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CAPSTONE 2: Study of S-033188 (Baloxavir Marboxil) Compared With Placebo or Oseltamivir in Patients With Influenza at High Risk of Influenza Complications

Sponsor
Shionogi (Industry)
Overall Status
Completed
CT.gov ID
NCT02949011
Collaborator
(none)
2,184
Enrollment
3
Arms
15.2
Actual Duration (Months)

Study Details

Study Description

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 improvement of influenza symptoms in patients with influenza presenting within 48 hours of symptom onset.

Condition or Disease Intervention/Treatment Phase
  • Drug: Baloxavir Marboxil
  • Drug: Placebo to Baloxavir Marboxil
  • Drug: Oseltamivir
  • Drug: Placebo to Oseltamivir
 Phase 3

Study Design

Study Type:
Interventional
Actual Enrollment :
2184 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Masking:
Double (Participant, Investigator)
Primary Purpose:
Treatment
Official 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 Patients With Influenza at High Risk of Influenza Complications
Actual Study Start Date :
Jan 11, 2017
Actual Primary Completion Date :
Apr 12, 2018
Actual Study Completion Date :
Apr 20, 2018

Arms and Interventions

Arm Intervention/Treatment
Experimental: Baloxavir Marboxil

Participants received either 40 mg or 80 mg of baloxavir marboxil orally on Day 1 based on body weight of < 80 kg or ≥ 80 kg at Screening, respectively. Participants also received placebo to oseltamivir orally twice a day (BID) on Days 1 to 5.

Drug: Baloxavir Marboxil
Tablets taken orally
Other Names:
  • S-033188
  • Xofluza®

    • Drug: Placebo to Oseltamivir
    Matching placebo capsules taken orally
    Active Comparator: Oseltamivir

    Participants received 75 mg oseltamivir twice a day on Days 1 to 5 and placebo to baloxavir marboxil on Day 1.

    Drug: Placebo to Baloxavir Marboxil
    Matching tablets taken orally

    Drug: Oseltamivir
    Capsules taken orally
    Other Names:
  • Tamiflu®

    		•
    Placebo Comparator: Placebo

    Participants received placebo to baloxavir marboxil on Day 1 and placebo to oseltamivir orally twice a day on Days 1 to 5.

    Drug: Placebo to Baloxavir Marboxil
    Matching tablets taken orally

    Drug: Placebo to Oseltamivir
    Matching placebo capsules taken orally

    Outcome Measures

    Primary Outcome Measures

    1. Time to Improvement of Influenza Symptoms [From Day 1 pretreatment up to Day 14]

      Participants assessed the severity of 7 influenza-associated symptoms (cough, sore throat, headache, nasal congestion, feverishness/chills, muscle/joint pain, and fatigue) on a 4-point scale (0 = no symptoms, 1= mild, 2 = moderate, and 3 = severe). Time to improvement of symptoms was defined as the time from the start of treatment to the time when all influenza symptoms were alleviated, maintained, or improved, as defined below, for a duration of at least 21.5 hours: Preexisting symptoms (cough, fatigue, or muscle/joint pain that existed prior to influenza) that were worse at baseline must have improved at least 1 point from baseline Preexisting symptoms not worse at baseline must have maintained baseline severity New symptoms must have alleviated, defined as a symptom score of none (0) or mild (1). Time to improvement of symptoms was analyzed using Kaplan-Meier (KM) methods; participants who did not experience improvement of symptom s were censored at the last observation.

    Secondary Outcome Measures

    1. Percentage of Participants With Positive Influenza Virus Titer at Each Time Point [Days 2, 3, 4 (optional), 5, 6 (optional), and 9]

      Virus titer was quantified from nasopharyngeal swabs (or throat swabs if nasopharyngeal swabbing was not feasible) using tissue culture methods. Positive influenza virus titer was defined as virus titer not less than the lower limit of quantification (0.7 log₁₀ of the 50% tissue culture infective dose (TCID₅₀/mL) among those assessed for virus titer on Days 2, 3, 4, 5, 6, and 9.

    2. Percentage of Participants With Positive Influenza Virus by RT-PCR at Each Time Point [Days 2, 3, 4 (optional), 5, 6 (optional), and 9.]

      Influenza virus ribonucleic acid (RNA) was quantified from nasopharyngeal swabs (or throat swabs, if nasopharyngeal swabbing was not feasible). The percentage of participants with detectable virus RNA (2.05 for flu A and 2.83 for flu B log₁₀ virus particles/mL) measured by reverse transcription polymerase chain reaction (RT-PCR) among those assessed on Days 2, 3, 4, 5, 6 and 9.

    3. Change From Baseline in Virus Titer at Each Time Point [Day 1 pretreatment (Baseline) and Days 2, 3, 4 (optional), 5, 6 (optional), and 9]

      Virus titer was quantified from nasopharyngeal swabs (or throat swabs if nasopharyngeal swabbing was not feasible) by tissue culture methods. If virus titer was less than the lower limit of quantification, the virus titer was imputed 0.7 (TCID₅₀/mL).

    4. Change From Baseline in Virus RNA (RT-PCR) at Each Time Point [Day 1 pretreatment (Baseline) and Days 2, 3, 4 (optional), 5, 6 (optional), and 9]

      Nasopharyngeal swabs (or throat swabs, if nasopharyngeal swabbing was not feasible) were obtained for viral quantitation. Virus RNA was measured by reverse transcription polymerase chain reaction (RT-PCR).

    5. Area Under the Curve (AUC) Adjusted by Baseline in Influenza Virus Titer [Day 1 to Day 9]

      This endpoint was defined as AUC of change from Baseline in virus titer from Day 1 to Day 9. AUC was calculated using the trapezoidal method.

    6. Area Under the Curve (AUC) Adjusted by Baseline in Viral RNA [Day 1 to Day 9]

      This endpoint was defined as AUC of change from baseline in the amount of virus RNA (RT-PCR) from Day 1 to Day 9. The AUC was calculated using the trapezoidal method.

    7. Time to Cessation of Viral Shedding Determined by Virus Titer [Day 1 to Day 9]

      Time to cessation of viral shedding by virus titer was defined as the time between the initiation of the study treatment and first time when the virus titer was below the limit of detection (0.7 log₁₀[TCID₅₀/mL]). The median and 95% confidence interval (CI) for time to cessation of viral shedding determined by virus titer was analyzed using the Kaplan-Meier (KM) method; participants whose virus titer had not reached cessation by the last observation time point were treated as censored at that time point.

    8. Time to Cessation of Viral Shedding Determined by Virus RNA [Day 1 to Day 9]

      Time to cessation of viral shedding by RT-PCR was defined as the time between the initiation of the study treatment and first time when the virus RNA was below the limit of detection measured by RT-PCR. Time to cessation of viral shedding by RT-PCR was analyzed using the KM method; participants whose virus RNA had not reached cessation by the last observation time point were treated as censored at that time point.

    9. Percentage of Participants Whose Symptoms Were Improved at Each Time Point [12, 24, 36, 48, 72, 96, 120, 144, 168, 192, and 216 hours after the initial dose of study treatment]

      Participants assessed the severity of 7 influenza-associated symptoms (cough, sore throat, headache, nasal congestion, feverishness or chills, muscle or joint pain, and fatigue) on a 4-point scale (0 = no symptoms, 1= mild, 2 = moderate, and 3 = severe). Improvement of symptoms was defined as all influenza symptoms alleviated, maintained, or improved, as defined below, for a duration of at least 21.5 hours: Preexisting symptoms (cough, fatigue, or muscle/joint pain that existed prior to influenza) judged to be worse at baseline must have improved at least 1 point from baseline severity Preexisting symptoms judged not to be worse at baseline must have maintained baseline severity New symptoms at baseline must have alleviated, defined as a symptom score of none (0) or mild (1).

    10. Time to Alleviation of Symptoms [Initiation of study treatment up to Day 14]

      Participants assessed the severity of seven influenza-associated symptoms (cough, sore throat, headache, nasal congestion, feverishness or chills, muscle or joint pain, and fatigue) on a 4-point scale (with 0 indicating no symptoms, 1 mild symptoms, 2 moderate symptoms, and 3 severe symptoms). Time to alleviation of symptoms was defined as the time from the start of the study treatment to the time when all seven influenza-related symptoms were assessed by the participant as absent (0) or mild (1) for at least 21.5 hours. Time to alleviation of symptoms was analyzed using Kaplan-Meier (KM) methods; participants who did not experience alleviation of symptoms were censored at the last observation time point.

    11. Time to Improvement of the Four Systemic Symptoms [Initiation of study treatment up to Day 14]

      Participants assessed the severity of 7 influenza-associated symptoms on a 4-point scale (from 0 = no symptoms to 3 = severe symptoms). Time to improvement of the 4 systemic symptoms was defined as the time between the initiation of study treatment to the time when all 4 systemic symptoms (headache, feverishness or chills, muscle or joint pain, and fatigue) were alleviated, maintained, or improved, as defined below, for a duration of at least 21.5 hours: Preexisting symptoms (cough, fatigue, or muscle/joint pain that existed prior to influenza) that were worse at baseline must have improved at least 1 point from baseline Preexisting symptoms not worse at baseline must have maintained baseline severity New symptoms at baseline must have alleviated, defined as a symptom score of none (0) or mild (1). Time to improvement of the 4 systemic symptoms was analyzed using KM methods; participants who did not experience improvement of symptoms were censored at the last observation.

    12. Time to Improvement of the Three Respiratory Symptoms [Initiation of study treatment up to Day 14]

      Participants assessed the severity of 7 influenza-associated symptoms on a 4-point scale (from 0 = no symptoms to 3 = severe symptoms). Time to improvement of the 3 respiratory symptoms was defined as the time from the start of study treatment to the time when all 3 respiratory symptoms (cough, sore throat, and nasal congestion) were alleviated, maintained, or improved, as defined below, for a duration of at least 21.5 hours: Preexisting symptoms (cough, fatigue, or muscle/joint pain that existed prior to influenza) that were worse at baseline must have improved at least 1 point from baseline Preexisting symptoms not worse at baseline must have maintained baseline severity New symptoms at baseline must have alleviated, defined as a symptom score of none (0) or mild (1). Time to improvement of the 3 respiratory symptoms was analyzed using KM methods; participants who did not experience improvement of symptoms were censored at the last observation time point.

    13. Time to Resolution of Fever [Initiation of study treatment up to Day 14]

      Time to resolution of fever was defined as the time between the initiation of the study treatment and the resolution of fever. The resolution of fever was defined as the time when the participant's self-measured axillary temperature became less than 37ºC and was maintained at less than 37ºC for at least 12 hours. Time to resolution of fever was analyzed using KM methods; participants who did not experience resolution of fever by the last observation time point were censored at that time point.

    14. Percentage of Participants Reporting Normal Temperature at Each Time Point [12, 24, 36, 48, 72, 96, 120, 144, 168, 192, and 216 hours after the initial dose of study treatment]

      Defined as the percentage of patrticipants whose axillary body temperature dropped to less than 37ºC after the initiation of the study treatment.

    15. Body Temperature at Each Time Point [12, 24, 36, 48, 72, 96 and 120 hours after the initial dose of study treatment]

      Participant's self-measured axillary temperature using an electronic thermometer.

    16. Time to Improvement of Individual Symptoms [Initiation of study treatment up to Day 14]

      Participants assessed the severity of 7 influenza-associated symptoms on a 4-point scale (0 = no symptoms to 3 = severe). Time to improvement of cough, fatigue, and muscle/joint pain was defined as the time from the start of treatment to the time when each symptom was alleviated, maintained, or improved, as defined below, for at least 21.5 hours: Preexisting symptoms that were worse at baseline must have improved at least 1 point from baseline Preexisting symptoms not worse at baseline must have maintained baseline severity New symptoms must have alleviated, defined as a score of 0 (None) or 1 (Mild). Time to improvement of sore throat, headache, nasal congestion, and feverish/chills was defined as the time from the start of treatment to the time when the symptom was assessed as 0 (None) or 1 (Mild) for at least 21.5 hours. Time to improvement of symptoms was analyzed using KM methods; participants with no improvement of symptoms were censored at the last observation.

    17. Time to Return to Preinfluenza Health Status [Baseline to Day 14]

      Participants were asked to record their preinfluenza health status on a scale from 0 (worst possible health) to 10 (normal health [for someone your age and condition]), and their health status at baseline and every day after initiation of study treatment on the same scale. Return to preinfluenza health status was defined as time from the initiation of the study treatment to the first time when the health status score was equal to or higher than the preinfluenza health status score. Time to return to preinfluenza health status was analyzed using KM methods; participants with a smaller number on the scale for health status by the last observation time point were censored at that time point.

    18. Percentage of Participants Requiring Systemic Antibiotics for Infections Secondary to Influenza Infection [Day 2 to Day 22]

      The percentage of participants who received systemic antibiotics for any of the predefined complications (sinusitis, otitis media, bronchitis and pneumonia).

    19. Percentage of Participants With Influenza-related Complications [Day 1 to Day 22]

      Defined as the percentage of patients who experience each influenza-related complication (hospitalization, death, sinusitis, otitis media, bronchitis, and radiologically-confirmed pneumonia) as an adverse event after the initiation of study treatment.

    20. Percentage of Participants With Adverse Events (AEs) [From first dose of study drug to Day 22]

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    12 Years and Older
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    Inclusion Criteria:

    1. Patients or their legal guardians who provide written informed consent to participate in the study on a voluntary basis. For adolescent patients, informed consent/assent of voluntary participation should be obtained in accordance with local requirements.

