033188 and placebo groups and the 
methodological details will be specified in the SAP.
9.13.3
Drug Susceptibility Testing for Test Substances
This analysis will be conducted for all patients and further details will be specified in the 


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SAP.
9.13.4
Health Economic Outcomes
EuroQol-5 Dimensions-5 Levels and EuroQol Visual Analog Scale
9.13.4.1
The combination of 5 scores for EQ-5D-5L and the VAS will be presented as:
Changes in the index value from baseline to each time point
Change in the VAS score from baseline to each time point
Work Productivity (WP) Questionnaire
9.13.4.2
Analysis variables and analysis methods will be specified in SAP.
9.13.5
Intrahousehold infection rate
The definition of the endpoint and the analysis method for the endpoint will be specified 
in the SAP.
9.14
Interim Analysis
No interim analysis is planned for this study.


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10. ADMINISTRATIVE CONSIDERATIONS
10.1 Study Administrative Structure 
Sponsor for Japan and 
Other Asian Countries:  
Shionogi & Co., Ltd. 
1-8, Doshomachi 3-chome, Chuo-ku, Osaka 541-0045, 
Japan
Sponsor for the United 
States: 
Shionogi Inc.
300 Campus Drive, Florham Park, NJ 07932 USA
Sponsor's Contact: 
Sponsor's Chief Medical 
Officer: 
Medical Monitor in PRA – 
Japan and Taiwan: 
Medical Monitor in PRA –   
the United States:
Medical Monitor in PRA – 
Asian countries except 
Japan and Taiwan:
Investigator and Medical 
Multicenter


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Institution:
Study Monitoring: 
Registration Center, IRT:
  
Clinical Laboratory for 
Japan and other Asian 
countries: 
Clinical Laboratory for the 
United States:
Bioanalytical Laboratory: 
Virology Testing Facility:


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eDiary: 
10.2 Institutional Review Board (IRB) Approval 
The IRB/IEC will safeguard the rights, safety, and well-being of the patients by 
reviewing the following study documents: the protocol, informed consent/assent form, 
written information on patient recruitment procedures (if applicable), other written 
information given to the patients, IB, safety updates, annual progress reports (if 
applicable), and any significant revisions to these documents.  The investigator or the 
sponsor will provide these study documents to the IRB/IEC.  The IRB/IEC will be 
appropriately constituted in accordance with ICH GCP, and local requirements, as 
applicable.  The study will be undertaken only after the IRB/IEC has given full approval 
and the investigator has received a document being approved.  
Amendments to the protocol will be subject to the same requirements as the initial review.  
The investigator will submit all periodic reports and updates as required by the IRB/IEC.
The investigator will inform the IRB/IEC of any reportable AEs. 
10.3 Ethical Conduct of the Study 
The study will be conducted in accordance with all appropriate regulatory requirements 
and under protocol approved by the IRB/IEC.  The study will be conducted in accordance 
with current ICH GCP, all appropriate patient privacy requirements, and the ethical 
principles that are outlined in the Declaration of Helsinki.   
10.4 Patient Information and Consent/Assent
The investigator will generate an informed consent/assent form for the study.  The 
sponsor will provide the investigators with a proposed informed consent/assent form that 
complies with the ICH GCP guidelines and regulatory requirements. The consent/assent
form will include all the elements required by the ICH GCP and any additional elements 
required by local regulations and will be reviewed and approved by the appropriate 
IRB/IEC before use.  The sponsor must agree to any changes to the proposed 
consent/assent form suggested by the investigator prior to submission to the IRB/IEC,
and the IRB/IEC approved version must be provided to the site monitor after IRB/IEC
approval.  
The investigator or subinvestigator will explain the nature, purpose and methods, 


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reasonable anticipated benefits and potential hazards of the study to the patient in simple 
terms by using the consent/assent form approved by the IRB/IEC before the patient is 
entered the study.  The method of obtaining and documenting informed consent/assent
will comply with ICH GCP and all applicable regulatory requirement(s).
10.5
Trial Participation Card 
Patients will be provided with a Trial Participation Card that provides the address and 
telephone number of the main contact for information on the study drugs and emergency 
contacts. The investigator and IRB will be instructed to keep this in their possession at all 
times. 
10.6
Patient Confidentiality
Procedures for protecting patient privacy must adhere to applicable data privacy laws and 
regulations.  In order to maintain patient privacy, all eCRFs, study drug accountability 
records, study reports, and communications will identify the patient by the patient
number.  The investigator will grant site monitor(s) and auditor(s) of the sponsor or a
designee and regulatory authorities access to all source documents for verification of data 
collected on the eCRFs and for verification of the data collection process.  The patient’s
confidentiality will be maintained and will not be made publicly available to the extent 
permitted by the applicable laws and regulations.  The investigator and the sponsor are 
responsible for ensuring that sensitive information is handled in accordance with local 
requirements (eg, Health Information Portability and Accountability Act [HIPAA]).
Appropriate consent and authorizations for use and disclosure and/or transfer (if 
applicable) of protected information must be obtained.
Data on patients collected on eCRFs during the study will be documented in an 
anonymous fashion and the patient will only be identified by the patient ID.  In the 
emergent or rare event that for safety or regulatory reasons it is necessary to identify a 
patient, the sponsor, and the investigator are bound to keep this information confidential.
10.7
Study Monitoring
The sponsor or designee will monitor the study to ensure that the study is conducted in 
accordance with ICH GCP requirements and protocol.  The study monitoring will be 
performed by a representative of the sponsor (site monitor) through on-site monitoring 
visits as frequently as necessary and frequent communications (e-mail, letter, telephone, 
and fax).  The site monitor will review data recorded on the eCRFs, verify the eCRFs 
entries with direct access to source documents, collect any safety/efficacy information on 
patients, verify that amounts of unused study drug are accurate, and check retention of 
source documents and essential documents.  
10.8
Case Report Forms and Source Documents
10.8.1
Case Report Forms
The sponsor or designee will supply eCRFs for each enrolled patient will be provided and 
historical information and study data, which are specified by the protocol, will be 
recorded on eCRFs by the investigator.  All patient data from study visits must be 


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collected on source documents and promptly entered in the eCRFs in accordance with the 
specific instructions given.  eCRF entries will be performed by an investigator, 
subinvestigator, and study coordinator(s) with written authorization.  Data should be 
entered within 3 days after each patient’s visit.
When queries are generated to the study center for resolution by the sponsor or designee, 
eCRF data will be corrected or a response will be recorded in accordance with the 
specific instructions given.  The investigator must ensure that data reported in the eCRF 
is accurate, complete, legible, and timely and sign the eCRFs to verify the integrity of the 
data recorded.
A list of the reference ranges for all laboratory tests to be undertaken will be collected 
prior to the initiation of the study.  The list of reference ranges for all laboratory tests 
should be updated if they are changed during the study.  If a central laboratory has been 
selected to perform any or all tests, it is essential that the reference ranges for all 
laboratory tests to be performed at the laboratory should also be collected.  
10.8.2
Source Data and Source Documents
Source documentation supporting the eCRF data should indicate the patient’s 
participation in the study and should document the dates and details of study procedures, 
AEs, and patient status.  However, the following data will be allowed as data which can 
be directly recorded in the eCRF: 
●
Reason for use of prior therapy and/or concomitant therapy
●
Severity, seriousness, and causal relationship to the study drug of AE
●
Any comments entered in the eCRF
Listed below are the data managed only in the eCRF (ie, items automatically-calculated 
by the EDC system):
●
Age
●
BMI
●
Respiratory rate (breaths/min)
The investigator must maintain the source documents such as laboratory reports, 
complete medical history, and physical examination reports.  All the source documents 
must be made accessible for verification by the site monitor(s), auditor(s), the IRB/IEC,
regulatory authority inspector(s).  Direct access to these documents must be guaranteed 
by the investigator, subinvestigator, or study coordinator, who must provide support at all 
times for these activities.  For all sources of original data required to complete the eCRFs, 
the sponsor and the site staff must thoroughly understand the nature and location of the 
source documents.  If electronic records are maintained at the study center, the method of 
verification must be specified in document within the study center.  
10.8.3
External Data
The following data will be reported in separate documents from the eCRFs.  


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●
Plasma concentrations of S-033447 (determined according to procedures specified 
in a separate document)
●
Results of virology tests (determined according to procedures specified in a
separate document)
●
Safety laboratory test
10.9
Committees
10.9.1
Independent Data Monitoring Committee
No independent data monitoring committee will be established for this study.
10.10 Termination or Suspension of the Study
10.10.1 Termination or Suspension of the Entire Study
The sponsor may prematurely terminate or suspend the study at any time for the 
following reasons:  
●
Ensuring safety of the study is difficult due to safety concerns (eg, occurrence of 
many serious treatment-related AEs)
●
Achieving the purpose of the study is considered impossible (eg, inadequate 
recruitment of patients)
If the study is prematurely terminated or suspended, the sponsor should promptly inform 
the investigators.  The investigator or subinvestigator should promptly inform the 
participating patients and change the study treatment to other appropriate therapy.  
For withdrawal criteria for individual patients, see Section 7.8.
10.10.2 Termination or Suspension of the Study by Study Center
The investigator may prematurely terminate or suspend the study in the study center with 
agreement of the sponsor at any time when the investigator considers that ensuring safety 
of the study is difficult due to safety concerns (eg, occurrence of many SAEs).
The sponsor may request the investigator to prematurely terminate or suspend the study 
in the study center at any time when major violations/deviations of protocol, other 
procedures, and ICH GCP guidelines were not improved.
If the study is prematurely terminated or suspended, the investigator or subinvestigator 
should promptly inform the corresponding IRB/IEC and participating patients and change 
the study treatment to other appropriate therapy(ies).  
10.11 Protocol Modifications and Deviations
The investigator will conduct the study in compliance with the protocol provided by the 
sponsor and approved by the IRB/IEC and the regulatory authority(ies).  Modifications to 
the protocol should not be performed without agreement of both the investigator and the 


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sponsor.  Changes to the protocol will require written IRB/IEC approval prior to 
implementation, except when the modification is needed to eliminate an immediate 
hazard(s) to the patients.  
The investigator or subinvestigator should document any deviation from the protocol and 
the reason.  If the investigator deviates from the protocol or makes a change to the 
protocol to eliminate an immediate hazard(s) to the patients, the record should be 
immediately submitted to the sponsor, the study center, and the IRB/IEC by the 
investigator and the IRB/IEC will provide expedited review and approval. After 
obtaining approval from the IRB/IEC, the investigator must obtain a written agreement of 
the sponsor through the study center.
When deviation from the protocol is required to eliminate immediate hazard(s) to the 
patients, the investigator will contact the sponsor, if circumstances permit, to discuss the 
planned course of action.  Any deviations from the protocol must be fully documented in
the source document.  
10.12 Data Management
The sponsor will be responsible for data management and analysis.  These procedures are 
specified in a separate document.
10.13 Retention of Data
The study documents must be maintained in accordance with the ICH GCP guidelines
and applicable regulatory requirements.  The investigator and study center should take 
measures to prevent accidental or premature destruction of these documents.
If the sponsor is granted manufacturing and marketing approval for the drug, the sponsor 
will promptly notify the head of the study center in writing.
Records will be retained for either of the following periods, whichever is later: 
●
Until the approval day of manufacturing/marketing of the study drug or 3 years 
after the decision to terminate the development is made
●
3 years after the date of discontinuation or completion of the study
However, the duration of retention may be prolonged with agreement with the sponsor.  
If the investigator withdraws from the responsibility of keeping the study records, 
custody must be transferred to an appropriate person willing to accept the responsibility.
10.14 Quality Control and Assurance
The sponsor or designee will implement and maintain quality control and quality 
assurance procedures with written standard operating procedures to ensure that the study 
is conducted and data are generated, documented, and reported in compliance with the 
protocol, ICH GCP, and applicable regulatory requirements.  
This study will be conducted in accordance with the provisions of the Declaration of 


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Helsinki and all revisions thereof; in accordance with the ICH GCP, and as required by
the applicable regulatory requirements.
The sponsor will provide training necessary for the study to the investigators and the 
study center personnel prior to the initiation of the study.
10.15 Publication and Disclosure Policy
All information regarding S-033188 provided by the sponsor to the investigator is 
privileged and confidential and must not be disclosed to any third party.  The investigator 
agrees to use this information to accomplish the study and will not use it for any other 
purposes without consent from the sponsor.  It is understood that there is an obligation to 
provide the sponsor with complete data obtained during the study.  The information 
obtained from the study will be used for the development of S-033188 and may be 
disclosed to regulatory authorities, other investigators, corporate partners, or consultants 
as required.  
The sponsor will retain the ownership of all data.  All proposed publications based on the 
study will be subject to the sponsor's approval requirements.
The key design elements of this protocol will be posted in a publicly accessible database.
10.16 Financial Disclosure
The information on financial disclosure for investigators will be addressed in a separate 
agreement between the sponsor and the investigator.