    2. Male or female patients ≥ 12 years at the time of signing the informed consent/assent form.

    3. Patients with a diagnosis of influenza confirmed by all of the following:

    4. Fever ≥ 38ºC (axillary) during the predose examinations or within the 4 hours prior if antipyretics were taken

    5. A positive rapid influenza diagnostic test (RIDT) result OR A patient with a negative RIDT may be enrolled if the patient reports contact with a known case of influenza within the prior 7 days and all other inclusion criteria are met.

    6. At least 1 each of the following general and respiratory symptoms associated with influenza is present with a severity of moderate or greater:

    1. General symptoms (headache, feverishness or chills, muscle or joint pain, or fatigue) ii. Respiratory symptoms (cough, sore throat, or nasal congestion)

    1. The time interval between the onset of symptoms and the predose examinations is 48 hours or less. The onset of symptoms is defined as either:

    2. Time of the first increase in body temperature (an increase of at least 1ºC from normal body temperature)

    3. Time when the patient experiences at least 1 new general or respiratory symptom

    4. If a women of childbearing potential, agrees to use a highly effective method of contraception for 3 months after the first dose of study drug

    5. Patients will be considered at high risk* of influenza complications due to the presence of at least 1 of the following inclusion criteria:

    6. Asthma or chronic lung disease (such as chronic obstructive pulmonary disease or cystic fibrosis)

    7. Endocrine disorders (including diabetes mellitus)

    8. Residents of long-term care facilities (eg, nursing homes)

    9. Compromised immune system (including patients receiving corticosteroids not exceeding 20 mg of prednisolone or equivalent, and patients being treated for human immunodeficiency virus [HIV] infection with a CD4 count > 350 cells/mm³ within the last 6 months)

    10. Neurological and neurodevelopmental disorders (including disorders of the brain, spinal cord, peripheral nerve, and muscle, eg, cerebral palsy, epilepsy [seizure disorders], stroke, muscular dystrophy, or spinal cord injury)

    11. Heart disease (such as congenital heart disease, congestive heart failure, or coronary artery disease), excluding hypertension without any other heart-related symptoms

    12. Adults aged ≥ 65 years

    13. American Indians and Alaskan Natives

    14. Blood disorders (such as sickle cell disease)

    15. Metabolic disorders (such as inherited metabolic disorders and mitochondrial disorders)

    16. Morbid obesity (body mass index ≥ 40 kg/m²)

    17. Women who are within 2 weeks postpartum and are not breastfeeding

    Exclusion Criteria:

    1. Patients with severe influenza virus infection requiring inpatient treatment.

    2. Patients with known allergy to oseltamivir (Tamiflu®).

    3. Patients unable to swallow tablets or capsules.

    4. Patients who have previously received baloxavir marboxil.

    5. Patients weighing ≤ 40 kg.

    6. Patients who have been exposed to an investigational drug within 30 days prior to the predose examinations.

    7. Women who are pregnant, breastfeeding, or have a positive pregnancy test at the predose examinations. The following female patients who have documentation of either a or b below do not need to undergo a pregnancy test at the predose examinations:

    8. Postmenopausal women (defined as cessation of regular menstrual periods for 2 years or more and confirmed by a follicle-stimulating hormone test)

    9. Women who are surgically sterile by hysterectomy, bilateral oophorectomy, or tubal ligation

    10. Patients with concurrent infections at the predose examinations requiring systemic antimicrobial therapy.

    11. Patients with liver disease associated with hepatic impairment.

    12. Patients with cancer within the last 5 years (unless nonmelanoma skin cancer).

    13. Patients with untreated HIV infection or treated HIV infection with a CD4 count below 350 cells/mm3 in the last 6 months.

    14. Patients with immunosuppression following organ or bone marrow transplants.

    15. Patients exceeding 20 mg of prednisolone or equivalent dose of chronic systemic corticosteroids.

    16. Patients who have received peramivir, laninamivir, oseltamivir, zanamivir, rimantadine, umifenovir or amantadine within 30 days prior to the predose examinations.

    17. Patients who have received an investigational monoclonal antibody for a viral disease in the last year.

    18. Patients with known creatinine clearance ≤ 60 mL/min.

    19. Patients who, in the opinion of the investigator, would be unlikely to comply with required study visits, self-assessments, and interventions

    Contacts and Locations

    Locations

    No locations specified.

    Sponsors and Collaborators

    • Shionogi

    Investigators

    • Study Director: Shionogi Clinical Trials Administrator Clinical Support Help Line, Shionogi

    Study Documents (Full-Text)

    More Information

    Publications

    None provided.
    Responsible Party:
    Shionogi
    ClinicalTrials.gov Identifier:
    NCT02949011
    Other Study ID Numbers:
    • 1602T0832
    • 2016-002688-32
    First Posted:
    Oct 31, 2016
    Last Update Posted:
    Nov 19, 2019
    Last Verified:
    Nov 1, 2019
    Keywords provided by Shionogi
    Tamiflu®
    Influenza
    Oseltamivir
    Flu
    S-033188
    Additional relevant MeSH terms:
    Influenza, Human
    Oseltamivir
    Baloxavir

    Study Results

    Participant Flow

    Recruitment Details This was a multicenter study conducted at 551 sites, including 242 sites in the United States, 142 sites in Japan, 48 sites in APAC (including Australia, New Zealand, Philippines, and South Korea), 98 sites in Europe (Belgium, Germany, Hungary, Latvia, Poland, Romania, and Spain), and 21 sites in South Africa.
    Pre-assignment Detail Eligible patients were randomized in a 1:1:1 ratio to 1 of 3 treatment groups. Participants were stratified by baseline symptom score (≤ 14 or ≥ 15), preexisting and worsened symptom (Yes or No), region (Asia, North America/Europe, or Southern Hemisphere), and patient's weight (< 80 kg or ≥ 80 kg).
    Arm/Group Title Baloxavir Marboxil Placebo Oseltamivir
    Arm/Group Description Participants received either 40 mg or 80 mg of baloxavir marboxil orally on Day 1 based on body weight of < 80 kg or ≥ 80 kg at Screening, respectively. Participants also received placebo to oseltamivir orally twice a day (BID) on Days 1 to 5. Participants received placebo to baloxavir marboxil on Day 1 and placebo to oseltamivir orally twice a day on Days 1 to 5. Participants received 75 mg oseltamivir twice a day on Days 1 to 5 and placebo to baloxavir marboxil on Day 1.
    Period Title: Overall Study
    STARTED 730 729 725
    Received Study Drug 728 728 722
    Intention to Treat Infected Population 388 386 389
    COMPLETED 697 695 683
    NOT COMPLETED 33 34 42

    Baseline Characteristics

    Arm/Group Title Baloxavir Marboxil Placebo Oseltamivir Total
    Arm/Group Description Participants received either 40 mg or 80 mg of baloxavir marboxil orally on Day 1 based on body weight of < 80 kg or ≥ 80 kg at Screening, respectively. Participants also received placebo to oseltamivir orally twice a day (BID) on Days 1 to 5. Participants received placebo to baloxavir marboxil on Day 1 and placebo to oseltamivir orally twice a day on Days 1 to 5. Participants received 75 mg oseltamivir twice a day on Days 1 to 5 and placebo to baloxavir marboxil on Day 1. Total of all reporting groups
    Overall Participants 388 386 389 1163
    Age (years) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [years]
    52.3
    (16.8)
    51.9
    (16.7)
    51.1
    (17.0)
    51.8
    (16.8)
    Age, Customized (Count of Participants)
    ≥ 12 to ≤ 19 years
    19
    4.9%
    17
    4.4%
    22
    5.7%
    58
    5%
    ≥ 20 to ≤ 29 years
    29
    7.5%
    22
    5.7%
    27
    6.9%
    78
    6.7%
    ≥ 30 to ≤ 39 years
    42
    10.8%
    58
    15%
    44
    11.3%
    144
    12.4%
    ≥ 40 to ≤ 49 years
    63
    16.2%
    55
    14.2%
    75
    19.3%
    193
    16.6%
    ≥ 50 to ≤ 59 years
    83
    21.4%
    101
    26.2%
    83
    21.3%
    267
    23%
    ≥ 60 to ≤ 64 years
    39
    10.1%
    30
    7.8%
    35
    9%
    104
    8.9%
    ≥ 65 to ≤ 74 years
    85
    21.9%
    76
    19.7%
    78
    20.1%
    239
    20.6%
    ≥ 75 years
    28
    7.2%
    27
    7%
    25
    6.4%
    80
    6.9%
    Sex: Female, Male (Count of Participants)
    Female
    195
    50.3%
    206
    53.4%
    198
    50.9%
    599
    51.5%
    Male
    193
    49.7%
    180
    46.6%
    191
    49.1%
    564
    48.5%
    Ethnicity (NIH/OMB) (Count of Participants)
    Hispanic or Latino
    62
    16%
    59
    15.3%
    56
    14.4%
    177
    15.2%
    Not Hispanic or Latino
    325
    83.8%
    327
    84.7%
    331
    85.1%
    983
    84.5%
    Unknown or Not Reported
    1
    0.3%
    0
    0%
    2
    0.5%
    3
    0.3%
    Race/Ethnicity, Customized (Count of Participants)
    American Indian or Alaska Native
    1
    0.3%
    2
    0.5%
    3
    0.8%
    6
    0.5%
    Asian
    167
    43%
    157
    40.7%
    163
    41.9%
    487
    41.9%
    Black or African American
    39
    10.1%
    30
    7.8%
    29
    7.5%
    98
    8.4%
    White
    178
    45.9%
    194
    50.3%
    188
    48.3%
    560
    48.2%
    Other
    3
    0.8%
    3
    0.8%
    6
    1.5%
    12
    1%
    Weight (Count of Participants)
    < 80 kg
    239
    61.6%
    232
    60.1%
    233
    59.9%
    704
    60.5%
    ≥ 80 kg
    149
    38.4%
    154
    39.9%
    156
    40.1%
    459
    39.5%
    Time to Treatment From Influenza Onset (Count of Participants)
    ≥ 0 to ≤ 12 hours
    27
    7%
    42
    10.9%
    37
    9.5%
    106
    9.1%
    > 12 to ≤ 24 hours
    151
    38.9%
    150
    38.9%
    119
    30.6%
    420
    36.1%
    > 24 to ≤ 36 hours
    114
    29.4%
    120
    31.1%
    141
    36.2%
    375
    32.2%
    > 36 to ≤ 48 hours
    95
    24.5%
    74
    19.2%
    92
    23.7%
    261
    22.4%
    Missing
    1
    0.3%
    0
    0%
    0
    0%
    1
    0.1%
    Influenza Virus Subtype Based on RT-PCR Assay (Count of Participants)
    A/H1N1pdm
    28
    7.2%
    17
    4.4%
    35
    9%
    80
    6.9%
    A/H3
    182
    46.9%
    185
    47.9%
    190
    48.8%
    557
    47.9%
    B
    167
    43%
    168
    43.5%
    149
    38.3%
    484
    41.6%
    Mixed infection
    4
    1%
    5
    1.3%
    5
    1.3%
    14
    1.2%
    Other
    7
    1.8%
    11
    2.8%
    10
    2.6%
    28
    2.4%
    Influenza Virus Titer (log₁₀[TCID₅₀/mL]) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [log₁₀[TCID₅₀/mL]]
    4.96
    (2.28)
    5.27
    (2.39)
    5.25
    (2.27)
    5.16
    (2.32)
    Influenza Virus Ribonucleic Acid (RNA) Load (log₁₀ virus particles/mL) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [log₁₀ virus particles/mL]
    6.72
    (1.43)
    6.87
    (1.54)
    6.81
    (1.37)
    6.80
    (1.45)
    Region (Count of Participants)
    Asia
    159
    41%
    151
    39.1%
    152
    39.1%
    462
    39.7%
    North America/Europe
    212
    54.6%
    216
    56%
    220
    56.6%
    648
    55.7%
    Southern Hemisphere
    17
    4.4%
    19
    4.9%
    17
    4.4%
    53
    4.6%
    Composite Symptom Score (Count of Participants)
    ≤ 14
    188
    48.5%
    188
    48.7%
    201
    51.7%
    577
    49.6%
    ≥ 15
    200
    51.5%
    198
    51.3%
    188
    48.3%
    586
    50.4%
    Preexisting Symptom Status (Count of Participants)
    Yes
    71
    18.3%
    76
    19.7%
    69
    17.7%
    216
    18.6%
    No
    317
    81.7%
    310
    80.3%
    320
    82.3%
    947
    81.4%

    Outcome Measures

    1. Primary Outcome
    Title Time to Improvement of Influenza Symptoms
    Description Participants assessed the severity of 7 influenza-associated symptoms (cough, sore throat, headache, nasal congestion, feverishness/chills, muscle/joint pain, and fatigue) on a 4-point scale (0 = no symptoms, 1= mild, 2 = moderate, and 3 = severe). Time to improvement of symptoms was defined as the time from the start of treatment to the time when all influenza symptoms were alleviated, maintained, or improved, as defined below, for a duration of at least 21.5 hours: Preexisting symptoms (cough, fatigue, or muscle/joint pain that existed prior to influenza) that were worse at baseline must have improved at least 1 point from baseline Preexisting symptoms not worse at baseline must have maintained baseline severity New symptoms must have alleviated, defined as a symptom score of none (0) or mild (1). Time to improvement of symptoms was analyzed using Kaplan-Meier (KM) methods; participants who did not experience improvement of symptom s were censored at the last observation.
    Time Frame From Day 1 pretreatment up to Day 14

    Outcome Measure Data

    Analysis Population Description
    Participants in the intention-to-treat infected population with available time to improvement of symptoms data.
    Arm/Group Title Baloxavir Marboxil Placebo Oseltamivir
    Arm/Group Description Participants received either 40 mg or 80 mg of baloxavir marboxil orally on Day 1 based on body weight of < 80 kg or ≥ 80 kg at Screening, respectively. Participants also received placebo to oseltamivir orally twice a day (BID) on Days 1 to 5. Participants received placebo to baloxavir marboxil on Day 1 and placebo to oseltamivir orally twice a day on Days 1 to 5. Participants received 75 mg oseltamivir twice a day on Days 1 to 5 and placebo to baloxavir marboxil on Day 1.
    Measure Participants 385 385 388
    Median (95% Confidence Interval) [hours]
    73.2
    102.3
    81.0
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Baloxavir Marboxil, Placebo
    Comments The primary analysis of the primary endpoint was a comparison between the baloxavir marboxil and placebo groups.
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value <0.0001
    Comments Adjusted p-value, two-sided significance level of 0.05
    Method Stratified generalized Wilcoxon test
    Comments Peto-Prentice's generalized Wilcoxon test stratified by baseline composite symptom score, preexisting and worsened symptoms, and region.
    Method of Estimation Estimation Parameter Median Difference
    Estimated Value -29.1
    Confidence Interval (2-Sided) 95%
    -42.8 to -14.6
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Baloxavir Marboxil, Oseltamivir
    Comments The comparison between the baloxavir marboxil and the oseltamivir groups was conducted as a secondary analysis only if a statistically significant difference was observed in the primary analysis in order to maintain control of overall type I error.
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.8347
    Comments Adjusted p-value, two-sided significance level of 0.05
    Method Stratified generalized Wilcoxon test
    Comments Peto-Prentice's generalized Wilcoxon test stratified by baseline composite symptom score, preexisting and worsened symptoms, and region.
    Method of Estimation Estimation Parameter Median Difference
    Estimated Value -7.7
    Confidence Interval (2-Sided) 95%
    -22.7 to 7.9
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 3
    Statistical Analysis Overview Comparison Group Selection Baloxavir Marboxil, Placebo
    Comments Analysis using the stratified log rank test was performed as a sensitivity analysis.
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.0008
    Comments The p-value was not adjusted for multiplicity, testing was conducted at the two-sided significance level of 0.05.
    Method Log Rank
    Comments Log rank test stratified by baseline composite symptom score, preexisting and worsened symptoms, and region.
    Statistical Analysis 4
    Statistical Analysis Overview Comparison Group Selection Baloxavir Marboxil, Oseltamivir
    Comments Analysis using the stratified log rank test was performed as a sensitivity analysis.
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.8449
    Comments The p-value was not adjusted for multiplicity, testing was conducted at the two-sided significance level of 0.05.
    Method Log Rank
    Comments Log rank test stratified by baseline composite symptom score, preexisting and worsened symptoms, and region.
    2. Secondary Outcome
    Title Percentage of Participants With Positive Influenza Virus Titer at Each Time Point
    Description Virus titer was quantified from nasopharyngeal swabs (or throat swabs if nasopharyngeal swabbing was not feasible) using tissue culture methods. Positive influenza virus titer was defined as virus titer not less than the lower limit of quantification (0.7 log₁₀ of the 50% tissue culture infective dose (TCID₅₀/mL) among those assessed for virus titer on Days 2, 3, 4, 5, 6, and 9.
    Time Frame Days 2, 3, 4 (optional), 5, 6 (optional), and 9

    Outcome Measure Data

    Analysis Population Description
    Participants in the intention-to-treat infected population with a positive influenza virus titer on Day 1 and with available virus titer data at each time point.
    Arm/Group Title Baloxavir Marboxil Placebo Oseltamivir
    Arm/Group Description Participants received either 40 mg or 80 mg of baloxavir marboxil orally on Day 1 based on body weight of < 80 kg or ≥ 80 kg at Screening, respectively. Participants also received placebo to oseltamivir orally twice a day (BID) on Days 1 to 5. Participants received placebo to baloxavir marboxil on Day 1 and placebo to oseltamivir orally twice a day on Days 1 to 5. Participants received 75 mg oseltamivir twice a day on Days 1 to 5 and placebo to baloxavir marboxil on Day 1.
    Measure Participants 355 353 360
    Day 2
    58.6
    15.1%
    86.9
    22.5%
    86.9
    22.3%
    Day 3
    31.7
    8.2%
    72.7
    18.8%
    60.0
    15.4%
    Day 4
    18.5
    4.8%
    50.0
    13%
    33.1
    8.5%
    Day 5
    16.0
    4.1%
    30.7
    8%
    20.4
    5.2%
    Day 6
    4.3
    1.1%
    16.0
    4.1%
    11.4
    2.9%
    Day 9
    2.8
    0.7%
    5.3
    1.4%
    0.9
    0.2%
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Baloxavir Marboxil, Placebo
    Comments Day 2
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value <0.0001
    Comments The p value was not adjusted for multiplicity, testing was conducted at the two-sided significance level of 0.05.
    Method Mantel Haenszel
    Comments Mantel Haenszel test stratified by baseline composite symptom score, preexisting and worsened symptoms, and region.
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Baloxavir Marboxil, Oseltamivir
    Comments Day 2
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value <0.0001
    Comments The p value was not adjusted for multiplicity, testing was conducted at the two-sided significance level of 0.05.
    Method Mantel Haenszel
    Comments Mantel Haenszel test stratified by baseline composite symptom score, preexisting and worsened symptoms, and region.
    Statistical Analysis 3
    Statistical Analysis Overview Comparison Group Selection Baloxavir Marboxil, Placebo
    Comments Day 3
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value <0.0001
    Comments The p value was not adjusted for multiplicity, testing was conducted at the two-sided significance level of 0.05.
    Method Mantel Haenszel
    Comments Mantel Haenszel test stratified by baseline composite symptom score, preexisting and worsened symptoms, and region.
    Statistical Analysis 4
    Statistical Analysis Overview Comparison Group Selection Baloxavir Marboxil, Oseltamivir
    Comments Day 3
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value <0.0001
    Comments The p value was not adjusted for multiplicity, testing was conducted at the two-sided significance level of 0.05.
    Method Mantel Haenszel
    Comments Mantel Haenszel test stratified by baseline composite symptom score, preexisting and worsened symptoms, and region.
    Statistical Analysis 5
    Statistical Analysis Overview Comparison Group Selection Baloxavir Marboxil, Placebo
    Comments Day 4
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value <0.0001
    Comments The p value was not adjusted for multiplicity, testing was conducted at the two-sided significance level of 0.05.
    Method Mantel Haenszel
    Comments Mantel Haenszel test stratified by baseline composite symptom score, preexisting and worsened symptoms, and region.
    Statistical Analysis 6
    Statistical Analysis Overview Comparison Group Selection Baloxavir Marboxil, Oseltamivir
    Comments Day 4
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.0044
    Comments The p value was not adjusted for multiplicity, testing was conducted at the two-sided significance level of 0.05.
    Method Mantel Haenszel
    Comments Mantel Haenszel test stratified by baseline composite symptom score, preexisting and worsened symptoms, and region.
    Statistical Analysis 7
    Statistical Analysis Overview Comparison Group Selection Baloxavir Marboxil, Placebo
    Comments Day 5
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value <0.0001
    Comments The p value was not adjusted for multiplicity, testing was conducted at the two-sided significance level of 0.05.
    Method Mantel Haenszel
    Comments Mantel Haenszel test stratified by baseline composite symptom score, preexisting and worsened symptoms, and region.
    Statistical Analysis 8
    Statistical Analysis Overview Comparison Group Selection Baloxavir Marboxil, Oseltamivir
    Comments Day 5
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.1146
    Comments The p value was not adjusted for multiplicity, testing was conducted at the two-sided significance level of 0.05.
    Method Mantel Haenszel
    Comments Mantel Haenszel test stratified by baseline composite symptom score, preexisting and worsened symptoms, and region.
    Statistical Analysis 9
    Statistical Analysis Overview Comparison Group Selection Baloxavir Marboxil, Placebo
    Comments Day 6
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.0046
    Comments The p value was not adjusted for multiplicity, testing was conducted at the two-sided significance level of 0.05.
    Method Mantel Haenszel
    Comments Mantel Haenszel test stratified by baseline composite symptom score, preexisting and worsened symptoms, and region.
    Statistical Analysis 10
    Statistical Analysis Overview Comparison Group Selection Baloxavir Marboxil, Oseltamivir
    Comments Day 6
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.441
    Comments The p value was not adjusted for multiplicity, testing was conducted at the two-sided significance level of 0.05.
    Method Mantel Haenszel
    Comments Mantel Haenszel test stratified by baseline composite symptom score, preexisting and worsened symptoms, and region.
    Statistical Analysis 11
    Statistical Analysis Overview Comparison Group Selection Baloxavir Marboxil, Placebo
    Comments Day 9
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.0929
    Comments The p value was not adjusted for multiplicity, testing was conducted at the two-sided significance level of 0.05.
    Method Mantel Haenszel
    Comments Mantel Haenszel test stratified by baseline composite symptom score, preexisting and worsened symptoms, and region.
    Statistical Analysis 12
    Statistical Analysis Overview Comparison Group Selection Baloxavir Marboxil, Oseltamivir
    Comments Day 9
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.0907
    Comments The p value was not adjusted for multiplicity, testing was conducted at the two-sided significance level of 0.05.
    Method Mantel Haenszel
    Comments Mantel Haenszel test stratified by baseline composite symptom score, preexisting and worsened symptoms, and region.
    3. Secondary Outcome
    Title Percentage of Participants With Positive Influenza Virus by RT-PCR at Each Time Point
    Description Influenza virus ribonucleic acid (RNA) was quantified from nasopharyngeal swabs (or throat swabs, if nasopharyngeal swabbing was not feasible). The percentage of participants with detectable virus RNA (2.05 for flu A and 2.83 for flu B log₁₀ virus particles/mL) measured by reverse transcription polymerase chain reaction (RT-PCR) among those assessed on Days 2, 3, 4, 5, 6 and 9.
    Time Frame Days 2, 3, 4 (optional), 5, 6 (optional), and 9.