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11. REFERENCE LIST
1. Reaper R, Landry, M. Rapid Diagnosis of Influenza. In Mandell, Douglas, and 
Bennett’s Principle and Practice of Infectious Diseases: Latest Developments in 
Influenza with Accompanying Clinics Review Articles. First Edition. Elsevier Inc. 
2014. p.2011-13.
2. Monto AS, Gravenstein S, Elliott M, Colopy M, Schweinle J. Clinical Signs and 
Symptoms Predicting Influenza Infection. Arch Intern Med 2000; 160: 3243-7.
3. Centers for Disease Control and Prevention. People at high risk of developing flu 
related complications.
http://www.cdc.gov/flu/about/disease/high_risk.htm (accessed 2016-10-19).
4. 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.
5. Treanor JJ, Hayden FG, Vrooman PS, et al. Efficacy and safety of the oral 
neuraminidase inhibitor oseltamivir in treating acute influenza: a randomized 
controlled trial. JAMA. 2000; 283: 1016-24.
6. Jefferson T, Jones MA, Doshi P, et al. Neuraminidase inhibitors for preventing and 
treating influenza in healthy adults and children. Cochrane Database Syst Rev. 2012 
Jan 18; 1: CD008965. doi; 2014;4: CD008965. 
7. Herna´n MA, Lipsitch M. Oseltamivir and risk of lower respiratory tract 
complications in patients with flu symptoms: a meta-analysis of eleven randomized 
clinical trials. Clin Infect Dis. 2011; 53: 277-9.
8. Jefferson T, Jones M, Doshi P, Spencer EA, Onakpoya I, Heneghan CJ. Oseltamivir 
for influenza in adults and children: systematic review of clinical study reports and 
summary of regulatory comments. BMJ. 2014; 348: g2545. 
9. Nicholson KG, Aoki FY, Osterhaus AD, et al. Efficacy and safety of oseltamivir in 
treatment of acute influenza: a randomised controlled trial. Neuraminidase Inhibitor 
Flu Treatment Investigator Group. Lancet 2000; 355: 1845-50.
10. Kashiwagi S, Kudoh S, Watanabe A, Yoshimura I. Clinical efficacy and safety of the 
selective oral neuraminidase inhibitor oseltamivir in treating acute influenza: placebo-
controlled double-blind multicenter phase III trial [in Japanese]. Kansenshogaku 
Zasshi [Jpn J Infect Dis] 2000; 74: 1044-61.
11. National Cancer Institute. Common Terminology Criteria for Adverse Events v4.0.
NCI, NIH, DHHS. May 29, 2009. NIH publication # 09-7473.
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-
14_QuickReference_8.5x11.pdf (accessed 2016-10-19)
12. Guidance for Industry. Influenza: Developing Drugs for Treatment and/or 
Prophylaxis. U.S. Department of Health and Human Services Food and Drug 
Administration Center for Drug Evaluation and Research (CDER). April 2011
Clinical Antimicrobial.
http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guid
ances/ucm091219.pdf (accessed 2016-10-19)


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Appendix 1
Time and Events Schedule
Treatment Period
Follow-up Period
D1
D2
D3
D4
D5
D6
D7
D8
D9
D10
D11
D12
D13
D14
D15
D22 or ET
V1
V2
V3
OpV1
V4
OpV2
V5
V6
V7
Visit Window (days)
-
-
+1
-
+1
-
±2
±3
±3
Informed Consent/Assent
X
Inclusion/Exclusion Criteria
X
Demographics
X
Medical History a
X
Rapid Influenza Diagnostic Test
X b
Randomization
X
Study Drug Dispensation
X
Study Drug Administration
X
X
X
X
X
Patient 
eDiary c
Body Temperature 
Measurement
X d
4 Times Daily
Twice Daily
Assessment of Severity 
of Influenza Symptoms
X d
Twice Daily
Once Daily
Assessment of Health
X d
Once Daily
Assessment of Health 
Prior to Influenza 
Symptoms
X d
EQ-5D-5L
X d
Twice Daily
Once Daily
X
Work Productivity Questionnaire
X (following resolution of symptoms)
Assessment of Influenza-related 
Complications (sinusitis, bronchitis, 
otitis media, pneumonia)
X
X
X
X
X
X
X
X
X
Full Physical Examination
X e, f
X e
Symptom-focused Physical 
Examination
X
X
X
X
X
X
X
Concomitant Therapies
X
X
X
X
X
X
X
X
Study Drug Accountability
X
X
X
X
X
Urine Pregnancy Test(WOCBP) g
X
X
X
Immunological Tests
X h
Routine Laboratory Tests
X
X
X
X
Influenza Antibody Titer Test
X h
X


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Nasopharyngeal 
(preferred)/pharyngeal (if 
nasopharyngeal cannot be collected) 
Swabs (Virology Test)
X h
X
X
X
X
X
X
X i
X i, j
Vital Sign Measurements
X
X
X
X
X
X
X
X
X
Electrocardiography
X
X
X
Pharmacokinetic Blood Samples
X k
X
X k
X
X k
Adverse Event Assessment
X
X
X
X
X
X
X
X
X
Interview for Meal Consumption
X
Intrahousehold Infection Interview
(for Japan only)
X
X
X
X
X
X
D = Day, ET = early termination, V = visit, OpV = optional visit.
a
Prior therapies will also be reviewed.
b
Not necessary if a site has performed a Rapid Influenza Diagnostic Test prior to consideration for the study.
c
The patient will measure or assess and record in the patient eDiary, body temperature 4 times daily (morning, noon, evening, and bedtime) from Days 1 to 3 and twice daily 
(morning and evening) from Days 4 to 14; severity of influenza symptoms twice daily (morning and evening) from Days 1 to 9 and once daily (evening) from Days 10 to 14;
assessment of health once daily (evening) from Days 1 to 14; and EQ-5D-5L twice daily (morning and evening) from Days 1 to 9 and once daily (evening) from Days 10 to 
14.
d
Predose; if the study treatment is initiated at 18:00 or later on Day 1, the patient will not need to perform Day 1 evening assessments.
e
Body weight will be measured.
f
Height will be measured in the predose examinations only.
g
Urine pregnancy test will be performed only for females who are not diagnosed as postmenopausal.
h
Predose.
i
Virology swabs will be collected if investigator determines that flu symptoms are persisting.
j
Virology swabs will be collected at the early termination.
k
Blood samples will be collected for the measurement of plasma drug concentrations at Visits 2 (Day 2) and 4 (Day 5). If circumstances permit, samples will also be collected 
at 0.5 to 4 hours post-dose at Visit 1 (Day 1), and at Visit 3 (Day 3) and Visit 6 (Day 15).


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Appendix 2 
QOL Questionnaire (EuroQol-5 Dimensions–5
Levels)


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Appendix 3
Work Productivity (WP) Questionnaire 
Work Productivity Questionnaire cover note:
To the investigator:
This questionnaire is designed to capture the impact of influenza symptoms on 
patients’ ability to work and perform normal activities.  We would like the patient 
to complete the questionnaire once, during the clinic visit following resolution of 
their symptoms
1. How many hours or days per week do you work (e.g., full or part time paid 
work, voluntary work, or studying)?
2. Due to your recent influenza illness, for how many hours or days were you 
unable to work? ___hours, or ____ days
3. Due to your recent influenza illness, for how many hours or days did you 
feel that your symptoms caused you to perform below your normal 
standard even though you attended work? ___hours, or _____days
4. Due to your recent influenza illness, for how many hours or days did you 
require someone to help you with your normal activities? ___ hours, or 
___ days


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Appendix 4
Assessment of Health Scale


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Appendix 5
Management and Discontinuation Criteria for 
Abnormal Liver Function Tests
Management and Discontinuation Criteria for Abnormal Liver Function tests have been 
designed to ensure patient safety and evaluate liver event etiology. (See Guidance for 
Industry Drug-Induced Liver Injury: Premarketing Clinical Evaluation, FDA: 2009) 
1. Abnormal Liver Chemistry Criteria:
The investigator or subinvestigator must review study patient laboratories to identify if 
any levels meet the following criteria:
a.
AST or ALT > 5 × ULN
b.
AST or ALT > 3 × ULN and total bilirubin > 2 × ULN or PT-INR > 1.5, if PT-INR 
is measured.
c.
AST or ALT > 3 × ULN with signs or symptoms compatible with hepatitis or 
hypersensitivity (eg, fatigue, nausea, vomiting, right upper quadrant pain or 
tenderness, jaundice, fever, rash, eosinophilia [>5%])
2. Action to be taken by Investigator:
If any abnormal liver chemistry criterion is met, the investigator or subinvestigator must 
do the following:
x
Patients must be instructed to discontinue study medication immediately.
x
Following the initial observed elevation, every effort should be made to have the 
patient return to the clinic within 72 hours to repeat liver function chemistries and for 
further hepatic evaluation.  
x
Every effort should be made to have the patients monitored 2 to 3 times per week 
until liver function chemistries (ALT, AST, ALP, total bilirubin) resolve, stabilize or 
return to within the normal range or to baseline levels.
x
This event must be reported to the sponsor as soon as possible but no later than
72 hours of learning after its occurrence on the Liver Event Form.
x
Consultation with a specialist such as a hepatologist is considered.
x
Liver imaging (ie, ultrasound, magnetic resonance imaging (MRI), computerized 
tomography) is considered.
x
For criteria b, the case must be reported as an SAE. 
3. Follow-up Examination:
If any of the abnormal liver chemistry criteria are met, the following assessments should 
be performed at the follow-up visit(s) and documented in the Liver Event Form:


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x
Clinical symptoms course
x
Alcohol use
x
Risk factors for nonalcoholic steatohepatitis (NASH) such as diabetes, obesity and 
hypertriglyceridemia
x
Autoimmune hepatitis/cholangitis
x
Wilson's disease
x
Laboratory Assessments
–
Viral hepatitis serology
o
Hepatitis A IgM antibody
o
Hepatitis B surface antigen (HBs antigen) and Hepatitis B core antibody 
(HBc antibody)
o
Hepatitis C RNA
o
Hepatitis E IgA antibody
o
Cytomegalovirus IgM antibody
o
Epstein-Barr viral capsid antigen IgM antibody
–
For patients with total bilirubin of > 1.5 × ULN, conjugated bilirubin should be 
measured
–
Complete blood count with differential to assess for eosinophilia
4. Restarting Study Medication Criteria
Patients that meet the abnormal liver chemistry criteria may re-start the administration of 
the study drug, but only if they do not meet the "Drug Discontinuation Criteria Due to 
Abnormal Liver Chemistry Tests".
Patients with ALT > 5 × ULN to ≤8 × ULN elevations for less than 2 weeks may restart
the study drug may at the discretion of the investigator and sponsor if both of the 
following conditions are met:
x
Subsequent liver function chemistries are lower or unchanged 
x
No signs or symptoms are consistent with hepatitis or hypersensitivity (eg, fatigue, 
nausea, vomiting, right upper quadrant pain or tenderness, jaundice, fever, rash or 
eosinophilia [>5%])
All patients that have met abnormal liver chemistry criteria must still be monitored 2 to 
3 times per week until liver function chemistries (ALT, AST, alkaline phosphatase, and 
total bilirubin) resolve, stabilize or return to within the normal range or to baseline levels.
5. Drug Discontinuation Criteria Due to Abnormal Liver Chemistry Tests
Patients must be discontinued from the study as described below:
AST or ALT > 8 × ULN, confirmed by follow-up testing (ie, initial abnormality is 
confirmed on subsequent testing), regardless of medical history or physical examination 
findings
AST or ALT > 5 × ULN, with elevations for more than 2 weeks or development of 


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concomitant signs or symptoms consistent with hepatitis or hypersensitivity (eg, fatigue, 
nausea, vomiting, right upper quadrant pain or tenderness, jaundice, fever, rash or 
eosinophilia [>5%])
AST or ALT > 3 × ULN and total bilirubin > 2 × ULN or PT-INR > 1.5, if PT-INR 
measured, confirmed by follow-up testing (ie, initial abnormality is confirmed on 
subsequent testing), regardless of medical history or physical examination findings. 
AST or ALT > 3 × ULN with signs or symptoms compatible with hepatitis or
hypersensitivity (eg, fatigue, nausea, vomiting, right upper quadrant pain or tenderness, 
jaundice, fever, rash or eosinophilia [>5%]), confirmed by follow-up testing (ie, initial 
laboratory abnormality is confirmed upon subsequent testing).
AST or ALT > 5 × ULN and the patient cannot be followed up weekly


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AST or ALT >5xULN and 
≤8xULN㻌
AST or ALT >8xULN
Plus total Bilirubin >2xULN 㻌
(or PT-INR >1.5 if 
measured)
With signs or symptoms 
compatible with hepatitis or 
hypersensitivity
•
The investigator or subinvestigator should not re-challenge the patient with the investigational product without consulting the sponsor.
•
Following the initial observed elevation, every effort should be made to have the patient return to the clinic within 72 hours to repeat liver 
function chemistries and for further hepatic evaluation  
•
Patients must be monitored 2 to 3 times per week until liver function chemistries (ALT, AST, ALP, total bilirubin) resolve, stabilize or 
return to within the normal range or to baseline levels. 
•
Consultation with a specialist such as a hepatologist is considered.
•
Liver imaging (ie, ultrasound, magnetic resonance imaging (MRI), computerized tomography) is considered.
•
When restarting drug, refer to the document content.
•
Discontinue IP 
•
Report as AE or SAE 
•
Report to the sponsor within 72 hours on the Liver Event Form 
•
Discontinue IP
•
Report as SAE 
•
Report to the sponsor 
within 72 hours on the 
Liver Event Form
AST or ALT >3xULN
Management and Discontinuation Criteria for Abnormal Liver Function Tests (LFT): Algorithm㻌

SAP_001.pdf: 
Shionogi Study Title:  
A Phase 3, Multicenter, Randomized, Double-blind 
Study of a Single Dose of S-033188 Compared with 
Placebo or Oseltamivir 75 mg Twice Daily for 5 
Days in Otherwise Healthy Patients with Influenza 
Shionogi Study Number: 
1601T0831 
ClinicalTrials.gov 
registration No. 
NCT02954354 
Study Document  
Statistical Analysis Plan  
 


STATISTICAL ANALYSIS PLAN
Study Title:
A Phase 3, Multicenter, Randomized, Double-blind 
Study of a Single Dose of S-033188 Compared with 
Placebo or Oseltamivir 75 mg Twice Daily for 5 Days 
in Otherwise Healthy Patients with Influenza
Study Number:
1601T0831
Study Phase:
3
Product Name:
S-033188
Sponsor:
Shionogi & Co., Ltd./Shionogi Inc.
Issue Date:
Version 2.0
6 July 2017
Confidentiality Statement
This document and the information contained herein or attached hereto (“Confidential 
Material”) are confidential and proprietary to Shionogi. This Confidential Material 
should only be viewed by those individuals or companies that have been given prior 
written authorization to do so by Shionogi (“Authorized Users”). This Confidential 
Material should not be made available in any form to any person or company, other 
than the Authorized Users and their respective employees or associates on a 
need-to-know basis, without the written consent from Shionogi.


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RECORDS ON REVISIONS
Version
Date
Author
Remarks
Version 1.0 
27 June, 2017 
First version
Collaborators: 
Version 1.1 
3 July, 2017 
Formatting changes were made. 
Version 2.0 
6 July, 2017 
9.2 15) Analysis population was 
changed and writting error was 
corrected.


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TABLE OF CONTENTS
RECORDS ON REVISIONS ............................................................................................. 2
TABLE OF CONTENTS.................................................................................................... 3
LIST OF IN-TEXT TABLES.............................................................................................. 4
1.
INTRODUCTION ...................................................................................................... 5
2.
OVERVIEW................................................................................................................ 5
3.
SUTDY OBJECTIVES............................................................................................... 5
3.1
Primary Objective............................................................................................. 5
3.2
Secondary Objective......................................................................................... 5
3.3
Other Efficacy Objective .................................................................................. 6
3.4
Safety Objectives .............................................................................................. 6
3.5
Pharmacokinetic Objectives.............................................................................. 6
3.6
Health Economic Outcomes Research Objective ............................................. 6
4.
OUTLINE OF STUDY DESIGN ............................................................................... 6
4.1
Study Blinding .................................................................................................. 6
4.2
Allocation Procedure ........................................................................................ 6
4.3
Target Sample Size............................................................................................ 6
5.
ANALYSIS POPULATIONS ..................................................................................... 8
5.1
Efficacy Populations ......................................................................................... 8
6.
HANDLING OF DATA IN ANALYSES.................................................................... 8
6.1
Statistical Analysis............................................................................................ 8
6.2
Statistical Tests.................................................................................................. 9
6.3
Acceptable Time Windows for Investigations, Observations, and 
Examinations..................................................................................................... 9
6.4
Handling of Missing Data................................................................................11
6.4.1
Handling of Virology Test Data in Consideration of the Stability 
Window..................................................................................................11
6.5
Definition........................................................................................................ 12
6.5.1
Display of Days of Study...................................................................... 12
6.5.2
Baseline................................................................................................. 12
7.
DEMOGRAPHIC VARIABLES AND OTHER BASELINE
CHARACTERISTICS .............................................................................................. 12
7.1
Subject Disposition......................................................................................... 12
7.2
Demographic and Baseline Characteristics .................................................... 13
8.
STUDY CONDUCT................................................................................................. 13
8.1
Treatment Exposure and Compliance............................................................. 13
8.2
Medical History .............................................................................................. 14
8.3
Prior and Concomitant Medication................................................................. 14


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9.
EFFICACY ANALYSIS ........................................................................................... 14
9.1
Primary Endpoint............................................................................................ 16
9.1.1
Analyses of Primary Endpoint.............................................................. 16
9.1.1.1
Primary Analysis................................................................................... 16
9.1.1.2
Secondary Analysis............................................................................... 17
9.1.1.3
Other Analysis....................................................................................... 17
9.1.1.4
Sensitivity Analysis............................................................................... 17
9.2
Secondary Endpoints ...................................................................................... 18
9.3
Other Endpoints .............................................................................................. 24
9.4
Analyses of the Secondary Endpoints............................................................. 26
9.5
Analyses of the Other Endpoints .................................................................... 29
9.6
Subgroup Analyses for Primary and Secondary Endpoint.............................. 32
10. SAFETY EVALUATION.......................................................................................... 33
10.1
Adverse Events ............................................................................................... 33
10.2
Clinical Laboratory......................................................................................... 35
10.3
Vital Signs....................................................................................................... 36
10.4
Electrocardiography (ECG) ............................................................................ 36
10.5
Subgroup Analyses for Safety Endpoint......................................................... 36
11. INTERIM ANALYSES............................................................................................. 36
12. PROGRAMMING SPECIFICATIONS.................................................................... 36
13. BLINDED REVIEW ................................................................................................ 39
14. SUMMARY OF CHANGES FROM PROTOCOL SPECIFIED ANALYSIS ......... 39
15. REFERENCES ......................................................................................................... 40
APPENDIX 1
TIME AND EVENTS SCHEDULE..................................................... 41
LIST OF IN-TEXT TABLES
Table 1 
Statistical Power to Compare between S-033188 and 
Oseltamivir.................................................................................... 7 
Table 2-1 
Acceptable Time Windows for Parameters of the Patient 
Diary ............................................................................................. 9 
Table 2-2 
Acceptable Time Windows for Parameters Other than Data 
from the Patient Diary................................................................. 10 
Table 3 
Statistical Methods Used to Analyze Each Endpoint.................. 15 
Table 4 
Priority of Categories.................................................................. 34 
Table 5 
Pre-specified Criteria .................................................................. 35 
Table 6 
Summary of the Number of Digits Displayed for Endpoints ..... 37 
Table 7 
Summary of the Number of Digits Displayed ............................ 37 
Table 8 
Category of Variable ................................................................... 38 


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1.
INTRODUCTION
This document describes the statistical methods to be used in the summary and analysis 
of data from Protocol 1601T0831. All decisions regarding final analysis, as defined in 
this statistical analysis plan (SAP), have been made prior to unblinding/database lock of 
the study data. Table, listing and figure mock-ups are described in the TLF shell 
document prepared separately. Details of the analyses of pharmacokinetics and 
pharmacokinetics/pharmacodynamics will also be described in a separate document.
All the analyses described in the SAP will be performed in the Biostatistics Dept., 
Shionogi & Co., Ltd.
2.
OVERVIEW
This is a randomized, double-blind, multicenter, parallel-group, placebo- and active
controlled study enrolling approximately 1494 patients diagnosed with influenza. 
Approximately 1350 patients aged 20 to 64 years and 144 patients aged 12 to 19 years 
will be enrolled. Patients in 20 to 64 years age stratum will be randomly assigned in a 
ratio of 2:2:1 to receive a single dose of 40 or 80 mg of S-033188 according to their 
weight category, 75 mg BID of oseltamivir for 5 days, or placebo. With the aim to 
achieve a broadly comparable exposure, patients who weigh < 80 kg at Screening will 
receive 40 mg of S-033188, and patients who weigh ≥ 80 kg at Screening will receive 80
mg of S-033188. Patients in 12 to 19 years age stratum will be randomly assigned in a 
ratio of 2:1 to receive a single dose of 40 or 80 mg (depending on weight) S-033188 or 
placebo.
For the schedule of this study, see Appendix 1.
3.
SUTDY OBJECTIVES
3.1
Primary Objective
y
To evaluate the efficacy of a single, oral dose of S-033188 compared with placebo
by measuring the time to alleviation of symptoms in patients with uncomplicated
influenza virus infection.
3.2
Secondary Objective
y
To evaluate the efficacy of a single, oral dose of S-033188 compared with 
oseltamivir 75 mg twice daily (BID) for 5 days by measuring the time to 
alleviation of symptoms in patients aged 20 to 64 years with uncomplicated 
influenza virus infection
y
To evaluate the efficacy of a single, oral dose of S-033188 compared with placebo 
by measuring the secondary endpoints in patients with uncomplicated influenza 
virus infection
y
To evaluate the efficacy of a single, oral dose of S-033188 compared with 
oseltamivir 75 mg BID for 5 days by measuring the secondary endpoints in 
patients with uncomplicated influenza virus infection


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3.3
Other Efficacy Objective
y
To evaluate the polymorphic and treatment-emergent amino acid substitutions in 
the polymerase acidic protein (PA) gene and drug susceptibility in patients with 
evaluable virus
3.4
Safety Objectives
y
To compare the safety and tolerability of a single dose of S-033188 with placebo
y
To compare the safety and tolerability of a single dose of S-033188 with 
oseltamivir 75 mg BID for 5 days
y
To compare the frequency of adverse events (AEs) in patients with influenza of a 
single dose of S-033188 with oseltamivir 75 mg BID for 5 days and with placebo
3.5
Pharmacokinetic Objectives
y
To determine the pharmacokinetics (PK) of the active form of S-033188, ie, 
S-033447, in patients with uncomplicated influenza virus infection
3.6
Health Economic Outcomes Research Objective
y
To compare the total quality-of-life change by measuring the EuroQol–5
Dimensions–5 Levels (EQ-5D-5L) and a work productivity (WP) questionnaire in 
patients treated with S-033188 compared with oseltamivir 75 mg BID for 5 days 
and placebo
4.
OUTLINE OF STUDY DESIGN
4.1
Study Blinding
The study will be conducted in a double-blind, double-dummy fashion by using placebo 
matching S-033188 and oseltamivir in appearance, labeling, and packaging. 
4.2
Allocation Procedure
Patients in 20 to 64 years age stratum will be randomized on a 2:2:1 basis to S-033188
group, oseltamivir group, or placebo group. Patients in 12 to 19 years age stratum will be 
randomized on a 2:1 basis to either S-033188 group or placebo group. An interactive 
response technology (IRT) will be used to assign patients to numbers for which treatment 
has already been randomly assigned. The randomization will also be stratified by region
(Japan/Asia, Rest of the world), body weight (< 80 kg, ≥ 80 kg) and baseline composite 
symptom score (≤ 11, ≥ 12).
4.3
Target Sample Size
The required sample size of the intention to treat infected (ITTI) Population will be 968
(93 patients in 12 to 19 years age stratum and 875 patients in 20 to 64 years age stratum).


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It is assumed that the RT-PCR positive rate for influenza A or B virus will be 65%.
Therefore, 1494 patients (144 patients in 12 to 19 years age stratum and 1350 patients in 
20 to 64 years age stratum) will be randomized to ensure an adequate number of patents 
in the ITTI Population.
The primary analysis will be to compare time to alleviation of symptoms between the
S-033188 group and the placebo group (both age strata combined). Based on the results 
of S-033188 Phase 2 study and the three placebo-controlled studies of oseltamivir, the 
difference between S-033188 and placebo will be assumed to be 28 hours. If the ratio of 
the median time to alleviation between the S-033188 group and the placebo group 
remains the same (i.e. 0.64: 49.5/77.7) in the proposed study, the difference can further 
be assumed to be 36 hours (64 hours in the S-033188 group, 100 hours in the placebo 
group). Patients will be randomized on a 2:1 basis to either S-033188 or placebo and the 
follow-up period will be 336 hours (14 days). Assuming that time to alleviation follows 
an exponential distribution, the study requires 618 patients in the ITTI Population in 
order for the stratified generalized Wilcoxon test to have 90% or more power with a 
two-sided significance level of 0.05. Assuming that the percentage of the number of 
patients in 12 to 19 years age stratum is 15%, the required breakdown will be 93 patients 
in 12 to 19 years age stratum (62 patients for the S-033188 group and 31 patients for the 
placebo group), 525 patients in 20 to 64 years age stratum (350 patients for the S-033188
group and 175 patients for the placebo group).
Using a 1:1 randomization ratio between the S-033188 and oseltamivir, ITTI Population 
of oseltamivir will be 350 patients to compare time to alleviation of symptoms between 
the S-033188 and the oseltamivir in 20 to 64 years age stratum. Table 1 shows the 
statistical power to compare between the S-033188 group and the oseltamivir group 
under several sets of difference in time to alleviation of symptoms.
Table 1
Statistical Power to Compare between S-033188 and 
Oseltamivir
Median time to alleviation of 
symptoms
(S-033188 group, oseltamivir group)
Statistical power for comparison between
the S-033188 group and the oseltamivir 
group
by stratified generalized Wilcoxon test
(72 hours, 84 hours)
42.1%
(70 hours, 84 hours)
54.8%
(68 hours, 84 hours)
67.4%
(66 hours, 84 hours)
78.5%
(64 hours, 84 hours)
87.2%


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5.
ANALYSIS POPULATIONS
5.1
Efficacy Populations
The definitions of the Intention-To-Treat-Infected (ITTI) Population and the Per-Protocol 
Set (PPS) as efficacy populations are provided below. In this study, the ITTI Population is 
the primary analysis population. The PPS is the secondary analysis population, and data 
from the PPS will be used to perform a sensitivity analysis for the primary analysis.
The following analysis populations will be analyzed for this study based on enrolled
patients with GCP compliance:
1) ITTI Population 
This population includes all patients who receive the study drug with a confirmed
diagnosis of influenza virus infection. Confirmation of influenza virus infection 
will be based on the results of RT-PCR on Day 1. The population will be analyzed 
according to the treatment to which the patients were randomized.
2) Per-Protocol Set (PPS) 
This population includes all subjects included in the ITTI Population and did not 
meet any of the following conditions:
y
Ineligible subjects
y
Subjects with non-comliance of treatment
–
Treatment compliance rate is less than 60%. The definition of treatment 
compliance rate shown in 8.1 will be used.
y
Subjects with inadequate follow-up
–
Subjects have no symptom data after initial treatment
y
Subjects with prohibited medication
y
Subjects with incorrect treatment allocation
3) Safety population 
This population includes all randomized patients who receive at least one dose of 
the study drug. The population will be analyzed according to the initial treatment 
that the patients actually received.
6.
HANDLING OF DATA IN ANALYSES
6.1
Statistical Analysis
Unless otherwise noted, continuous variables will be summarized by using the number of 
non-missing observations, arithmetic mean, standard deviation (SD), median, minimum, 
and maximum values as summary statistics; categorical variables will be summarized by
using the frequency count and the percentage of subjects in each category as summary 
statistics.  
Subject study data, including data not appearing in tables, will be presented in by-subject 
data listings. In general, all tables will be presented by treatment group.  Individual 