    Outcome Measure Data

    Analysis Population Description
    Participants in the intention-to-treat infected population with positive influenza virus RNA determined by RT-PCR on Day 1 and with available data at each time point.
    Arm/Group Title Baloxavir Marboxil Placebo Oseltamivir
    Arm/Group Description Participants received either 40 mg or 80 mg of baloxavir marboxil orally on Day 1 based on body weight of < 80 kg or ≥ 80 kg at Screening, respectively. Participants also received placebo to oseltamivir orally twice a day (BID) on Days 1 to 5. Participants received placebo to baloxavir marboxil on Day 1 and placebo to oseltamivir orally twice a day on Days 1 to 5. Participants received 75 mg oseltamivir twice a day on Days 1 to 5 and placebo to baloxavir marboxil on Day 1.
    Measure Participants 388 386 389
    Day 2
    96.0
    24.7%
    96.3
    24.9%
    96.0
    24.7%
    Day 3
    92.5
    23.8%
    95.4
    24.7%
    95.1
    24.4%
    Day 4
    86.5
    22.3%
    91.0
    23.6%
    86.4
    22.2%
    Day 5
    84.9
    21.9%
    88.6
    23%
    86.1
    22.1%
    Day 6
    71.8
    18.5%
    78.0
    20.2%
    71.8
    18.5%
    Day 9
    54.5
    14%
    64.9
    16.8%
    57.7
    14.8%
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Baloxavir Marboxil, Placebo
    Comments Day 2
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.7383
    Comments The p value was not adjusted for multiplicity, testing was conducted at the two-sided significance level of 0.05.
    Method Mantel Haenszel
    Comments Mantel Haenszel test stratified by baseline composite symptom score, preexisting and worsened symptoms, and region.
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Baloxavir Marboxil, Oseltamivir
    Comments Day 2
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.9619
    Comments The p value was not adjusted for multiplicity, testing was conducted at the two-sided significance level of 0.05.
    Method Mantel Haenszel
    Comments Mantel Haenszel test stratified by baseline composite symptom score, preexisting and worsened symptoms, and region.
    Statistical Analysis 3
    Statistical Analysis Overview Comparison Group Selection Baloxavir Marboxil, Placebo
    Comments Day 3
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.0576
    Comments The p value was not adjusted for multiplicity, testing was conducted at the two-sided significance level of 0.05.
    Method Mantel Haenszel
    Comments Mantel Haenszel test stratified by baseline composite symptom score, preexisting and worsened symptoms, and region.
    Statistical Analysis 4
    Statistical Analysis Overview Comparison Group Selection Baloxavir Marboxil, Oseltamivir
    Comments Day 3
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.1237
    Comments The p value was not adjusted for multiplicity, testing was conducted at the two-sided significance level of 0.05.
    Method Mantel Haenszel
    Comments Mantel Haenszel test stratified by baseline composite symptom score, preexisting and worsened symptoms, and region.
    Statistical Analysis 5
    Statistical Analysis Overview Comparison Group Selection Baloxavir Marboxil, Placebo
    Comments Day 4
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.3071
    Comments The p value was not adjusted for multiplicity, testing was conducted at the two-sided significance level of 0.05.
    Method Mantel Haenszel
    Comments Mantel Haenszel test stratified by baseline composite symptom score, preexisting and worsened symptoms, and region.
    Statistical Analysis 6
    Statistical Analysis Overview Comparison Group Selection Baloxavir Marboxil, Oseltamivir
    Comments Day 4
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.9603
    Comments The p value was not adjusted for multiplicity, testing was conducted at the two-sided significance level of 0.05.
    Method Mantel Haenszel
    Comments Mantel Haenszel test stratified by baseline composite symptom score, preexisting and worsened symptoms, and region.
    Statistical Analysis 7
    Statistical Analysis Overview Comparison Group Selection Baloxavir Marboxil, Placebo
    Comments Day 5
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.0784
    Comments The p value was not adjusted for multiplicity, testing was conducted at the two-sided significance level of 0.05.
    Method Mantel Haenszel
    Comments Mantel Haenszel test stratified by baseline composite symptom score, preexisting and worsened symptoms, and region.
    Statistical Analysis 8
    Statistical Analysis Overview Comparison Group Selection Baloxavir Marboxil, Oseltamivir
    Comments Day 5
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.5547
    Comments The p value was not adjusted for multiplicity, testing was conducted at the two-sided significance level of 0.05.
    Method Mantel Haenszel
    Comments Mantel Haenszel test stratified by baseline composite symptom score, preexisting and worsened symptoms, and region.
    Statistical Analysis 9
    Statistical Analysis Overview Comparison Group Selection Baloxavir Marboxil, Placebo
    Comments Day 6
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.3087
    Comments The p value was not adjusted for multiplicity, testing was conducted at the two-sided significance level of 0.05.
    Method Mantel Haenszel
    Comments Mantel Haenszel test stratified by baseline composite symptom score, preexisting and worsened symptoms, and region.
    Statistical Analysis 10
    Statistical Analysis Overview Comparison Group Selection Baloxavir Marboxil, Oseltamivir
    Comments Day 6
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.9106
    Comments The p value was not adjusted for multiplicity, testing was conducted at the two-sided significance level of 0.05.
    Method Mantel Haenszel
    Comments Mantel Haenszel test stratified by baseline composite symptom score, preexisting and worsened symptoms, and region.
    Statistical Analysis 11
    Statistical Analysis Overview Comparison Group Selection Baloxavir Marboxil, Placebo
    Comments Day 9
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.0017
    Comments The p value was not adjusted for multiplicity, testing was conducted at the two-sided significance level of 0.05.
    Method Mantel Haenszel
    Comments Mantel Haenszel test stratified by baseline composite symptom score, preexisting and worsened symptoms, and region.
    Statistical Analysis 12
    Statistical Analysis Overview Comparison Group Selection Baloxavir Marboxil, Oseltamivir
    Comments Day 9
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.3068
    Comments The p value was not adjusted for multiplicity, testing was conducted at the two-sided significance level of 0.05.
    Method Mantel Haenszel
    Comments Mantel Haenszel test stratified by baseline composite symptom score, preexisting and worsened symptoms, and region.
    4. Secondary Outcome
    Title Change From Baseline in Virus Titer at Each Time Point
    Description Virus titer was quantified from nasopharyngeal swabs (or throat swabs if nasopharyngeal swabbing was not feasible) by tissue culture methods. If virus titer was less than the lower limit of quantification, the virus titer was imputed 0.7 (TCID₅₀/mL).
    Time Frame Day 1 pretreatment (Baseline) and Days 2, 3, 4 (optional), 5, 6 (optional), and 9

    Outcome Measure Data

    Analysis Population Description
    Participants in the intention-to-treat infected population with positive influenza virus titer on Day 1 and with available virus titer data at each time point.
    Arm/Group Title Baloxavir Marboxil Placebo Oseltamivir
    Arm/Group Description Participants received either 40 mg or 80 mg of baloxavir marboxil orally on Day 1 based on body weight of < 80 kg or ≥ 80 kg at Screening, respectively. Participants also received placebo to oseltamivir orally twice a day (BID) on Days 1 to 5. Participants received placebo to baloxavir marboxil on Day 1 and placebo to oseltamivir orally twice a day on Days 1 to 5. Participants received 75 mg oseltamivir twice a day on Days 1 to 5 and placebo to baloxavir marboxil on Day 1.
    Measure Participants 355 353 360
    Day 2
    -3.36
    (2.21)
    -1.25
    (2.27)
    -1.76
    (2.20)
    Day 3
    -3.92
    (2.22)
    -2.99
    (2.55)
    -3.26
    (2.50)
    Day 4
    -3.99
    (2.00)
    -3.79
    (2.75)
    -3.75
    (2.26)
    Day 5
    -4.32
    (2.16)
    -4.38
    (2.31)
    -4.41
    (2.12)
    Day 6
    -4.07
    (2.05)
    -4.68
    (2.22)
    -4.39
    (1.97)
    Day 9
    -4.53
    (2.11)
    -4.91
    (2.08)
    -4.78
    (2.07)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Baloxavir Marboxil, Placebo
    Comments Day 2
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value <0.0001
    Comments The p value was not adjusted for multiplicity, testing was conducted at the two-sided significance level of 0.05.
    Method van Elteren test
    Comments Van Elteren test stratified by baseline composite symptom score, preexisting and worsened symptoms, and region.
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Baloxavir Marboxil, Oseltamivir
    Comments Day 2
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value <0.0001
    Comments The p value was not adjusted for multiplicity, testing was conducted at the two-sided significance level of 0.05.
    Method van Elteren test
    Comments Van Elteren test stratified by baseline composite symptom score, preexisting and worsened symptoms, and region.
    Statistical Analysis 3
    Statistical Analysis Overview Comparison Group Selection Baloxavir Marboxil, Placebo
    Comments Day 3
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value <0.0001
    Comments The p value was not adjusted for multiplicity, testing was conducted at the two-sided significance level of 0.05.
    Method van Elteren test
    Comments Van Elteren test stratified by baseline composite symptom score, preexisting and worsened symptoms, and region.
    Statistical Analysis 4
    Statistical Analysis Overview Comparison Group Selection Baloxavir Marboxil, Oseltamivir
    Comments Day 3
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.0024
    Comments The p value was not adjusted for multiplicity, testing was conducted at the two-sided significance level of 0.05.
    Method van Elteren test
    Comments Van Elteren test stratified by baseline composite symptom score, preexisting and worsened symptoms, and region.
    Statistical Analysis 5
    Statistical Analysis Overview Comparison Group Selection Baloxavir Marboxil, Placebo
    Comments Day 4
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.9127
    Comments The p value was not adjusted for multiplicity, testing was conducted at the two-sided significance level of 0.05.
    Method ven Elteren test
    Comments Van Elteren test stratified by baseline composite symptom score, preexisting and worsened symptoms, and region.
    Statistical Analysis 6
    Statistical Analysis Overview Comparison Group Selection Baloxavir Marboxil, Oseltamivir
    Comments Day 4
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.5361
    Comments The p value was not adjusted for multiplicity, testing was conducted at the two-sided significance level of 0.05.
    Method van Elteren test
    Comments Van Elteren test stratified by baseline composite symptom score, preexisting and worsened symptoms, and region.
    Statistical Analysis 7
    Statistical Analysis Overview Comparison Group Selection Baloxavir Marboxil, Placebo
    Comments Day 5
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.5739
    Comments The p value was not adjusted for multiplicity, testing was conducted at the two-sided significance level of 0.05.
    Method van Elteren test
    Comments Van Elteren test stratified by baseline composite symptom score, preexisting and worsened symptoms, and region.
    Statistical Analysis 8
    Statistical Analysis Overview Comparison Group Selection Baloxavir Marboxil, Oseltamivir
    Comments Day 5
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.5466
    Comments The p value was not adjusted for multiplicity, testing was conducted at the two-sided significance level of 0.05.
    Method van Elteren test
    Comments Van Elteren test stratified by baseline composite symptom score, preexisting and worsened symptoms, and region.
    Statistical Analysis 9
    Statistical Analysis Overview Comparison Group Selection Baloxavir Marboxil, Placebo
    Comments Day 6
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.0543
    Comments The p value was not adjusted for multiplicity, testing was conducted at the two-sided significance level of 0.05.
    Method van Elteren test
    Comments Van Elteren test stratified by baseline composite symptom score, preexisting and worsened symptoms, and region.
    Statistical Analysis 10
    Statistical Analysis Overview Comparison Group Selection Baloxavir Marboxil, Oseltamivir
    Comments Day 6
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.4677
    Comments The p value was not adjusted for multiplicity, testing was conducted at the two-sided significance level of 0.05.
    Method van Elteren test
    Comments Van Elteren test stratified by baseline composite symptom score, preexisting and worsened symptoms, and region.
    Statistical Analysis 11
    Statistical Analysis Overview Comparison Group Selection Baloxavir Marboxil, Placebo
    Comments Day 9
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.0266
    Comments The p value was not adjusted for multiplicity, testing was conducted at the two-sided significance level of 0.05.
    Method van Elteren test
    Comments Van Elteren test stratified by baseline composite symptom score, preexisting and worsened symptoms, and region.
    Statistical Analysis 12
    Statistical Analysis Overview Comparison Group Selection Baloxavir Marboxil, Oseltamivir
    Comments Day 9
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.1281
    Comments The p value was not adjusted for multiplicity, testing was conducted at the two-sided significance level of 0.05.
    Method van Elteren test
    Comments Van Elteren test stratified by baseline composite symptom score, preexisting and worsened symptoms, and region.
    5. Secondary Outcome
    Title Change From Baseline in Virus RNA (RT-PCR) at Each Time Point
    Description Nasopharyngeal swabs (or throat swabs, if nasopharyngeal swabbing was not feasible) were obtained for viral quantitation. Virus RNA was measured by reverse transcription polymerase chain reaction (RT-PCR).
    Time Frame Day 1 pretreatment (Baseline) and Days 2, 3, 4 (optional), 5, 6 (optional), and 9

    Outcome Measure Data

    Analysis Population Description
    Participants in the intention-to-treat infected population with positive RT-PCR on Day 1 and with available virus RNA data at each time point.
    Arm/Group Title Baloxavir Marboxil Placebo Oseltamivir
    Arm/Group Description Participants received either 40 mg or 80 mg of baloxavir marboxil orally on Day 1 based on body weight of < 80 kg or ≥ 80 kg at Screening, respectively. Participants also received placebo to oseltamivir orally twice a day (BID) on Days 1 to 5. Participants received placebo to baloxavir marboxil on Day 1 and placebo to oseltamivir orally twice a day on Days 1 to 5. Participants received 75 mg oseltamivir twice a day on Days 1 to 5 and placebo to baloxavir marboxil on Day 1.
    Measure Participants 388 386 389
    Day 2
    -1.13
    (1.20)
    -0.62
    (1.34)
    -0.76
    (1.18)
    Day 3
    -2.09
    (1.45)
    -1.57
    (1.66)
    -1.77
    (1.45)
    Day 4
    -2.77
    (1.42)
    -2.09
    (1.84)
    -2.34
    (1.63)
    Day 5
    -3.09
    (1.58)
    -2.77
    (1.67)
    -3.04
    (1.46)
    Day 6
    -3.33
    (1.48)
    -3.19
    (1.77)
    -3.41
    (1.38)
    Day 9
    -3.89
    (1.51)
    -3.78
    (1.65)
    -3.99
    (1.39)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Baloxavir Marboxil, Placebo
    Comments Day 2
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value <0.0001
    Comments The p value was not adjusted for multiplicity, testing was conducted at the two-sided significance level of 0.05.
    Method van Elteren test
    Comments Van Elteren test stratified by baseline composite symptom score, preexisting and worsened symptoms, and region.
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Baloxavir Marboxil, Oseltamivir
    Comments Day 2
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value <0.0001
    Comments The p value was not adjusted for multiplicity, testing was conducted at the two-sided significance level of 0.05.
    Method van Elteren test
    Comments Van Elteren test stratified by baseline composite symptom score, preexisting and worsened symptoms, and region.
    Statistical Analysis 3
    Statistical Analysis Overview Comparison Group Selection Baloxavir Marboxil, Placebo
    Comments Day 3
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value <0.0001
    Comments The p value was not adjusted for multiplicity, testing was conducted at the two-sided significance level of 0.05.
    Method van Elteren test
    Comments Van Elteren test stratified by baseline composite symptom score, preexisting and worsened symptoms, and region.
    Statistical Analysis 4
    Statistical Analysis Overview Comparison Group Selection Baloxavir Marboxil, Oseltamivir
    Comments Day 3
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.0015
    Comments The p value was not adjusted for multiplicity, testing was conducted at the two-sided significance level of 0.05.
    Method van Elteren test
    Comments Van Elteren test stratified by baseline composite symptom score, preexisting and worsened symptoms, and region.
    Statistical Analysis 5
    Statistical Analysis Overview Comparison Group Selection Baloxavir Marboxil, Placebo
    Comments Day 4
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.0028
    Comments The p value was not adjusted for multiplicity, testing was conducted at the two-sided significance level of 0.05.
    Method van Elteren test
    Comments Van Elteren test stratified by baseline composite symptom score, preexisting and worsened symptoms, and region.
    Statistical Analysis 6
    Statistical Analysis Overview Comparison Group Selection Baloxavir Marboxil, Oseltamivir
    Comments Day 4
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.0265
    Comments The p value was not adjusted for multiplicity, testing was conducted at the two-sided significance level of 0.05.
    Method van Elteren test
    Comments Van Elteren test stratified by baseline composite symptom score, preexisting and worsened symptoms, and region.
    Statistical Analysis 7
    Statistical Analysis Overview Comparison Group Selection Baloxavir Marboxil, Placebo
    Comments Day 5
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.0247
    Comments The p value was not adjusted for multiplicity, testing was conducted at the two-sided significance level of 0.05.
    Method van Elteren test
    Comments Van Elteren test stratified by baseline composite symptom score, preexisting and worsened symptoms, and region.
    Statistical Analysis 8
    Statistical Analysis Overview Comparison Group Selection Baloxavir Marboxil, Oseltamivir
    Comments Day 5
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.5298
    Comments The p value was not adjusted for multiplicity, testing was conducted at the two-sided significance level of 0.05.
    Method van Elteren test
    Comments Van Elteren test stratified by baseline composite symptom score, preexisting and worsened symptoms, and region.
    Statistical Analysis 9
    Statistical Analysis Overview Comparison Group Selection Baloxavir Marboxil, Placebo
    Comments Day 6
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.9554
    Comments The p value was not adjusted for multiplicity, testing was conducted at the two-sided significance level of 0.05.
    Method van Elteren test
    Comments Van Elteren test stratified by baseline composite symptom score, preexisting and worsened symptoms, and region.
    Statistical Analysis 10
    Statistical Analysis Overview Comparison Group Selection Baloxavir Marboxil, Oseltamivir
    Comments Day 6
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.9075
    Comments The p value was not adjusted for multiplicity, testing was conducted at the two-sided significance level of 0.05.
    Method van Elteren test
    Comments Van Elteren test stratified by baseline composite symptom score, preexisting and worsened symptoms, and region.
    Statistical Analysis 11
    Statistical Analysis Overview Comparison Group Selection Baloxavir Marboxil, Placebo
    Comments Day 9
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.7624
    Comments The p value was not adjusted for multiplicity, testing was conducted at the two-sided significance level of 0.05.
    Method van Elteren test
    Comments Van Elteren test stratified by baseline composite symptom score, preexisting and worsened symptoms, and region.
    Statistical Analysis 12
    Statistical Analysis Overview Comparison Group Selection Baloxavir Marboxil, Oseltamivir
    Comments Day 9
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.6156
    Comments The p value was not adjusted for multiplicity, testing was conducted at the two-sided significance level of 0.05.
    Method van Elteren test
    Comments Van Elteren test stratified by baseline composite symptom score, preexisting and worsened symptoms, and region.
    6. Secondary Outcome
    Title Area Under the Curve (AUC) Adjusted by Baseline in Influenza Virus Titer
    Description This endpoint was defined as AUC of change from Baseline in virus titer from Day 1 to Day 9. AUC was calculated using the trapezoidal method.
    Time Frame Day 1 to Day 9