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subject data and any derived data will be presented by treatment and subject.  All 
analyses and tabulations will be performed by using the SAS Version 9.2 or higher.
6.2
Statistical Tests
All statistical tests will be performed at the 0.05 significance level using two-sided tests, 
unless otherwise noted.
The primary endpoint will first be compared between the S-033188 and placebo groups 
(primary analysis). Together with the primary efficacy analysis, comparison between the 
S-033188 and the oseltamivir groups (secondary analysis) will be conducted. For the
submission to countries other than Japan, only if statistically significant difference will be 
observed in primary analysis , secondary analysis will be performed in order to maintain 
control of overall Type I error.
6.3
Acceptable Time Windows for Investigations, Observations, and 
Examinations
The acceptable time windows shown in Table 2-1 and 2-2. The acceptable time windows 
shown in Table 2-1 will be used to collect data from the patient diary.
Table 2-1
Acceptable Time Windows for Parameters of the Patient 
Diary
Time Point
Specified Assessment Time 
Point
Acceptable Time Window
12 hours post-dose
Time of first dosing + 12 hours
Between ≥6 and < 18 hours after first dosing
24 hours post-dose
Time of first dosing + 24 hours
Between ≥18 and < 30 hours after first dosing
36 hours post-dose
Time of first dosing + 36 hours
Between ≥30 and < 42 hours after first dosing
48 hours post-dose
Time of first dosing + 48 hours
Between ≥42 and < 54 hours after first dosing
60 hours post-dose 
Time of first dosing + 60 hours
Between ≥ 54 and < 66 hours after first dosing
72 hours post-dose
Time of first dosing + 72 hours
Between ≥66 and < 78 hours after first dosing
84 hours post-dose
Time of first dosing + 84 hours
Between ≥ 78 and < 90 hours after first dosing
96 hours post-dose
Time of first dosing + 96 hours
Between ≥90 and < 102 hours after first dosing
108 hours post-dose
Time of first dosing + 108 hours
Between ≥ 102 and < 114 hours after first dosing
120 hours post-dose
Time of first dosing + 120 hours
Between ≥114 and < 126 hours after first dosing
132 hours post-dose
Time of first dosing + 132 hours
Between ≥ 126 and < 138 hours after first dosing
144 hours post-dose
Time of first dosing + 144 hours
Between ≥138 and < 150 hours after first dosing
156 hours post-dose
Time of first dosing + 156 hours
Between ≥ 150 and < 162 hours after first dosing
168 hours post-dose
Time of first dosing + 168 hours
Between ≥162 and < 174 hours after first dosing
180 hours post-dose
Time of first dosing + 180 hours
Between ≥ 174 and < 186 hours after first dosing
192 hours post-dose
Time of first dosing + 192 hours
Between ≥186 and < 198 hours after first dosing
204 hours post-dose
Time of first dosing + 204 hours
Between ≥ 198 and < 210 hours after first dosing
216 hours post-dose
Time of first dosing + 216 hours
Between ≥210 and < 222 hours after first dosing
240 hours postdose
Time of dosing + 240 hours
Between ≥ 228 and < 252 hours after dosing
264 hours postdose
Time of dosing + 264 hours
Between ≥ 252 and < 276 hours after dosing
288 hours postdose
Time of dosing + 288 hours
Between ≥ 276 and < 300 hours after dosing


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Time Point
Specified Assessment Time 
Point
Acceptable Time Window
312 hours postdose
Time of dosing + 312 hours
Between ≥300 and < 324 hours after dosing
336 hours postdose
Time of dosing + 336 hours
Between ≥324 and < 348 hours after dosing
528 hours postdose
Time of dosing + 528 hours
Between ≥ 456 and < 600 hours after dosing
The acceptable time windows shown in Table 2-2 will be used for the assessment of 
items other than data from the patient diary.
Table 2-2
Acceptable Time Windows for Parameters Other than 
Data from the Patient Diary
Measurements collected within the acceptable time window for each scheduled 
assessment time point, including data obtained at the time of withdrawal, will be used for 
the analyses of all endpoints at each assessment time point. For all patients with multiple 
measurements within a visit window, the measurement obtained closest to the target time 
point will be used. If two measurements collected with the same time deviation exist 
before and after the target time point, the measurement obtained before the target time 
point will be adopted for analysis. The assessment time point having no measurements 
within the corresponding acceptable time window will be considered as missing.
In the patient diary, if there are multiple measurements which may be adopted for a
scheduled assessment, even though the above rules have been strictly followed, the 
measurements of the earlier assessment date or the earlier assessment time of day will be 
adopted (with the priority given to morning, followed by afternoon, evening, and bedtime,
in this order). If multiple measurements collected with the same time (date and hour) for 
body temperature, the highest measurement will be adopted.
Time Point
Acceptable Time Window
Pre-dose at Visit 1 (Day 1: Day -2 to Day1)
Predose from Day -2 to Day 1 for safety assessment
Pre-dose at Visit 1 (Day 1)
Predose on Day 1 for efficacy assessment
Post-dose at Visit 1 (Day 1)
QOL assessment with EQ-5D-5L questionnaire:
by 0.5 hour post-dose on Day 1
Other measurements:
0.5 to 4 hours post-dose on Day 1
Visit 2 (Day 2)
Day 2
Visit 3 (Day 3)
Between Day 3 and Day 4
Optional-Visit 1 (Day 4)
Day 4
Visit 4 (Day 5)
Between Day 5 and Day 6
Optional Visit 2 (Day 6)
Day 6
Visit 5 (Day 9)
Between Day 7 and Day 11
Visit 6 (Day 15)
Between Day 12 and Day 18
Visit 7 (Day 22)
Between Day 19 and Day 25
Early termination
Date of early termination + 3 days


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In the assessment of items from other than the patient diary, if there are multiple 
measurements which may be adopted for a scheduled assessment time point (even though 
the above rules have been strictly followed), the measurements at the time point entered 
in the CRF will be adopted.
6.4
Handling of Missing Data
Missing data will not be imputed. 

Patients who do not experience alleviation of symptoms will be censored at the 
last observation time point, except in the case of sensitive analysis for primary 
analysis.
–
If all symptoms were missing after baseline, time to alleviation of symptoms,
time to alleviation of symptoms excluded cough, time to alleviation of the 4 
systemic symptoms, time to alleviation of the 3 respiratory symptoms and 
time to alleviation of individual symptoms will be handled as missing.

For the sensitive analysis for primary endpoint, the patients who do not 
experience alleviation of symptoms will be treated as follows.
–
If patients who discontinue from the study and still have influenza symptoms, 
time to alleviation of symptoms will be censored as 14 days.
–
In consideration of treatment duration of the oseltamivir group.
x
If patients who discontinue until Day 5 and still have influenza, time to 
alleviation of symptoms will be censored at the last observation time 
point.
x
If patients who discontinue after Day 5 and still have influenza, time to 
alleviation of symptoms will be censored as 14 days.
–
In consideration of the reason of the discontinuation.
x
If patients discontinue due to AE or lack of efficacy, time to alleviation of 
symptoms will be censored as 14 days.
x
If patients discontinue due to other reason, time to alleviation of symptoms 
of the patients will be censored at the last observation time point.
6.4.1
Handling of Virology Test Data in Consideration of the Stability 
Window
Sample processing time is defined as the time between the time of sample collecting and
the time of sample aliquotting recorded in the shipment manifest from Eurofins. Any 
quantitative virus titer and quantitative PCR samples processed within 96 hour as sample 
processing time will be included for analysis. The qualitative PCR before initial dosing is 
excluded from the 96 hour turn-around requirement. All qualitative PCRs before initial 
dosing will be considered evaluable regardless of sampling and aliquotting time.

If the time of sample aliquotting is not recorded at Eurofins, sample processing 
time will be treated as missing.


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6.5
Definition
6.5.1
Display of Days of Study
The date of the first dose and the day before the first dose of the S-033188/Placebo will 
be designated as Day 1 and Day -1, respectively.
6.5.2
Baseline
For influenza symptoms scores, the measurement entered in the CRF is defined as 
baseline. If there are influenza symptoms scores entered in the e-Diary prior to the initial 
dosing, these measurements will not be used for analysis.
For body temperature, assessment of health and EQ-5D-5L, the measurement with the 
following two conditions is defined as baseline. If there are multiple measurements which 
may be adopted, the measurement obtained at the earliest time will be used, otherwise 
measurements prior to the initial dosing will not be used for analysis.
y
Data observed when e-diary is set up
y
Data observed when first administration and sending are occurred on the same 
day
For assessment of health prior to influenza symptoms, the measurement with the 
following condition is defined as health status prior to influenza symptoms. If there are 
multiple measurements which may be adopted, the measurement obtained at the earliest
time will be used.
y
Data observed when first administration and sending are occurred on the same 
day
For efficacy assessments other than above, baseline is defined as the measurement 
obtained before the first administration at Visit 1 (predose).
For safety assessments other than above, baseline is defined as the last measurement
obtained before the first administration.
7.
DEMOGRAPHIC VARIABLES AND OTHER BASELINE
CHARACTERISTICS
7.1
Subject Disposition
1) Among all randomized subjects, the numbers of subjects who complete the study 
and subjects who discontinue the study will be tabulated by treatment group. For 
subjects who discontinue the study, reasons for withdrawal will also be tabulated 
by treatment group.
2) The number and percentage of subjects included in each of the ITTI and the PPS 
Populations among all randomized subjects will be calculated for the S-033188 
group and Placebo group. For the subjects excluded from each population, the 


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reason for exclusion will be summarized. Fisher’s exact test will be performed 
with a two-sided significance level of 0.15 to check differences among the 
treatment groups regarding the distribution of subjects in the ITTI and the PPS 
Populations. For the patients aged 20 to 64 years, the similar analyses will be 
applied in the S-033188 group and Oseltamivir group.
3) The number and percentage of subjects included in the Safety population among 
all randomized subjects will be calculated by prescribed treatment group. For the 
subjects excluded from the Safety population, the reason for exclusion will be 
summarized. For patients who receive at least one dose of the study drug, the 
treatment that the patients actually received will be defined as prescribed 
treatment. For patients who don’t receive one dose of the study drug, the 
treatment to which the patients were randomized will be defined as prescribed 
treatment.
7.2
Demographic and Baseline Characteristics
The following demographic and baseline characteristics among the ITTI and Safety 
Populations will be summarized using descriptive statistics for the S-033188 group,
Oseltamivir group and placebo group. For quantitative data, the descriptive statistics will 
be calculated. For qualitative data, the frequency of each category and the percentage of 
subjects in each category among all subjects included in the analysis population will be 
presented. 
For the patients aged 20 to 64 years in the ITTI Population, the following demographic 
and baseline characteristics will be summarized in the same manner.

Continuous variable
Age, height, body weight, BMI, total score of influenza symptoms and body 
temperature

Categorical variable
Age, body weight, sex, region, race, ethnicity, time to treatment from flu onset, 
presence or absence of flu vaccination, prior drug, prior therapy, medical history,
smoking habits, presence or absence of meal before initial study treatment,
duration between meal and administration (hours) (definition: absolute value of 
“time of dosing on Day 1” minus “time of meal obtained closest to the time of 
dosing on Day 1”), composite symptom scores, presence or absence of meal after 
initial study treatment, influenza virus subtype based on RT-PCR and influenza 
virus subtype based on RIDT (Rapid Influenza Diagnostic Test).
8.
STUDY CONDUCT
8.1
Treatment Exposure and Compliance
The duration of treatment exposure will be summarized with descriptive statistics by the 
S-033188 group and oseltamivir group for the safety population.


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The duration of treatment exposure [day] is defined as the dosing period during which a 
subject took medication as follows;
{(final dose date) – (initial dose date) + 1}
If a patient does not taken any study drug, the duration of treatment exposure will be 
defined as 0.
The treatment compliance rate will be summarized with descriptive statistics by the 
treatment group for the safety population. In addition, the frequency of each category and 
the percentage of subjects in each category among all subjects included in the analysis 
population will be presented.
The treatment compliance rate [%] is defined as;
100×{(actual frequency of treatment exposure) / (expected frequency of treatment exposure by 
early discontinuation of treatment)} 
8.2
Medical History
Prior and concomitant medical histories will be coded using the MedDRA Version 19.1.
Medical history (concurrent and previous disease) will be presented by treatment group
for the Safety population.
8.3
Prior and Concomitant Medication
Prior and concomitant drugs will be coded using the World Health Organization (WHO) 
Drug Dictionary. Medication consists of drug and therapy. Prior medication is defined as 
all medications taken before Day 1 of study administration. Concomitant medication is 
defined as all medications taken on Day 1 or later. The drug and therapy can be also 
classified as both prior and concomitant.
For Safety population, the number of subjects who took prior drug and concomitant drug,
and corresponding proportion will be summarized by WHO class and preferred term for 
each treatment group. For Safety populatios, the number of subjects who took prior 
therapy and concomitant therapy, and corresponding proportion will be summarized for 
each treatment group.
For ITTI Population, frequency of acetaminophen use will be summarized for each 
treatment group. Even though the date or time of acetaminophen use is missing, the 
frequency is counted. Wilcoxon rank sum test will be used to compare in frequency
between the S-033188 group and the placebo or the Oseltamivir group. The two-sided 
significance level will be set at 0.15 in these analyses.
9.
EFFICACY ANALYSIS
In the ITTI Population that is the primary analysis population, the primary endpoint and 
all secondary endpoints will be analyzed. For the PPS that is a secondary analysis 
population, only the primary endpoint will be analyzed. Table 3 summarizes the primary 