    Outcome Measure Data

    Analysis Population Description
    Participants in the intention-to-treat infected population with a positive virus titer on Day 1 and available sample on Day 9.
    Arm/Group Title Baloxavir Marboxil Placebo Oseltamivir
    Arm/Group Description Participants received either 40 mg or 80 mg of baloxavir marboxil orally on Day 1 based on body weight of < 80 kg or ≥ 80 kg at Screening, respectively. Participants also received placebo to oseltamivir orally twice a day (BID) on Days 1 to 5. Participants received placebo to baloxavir marboxil on Day 1 and placebo to oseltamivir orally twice a day on Days 1 to 5. Participants received 75 mg oseltamivir twice a day on Days 1 to 5 and placebo to baloxavir marboxil on Day 1.
    Measure Participants 355 353 360
    Mean (Standard Deviation) [log₁₀[TCID₅₀/mL]*hours]
    -727.7
    (367.2)
    -660.2
    (372.3)
    -695.5
    (360.5)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Baloxavir Marboxil, Placebo
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.0340
    Comments The p value was not adjusted for multiplicity, testing was conducted at the two-sided significance level of 0.05.
    Method van Elteren test
    Comments Van Elteren test stratified by baseline composite symptom score, preexisting and worsened symptoms, and region.
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Baloxavir Marboxil, Oseltamivir
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.2766
    Comments The p value was not adjusted for multiplicity, testing was conducted at the two-sided significance level of 0.05.
    Method van Elteren test
    Comments Van Elteren test stratified by baseline composite symptom score, preexisting and worsened symptoms, and region.
    7. Secondary Outcome
    Title Area Under the Curve (AUC) Adjusted by Baseline in Viral RNA
    Description This endpoint was defined as AUC of change from baseline in the amount of virus RNA (RT-PCR) from Day 1 to Day 9. The AUC was calculated using the trapezoidal method.
    Time Frame Day 1 to Day 9

    Outcome Measure Data

    Analysis Population Description
    Participants in the intention-to-treat infected population with a positive virus RNA determined by RT-PCR at baseline and available sample on Day 9.
    Arm/Group Title Baloxavir Marboxil Placebo Oseltamivir
    Arm/Group Description Participants received either 40 mg or 80 mg of baloxavir marboxil orally on Day 1 based on body weight of < 80 kg or ≥ 80 kg at Screening, respectively. Participants also received placebo to oseltamivir orally twice a day (BID) on Days 1 to 5. Participants received placebo to baloxavir marboxil on Day 1 and placebo to oseltamivir orally twice a day on Days 1 to 5. Participants received 75 mg oseltamivir twice a day on Days 1 to 5 and placebo to baloxavir marboxil on Day 1.
    Measure Participants 360 349 349
    Mean (Standard Deviation) [log₁₀ virus particles/mL*hours]
    -490.9
    (249.3)
    -434.9
    (269.3)
    -482.2
    (233.2)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Baloxavir Marboxil, Placebo
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.0072
    Comments The p value was not adjusted for multiplicity, testing was conducted at the two-sided significance level of 0.05.
    Method van Elteren test
    Comments Van Elteren test stratified by baseline composite symptom score, preexisting and worsened symptoms, and region.
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Baloxavir Marboxil, Oseltamivir
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.7330
    Comments The p value was not adjusted for multiplicity, testing was conducted at the two-sided significance level of 0.05.
    Method van Elteren test
    Comments Van Elteren test stratified by baseline composite symptom score, preexisting and worsened symptoms, and region.
    8. Secondary Outcome
    Title Time to Cessation of Viral Shedding Determined by Virus Titer
    Description Time to cessation of viral shedding by virus titer was defined as the time between the initiation of the study treatment and first time when the virus titer was below the limit of detection (0.7 log₁₀[TCID₅₀/mL]). The median and 95% confidence interval (CI) for time to cessation of viral shedding determined by virus titer was analyzed using the Kaplan-Meier (KM) method; participants whose virus titer had not reached cessation by the last observation time point were treated as censored at that time point.
    Time Frame Day 1 to Day 9

    Outcome Measure Data

    Analysis Population Description
    Participants in the intention-to-treat infected population with a positive virus titer on Day 1 whose time to cessation of viral shedding by virus titer was not missing.
    Arm/Group Title Baloxavir Marboxil Placebo Oseltamivir
    Arm/Group Description Participants received either 40 mg or 80 mg of baloxavir marboxil orally on Day 1 based on body weight of < 80 kg or ≥ 80 kg at Screening, respectively. Participants also received placebo to oseltamivir orally twice a day (BID) on Days 1 to 5. Participants received placebo to baloxavir marboxil on Day 1 and placebo to oseltamivir orally twice a day on Days 1 to 5. Participants received 75 mg oseltamivir twice a day on Days 1 to 5 and placebo to baloxavir marboxil on Day 1.
    Measure Participants 352 352 356
    Median (95% Confidence Interval) [hours]
    48.0
    96.0
    96.0
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Baloxavir Marboxil, Placebo
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value <0.0001
    Comments The p value was not adjusted for multiplicity, testing was conducted at the two-sided significance level of 0.05.
    Method Generalized Wilcoxon test
    Comments Peto-Prentice's generalized Wilcoxon test stratified by baseline composite symptom score, preexisting and worsened symptoms, and region
    Method of Estimation Estimation Parameter Median Difference
    Estimated Value -48.0
    Confidence Interval (2-Sided) 95%
    -48.0 to -48.0
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Baloxavir Marboxil, Oseltamivir
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value <0.0001
    Comments The p value was not adjusted for multiplicity, testing was conducted at the two-sided significance level of 0.05.
    Method Generalized Wilcoxon test
    Comments Peto-Prentice's generalized Wilcoxon test stratified by baseline composite symptom score, preexisting and worsened symptoms, and region
    Method of Estimation Estimation Parameter Median Difference
    Estimated Value -48.0
    Confidence Interval (2-Sided) 95%
    -48.0 to -24.0
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    9. Secondary Outcome
    Title Time to Cessation of Viral Shedding Determined by Virus RNA
    Description Time to cessation of viral shedding by RT-PCR was defined as the time between the initiation of the study treatment and first time when the virus RNA was below the limit of detection measured by RT-PCR. Time to cessation of viral shedding by RT-PCR was analyzed using the KM method; participants whose virus RNA had not reached cessation by the last observation time point were treated as censored at that time point.
    Time Frame Day 1 to Day 9

    Outcome Measure Data

    Analysis Population Description
    Participants in the intention-to-treat infected population with positive influenza virus RNA determined by RT-PCR on Day 1 whose time to cessation of viral shedding by RT-PCR.
    Arm/Group Title Baloxavir Marboxil Placebo Oseltamivir
    Arm/Group Description Participants received either 40 mg or 80 mg of baloxavir marboxil orally on Day 1 based on body weight of < 80 kg or ≥ 80 kg at Screening, respectively. Participants also received placebo to oseltamivir orally twice a day (BID) on Days 1 to 5. Participants received placebo to baloxavir marboxil on Day 1 and placebo to oseltamivir orally twice a day on Days 1 to 5. Participants received 75 mg oseltamivir twice a day on Days 1 to 5 and placebo to baloxavir marboxil on Day 1.
    Measure Participants 385 385 384
    Median (95% Confidence Interval) [hours]
    216.0
    240.0
    216.0
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Baloxavir Marboxil, Placebo
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.0006
    Comments The p value was not adjusted for multiplicity, testing was conducted at the two-sided significance level of 0.05.
    Method Generalized Wilcoxon test
    Comments Peto-Prentice's generalized Wilcoxon test stratified by baseline composite symptom score, preexisting and worsened symptoms, and region
    Method of Estimation Estimation Parameter Median Difference
    Estimated Value -24.0
    Confidence Interval (2-Sided) 95%
    -96.0 to 0.0
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Baloxavir Marboxil, Oseltamivir
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.2370
    Comments The p value was not adjusted for multiplicity, testing was conducted at the two-sided significance level of 0.05.
    Method Generalized Wilcoxon test
    Comments Peto-Prentice's generalized Wilcoxon test stratified by baseline composite symptom score, preexisting and worsened symptoms, and region
    Method of Estimation Estimation Parameter Median Difference
    Estimated Value 0.0
    Confidence Interval (2-Sided) 95%
    -48.0 to 24.0
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    10. Secondary Outcome
    Title Percentage of Participants Whose Symptoms Were Improved at Each Time Point
    Description Participants assessed the severity of 7 influenza-associated symptoms (cough, sore throat, headache, nasal congestion, feverishness or chills, muscle or joint pain, and fatigue) on a 4-point scale (0 = no symptoms, 1= mild, 2 = moderate, and 3 = severe). Improvement of symptoms was defined as all influenza symptoms alleviated, maintained, or improved, as defined below, for a duration of at least 21.5 hours: Preexisting symptoms (cough, fatigue, or muscle/joint pain that existed prior to influenza) judged to be worse at baseline must have improved at least 1 point from baseline severity Preexisting symptoms judged not to be worse at baseline must have maintained baseline severity New symptoms at baseline must have alleviated, defined as a symptom score of none (0) or mild (1).
    Time Frame 12, 24, 36, 48, 72, 96, 120, 144, 168, 192, and 216 hours after the initial dose of study treatment