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endpoint, secondary endpoints, other endpoints and statistical methods used to analyze 
these endpoints. The detailed statistical methods are described in later sections.
The analysis of each efficacy endpoint will consist of comparison between the S-033188
group (40 mg and 80 mg combined) and the placebo group using data of the two age 
strata pooled (i.e., 12 to 64 years age), and comparison between the S-033188 group (40 
mg and 80 mg combined) and the oseltamivir group using data of 20 to 64 years age 
stratum.
Table 3
Statistical Methods Used to Analyze Each Endpoint
Endpoint Analysis
Statistical 
Method
Primary Endpoint
Time to alleviation of symptoms
1, 2, 9, 10, 11
Secondary 
Endpoints
Proportion of patients positive for influenza virus titer
3, 13
Proportion of patients positive by RT-PCR
3, 13
Change from baseline in virus titer 
4, 12
Change from baseline in the amount of virus RNA (RT-PCR)
4, 12
Area under the curve adjusted by baseline in virus titer
4, 12
Area under the curve adjusted by baseline in the amount of 
virus RNA (RT-PCR)
4, 12
Time to cessation of viral shedding by virus titer
1, 9, 10,11
Time to cessation of viral shedding by RT-PCR
1, 9, 10,11
Proportion of patients whose symptoms has been alleviated
3, 13
Time to alleviation of the 4 systemic symptoms
1, 9, 10,11*
Time to alleviation of the 3 respiratory symptoms
1, 9, 10,11*
Change from baseline in composite symptom score
6, 12
Time to resolution of fever
1, 9, 10,11
Proportion of patients reporting normal temperature
3, 13
Body temperature
6, 12
Time to alleviation of individual symptoms
1, 9, 10,11*
Time to return to preinfluenza health status
1, 9, 10,11*
Incidence of influenza-related complications
5, 13
Other Endpoints
Serum influenza antibody titer
7, 13, 14
Polymorphic and treatment-emergent amino acid substitutions 
in the PA gene of evaluable virus
13
Drug susceptibility in patients with evaluable virus
12
EQ-5D-5L and EQ VAS
12
Work productivity questionnaire
12
Intrahousehold infection rate
8
*
Treatment group difference in median time
[Statistical test methods]
1.
Stratified Peto-Prentice's generalized Wilcoxon test


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2.
Stratified log rank test
3.
Mantel-Haenszel test
4.
van Elteren test
5.
Fisher’s exact test
6.
Analysis of covariance (ANCOVA)
7.
Wilcoxon rank sum test
8.
Poisson regression model
[Summarization methods]
9.
Kaplan-Meier curve
10. Median time and its 95% CI
11. Treatment group difference in median time and its 95% CI (Bootstrap method)
12. Summary statistics (continuous variables)
13. Summary statistics (categorical variables)
14. Geometric mean
9.1
Primary Endpoint
The primary efficacy endpoint is the time to alleviation of symptoms (unit: hours), which 
is defined as the time between the initiation of the study treatment and the alleviation of 
influenza symptoms. The alleviation of symptoms is defined as the time when all of 7 
influenza symptoms (cough, sore throat, headache, nasal congestion, feverishness or 
chills, muscle or joint pain, and fatigue) have been assessed by the patient as 0 (None) or 
1 (Mild) in the patient eDiary, for a duration of at least 21.5 hours (24 hours − 10%).
9.1.1
Analyses of Primary Endpoint
9.1.1.1
Primary Analysis
Time to alleviation of symptoms will be compared between the S-033188 group and the 
placebo group using the stratified Peto-Prentice’s generalized Wilcoxon test with 
composite symptoms score at baseline (≤ 11 or ≥ 12) and region (Japan/Asia or Rest of 
the world) as stratification factors. Patients who do not experience alleviation of 
symptoms will be censored at the last observation time point. If at least one of the 7 
influenza symptom scores is missing at date and time of assessment that patients have, 
missing assessments of influenza symptoms conservatively will be treated as having 
moderate or severe symptoms (as failures) at the corresponding date and time of 
assessment.
[Comparison between the S-033188 group and the placebo group]
proc lifetest data = analysisdata;
where TRTP in ("S-033188", "Placebo");
time TIME * CENSOR (0);
strata SCOREC REGION / group = TRTP test = PETO ;
run;quit;

TRTP: Treatment group

TIME: Time to alleviation of symptoms


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
SCOREC: Category of baseline composite symptom score (≤11 or ≥12)

REGION: Category of region (Japan/Asia or Rest of the world)
The same analysis in PPS will be performed as a sensitivity analysis.
9.1.1.2
Secondary Analysis
Time to alleviation of symptoms will be compared between the S-033188 group and the 
Oseltamivir group using the stratified Peto-Prentice’s generalized Wilcoxon test with 
composite symptoms score at baseline (≤ 11 or ≥ 12) and region (Japan/Asia or Rest of 
the world) as stratification factors. Patients who do not experience alleviation of 
symptoms will be censored at the last observation time point. If at least one of the 7 
influenza symptom scores is missing at date and time of assessment that patients have, 
missing assessments of influenza symptoms conservatively will be treated as having 
moderate or severe symptoms (as failures) at the corresponding date and time of 
assessment.
The same analysis in PPS will be performed as a sensitivity analysis.
9.1.1.3
Other Analysis
The Kaplan-Meier survival curve will be plotted for each treatment group, and the 
median time to alleviation of symptoms and its 95% CI will be calculated. The 
Greenwood method will be used in the calculation of the CIs. In addition, the treatment 
group difference in median time and its 95% CI will be estimated. The 95% CI of 
difference of median time will be obtained by the bootstrap percentile method. The 
10,000 bootstrap samples will be generated by the following SAS code. A random seed of 
16010831 and 16010832 will be used for comparison between the S-033188 and the
Placebo or the Oseltamivir, respectively. Then, the treatment group difference in median 
time will be calculated by each bootstrapped sample and its 95% CI will be constructed 
using percentiles of the bootstrap distribution.
proc surveyselect data = analysisdata seed = 16010831 out = bootstap method = urs 
rate = 1.0 rep = 10000 outhits;
strata TRTP;
run;quit;

TRTP: Treatment group
The same analysis in PPS will be performed as a sensitivity analysis.
9.1.1.4
Sensitivity Analysis
1) Time to alleviation of symptoms will be compared between the S-033188 group 
and the placebo group using the stratified log rank test with composite symptoms
score at baseline (≤ 11 or ≥ 12) and region (Japan/Asia or Rest of the world) as 
stratification factors. Patients who do not experience alleviation of symptoms will 


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be censored at the last observation time point. The same analysis will be applied 
to compare the S-033188 group with the Oseltamivir group.
2) If patients who discontinue from the study and still have influenza symptoms,
they will be treated as follows in the similar analysis at section 9.1.1.1, 9.1.1.2
and 9.1.1.3 (excluding analyses of PPS population and 95% CI for group 
difference in median time).

If patients who discontinue from the study and still have influenza symptoms, 
time to alleviation of symptoms will be censored as 14 days.

In consideration of treatment duration of the Oseltamivir group.
x
If patients who discontinue until Day 5 and still have influenza, time to 
alleviation of symptoms will be censored at the last observation time 
point.
x
If patients who discontinue after Day 5 and still have influenza, time to 
alleviation of symptoms will be censored as 14 days.

In consideration of the reason of the discontinuation.
x
If patients discontinue due to AE or lack of efficacy, time to alleviation of 
symptoms will be censored as 14 days.
x
If patients discontinue due to other reason, time to alleviation of symptoms
of the patients will be censored at the last observation time point.
3) Time to alleviation of symptoms excluding cough will be compared between the 
S-033188 group and the placebo group using the stratified Peto-Prentice’s 
generalized Wilcoxon test with composite symptoms score at baseline (≤ 11 or ≥ 
12) and region (Japan/Asia or Rest of the world) as stratification factors. Patients 
who do not experience alleviation of symptoms will be censored at the last 
observation time point. If at least one of the 6 influenza symptom scores is 
missing at date and time of assessment that patients have, missing assessments of 
influenza symptoms conservatively will be treated as having moderate or severe 
symptoms (as failures) at the corresponding date and time of assessment. The 
same analysis will be applied to compare the S-033188 group with the 
Oseltamivir group. This alleviation of symptoms excluding cough is defined as 
the time when all of 6 influenza symptoms (sore throat, headache, nasal 
congestion, feverishness or chills, muscle or joint pain, and fatigue) have been 
assessed by the patient as 0 (None) or 1 (Mild) in the patient eDiary, for a 
duration of at least 21.5 hours (24 hours − 10%).
9.2
Secondary Endpoints
1) Proportion of patients positive for influenza virus titer (unit: %)
Proportion of patients positive for influenza virus titer is defined as the percentage 
of patients whose virus titer is not less than the lower limit of quantification (0.7 
log10TCID50/mL) among those assessed for virus titer on Days 2, 3, 4, 5, 6 and 9.
Patients with a positive virus titer on Day 1 will be included in this analysis.


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2) Proportion of patients positive by RT-PCR (unit: %)
Proportion of patients positive by RT-PCR is defined as the percentage of patients 
with detectable virus RNA (2.05 for flu A and 2.83 for flu B log10 vp/mL) among
those assessed by RT-PCR on Days 2, 3, 4, 5, 6 and 9.
Patients with a positive by RT-PCR on Day 1 will be included in this analysis.
3) Change from baseline in virus titer (unit: log10TCID50/mL)
Change from baseline in virus titer is defined as the change from baseline in virus 
titer on Days 2, 3, 4, 5, 6 and 9. If virus titer is less than the lower limit of 
quantification, the virus titer will be imputed 0.7 (TCID50/mL).
Patients with a positive virus titer on Day 1 will be included in this analysis.
4) Change from baseline in the amount of virus RNA (RT-PCR) (unit: log10 virus 
particles/mL)
Change from baseline in the amount of virus RNA is defined as the change from 
baseline in the amount of virus RNA on Days 2, 3, 4, 5, 6 and 9. If the amount of 
virus RNA is less than the lower limit of quantificationand greater than or equal 
to the lower limit of detection, the amount of virus RNA will be imputed 2.18 for 
flu A and 2.93 for flu B (log10 virus particles/mL). If the amount of virus RNA is 
less than the lower limit of detection, the amount of virus RNA will be imputed 
2.05 for flu A and 2.83 for flu B (log10 vp/mL).If a patient is infected with one 
virus type, the amount of virus RNA for infected virus type will be used for 
analysis. If a patient is infected with multiple virus types, the sum of those amount 
of virus RNA will be used for analysis. If the amount of virus RNA is missing for 
at least one of the multiple infected virus types collected on the same date, the 
amount of multiple virus RNA will be handled as missing at the corresponding 
date of assessment.
Patients with a positive by RT-PCR on Day 1 will be included in this analysis.
5) Area under the curve adjusted by baseline in virus titer
(unit: log10TCID50/mL×hours)
This endpoint is defined as AUC of change from baseline in virus titer from Day 
1 to Day 9. AUC is calculated using the trapezoidal method. AUC of change from 
time 0 (t0) to time K (tK) is given by the formula




¦
 





K
k
k
k
k
k
t
t
y
y
y
1
1
0
1
2
2
where tk (hours) represents the date of the kth viral titer assessment (k = 0, ..., K)
and yk represents the log10 value of the kth viral titer assessment (TCID50/mL). The 
lower limit is defined as 0.7 (TCID50/mL). One day is equal to 24-hours.
Patients with a positive virus titer on Day 1 and available sample on Day 9 will be 
included in this analysis.


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6) Area under the curve adjusted by baseline in the amount of virus RNA (RT-PCR)
(unit: log10 virus particles/mL×hours)
This endpoint is defined as AUC of change from baseline in the amount of virus 
RNA (RT-PCR) from Day 1 to Day 9. The AUC is calculated using the same 
formula described in ‘Area under the curve adjusted by baseline in virus titer’.
The lower limit of quantification and greater than or equal to the lower limit of 
detection is defined as 2.18 for flu A and 2.93 for flu B (log10 virus particles/mL).
The amount of virus RNA is less than the lower limit of detection, the amount of 
virus RNA will be imputed 2.05 for flu A and 2.83 for flu B (log10 vp/mL).If a 
patient is infected with one virus type, the amount of virus RNA for infected virus 
type will be used for analysis. If a patient is infected with multiple virus types, the 
sum of those the amount of virus RNA will be used for analysis. If the amount of 
virus RNA is missing for at least one of the multiple infected virus types collected 
on the same date, the amount of multiple virus RNA will be handled as missing at 
the corresponding date of assessment.
Patients with a positive by RT-PCR on Day 1 and available sample on Day 9 will 
be included in this analysis.
7) Time to cessation of viral shedding by virus titer (unit: hours)
This endpoint is defined as the time between the initiation of the study treatment 
and first time when the virus titer is below the limit of detection (0.7 
log10TCID50/mL). Patients whose virus titer have not reached cessation by the 
last observation time point will treated as censored at that time point. One day is 
converted into 24 hours.
Patients with a positive virus titer on Day 1 will be included in this analysis.
8) Time to cessation of viral shedding by RT-PCR (unit: hours)
This endpoint is defined as the time between the initiation of the study treatment 
and first time when the virus RNA by RT-PCR is below the limit of detection.
Patients whose virus RNA have not reached cessation by the last observation time 
point will treated as censored at that time point. For the patients with multiple 
virus types, this endpoint is defined as the time between the initiation of the study 
treatment and first time when the virus RNA by RT-PCR is below the limit of 
detection for all virus types. One day is converted into 24 hours.
Patients with a positive virus RNA on Day 1 will be included in this analysis.
9) Proportion of patients whose symptoms have been alleviated (unit: %)
This endpoint is defined as the percentage of patients whose symptoms have been 
alleviated at 12, 24, 36, 48, 72, 96, 120, 144, 168, 192 and 216 hours after the 
initial of study treatment. The alleviation of symptoms is defined as the time when 
all of 7 symptoms have been assessed by the patient as 0 (None) or 1 (Mild) in the 
patient eDiary.
10) Time to alleviation of the 4 systemic symptoms (unit: hours)
The endpoint is the time to alleviation of the 4 systemic symptoms (headache, 
feverishness or chills, muscle or joint pain, and fatigue), which is defined as the 


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time between the initiation of the study treatment and the alleviation of influenza 
symptoms. The alleviation of the 4 symptoms is defined as the time when all of 
the 4 systemic symptoms have been assessed by the patient as 0 (None) or 1 
(Mild) in the patient eDiary, for a duration of at least 21.5 hours (24 hours − 
10%).
Patients who do not experience alleviation of symptoms by the last observation 
time point will be censored at that time point. If at least one of the 4 influenza 
symptom scores is missing at date and time of assessment that patients have, 
missing assessments of influenza symptoms conservatively will be treated as 
having moderate or severe symptoms (as failures) at the corresponding date and 
time of assessment.
11) Time to alleviation of the 3 respiratory symptoms (unit: hours)
The endpoint is the time to alleviation of the 3 respiratory symptoms (cough, sore 
throat, and nasal congestion), which is defined as the time between the initiation 
of the study treatment and the alleviation of influenza symptoms. The alleviation 
of the 3 symptoms is defined as the time when all of the 3 respiratory symptoms 
have been assessed by the patient as 0 (None) or 1 (Mild) in the patient eDiary, 
for a duration of at least 21.5 hours (24 hours − 10%). Patients who do not 
experience alleviation of symptoms by the last observation time point will be
censored at that time point. If at least one of the 3 influenza symptom scores is 
missing at date and time of assessment that patients have, missing assessments of 
influenza symptoms conservatively will be treated as having moderate or severe 
symptoms (as failures) at the corresponding date and time of assessment.
12) Time to alleviation of individual symptoms (unit: hours)
Time to alleviation of cough symptom is defined as the time from the start of 
treatment to the start of the time period when cough symptom have been assessed 
by the patient as 0 (None) or 1 (Mild) in the patient eDiary, for a duration of at 
least 21.5 hours (24 hours − 10%). The following endpoints are defined in a 
similar way. Patients who do not experience alleviation of symptoms by the last 
observation time point will be censored at that time point. If symptom score is 
missing at date and time of assessment that patients have, missing assessment of 
influenza symptom conservatively will be treated as having moderate or severe 
symptoms (as failures) at the corresponding date and time of assessment.
Patients whose symptom at baseline is assessed as 0 (None) or 1 (Mild) will be 
excluded from the analysis.

Time to alleviation of sore throat symptom

Time to alleviation of headache symptom

Time to alleviation of nasal congestion symptom

Time to alleviation of feeling feverish or having chills symptom

Time to alleviation of aches and pains of the muscle or joints symptom

Time to alleviation of fatigue symptom


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13) Change from baseline in composite symptom score
This endpoint is defined as the change from baseline in the total score of 7 
influenza symptoms (cough, sore throat, headache, nasal congestion, feverishness 
or chills, muscle or joint pain, and fatigue) as assessed by the patient in the patient 
eDiary at 12, 24, 36, 48, 72, 96, 120, 144, 168, 192 and 216 hours. “None”,
“Mild”, “Moderate” and “Severe” will be scored as 0, 1, 2 and 3, respectively. If 
at least one of the 7 influenza symptom scores is missing at date and time of 
assessment that patients have, composite symptom score will be handled as 
missing at the corresponding date and time of assessment.
14) Time to resolution of fever (unit: hours)
Time to resolution of fever is defined as the time between the initiation of the 
study treatment and the resolution of fever. The resolution of fever is defined as 
the time when the patient’s self-measured axillary temperature becomes less than 
37ºC and is maintained at less than 37ºC for duration of at least 12 hours. Patients 
who do not experience resolution of fever by the last observation time point will 
be censored at that time point. If body temperature is missing at date and time of 
assessment that patients have, missing assessments of body temperature
conservatively will be treated as having more than 37 ºC (as failures) at the 
corresponding date and time of assessment. Patients whose body temperature at 
baseline is less than 37ºC will be excluded from the analysis. Body temperature
obtained when e-diary is set up after initial dosing will not be used for analysis.
Because these data may be observed due to e-dairy system’s incorrect setting.
15) Proportion of patients reporting normal temperature (unit: %)
Proportion of patients reporting normal temperature is defined as the percentage 
of patients whose axillary temperature drops to less than 37ºC after the initiation 
of the study treatment at 12, 24, 36, 48, 72, 96, 120, 144, 168, 192 and 216 hours.
Body temperature obtained when e-diary is set up after initial dosing will not be 
used for analysis. Because these data may be observed due to e-dairy system’s 
incorrect setting.
Patients whose body temperature at baseline is less than 37ºC will be excluded 
from the analysis.
16) Body temperature (unit: degree)
Body temperature is defined as measured axillary temperature at 12, 24, 36, 48, 
72, 96 and 120 hours. Body temperature obtained when e-diary is set up after 
initial dosing will not be used for analysis. Because these data may be observed 
due to e-dairy system’s incorrect setting.
17) Time to return to preinfluenza health status (unit: hours)
Patients will be asked to record their preinfluenza health status between 0 (worst
possible health) and 10 (normal health [for someone your age and your health
condition]). Time to return to preinfluenza health status is defined as the time 
from the initiation of the study treatment to the first time when health status score 
is equal to or higher than the preinfluenza health status score. Patients who have 


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smaller number on scale for preinfluenza health status by the last observation time 
point will be censored at that time point. If preinfluenza health status is missing at 
date and time of assessment that patients have, missing assessments of 
preinfluenza health status conservatively will be treated as having less than 
preinfluenza health status at the corresponding date and time of assessment.
Patients whose health status score at baseline is equal to or higher than the 
preinfluenza health status score will be excluded from the analysis. Health status 
score obtained when e-diary is set up after initial dosing will not be used for 
analysis. Because these data may be observed due to e-dairy system’s incorrect 
setting.
18) Incidence of influenza-related complications (unit: %)
This endpoint is defined as the percentage of patients who experience each 
influenza-related complication (hospitalization, death, sinusitis, otitis media, 
bronchitis, and radiologically confirmed pneumonia) as an AE after the initiation 
of the study treatment. A specific complication eCRF with diagnostic criteria for 
the complications of sinusitis, otitis media, bronchitis and pneumonia will be 
provided as following rules.

Sinusitis
y
‘Sinusitis’ in the ‘Form Incidence of influenza-related complications’ is 
‘Yes’
y
And ‘Did these symptoms start after the influenza treatment was given 
on Day 1?’ in the ’Form Sinusitis’ is ‘Yes’
y
And ‘Does the patient have a purulent nasal discharge?’ in the ’Form 
Sinusitis’ is ‘Yes’
y
And ‘Does the patient have facial pain, pressure sensation, or sensation 
of fullness?’ in the ’Form Sinusitis’ is ‘Yes’
y
And ‘Does the patient have nasal obstruction, congestion or stuffiness?’ 
in the ’Form Sinusitis’ is ‘Yes’

Otitis media
x
‘Otitis media’ in the ‘Form Incidence of influenza-related complications’ 
is ‘Yes’
x
And ‘Did these symptoms start after the influenza treatment was given 
on Day 1?’ in the ’Form Otitis Media’ is ‘Yes’
x
And ‘Does the patient have pain or fullness in one or more ears?’ in 
the ’Form Otitis Media’ is ‘Yes’
x
And ‘Does the patient have tympanic membrane bulging or fullness on 
otoscopy?’ in the ’Form Otitis Media’ is ‘Yes’

Bronchitis 
x
‘Bronchitis’ in the ‘Form Incidence of influenza-related complications’ is 
‘Yes’


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x
And ‘Did these symptoms start after the influenza treatment was given 
on Day 1?’ in the ’Form Bronchitis’ is ‘Yes’
x
And ‘Does the subject have a productive cough that has got worse after 
Day 1?’ in the ’Form Bronchitis’ is ‘Yes’

Pneumonia
x
‘Pneumonia’ in the ‘Form Incidence of influenza-related complications’ is 
‘Yes’
x
And ‘Did these symptoms start after the influenza treatment was given 
on Day 1?’ in the ’Form Pneumonia’ is ‘Yes’
x
And ‘Does the patient have worsening cough since starting study 
treatment?’ in the ’Form Pneumonia’ is ‘Yes’
x
And ‘Does a Chest X Ray confirm pneumonia i.e. consolidation?’ in 
the ’Form Pneumonia’ is ‘Yes’
9.3
Other Endpoints
1) Serum influenza antibody titer
This endpoint is defined as the ratio of value on Day 22 to that on Day 1.
2) Polymorphic and treatment-emergent amino acid substitutions in the PA geneof 
evaluable virus
This endpoints is defined as follows:
–
The percentage of samples which have polymorphic amino acid substitutions 
on Day 1 compared to the reference sequence
–
The percentage of samples which have treatment-emergent amino acid 
substitutions between Day 1 and the time point when last positive RT-PCR is 
obtained
For treatment-emergent amino acid substitutions in the PA gene, sequencing data 
obtained at the baseline (Day 1) and last RT-PCR positive timepoint will be 
compared for treatment-emergent amino acid substitutions in the PA gene in the 
S-033188 group and placebo group, respectively. 
For polymorphic amino acid substitutions in the PA gene, sequencing data 
obtained at the baseline (Day 1) will be compared to that of the reference 
sequence in the S-033188 group and the placebo group, respectively.
The patients who have sequencing performed will be included in this analysis.
3) Drug susceptibility in patients with evaluable virus (unit: EC50 nM, IC50nM)
This endpoints is defined as follows:
–
EC50 for S-033447 at baseline
–
IC50 for oseltamivir at baseline
–
The ratio of EC50 for S-033447 realative to EC50 for reference stain
–
The ratio of IC50 for oseltamivir realative to IC50 for reference stain
If the EC50 is less than the lower limit, the EC50 will be imputed the lower limit


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value (0.03 nM). If the EC50 is greater than upper limit, the EC50 will be imputed 
as the value of upper limit (1000 nM).
If the IC50 is less than the detection limit, the IC50 will be imputed detection limit 
value (0.01 nM). If the IC50 is greater than upper limit, the IC50 will be imputed 
as the value of upper limit (10000 nM).
The patients with a detected value at baseline will be included in this analysis. 
However, the patients infected with multiple virus types will be excluded from 
this analysis.
4) EQ-5D-5L and EQ VAS
These endpoints consist of the change from baseline in the index value calculated 
from the EQ-5D-5L questionnaire and that in EQ VAS score on Day 1, 2, 3, 4, 5, 
6, 7, 8, 9, 10, 11, 12, 13, 14 and 22. The index value will be recorded twice daily 
(morning and evening) from Day 1 to Day 9, and once daily (evening) from Day 
10 to 14, and Day 22. A conversion table proposed by Ikeda et al. (2015) [1] will 
be used to convert EQ-5D-5L status to index value.
The EQ-5D-5L and EQ VAS data obtained when e-diary is set up after initial 
administration will not be used for analysis. Because these data may be observed 
due to e-dairy system’s incorrect setting. In addition, the EQ-5D-5L and EQ VAS 
data observed in the evening after Day 15 will be excluded from this analysis. 
Because these data may be observed at unplanned time point in the protocol due 
to e-dairy system’s incorrect setting. Only if evening data observed on the last 
visit date but no data whose timepoint is ‘Visit’ are collected, the data will be 
included in the analysis.
5) Work productivity (WP) questionnaire
The WP questionnaire consists of 4 questions regarding employment, hours 
worked, productivity while at work, and requirement for personal assistance. The 
following 2 endpoints are derived from Q1 to Q3 questions.
The percentage of absenteeism due to influenza illness is defined as follows;
100×(duration unable to work due to influenza illness: Q2) / (duration of working 
per 21 days: Q1×21 days/7 days) (unit: %)
The patients whose Q1 and Q2 were observed with the same unit will be included 
in this analysis.
The percentage of work productivity loss due to influenza illness is defined as 
follows;
100×{(duration unable to work due to influenza illness: Q2) + (duration of 
working below normal standard: Q3)}/ (duration of working per 21 days: Q1×21
days/7 days) (unit: %)
The patients whose Q1,Q2 and Q3 were observed with the same unit will be 
included in this analysis.


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6) Intrahousehold infection rate (for Japan site only)
Intrahousehold infection rate in each patient is defined as follows
100×(the number of household members infected between Day 1 and Day 15) / 
{(the number of household members, excluding the patient him/herself) – (the 
number of household members infected by Day 1)} (unit: %)
The patients who have no household members or whose all household members 
has already been infected by Day 1 will be excluded from the analysis population.
When a part of the date of influenza diagnosis is observed for a household 
member, he/she is defined as a influenza case in household. If any part of the date 
of his/her influenza diagnosis is missing, he/she will be diagnosed between Day 1 
and Day 15.
For each of the following time periods, definition of this endpoint will be defined 
as below.

100×(the number of household members infected between Day 1 and Day 3) / 
{(the number of household members, excluding the patient him/herself) – (the 
number of household members infected by Day 1)} (unit: %)

100×(the number of household members infected between Day 1 and Day 4) / 
{(the number of household members, excluding the patient him/herself) – (the 
number of household members infected by Day 1)} (unit: %)

100×(the number of household members infected between Day 1 and Day 6) / 
{(the number of household members, excluding the patient him/herself) – (the 
number of household members infected by Day 1)} (unit: %)

100×(the number of household members infected between Day 1 and Day 11)
/ {(the number of household members, excluding the patient him/herself) –
(the number of household members infected by Day 1)} (unit: %)
9.4
Analyses of the Secondary Endpoints
The analysis population for the following analyses will be the ITTI Population unless 
otherwise specified.
1) Proportion of patients positive for influenza virus titer and virus RNA by RT-PCR
y
The proportion of patients positive for influenza virus titer/virus RNA 
(RT-PCR) at each scheduled time point will be calculated. The 95% CIs will 
be calculated by the Clopper-Pearson method.
y
The Mantel-Haenszel test with baseline composite symptom score (≤11 or 
≥12) and region (Japan/Asia, Rest of the world) as stratification factors will be 
used to compare these endpoints between two groups at each scheduled time 
point. 
2) Change from baseline in virus titer and in the amount of virus RNA (RT-PCR)
y
The summary statistics for the change from baseline in virus titer and in the 
amount of virus RNA (RT-PCR) will be presented by treatment group at each 
scheduled time point.