    Outcome Measure Data

    Analysis Population Description
    Participants in the intention-to-treat infected population with available symptoms data at each time point.
    Arm/Group Title Baloxavir Marboxil Placebo Oseltamivir
    Arm/Group Description Participants received either 40 mg or 80 mg of baloxavir marboxil orally on Day 1 based on body weight of < 80 kg or ≥ 80 kg at Screening, respectively. Participants also received placebo to oseltamivir orally twice a day (BID) on Days 1 to 5. Participants received placebo to baloxavir marboxil on Day 1 and placebo to oseltamivir orally twice a day on Days 1 to 5. Participants received 75 mg oseltamivir twice a day on Days 1 to 5 and placebo to baloxavir marboxil on Day 1.
    Measure Participants 388 386 389
    12 hours
    9.1
    2.3%
    8.6
    2.2%
    8.1
    2.1%
    24 hours
    18.8
    4.8%
    14.2
    3.7%
    19.6
    5%
    36 hours
    33.9
    8.7%
    21.1
    5.5%
    31.0
    8%
    48 hours
    38.0
    9.8%
    28.8
    7.5%
    39.9
    10.3%
    72 hours
    56.0
    14.4%
    41.8
    10.8%
    56.0
    14.4%
    96 hours
    65.9
    17%
    53.4
    13.8%
    61.1
    15.7%
    120 hours
    72.3
    18.6%
    64.6
    16.7%
    72.4
    18.6%
    144 hours
    78.1
    20.1%
    69.6
    18%
    77.6
    19.9%
    168 hours
    80.1
    20.6%
    72.7
    18.8%
    79.6
    20.5%
    192 hours
    83.6
    21.5%
    78.0
    20.2%
    85.6
    22%
    216 hours
    85.8
    22.1%
    78.7
    20.4%
    88.2
    22.7%
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Baloxavir Marboxil, Placebo
    Comments 12 hours
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.7698
    Comments The p value was not adjusted for multiplicity, testing was conducted at the two-sided significance level of 0.05.
    Method Mantel Haenszel
    Comments Mantel-Haenszel test stratified by baseline composite symptom score, preexisting and worsened symptoms, and region.
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Baloxavir Marboxil, Oseltamivir
    Comments 12 hours
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.5777
    Comments The p value was not adjusted for multiplicity, testing was conducted at the two-sided significance level of 0.05.
    Method Mantel Haenszel
    Comments Mantel-Haenszel test stratified by baseline composite symptom score, preexisting and worsened symptoms, and region.
    Statistical Analysis 3
    Statistical Analysis Overview Comparison Group Selection Baloxavir Marboxil, Placebo
    Comments 24 hours
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.1112
    Comments The p value was not adjusted for multiplicity, testing was conducted at the two-sided significance level of 0.05.
    Method Mantel Haenszel
    Comments Mantel-Haenszel test stratified by baseline composite symptom score, preexisting and worsened symptoms, and region.
    Statistical Analysis 4
    Statistical Analysis Overview Comparison Group Selection Baloxavir Marboxil, Oseltamivir
    Comments 24 hours
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.6483
    Comments The p value was not adjusted for multiplicity, testing was conducted at the two-sided significance level of 0.05.
    Method Mantel Haenszel
    Comments Mantel-Haenszel test stratified by baseline composite symptom score, preexisting and worsened symptoms, and region.
    Statistical Analysis 5
    Statistical Analysis Overview Comparison Group Selection Baloxavir Marboxil, Placebo
    Comments 36 hours
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.0004
    Comments The p value was not adjusted for multiplicity, testing was conducted at the two-sided significance level of 0.05.
    Method Mantel Haenszel
    Comments Mantel-Haenszel test stratified by baseline composite symptom score, preexisting and worsened symptoms, and region.
    Statistical Analysis 6
    Statistical Analysis Overview Comparison Group Selection Baloxavir Marboxil, Oseltamivir
    Comments 36 hours
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.5625
    Comments The p value was not adjusted for multiplicity, testing was conducted at the two-sided significance level of 0.05.
    Method Mantel Haenszel
    Comments Mantel-Haenszel test stratified by baseline composite symptom score, preexisting and worsened symptoms, and region.
    Statistical Analysis 7
    Statistical Analysis Overview Comparison Group Selection Baloxavir Marboxil, Placebo
    Comments 48 hours
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.0072
    Comments The p value was not adjusted for multiplicity, testing was conducted at the two-sided significance level of 0.05.
    Method Mantel Haenszel
    Comments Mantel-Haenszel test stratified by baseline composite symptom score, preexisting and worsened symptoms, and region.
    Statistical Analysis 8
    Statistical Analysis Overview Comparison Group Selection Baloxavir Marboxil, Oseltamivir
    Comments 48 hours
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.6234
    Comments The p value was not adjusted for multiplicity, testing was conducted at the two-sided significance level of 0.05.
    Method Mantel Haenszel
    Comments Mantel-Haenszel test stratified by baseline composite symptom score, preexisting and worsened symptoms, and region.
    Statistical Analysis 9
    Statistical Analysis Overview Comparison Group Selection Baloxavir Marboxil, Placebo
    Comments 72 hours
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.0002
    Comments The p value was not adjusted for multiplicity, testing was conducted at the two-sided significance level of 0.05.
    Method Mantel Haenszel
    Comments Mantel-Haenszel test stratified by baseline composite symptom score, preexisting and worsened symptoms, and region.
    Statistical Analysis 10
    Statistical Analysis Overview Comparison Group Selection Baloxavir Marboxil, Oseltamivir
    Comments 72 hours
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.9547
    Comments The p value was not adjusted for multiplicity, testing was conducted at the two-sided significance level of 0.05.
    Method Mantel Haenszel
    Comments Mantel-Haenszel test stratified by baseline composite symptom score, preexisting and worsened symptoms, and region.
    Statistical Analysis 11
    Statistical Analysis Overview Comparison Group Selection Baloxavir Marboxil, Placebo
    Comments 96 hours
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.0012
    Comments The p value was not adjusted for multiplicity, testing was conducted at the two-sided significance level of 0.05.
    Method Mantel Haenszel
    Comments Mantel-Haenszel test stratified by baseline composite symptom score, preexisting and worsened symptoms, and region.
    Statistical Analysis 12
    Statistical Analysis Overview Comparison Group Selection Baloxavir Marboxil, Oseltamivir
    Comments 96 hours
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.1860
    Comments The p value was not adjusted for multiplicity, testing was conducted at the two-sided significance level of 0.05.
    Method Mantel Haenszel
    Comments Mantel-Haenszel test stratified by baseline composite symptom score, preexisting and worsened symptoms, and region.
    Statistical Analysis 13
    Statistical Analysis Overview Comparison Group Selection Baloxavir Marboxil, Placebo
    Comments 120 hours
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.0274
    Comments The p value was not adjusted for multiplicity, testing was conducted at the two-sided significance level of 0.05.
    Method Mantel Haenszel
    Comments Mantel-Haenszel test stratified by baseline composite symptom score, preexisting and worsened symptoms, and region.
    Statistical Analysis 14
    Statistical Analysis Overview Comparison Group Selection Baloxavir Marboxil, Oseltamivir
    Comments 120 hours
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.9635
    Comments The p value was not adjusted for multiplicity, testing was conducted at the two-sided significance level of 0.05.
    Method Mantel Haenszel
    Comments Mantel-Haenszel test stratified by baseline composite symptom score, preexisting and worsened symptoms, and region.
    Statistical Analysis 15
    Statistical Analysis Overview Comparison Group Selection Baloxavir Marboxil, Placebo
    Comments 144 hours
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.0081
    Comments The p value was not adjusted for multiplicity, testing was conducted at the two-sided significance level of 0.05.
    Method Mantel Haenszel
    Comments Mantel-Haenszel test stratified by baseline composite symptom score, preexisting and worsened symptoms, and region.
    Statistical Analysis 16
    Statistical Analysis Overview Comparison Group Selection Baloxavir Marboxil, Oseltamivir
    Comments 144 hours
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.7425
    Comments The p value was not adjusted for multiplicity, testing was conducted at the two-sided significance level of 0.05.
    Method Mantel Haenszel
    Comments Mantel-Haenszel test stratified by baseline composite symptom score, preexisting and worsened symptoms, and region.
    Statistical Analysis 17
    Statistical Analysis Overview Comparison Group Selection Baloxavir Marboxil, Placebo
    Comments 168 hours
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.0209
    Comments The p value was not adjusted for multiplicity, testing was conducted at the two-sided significance level of 0.05.
    Method Mantel Haenszel
    Comments Mantel-Haenszel test stratified by baseline composite symptom score, preexisting and worsened symptoms, and region.
    Statistical Analysis 18
    Statistical Analysis Overview Comparison Group Selection Baloxavir Marboxil, Oseltamivir
    Comments 168 hours
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.7448
    Comments The p value was not adjusted for multiplicity, testing was conducted at the two-sided significance level of 0.05.
    Method Mantel Haenszel
    Comments Mantel-Haenszel test stratified by baseline composite symptom score, preexisting and worsened symptoms, and region.
    Statistical Analysis 19
    Statistical Analysis Overview Comparison Group Selection Baloxavir Marboxil, Placebo
    Comments 192 hours
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.0644
    Comments The p value was not adjusted for multiplicity, testing was conducted at the two-sided significance level of 0.05.
    Method Mantel Haenszel
    Comments Mantel-Haenszel test stratified by baseline composite symptom score, preexisting and worsened symptoms, and region.
    Statistical Analysis 20
    Statistical Analysis Overview Comparison Group Selection Baloxavir Marboxil, Oseltamivir
    Comments 192 hours
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.4931
    Comments The p value was not adjusted for multiplicity, testing was conducted at the two-sided significance level of 0.05.
    Method Mantel Haenszel
    Comments Mantel-Haenszel test stratified by baseline composite symptom score, preexisting and worsened symptoms, and region.
    Statistical Analysis 21
    Statistical Analysis Overview Comparison Group Selection Baloxavir Marboxil, Placebo
    Comments 216 hours
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.0708
    Comments The p value was not adjusted for multiplicity, testing was conducted at the two-sided significance level of 0.05.
    Method Mantel Haenszel
    Comments Mantel-Haenszel test stratified by baseline composite symptom score, preexisting and worsened symptoms, and region.
    Statistical Analysis 22
    Statistical Analysis Overview Comparison Group Selection Baloxavir Marboxil, Oseltamivir
    Comments 216 hours
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.4024
    Comments The p value was not adjusted for multiplicity, testing was conducted at the two-sided significance level of 0.05.
    Method Mantel Haenszel
    Comments Mantel-Haenszel test stratified by baseline composite symptom score, preexisting and worsened symptoms, and region.
    11. Secondary Outcome
    Title Time to Alleviation of Symptoms
    Description Participants assessed the severity of seven influenza-associated symptoms (cough, sore throat, headache, nasal congestion, feverishness or chills, muscle or joint pain, and fatigue) on a 4-point scale (with 0 indicating no symptoms, 1 mild symptoms, 2 moderate symptoms, and 3 severe symptoms). Time to alleviation of symptoms was defined as the time from the start of the study treatment to the time when all seven influenza-related symptoms were assessed by the participant as absent (0) or mild (1) for at least 21.5 hours. Time to alleviation of symptoms was analyzed using Kaplan-Meier (KM) methods; participants who did not experience alleviation of symptoms were censored at the last observation time point.
    Time Frame Initiation of study treatment up to Day 14

    Outcome Measure Data

    Analysis Population Description
    Participants in the intention-to-treat infected population with available time to alleviation of symptoms data.
    Arm/Group Title Baloxavir Marboxil Placebo Oseltamivir
    Arm/Group Description Participants received either 40 mg or 80 mg of baloxavir marboxil orally on Day 1 based on body weight of < 80 kg or ≥ 80 kg at Screening, respectively. Participants also received placebo to oseltamivir orally twice a day (BID) on Days 1 to 5. Participants received placebo to baloxavir marboxil on Day 1 and placebo to oseltamivir orally twice a day on Days 1 to 5. Participants received 75 mg oseltamivir twice a day on Days 1 to 5 and placebo to baloxavir marboxil on Day 1.
    Measure Participants 385 385 388
    Median (95% Confidence Interval) [hours]
    77.0
    102.8
    85.6
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Baloxavir Marboxil, Placebo
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value <0.0001
    Comments The p value was not adjusted for multiplicity, testing was conducted at the two-sided significance level of 0.05.
    Method Generalized Wilcoxon test
    Comments Peto-Prentice's generalized Wilcoxon test stratified by baseline composite symptom score, preexisting and worsened symptoms, and region.
    Method of Estimation Estimation Parameter Median Difference
    Estimated Value -25.8
    Confidence Interval () %
    to
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Baloxavir Marboxil, Oseltamivir
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.9127
    Comments The p value was not adjusted for multiplicity, testing was conducted at the two-sided significance level of 0.05.
    Method Generalized Wilcoxon test
    Comments Peto-Prentice's generalized Wilcoxon test stratified by baseline composite symptom score, preexisting and worsened symptoms, and region.
    Method of Estimation Estimation Parameter Median Difference
    Estimated Value -8.6
    Confidence Interval () %
    to
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    12. Secondary Outcome
    Title Time to Improvement of the Four Systemic Symptoms
    Description Participants assessed the severity of 7 influenza-associated symptoms on a 4-point scale (from 0 = no symptoms to 3 = severe symptoms). Time to improvement of the 4 systemic symptoms was defined as the time between the initiation of study treatment to the time when all 4 systemic symptoms (headache, feverishness or chills, muscle or joint pain, and fatigue) were alleviated, maintained, or improved, as defined below, for a duration of at least 21.5 hours: Preexisting symptoms (cough, fatigue, or muscle/joint pain that existed prior to influenza) that were worse at baseline must have improved at least 1 point from baseline Preexisting symptoms not worse at baseline must have maintained baseline severity New symptoms at baseline must have alleviated, defined as a symptom score of none (0) or mild (1). Time to improvement of the 4 systemic symptoms was analyzed using KM methods; participants who did not experience improvement of symptoms were censored at the last observation.
    Time Frame Initiation of study treatment up to Day 14

    Outcome Measure Data

    Analysis Population Description
    Participants in the intention-to-treat infected population with available time to improvement of the 4 systemic symptoms data.
    Arm/Group Title Baloxavir Marboxil Placebo Oseltamivir
    Arm/Group Description Participants received either 40 mg or 80 mg of baloxavir marboxil orally on Day 1 based on body weight of < 80 kg or ≥ 80 kg at Screening, respectively. Participants also received placebo to oseltamivir orally twice a day (BID) on Days 1 to 5. Participants received placebo to baloxavir marboxil on Day 1 and placebo to oseltamivir orally twice a day on Days 1 to 5. Participants received 75 mg oseltamivir twice a day on Days 1 to 5 and placebo to baloxavir marboxil on Day 1.
    Measure Participants 385 385 388
    Median (95% Confidence Interval) [hours]
    51.7
    66.8
    49.4
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Baloxavir Marboxil, Placebo
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.0013
    Comments The p value was not adjusted for multiplicity, testing was conducted at the two-sided significance level of 0.05.
    Method Generalized Wilcoxon test
    Comments Peto-Prentice's generalized Wilcoxon test stratified by baseline composite symptom score, preexisting and worsened symptoms, and region.
    Method of Estimation Estimation Parameter Median Difference
    Estimated Value -15.1
    Confidence Interval () %
    to
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Baloxavir Marboxil, Oseltamivir
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.8498
    Comments The p value was not adjusted for multiplicity, testing was conducted at the two-sided significance level of 0.05.
    Method Generalized Wilcoxon test
    Comments Peto-Prentice's generalized Wilcoxon test stratified by baseline composite symptom score, preexisting and worsened symptoms, and region.
    Method of Estimation Estimation Parameter Median Difference
    Estimated Value 2.3
    Confidence Interval () %
    to
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    13. Secondary Outcome
    Title Time to Improvement of the Three Respiratory Symptoms
    Description Participants assessed the severity of 7 influenza-associated symptoms on a 4-point scale (from 0 = no symptoms to 3 = severe symptoms). Time to improvement of the 3 respiratory symptoms was defined as the time from the start of study treatment to the time when all 3 respiratory symptoms (cough, sore throat, and nasal congestion) were alleviated, maintained, or improved, as defined below, for a duration of at least 21.5 hours: Preexisting symptoms (cough, fatigue, or muscle/joint pain that existed prior to influenza) that were worse at baseline must have improved at least 1 point from baseline Preexisting symptoms not worse at baseline must have maintained baseline severity New symptoms at baseline must have alleviated, defined as a symptom score of none (0) or mild (1). Time to improvement of the 3 respiratory symptoms was analyzed using KM methods; participants who did not experience improvement of symptoms were censored at the last observation time point.
    Time Frame Initiation of study treatment up to Day 14

    Outcome Measure Data

    Analysis Population Description
    Participants in the intention-to-treat infected population with available time to improvement of the 3 respiratory symptoms data.
    Arm/Group Title Baloxavir Marboxil Placebo Oseltamivir
    Arm/Group Description Participants received either 40 mg or 80 mg of baloxavir marboxil orally on Day 1 based on body weight of < 80 kg or ≥ 80 kg at Screening, respectively. Participants also received placebo to oseltamivir orally twice a day (BID) on Days 1 to 5. Participants received placebo to baloxavir marboxil on Day 1 and placebo to oseltamivir orally twice a day on Days 1 to 5. Participants received 75 mg oseltamivir twice a day on Days 1 to 5 and placebo to baloxavir marboxil on Day 1.
    Measure Participants 385 385 388
    Median (95% Confidence Interval) [hours]
    63.6
    87.8
    62.1
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Baloxavir Marboxil, Placebo
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.0001
    Comments The p value was not adjusted for multiplicity, testing was conducted at the two-sided significance level of 0.05.
    Method Generalized Wilcoxon test
    Comments Peto-Prentice's generalized Wilcoxon test stratified by baseline composite symptom score, preexisting and worsened symptoms, and region.
    Method of Estimation Estimation Parameter Median Difference
    Estimated Value -24.1
    Confidence Interval () %
    to
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Baloxavir Marboxil, Oseltamivir
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.9237
    Comments The p value was not adjusted for multiplicity, testing was conducted at the two-sided significance level of 0.05.
    Method Generalized Wilcoxon test
    Comments Peto-Prentice's generalized Wilcoxon test stratified by baseline composite symptom score, preexisting and worsened symptoms, and region.
    Method of Estimation Estimation Parameter Median Difference
    Estimated Value 1.5
    Confidence Interval () %
    to
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    14. Secondary Outcome
    Title Time to Resolution of Fever
    Description Time to resolution of fever was defined as the time between the initiation of the study treatment and the resolution of fever. The resolution of fever was defined as the time when the participant's self-measured axillary temperature became less than 37ºC and was maintained at less than 37ºC for at least 12 hours. Time to resolution of fever was analyzed using KM methods; participants who did not experience resolution of fever by the last observation time point were censored at that time point.
    Time Frame Initiation of study treatment up to Day 14

    Outcome Measure Data

    Analysis Population Description
    Participants in the intention-to-treat infected population whose body temperature at baseline was more than 37°C and time to resolution of fever was not missing
    Arm/Group Title Baloxavir Marboxil Placebo Oseltamivir
    Arm/Group Description Participants received either 40 mg or 80 mg of baloxavir marboxil orally on Day 1 based on body weight of < 80 kg or ≥ 80 kg at Screening, respectively. Participants also received placebo to oseltamivir orally twice a day (BID) on Days 1 to 5. Participants received placebo to baloxavir marboxil on Day 1 and placebo to oseltamivir orally twice a day on Days 1 to 5. Participants received 75 mg oseltamivir twice a day on Days 1 to 5 and placebo to baloxavir marboxil on Day 1.
    Measure Participants 380 385 383
    Median (95% Confidence Interval) [hours]
    30.8
    50.7
    34.3
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Baloxavir Marboxil, Placebo
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value <0.0001
    Comments The p value was not adjusted for multiplicity, testing was conducted at the two-sided significance level of 0.05.
    Method Generalized Wilcoxon test
    Comments Peto-Prentice's generalized Wilcoxon test stratified by baseline composite symptom score, preexisting and worsened symptoms, and region.
    Method of Estimation Estimation Parameter Median Difference
    Estimated Value -19.8
    Confidence Interval (2-Sided) 95%
    -28.8 to -12.5
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Baloxavir Marboxil, Oseltamivir
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.2425
    Comments The p value was not adjusted for multiplicity, testing was conducted at the two-sided significance level of 0.05.
    Method Generalized Wilcoxon test
    Comments Peto-Prentice's generalized Wilcoxon test stratified by baseline composite symptom score, preexisting and worsened symptoms, and region.
    Method of Estimation Estimation Parameter Median Difference
    Estimated Value -3.5
    Confidence Interval (2-Sided) 95%
    -9.1 to 2.7
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    15. Secondary Outcome
    Title Percentage of Participants Reporting Normal Temperature at Each Time Point
    Description Defined as the percentage of patrticipants whose axillary body temperature dropped to less than 37ºC after the initiation of the study treatment.
    Time Frame 12, 24, 36, 48, 72, 96, 120, 144, 168, 192, and 216 hours after the initial dose of study treatment

    Outcome Measure Data

    Analysis Population Description
    Participants in the intention-to-treat infected population whose body temperature at baseline was more than 37°C and with available body temperature data at each time point.
    Arm/Group Title Baloxavir Marboxil Placebo Oseltamivir
    Arm/Group Description Participants received either 40 mg or 80 mg of baloxavir marboxil orally on Day 1 based on body weight of < 80 kg or ≥ 80 kg at Screening, respectively. Participants also received placebo to oseltamivir orally twice a day (BID) on Days 1 to 5. Participants received placebo to baloxavir marboxil on Day 1 and placebo to oseltamivir orally twice a day on Days 1 to 5. Participants received 75 mg oseltamivir twice a day on Days 1 to 5 and placebo to baloxavir marboxil on Day 1.
    Measure Participants 385 386 386
    12 hours
    29.7
    7.7%
    24.6
    6.4%
    25.9
    6.7%
    24 hours
    51.1
    13.2%
    43.2
    11.2%
    54.3
    14%
    36 hours
    68.1
    17.6%
    47.4
    12.3%
    64.1
    16.5%
    48 hours
    77.4
    19.9%
    59.3
    15.4%
    76.4
    19.6%
    72 hours
    84.0
    21.6%
    71.7
    18.6%
    82.6
    21.2%
    96 hours
    87.5
    22.6%
    79.8
    20.7%
    85.8
    22.1%
    120 hours
    86.2
    22.2%
    86.6
    22.4%
    88.4
    22.7%
    144 hours
    90.0
    23.2%
    86.1
    22.3%
    87.4
    22.5%
    168 hours
    87.9
    22.7%
    88.1
    22.8%
    87.7
    22.5%
    192 hours
    89.0
    22.9%
    87.5
    22.7%
    90.5
    23.3%
    216 hours
    89.1
    23%
    89.9
    23.3%
    89.6
    23%
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Baloxavir Marboxil, Placebo
    Comments 12 hours
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.1713
    Comments The p value was not adjusted for multiplicity, testing was conducted at the two-sided significance level of 0.05.
    Method Mantel Haenszel
    Comments Mantel Haenszel test stratified by baseline composite symptom score, preexisting and worsened symptoms, and region.
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Baloxavir Marboxil, Oseltamivir
    Comments 12 hours
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.2249
    Comments The p value was not adjusted for multiplicity, testing was conducted at the two-sided significance level of 0.05.
    Method Mantel Haenszel
    Comments Mantel Haenszel test stratified by baseline composite symptom score, preexisting and worsened symptoms, and region.
    Statistical Analysis 3
    Statistical Analysis Overview Comparison Group Selection Baloxavir Marboxil, Placebo
    Comments 24 hours
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.0387
    Comments The p value was not adjusted for multiplicity, testing was conducted at the two-sided significance level of 0.05.
    Method Mantel Haenszel
    Comments Mantel Haenszel test stratified by baseline composite symptom score, preexisting and worsened symptoms, and region.
    Statistical Analysis 4
    Statistical Analysis Overview Comparison Group Selection Baloxavir Marboxil, Oseltamivir
    Comments 24 hours
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.3915
    Comments The p value was not adjusted for multiplicity, testing was conducted at the two-sided significance level of 0.05.
    Method Mantel Haenszel
    Comments Mantel Haenszel test stratified by baseline composite symptom score, preexisting and worsened symptoms, and region.
    Statistical Analysis 5
    Statistical Analysis Overview Comparison Group Selection Baloxavir Marboxil, Placebo
    Comments 36 hours
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value <0.0001
    Comments The p value was not adjusted for multiplicity, testing was conducted at the two-sided significance level of 0.05.
    Method Mantel Haenszel
    Comments Mantel Haenszel test stratified by baseline composite symptom score, preexisting and worsened symptoms, and region.
    Statistical Analysis 6
    Statistical Analysis Overview Comparison Group Selection Baloxavir Marboxil, Oseltamivir
    Comments 36 hours
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.2617
    Comments The p value was not adjusted for multiplicity, testing was conducted at the two-sided significance level of 0.05.
    Method Mantel Haenszel
    Comments Mantel Haenszel test stratified by baseline composite symptom score, preexisting and worsened symptoms, and region.
    Statistical Analysis 7
    Statistical Analysis Overview Comparison Group Selection Baloxavir Marboxil, Placebo
    Comments 48 hours
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value <0.0001
    Comments The p value was not adjusted for multiplicity, testing was conducted at the two-sided significance level of 0.05.
    Method Mantel Haenszel
    Comments Mantel Haenszel test stratified by baseline composite symptom score, preexisting and worsened symptoms, and region.
    Statistical Analysis 8
    Statistical Analysis Overview Comparison Group Selection Baloxavir Marboxil, Oseltamivir
    Comments 48 hours
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.8808
    Comments The p value was not adjusted for multiplicity, testing was conducted at the two-sided significance level of 0.05.
    Method Mantel Haenszel
    Comments Mantel Haenszel test stratified by baseline composite symptom score, preexisting and worsened symptoms, and region.
    Statistical Analysis 9
    Statistical Analysis Overview Comparison Group Selection Baloxavir Marboxil, Placebo
    Comments 72 hours
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.0001
    Comments The p value was not adjusted for multiplicity, testing was conducted at the two-sided significance level of 0.05.
    Method Mantel Haenszel
    Comments Mantel Haenszel test stratified by baseline composite symptom score, preexisting and worsened symptoms, and region.
    Statistical Analysis 10
    Statistical Analysis Overview Comparison Group Selection Baloxavir Marboxil, Oseltamivir
    Comments 72 hours
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.5923
    Comments The p value was not adjusted for multiplicity, testing was conducted at the two-sided significance level of 0.05.
    Method Mantel Haenszel
    Comments Mantel Haenszel test stratified by baseline composite symptom score, preexisting and worsened symptoms, and region.
    Statistical Analysis 11
    Statistical Analysis Overview Comparison Group Selection Baloxavir Marboxil, Placebo
    Comments 96 hours
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.0064
    Comments The p value was not adjusted for multiplicity, testing was conducted at the two-sided significance level of 0.05.
    Method Mantel Haenszel
    Comments Mantel Haenszel test stratified by baseline composite symptom score, preexisting and worsened symptoms, and region.
    Statistical Analysis 12
    Statistical Analysis Overview Comparison Group Selection Baloxavir Marboxil, Oseltamivir
    Comments 96 hours
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.6746
    Comments The p value was not adjusted for multiplicity, testing was conducted at the two-sided significance level of 0.05.
    Method Mantel Haenszel
    Comments Mantel Haenszel test stratified by baseline composite symptom score, preexisting and worsened symptoms, and region.
    Statistical Analysis 13
    Statistical Analysis Overview Comparison Group Selection Baloxavir Marboxil, Placebo
    Comments 120 hours
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.8167
    Comments The p value was not adjusted for multiplicity, testing was conducted at the two-sided significance level of 0.05.
    Method Mantel Haenszel
    Comments Mantel Haenszel test stratified by baseline composite symptom score, preexisting and worsened symptoms, and region.
    Statistical Analysis 14
    Statistical Analysis Overview Comparison Group Selection Baloxavir Marboxil, Oseltamivir
    Comments 120 hours
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.3773
    Comments The p value was not adjusted for multiplicity, testing was conducted at the two-sided significance level of 0.05.
    Method Mantel Haenszel
    Comments Mantel Haenszel test stratified by baseline composite symptom score, preexisting and worsened symptoms, and region.
    Statistical Analysis 15
    Statistical Analysis Overview Comparison Group Selection Baloxavir Marboxil, Placebo
    Comments 144 hours
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.1041
    Comments The p value was not adjusted for multiplicity, testing was conducted at the two-sided significance level of 0.05.
    Method Mantel Haenszel
    Comments Mantel Haenszel test stratified by baseline composite symptom score, preexisting and worsened symptoms, and region.
    Statistical Analysis 16
    Statistical Analysis Overview Comparison Group Selection Baloxavir Marboxil, Oseltamivir
    Comments 144 hours
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.3328
    Comments The p value was not adjusted for multiplicity, testing was conducted at the two-sided significance level of 0.05.
    Method Mantel Haenszel
    Comments Mantel Haenszel test stratified by baseline composite symptom score, preexisting and worsened symptoms, and region.
    Statistical Analysis 17
    Statistical Analysis Overview Comparison Group Selection Baloxavir Marboxil, Placebo
    Comments 168 hours
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.7867
    Comments The p value was not adjusted for multiplicity, testing was conducted at the two-sided significance level of 0.05.
    Method Mantel Haenszel
    Comments Mantel Haenszel test stratified by baseline composite symptom score, preexisting and worsened symptoms, and region.
    Statistical Analysis 18
    Statistical Analysis Overview Comparison Group Selection Baloxavir Marboxil, Oseltamivir
    Comments 168 hours
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.8640
    Comments The p value was not adjusted for multiplicity, testing was conducted at the two-sided significance level of 0.05.
    Method Mantel Haenszel
    Comments Mantel Haenszel test stratified by baseline composite symptom score, preexisting and worsened symptoms, and region.
    Statistical Analysis 19
    Statistical Analysis Overview Comparison Group Selection Baloxavir Marboxil, Placebo
    Comments 192 hours
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.6465
    Comments The p value was not adjusted for multiplicity, testing was conducted at the two-sided significance level of 0.05.
    Method Mantel Haenszel
    Comments Mantel Haenszel test stratified by baseline composite symptom score, preexisting and worsened symptoms, and region.
    Statistical Analysis 20
    Statistical Analysis Overview Comparison Group Selection Baloxavir Marboxil, Oseltamivir
    Comments 192 hours
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.4265
    Comments The p value was not adjusted for multiplicity, testing was conducted at the two-sided significance level of 0.05.
    Method Mantel Haenszel
    Comments Mantel Haenszel test stratified by baseline composite symptom score, preexisting and worsened symptoms, and region.
    Statistical Analysis 21
    Statistical Analysis Overview Comparison Group Selection Baloxavir Marboxil, Placebo
    Comments 216 hours
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.6568
    Comments The p value was not adjusted for multiplicity, testing was conducted at the two-sided significance level of 0.05.
    Method Mantel Haenszel
    Comments Mantel Haenszel test stratified by baseline composite symptom score, preexisting and worsened symptoms, and region.
    Statistical Analysis 22
    Statistical Analysis Overview Comparison Group Selection Baloxavir Marboxil, Oseltamivir
    Comments 216 hours
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.6102
    Comments The p value was not adjusted for multiplicity, testing was conducted at the two-sided significance level of 0.05.
    Method Mantel Haenszel
    Comments Mantel Haenszel test stratified by baseline composite symptom score, preexisting and worsened symptoms, and region.
    16. Secondary Outcome
    Title Body Temperature at Each Time Point
    Description Participant's self-measured axillary temperature using an electronic thermometer.
    Time Frame 12, 24, 36, 48, 72, 96 and 120 hours after the initial dose of study treatment