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y
Van Elteren test with baseline composite symptom score (≤11 or ≥12) and 
region (Japan/Asia, Rest of the world) as stratification factors will be used to 
compare these endpoints between two groups at each scheduled time point. 
The p value for the Van Elteren test is defined as the p value for “Row Mean 
Scores Differ” in the “Alternative Hypothesis of Cochran-Mantel-Haenszel 
Statistics”, using the following SAS code.
[Example: Comparison between the S-033188 group and the placebo group]
proc freq data= analysisdata;
table REGION*SCOREC*TRTP*VARIABLE / cmh2 scores=modridit 
noprint;
where TRTP in ("S-033188", "Placebo");
run;

SCOREC: Category of Baseline composite symptom score (≤11 or ≥12)

TRTP: Treatment group

VARIABLE: Response variable
3) Area under the curve adjusted by baseline in virus titer and in the amount of virus 
RNA (RT-PCR)
y
The similar analyses for the change from baseline in virus titer and the amount 
of virus RNA will be performed with the area under the curve adjusted by 
baseline as the response variable.
4) Time to cessation of viral shedding by virus titer/by virus RNA
The patients with a positive virus titer/the amount of virus RNA on Day 1 (i.e., 
patients whose virus titer/the amount of virus RNA is equal to the lower limit of 
detection or higher) will be included in the following analysis.
y
The similar analyses for the primary endpoint (Section 9.1.1.1, 9.1.1.2 and 
9.1.1.3, excluding analyses of PPS population) will be performed with time to 
cessation of viral shedding by virus titer/RT-PCR. The seed of bootstrapping 
will be used 16010832.
5) Proportion of patients whose symptoms has been alleviated
y
The proportion of patients whose symptoms has been alleviated at each 
scheduled time point will be calculated. The 95% CIs will be calculated by the 
Clopper-Pearson method.
y
The Mantel-Haenszel test with baseline composite symptom score (≤11 or 
≥12) and region (Japan/Asia, Rest of the world) as stratification factors will be 
used to compare these endpoints between two groups at each scheduled time 
point. 
6) Time to alleviation of the 4 systemic symptoms/3 respiratory symptoms
y
The similar analyses for the primary endpoint (Section 9.1.1.1, 9.1.1.2 and 
9.1.1.3, excluding analyses of PPS population and 95% CI for group 
difference in median time) will be performed with time to alleviation of the 4 
systemic symptoms/3 respiratory symptoms.


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7) Change from baseline in composite symptom score
y
The summary statistics for the change from baseline in composite symptom 
score will be presented by treatment group at each scheduled time point.
y
Analysis of covariance (ANCOVA) with baseline composite symptom score
and region (Japan/Asia, Rest of the world) as covariates will be used to 
compare the change from baseline in the composite symptoms score between 
two groups at each scheduled time point.

The least squares mean (LSM) change and its standard error of means 
(SE) in each group, the difference between two groups in LSM change, SE, 
and 95% CI, and p values will be calculated. 
[Comparison between the S-033188 group and the placebo group]
proc mixed data= analysisdata;
class REGION TRTP;
model CHG = TRTP bSCORE REGION /cl;
lsmeans TRTP;
estimate "S-033188 vs Placebo" TRTP 1 -1/cl;
run;

TRTP: Treatment group

CHG: Change from baseline in the composite symptoms score

bSCORE: Composite symptoms score at baseline
[Comparison between the S-033188 group and the Oseltamivir group]
proc mixed data= analysisdata;
class REGION TRTP;
model CHG = TRTP bSCORE REGION /cl;
lsmeans TRTP;
estimate "S-033188 vs Oseltamivir" TRTP 1 -1/cl;
run;

TRTP: Treatment group

CHG: Change from baseline in the composite symptoms score

bSCORE: Composite symptoms score at baseline
8) Time to resolution of fever 
y
An analysis similar to that for the primary endpoint (Section 9.1.1.1, 9.1.1.2 
and 9.1.1.3, excluding analyses of PPS population) will be performed with the 
time to resolution of fever as the response variable. The seed of bootstrapping 
will be used 16010833.


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9) Proportion of patients reporting normal temperature
y
An analysis similar to that for the proportion of patients positive for influenza 
virus titer and by RT-PCR will be performed with the proportion of patients 
reporting normal temperature.
10) Body temperature by time point
y
An analysis similar to that for the change from baseline in composite 
symptom score will be performed with the body temperature. Body 
temperature at baseline will be added to the covariates in performing 
ANCOVA.
11) Time to alleviation of individual symptoms
y
The similar analyses for the primary endpoint (Section 9.1.1.1, 9.1.1.2 and 
9.1.1.3, excluding analyses of PPS population and 95% CI for group 
difference in median time) will be performed with time to alleviation of 
individual symptoms.
12) Time to return to preinfluenza health status
y
The similar analyses for the primary endpoint (Section 9.1.1.1, 9.1.1.2 and 
9.1.1.3, excluding analyses of PPS population and 95% CI for group 
difference in median time) will be performed with time to return to 
preinfluenza health status.
13) Incidence of influenza-related complications
y
The incidence of each complication (hospitalization, death, sinusitis, otitis 
media, bronchitis, and radiologically confirmed pneumonia) and its 95% CI 
will be calculated by treatment group. The 95% CIs will be calculated by the 
Clopper-Pearson method.
y
Fisher’s exact test will be used will be used to compare incidence between two 
groups for each complication.
9.5
Analyses of the Other Endpoints
1) Serum Influenza Antibody Titer
y
Serum antibody titers measured on Day 1 and Day 22 will be categorized, and 
the frequency of each category and the corresponding percentage will be 
summarized by influenza virus subtype based on RT-PCR and treatment 
group. 
y
The ratio of value at Day 22 to that at Day 1 will be categorized, and the 
frequency of each category and the corresponding percentage will be tabulated 
by influenza virus subtype based on RT-PCR and treatment group. 
y
If serum antibody titer will be observed < 10 and > 1280, the ratio of value 
at Day 22 to that at Day 1 will be calculated using 10 and 1280, 
respecitively.
y
The categorized serum antibody titers at Day 1 and at Day 22 will be 
cross-tabulated. 


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y
The geometric mean value of the ratio of value at Day 22 to that at Day 1 will 
be calculated, and the Wilcoxon rank sum test will be used to compare the 
ratio between two groups.
If serum antibody titer will be observed < 40due to haemolytic serum sample, the 
observation will be handled as missing data for the above analyses.
2) Polymorphic and treatment-emergent amino acid substitutions in the PA Gene of 
Evaluable Virus
The patients who have sequencing performed will be included in the following 
analysis.
y
For the S-033188 group and the placebo group, amino acid substitutions data 
at the Day 1 and at the last RT-PCR positive time point will be cross-tabulated 
by each amino acid position in PA, influenza virus type and subtype of 
sequence sample and treatment group, in consiration of reference sequence.
3) Drug Susceptibility of Evaluable Virus
y
The summary statistics for EC50 and IC50 at baseline will be presented by 
influenza virus type and subtype based on RT-PCR and treatment group.
y
The summary statistics for the ratio of EC50 at baseline relative to EC50 for 
reference stain and the ratio of IC50 at baseline relative to IC50 for reference 
stain will be presented by influenza virus type and subtype based on RT-PCR 
and treatment group. For the patients infected with influenza A virus 
(A/H1N1pdm or A/H3), EC50 of reference strain A/Victoria/361/2011 and 
IC50 of reference strain A/Puerto/Rico/8/34 will be used. For the patients 
infected with influenza B virus, EC50 of reference stain B/Wisconsin/1/2010 
and IC50 of reference strain B/Lee/40 will be used.
4) Change in EQ-5D-5L and EQ VAS
y
The summary statistics for change in the index value and change in VAS score 
will be presented by treatment group at each scheduled time point.
5) Work Productivity Questionnaire
y
The summary statistics for the percentage of absenteeism due to influenza 
illness and the percentage of work productivity loss due to influenza illness 
will be presented by treatment group. 
y
For Question 4 in Work Productivity (WP) Questionnaire, the summary 
statistics for the number of days required for personal assistance will be 
presented by treatment group. One day is equal to 24-hours.
6)
Intrahousehold infection rate
Let K be the total number of patients included in this analysis, yk be the number of kth
patient’s household members infected between Day 1 and Day 15, and nk be the number 
of kth patient’s household members uninfected by Day 1 (k = 1, ..., K). Under the 
assumption that yk is distributed according to Poisson distribution with mean μk, the 
following Poisson regression model will be applied;


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k
k
k
x
n
1
0
log
log
E
E
P


 
In the model, ݔ௞is a group indicator variable for the kth patient, i.e., ݔ௞= 1 for the 
S-033188 group, ݔ௞= 0 for the control group (the placebo group or the oseltamivir 
group). The
0
E is an intercept parameter,
1
E is a regression parameter. Intrahousehold
infection rates for the S-033188 group and the control group are given by
)
exp(
1
0
E
E 
and
)
exp(
0
E
, respectively. Estimate and 95% CI of intrahousehold infection rate of each 
treatment group and comparison between two treatment groups will be carried out using 
the following SAS code. In addition, a risk ratio of the S-033188 group to the control 
group and the corresponding 95% CI will be estimated by the above Poisson regression 
model.
Data analysisdata;
set analysisdata;
lnum=log(NUM);
run;
[Comparison between the S-033188 group and the placebo group]
proc genmod data = analysisdata;
class TRTP;
model RES = TRTP / dist = poisson link = log offset = lnum;
lsmeans TRTP / cl exp;
estimate "S-033188 vs Placebo" TRTP 1 -1 / exp;
run;

NUM: Number of household members uninfected by Day 1

TRTP: Treatment group (1:S-033188, 2:Placebo)

RES: Number of household members infected between Day 1 and Day 15
[Comparison between the S-033188 group and the Oseltamivir group]
proc genmod data = analysisdata;
class TRTP;
model RES = TRTP / dist = poisson link = log offset = lnum;
lsmeans TRTP / cl exp;
estimate "S-033188 vs Oseltamivir" TRTP 1 -1 / exp;
run;

NUM: Number of household members uninfected by Day 1

TRTP: Treatment group (1:S-033188, 3:Oseltamivir)

RES: Number of household members infected between Day 1 and Day 15


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The similar Poisson regression model will be applied using the number of household 
members yk infected during each of the following time periods as a response variable;

From Day1 to Day 3

From Day 1 to Day 4

From Day1 to Day 6

From Day 1 to Day 11
9.6
Subgroup Analyses for Primary and Secondary Endpoint
Analyses of time to alleviation of symptoms (Section 9.1.1.1, 9.1.1.2, Kaplan-Meier 
curve, the median time to alleviation of symptoms and its 95% CI) will be presented for 
the following subgroup 1), 2), 3) and 4).
Subgroup analyses will be performed for the ITTI Population in the following subgroups.
1) Total score of influenza symptoms at baseline
¾ ≤11 points
¾ ≥12 points
Stratified Peto-Prentice’s generalized Wilcoxon test with region (Japan/Asia or 
Rest of the world) as stratification factors will be applied.
2) Region
¾ Japan/Asia
¾ Rest of the world
Stratified Peto-Prentice’s generalized Wilcoxon test with composite symptoms
score at baseline (≤ 11 or ≥ 12) as stratification factors will be applied.
3) Body weight
¾ < 80 kg
¾ ≥80 kg
4) Influenza virus type based on RT-PCR
¾ A/H1pdm
¾ A/H3
¾ B
5) Time to treatment from flu onset
¾ 0 hours ≤ to ≤ 24 hours
¾ 24 hours < to ≤48 hours
Analyses of time to alleviation of symptoms (Section 9.1.1.1, 9.1.1.2, the median time to 
alleviation of symptoms and its 95% CI) will be presented for the following subgroup 5)
and 6).


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6) Meals before and after dosing
¾ Dosing > 4 hours before or > 4 hours after food taken
¾ Dosing within 2-4 hours before or 2-4 hours after food intaken
¾ Dosing < 2 hours before or < 2 after food intaken
If a subject has had meals both before and after dosing, the priority will be given 
to a category closer to the time of dosing. If multiple applicable categories exist 
even under this condition, data obtained before dosing will be adopted.
7) Age
¾ < 18 years
¾ ≥18 years
For the proportion of patients positive for influenza virus titer/RT-PCR, change from 
baseline in virus titer/amount of virus RNA (RT-PCR), area under the curve adjusted by 
baseline in virus titer/RT-PCR and time to cessation of viral shedding by virus 
titer/RT-PCR, these analyses will be presented for the following subgroup 8). Analyses of 
intrahouse infection rate will be presented for the following subgroup 8)
8) Influenza virus type and subtype based on RT-PCR
¾ A/H1pdm
¾ A/H3
¾ B
For the proportion of patients positive for influenza virus titer, change from baseline in 
virus titer for the following subgroup 9). 
9) Influenza virus type and subtype based on RT-PCR
¾ A/H1pdm
¾ A/H3
¾ B
10. SAFETY EVALUATION
The following analyses will be performed in the safety population.
10.1
Adverse Events
AEs will be classified by system organ class and preferred term using Medical Dictionary 
for Regulatory Activities (MedDRA) Version 19.1. Of reported AEs on the eCRF, AEs 
reported after the initial dose of study drug will be used for safety analyses.
1) The number and proportion of patients who experienced at least 1 AE will be 
tabulated by treatment group. Their 95 % CIs will also be calculated with 
Clopper-Pearson method. In addition, the proportion will be compared with 
placebo group or oseltamivir group by using Fisher’s exact test will be calculated. 
The number of events will also be tabulated. Death, other serious AEs, AEs 


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leading to withdrawal of the study drug, and treatment-related AEs will be 
summarized in the same manner as the overall summary of AEs. The definition of 
death, serious AEs, AEs leading to withdrawal, other severe AEs, 
treatment-related AEs are shown below.
Term
Definition
Death
AEs with “Fatal” in terms of outcome.
Other serious AEs
(Serious AEs excluding death)
AEs with “Serious” in terms of seriousness excluding 
death
AEs leading to withdrawal of the 
study drug
AEs with “Drug withdrawn” in terms of the action taken 
for study drug.
Treatment-related AEs
AEs with “Related” in terms of the causal relationship 
with study drug.
2) The number and proportion of patients who experienced AEs will be tabulated by 
system organ class (SOC) and preferred term (PT) for each treatment group. For 
these summaries, patients with multiple AEs will be counted only once within an 
SOC and PT. Serious AEs, Treatment-related AEs and serious treatment-related 
AEs will be summarized in a similar manner. In addition, proportion of patients
who experienced AEs of 2% or higher in any the dose treatment groups will be 
tabulated by SOC and PT.
3) The number and proportion of patients who experienced AEs in each category of 
timing of onset, severity, and outcome will be tabulated by SOC and PT for each 
treatment group. For these summaries, patients with multiple AEs will be counted 
only once by the highest priority shown in Table 4 within an SOC and preferred 
term. Treatment-related AEs will be summarized in a similar manner. The 
time-of-onset categories include Week 1 (1 to 7 days post-dose), Week 2 (8 to 14 
days post-dose), and Week ≥3 (≥15 days post-dose). Each AE will be classified 
into a time-of-onset category based on the number of days to onset which is 
calculated as (Date of AE onset – Date of dosing + 1). If a subject experienced 
multiple episodes of the same AE at different times of onset, the subject will be 
counted once each in the relevant time-of-onset categories.
Table 4
Priority of Categories
Category
Priority
Severity
Outcome
Timing of onset (day)
1
Grade 5
Fatal
≥1 to ≤7
2
Grade 4
Recovered/Resolved with 
sequelae
≥8 to ≤14
3
Grade 3
Not recovered/Not resolved
≥15
4
Grade 2
Recovering/Resolving
5
Grade 1
Recovered/Resolved
6
Unknown
4) AEs realated hepatic disorders (SMQ code=20000006) will be listed.


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10.2
Clinical Laboratory
1) For each of the hematological and biochemical test parameters, summary statistics 
of observed values and changes from baseline at each time point will be presented 
by treatment group at each scheduled time point.
2) For each of the hematological and biochemical test parameters, the plot of the 
baseline value and last observation value is presented for all patients. Last 
observation value is defined as the value at the last time point in all observed time 
points within acceptable window and the time point of early termination within 
acceptable window.
3) For each urinalysis parameter, the frequency of each category will be summarized 
by treatment group at each scheduled time point.
4) Each observed value will be classified into three categories: “within the normal 
range,” “higher than normal,” and “lower than normal.” The frequency of each 
category will be summarized by treatment group at each scheduled time point.
5) The number and proportion of patients who meet the pre-specified criteria shown 
in Table 5 will be presented by treatment group during the study. If a patient meet
multiple criterion in all observed time points, the patient will be counted only 
once within the worst category.
Table 5
Pre-specified Criteria
Term
Criteria
ALT (U/L)
≤3 × ULN
>3 to ≤5 × ULN
>5 to ≤20 × ULN
>20 × ULN
AST (U/L)
≤3 × ULN
>3 to ≤5 × ULN
>5 to ≤20 × ULN
>20 × ULN
Total Bilirubin (mg/dL)
<1.5 × ULN
≥1.5 to <3 × ULN
>3 to ≤10 × ULN
>10 × ULN
AST (U/L) or ALT (U/L)
≤3 × ULN
>3 to ≤5 × ULN
>5 to ≤20 × ULN
>20 × ULN
AST (U/L) or ALT (U/L) and Total bilirubin (mg/dL)
Meet all of the following criteria:
x
AST > 3 × ULN or ALT > 3 × 
ULN
x
Total bilirubin value > 2 × ULN
ULN = upper limit of normal.


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10.3
Vital Signs
For each of the vital signs (diastolic blood pressures, systolic blood pressures, respiratory 
rate and pulse rate), summary statistics of observation and the change from baseline will 
be presented by treatment group at each scheduled time point. For each of the vital sign 
parameters, the plot of the baseline value and last observation value is presented for all 
patients in the safety population. Last observation value is defined as the value at the last 
time point in all observed time points within acceptable window and the time point of 
early termination within acceptable window.
10.4
Electrocardiography (ECG)
The frequency of each ECG findings will be summarized by treatment group at each 
scheduled time point. Each ECG findings will be classified into three categories: 
“normal,” “abnormal-not clinically significant,” and “abnormal-clinically significant.”
10.5
Subgroup Analyses for Safety Endpoint
Analyses of adverse events (Section 10.1 1) and 2), except proportion of patients who 
experienced AEs of 2% or higher) will be presented for the following subgroup 1) and 2).
Subgroup analyses will be performed for the Safety population.
1) Body weight
¾ < 80 kg
¾ ≥80 kg
2) Age
¾ < 18 years
¾ ≥18 years
11. INTERIM ANALYSES
No interim analysis is planned in this study.
12. PROGRAMMING SPECIFICATIONS
Unless otherwise specified, the following conventions should be used when constructing 
the analysis tables, figures and listings are prepared:
y
Every summary table and figure should clearly specify the analysis population 
being summarized. Listings will be prepared for all patients randomized.
y
Treatment group of the S-033188 in the listings will be reported as following 
rules.

S-033188 40 mg: Kit number (1) was assigned and the S-033188 was 
administered

S-033188 80 mg: Both kit number (1) and (2) were assigned and the S-033188
was administered


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y
Number of digits to be displayed for calculated values
For the following endpoints, data will be rounded off to 8 decimal places, and the 
rounded values will be used for analysis. Table 6 is shown the summary of the number of 
digit displayed for each endpoint.
Table 6
Summary of the Number of Digits Displayed for 
Endpoints
No. of digits displayed
(after the decimal point)
Endpoint
Minimum
Maximum
Mean
Median
SD
CI
Time to alleviation of symptoms
Time to cessation of viral shedding by virus titer/ RT-PCR
Time to alleviation of the 4 systemic symptoms
Time to alleviation of the 3 respiratory symptoms
Time to resolution of fever
Time to alleviation of individual symptoms
Time to return to preinfluenza health status
Area under the curve adjusted by baseline in virus titer
Area under the curve adjusted by baseline in the amount of 
virus RNA (RT-PCR)
Drug susceptibility in patients with evaluable virus: the ratio 
of EC50/IC50 at baseline relative to EC50/IC50 for 
reference
Time Required for Personal Assistance Due to Influenza 
Illness
1
1
1
Index value
Percentage of absenteeism due to influenza illness
Percentage of work productivity loss due to influenza illness
3
3
3
Change from baseline in influenza virus titer
Change from baseline in amount of virus RNA
2
2
2
Treatment compliance rate
1
2
2
Summary statistics will be displayed to the number of digits as shown in Table 7.
Table 7
Summary of the Number of Digits Displayed
No. of digits displayed
p value
Round off to 4 decimal places.
However, p value of <0.0001 will be displayed as “<.0001.”
No. of subjects
Display as a whole number.
Mean, SD, median, adjusted mean, 
SE, 95% CI
One decimal place beyond the number of decimal places 
with which the original endpoint is presented.
Minimum, maximum
Same number of digits of the observed data
Percentage (%)
Round off to 1 decimal place.


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y
Categories used for summarization
Basically, categories described in CRFs will be used for summarization. If data need to be 
categorized, the data should be categorized according to Table 8 below. 
Table 8
Category of Variable
Variable
Category
Age
12-19 years, 20-29 years, 30-39 years, 40-49 years, 
50-59 years, 60-64 years
Body weight
<80 kg, ≥80 kg
Timing of meal before and after dosing
<2 hours, 2 to 4 hours, > 4 hours
Time of onset of influenza symptoms
0-12 hours, 12-24 hours, 24-36 hours, 36-48 hours
Influenza virus subtype based on RIDT
A, B, A and B, Negative, Unknown
Influenza virus subtype based on 
RT-PCR
A/H1N1pdm: A/H1N1pdm
A/H3: A/H3
B:B
Mixed infection: A/H1N1pdm and B, A/H3 and B, 
A/Unknown and B, A/ND and B, A/H1N1pdm and A/H3 
and B, A/H1N1pdm and A/H3
Other: A/Unknown, A/ND, Unknown
Negative:
The above virus subtype classification is derived from 
the following specification:

A/H1N1pdm: H1_2009

A/H3: H3

A/H1N1pdm and A/H3: H1_2009/H3

A/ND: ND

A/Unknown: UNKNOWN
Virus subtype classification used for 
subgroup analysis
A/H1N1pdm, A/H3, B
Serum influenza antibody titer
(Day 1, Day 22)
<10, ≥10 to <20, ≥20 to < 40, ≥40 to < 80, ≥80 to <160,
≥160
Serum influenza antibody titer
(Ratio of Day 22 relative to Day 1)
<4, ≥4 to <8, ≥8 to <16, ≥16 to <32, ≥32 to <64, ≥64 to 
<128, ≥128 to <256, ≥256
Composite symptoms score at baseline
≤11, ≥12
Treatment compliance rate
<80, ≥80
Acetaminophen use
0, 1-2, 3-4, ≥5
Time of onset of AE
Week 1 (≥1 day to <8 days), Week 2 (≥8 days to <15 
days), Week ≥3 (≥15 days)
Urine protein
-, 1+, 2+, 3+, Unknown
Urine glucose
-, 1+, 2+, 3+, 4+, Unknown
Urobilinogen
-, 1+, 2+, 3+, 4+, Unknown
Urine occult blood
-, 1+, 2+, 3+, 4+, Unknown


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13. BLINDED REVIEW
PCR positive rate at baseline will be estimated during the study.
14. SUMMARY OF CHANGES FROM PROTOCOL SPECIFIED 
ANALYSIS
In Protocol section 9.11.1, the following analysis will be changed.

The summary for action taken with the study drug will be presented by system 
organ class and preferred term. Due to single dose of S-033188, this analysis is 
not performed.


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15. REFERENCES
[1]
Ikeda S., et al. Developing a Japanese version of the EQ-5D-5L value set, J. Natl. 
Inst. Public Health, 64 (1): 2015 p.47-55


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Appendix 1
Time and Events Schedule
Treatment Period
Follow-up Period
D1
D2
D3
D4
D5
D6
D7
D8
D9
D10
D11
D12
D13
D14
D15
D22 or 
ET
V1
V2
V3
OpV
1
V4
OpV
2
V5
V6
V7
Visit Window (days)
-
-
+1
-
+1
-
±2
±3
±3
Informed Consent/Assent
X
Inclusion/Exclusion Criteria
X
Demographics
X
Medical History a
X
Rapid Influenza Diagnostic Test
X b
Randomization
X
Study Drug Dispensation
X
Study Drug Administration
X
X
X
X
X
Patient 
eDiary c
Body Temperature 
Measurement
X d
4 Times 
Daily
Twice Daily
Assessment of Severity of 
Influenza Symptoms
X d
Twice Daily
Once Daily
Assessment of Health
X d
Once Daily
Assessment of Health 
Prior to Influenza 
Symptoms
X d
EQ-5D-5L
X d
Twice Daily
Once Daily
X
Work Productivity Questionnaire
X (following resolution of symptoms)
Assessment of Influenza-related 
Complications (sinusitis, bronchitis, 
otitis media, pneumonia)
X
X
X
X
X
X
X
X
X
Full Physical Examination
X e, f
X e
Symptom-focused Physical 
Examination
X
X
X
X
X
X
X
Concomitant Therapies
X
X
X
X
X
X
X
X


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Treatment Period
Follow-up Period
D1
D2
D3
D4
D5
D6
D7
D8
D9
D10
D11
D12
D13
D14
D15
D22 or 
ET
V1
V2
V3
OpV
1
V4
OpV
2
V5
V6
V7
Study Drug Accountability
X
X
X
X
X
Urine Pregnancy Test(WOCBP) g
X
X
X
Immunological Tests
X h
Routine Laboratory Tests
X
X
X
X
Influenza Antibody Titer Test
X h
X
Nasal/Throat Swabs (Virology Test)
X h
X
X
X
X
X
X
X i
X i, j
Vital Sign Measurements
X
X
X
X
X
X
X
X
X
Electrocardiography
X
X
X
Pharmacokinetic Blood Samples
X k
X
X k
X
X k
Adverse Event Assessment
X
X
X
X
X
X
X
X
X
Interview for Meal Consumption
X
Intrahousehold Infection Interview
(for Japan only)
X
X
X
X
X
X
1. D = Day, ET = early termination, V = visit, OpV = optional visit.
a
Prior therapies will also be reviewed.
b
Not necessary if a site has performed a Rapid Influenza Diagnostic Test prior to consideration for the study.
c
The patient will measure or assess and record in the patient eDiary, body temperature 4 times daily (morning, noon, evening, and bedtime) from Days 1 to 3 and twice daily 
(morning and evening) from Days 4 to 14; severity of influenza symptoms twice daily (morning and evening) from Days 1 to 9 and once daily (evening) from Days 10 to 14; 
assessment of health once daily (evening) from Days 1 to 14; and EQ-5D-5L twice daily (morning and evening) from Days 1 to 9 and once daily (evening) from Days 10 to 
14.
d
Predose; if the study treatment is initiated at 18:00 or later on Day 1, the patient will not need to perform Day 1 evening assessments.
e
Body weight will be measured.
f
Height will be measured in the predose examinations only.
g
Urine pregnancy test will be performed only for females who are not diagnosed as postmenopausal.
h
Predose.
i
Virology swabs will be collected if investigator determines that flu symptoms are persisting.
j
Virology swabs will be collected at the early termination.
k
Blood samples will be collected for the measurement of plasma drug concentrations at Visits 2 (Day 2) and 4 (Day 5). If circumstances permit, samples will also be collected 
at 0.5 to 4 hours post-dose at Visit 1 (Day 1), and at Visit 3 (Day 3) and Visit 6 (Day 15).