    Outcome Measure Data

    Analysis Population Description
    Participants in the intention-to-treat infected population with available temperature data at each time point.
    Arm/Group Title Baloxavir Marboxil Placebo Oseltamivir
    Arm/Group Description Participants received either 40 mg or 80 mg of baloxavir marboxil orally on Day 1 based on body weight of < 80 kg or ≥ 80 kg at Screening, respectively. Participants also received placebo to oseltamivir orally twice a day (BID) on Days 1 to 5. Participants received placebo to baloxavir marboxil on Day 1 and placebo to oseltamivir orally twice a day on Days 1 to 5. Participants received 75 mg oseltamivir twice a day on Days 1 to 5 and placebo to baloxavir marboxil on Day 1.
    Measure Participants 388 386 389
    12 hours
    37.39
    (0.07)
    37.53
    (0.07)
    37.43
    (0.07)
    24 hours
    36.84
    (0.06)
    37.02
    (0.06)
    36.80
    (0.06)
    36 hours
    36.58
    (0.06)
    36.94
    (0.06)
    36.62
    (0.06)
    48 hours
    36.44
    (0.06)
    36.77
    (0.06)
    36.50
    (0.06)
    72 hours
    36.30
    (0.05)
    36.46
    (0.05)
    36.29
    (0.05)
    96 hours
    36.26
    (0.05)
    36.35
    (0.05)
    36.24
    (0.05)
    120 hours
    36.26
    (0.05)
    36.27
    (0.05)
    36.21
    (0.05)
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Baloxavir Marboxil, Placebo
    Comments 12 hours
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.0408
    Comments The p value was not adjusted for multiplicity, testing was conducted at the two-sided significance level of 0.05.
    Method ANCOVA
    Comments ANCOVA with baseline composite symptom score, preexisting and worsened symptom, region, and body temperature at baseline as covariates.
    Method of Estimation Estimation Parameter LS Mean Difference
    Estimated Value -0.14
    Confidence Interval (2-Sided) 95%
    -0.28 to -0.01
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 0.07
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Baloxavir Marboxil, Oseltamivir
    Comments 12 hours
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.5324
    Comments The p value was not adjusted for multiplicity, testing was conducted at the two-sided significance level of 0.05.
    Method ANCOVA
    Comments ANCOVA with baseline composite symptom score, preexisting and worsened symptom, region, and body temperature at baseline as covariates.
    Method of Estimation Estimation Parameter LS Mean Difference
    Estimated Value -0.04
    Confidence Interval (2-Sided) 95%
    -0.18 to 0.09
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 0.07
    Estimation Comments
    Statistical Analysis 3
    Statistical Analysis Overview Comparison Group Selection Baloxavir Marboxil, Placebo
    Comments 24 hours
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.0025
    Comments The p value was not adjusted for multiplicity, testing was conducted at the two-sided significance level of 0.05.
    Method ANCOVA
    Comments ANCOVA with baseline composite symptom score, preexisting and worsened symptom, region, and body temperature at baseline as covariates.
    Method of Estimation Estimation Parameter LS Mean Difference
    Estimated Value -0.18
    Confidence Interval (2-Sided) 95%
    -0.30 to -0.06
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 0.06
    Estimation Comments
    Statistical Analysis 4
    Statistical Analysis Overview Comparison Group Selection Baloxavir Marboxil, Oseltamivir
    Comments 24 hours
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.4874
    Comments The p value was not adjusted for multiplicity, testing was conducted at the two-sided significance level of 0.05.
    Method ANCOVA
    Comments ANCOVA with baseline composite symptom score, preexisting and worsened symptom, region, and body temperature at baseline as covariates.
    Method of Estimation Estimation Parameter LS Mean Difference
    Estimated Value 0.04
    Confidence Interval (2-Sided) 95%
    -0.08 to 0.16
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 0.06
    Estimation Comments
    Statistical Analysis 5
    Statistical Analysis Overview Comparison Group Selection Baloxavir Marboxil, Placebo
    Comments 36 hours
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value <0.0001
    Comments The p value was not adjusted for multiplicity, testing was conducted at the two-sided significance level of 0.05.
    Method ANCOVA
    Comments ANCOVA with baseline composite symptom score, preexisting and worsened symptom, region, and body temperature at baseline as covariates.
    Method of Estimation Estimation Parameter LS Mean Difference
    Estimated Value -0.36
    Confidence Interval (2-Sided) 95%
    -0.47 to -0.24
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 0.06
    Estimation Comments
    Statistical Analysis 6
    Statistical Analysis Overview Comparison Group Selection Baloxavir Marboxil, Oseltamivir
    Comments 36 hours
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.5414
    Comments The p value was not adjusted for multiplicity, testing was conducted at the two-sided significance level of 0.05.
    Method ANCOVA
    Comments ANCOVA with baseline composite symptom score, preexisting and worsened symptom, region, and body temperature at baseline as covariates.
    Method of Estimation Estimation Parameter LS Mean Difference
    Estimated Value -0.04
    Confidence Interval (2-Sided) 95%
    -0.15 to 0.08
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 0.06
    Estimation Comments
    Statistical Analysis 7
    Statistical Analysis Overview Comparison Group Selection Baloxavir Marboxil, Placebo
    Comments 48 hours
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value <0.0001
    Comments The p value was not adjusted for multiplicity, testing was conducted at the two-sided significance level of 0.05.
    Method ANCOVA
    Comments ANCOVA with baseline composite symptom score, preexisting and worsened symptom, region, and body temperature at baseline as covariates.
    Method of Estimation Estimation Parameter LS Mean Difference
    Estimated Value -0.33
    Confidence Interval (2-Sided) 95%
    -0.44 to -0.22
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 0.06
    Estimation Comments
    Statistical Analysis 8
    Statistical Analysis Overview Comparison Group Selection Baloxavir Marboxil, Oseltamivir
    Comments 48 hours
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.3185
    Comments The p value was not adjusted for multiplicity, testing was conducted at the two-sided significance level of 0.05.
    Method ANCOVA
    Comments ANCOVA with baseline composite symptom score, preexisting and worsened symptom, region, and body temperature at baseline as covariates.
    Method of Estimation Estimation Parameter LS Mean Difference
    Estimated Value -0.06
    Confidence Interval (2-Sided) 95%
    -0.17 to 0.05
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 0.06
    Estimation Comments
    Statistical Analysis 9
    Statistical Analysis Overview Comparison Group Selection Baloxavir Marboxil, Placebo
    Comments 72 hours
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.0025
    Comments The p value was not adjusted for multiplicity, testing was conducted at the two-sided significance level of 0.05.
    Method ANCOVA
    Comments ANCOVA with baseline composite symptom score, preexisting and worsened symptom, region, and body temperature at baseline as covariates.
    Method of Estimation Estimation Parameter LS Mean Difference
    Estimated Value -0.16
    Confidence Interval (2-Sided) 95%
    -0.26 to -0.06
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 0.05
    Estimation Comments
    Statistical Analysis 10
    Statistical Analysis Overview Comparison Group Selection Baloxavir Marboxil, Oseltamivir
    Comments 72 hours
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.8299
    Comments The p value was not adjusted for multiplicity, testing was conducted at the two-sided significance level of 0.05.
    Method ANCOVA
    Comments ANCOVA with baseline composite symptom score, preexisting and worsened symptom, region, and body temperature at baseline as covariates.
    Method of Estimation Estimation Parameter LS Mean Difference
    Estimated Value 0.01
    Confidence Interval (2-Sided) 95%
    -0.09 to 0.11
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 0.05
    Estimation Comments
    Statistical Analysis 11
    Statistical Analysis Overview Comparison Group Selection Baloxavir Marboxil, Placebo
    Comments 96 hours
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.0878
    Comments The p value was not adjusted for multiplicity, testing was conducted at the two-sided significance level of 0.05.
    Method ANCOVA
    Comments ANCOVA with baseline composite symptom score, preexisting and worsened symptom, region, and body temperature at baseline as covariates.
    Method of Estimation Estimation Parameter LS Mean Difference
    Estimated Value -0.09
    Confidence Interval (2-Sided) 95%
    -0.19 to 0.01
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 0.05
    Estimation Comments
    Statistical Analysis 12
    Statistical Analysis Overview Comparison Group Selection Baloxavir Marboxil, Oseltamivir
    Comments 96 hours
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.7498
    Comments The p value was not adjusted for multiplicity, testing was conducted at the two-sided significance level of 0.05.
    Method ANCOVA
    Comments ANCOVA with baseline composite symptom score, preexisting and worsened symptom, region, and body temperature at baseline as covariates.
    Method of Estimation Estimation Parameter LS Mean Difference
    Estimated Value 0.02
    Confidence Interval (2-Sided) 95%
    -0.09 to 0.12
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 0.05
    Estimation Comments
    Statistical Analysis 13
    Statistical Analysis Overview Comparison Group Selection Baloxavir Marboxil, Placebo
    Comments 120 hours
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.8030
    Comments The p value was not adjusted for multiplicity, testing was conducted at the two-sided significance level of 0.05.
    Method ANCOVA
    Comments ANCOVA with baseline composite symptom score, preexisting and worsened symptom, region, and body temperature at baseline as covariates.
    Method of Estimation Estimation Parameter LS Mean Difference
    Estimated Value -0.01
    Confidence Interval (2-Sided) 95%
    -0.11 to 0.09
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 0.05
    Estimation Comments
    Statistical Analysis 14
    Statistical Analysis Overview Comparison Group Selection Baloxavir Marboxil, Oseltamivir
    Comments 120 hours
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.3577
    Comments The p value was not adjusted for multiplicity, testing was conducted at the two-sided significance level of 0.05.
    Method ANCOVA
    Comments ANCOVA with baseline composite symptom score, preexisting and worsened symptom, region, and body temperature at baseline as covariates.
    Method of Estimation Estimation Parameter LS Mean Difference
    Estimated Value 0.05
    Confidence Interval (2-Sided) 95%
    -0.05 to 0.15
    Parameter Dispersion Type: Standard Error of the Mean
    Value: 0.05
    Estimation Comments
    17. Secondary Outcome
    Title Time to Improvement of Individual Symptoms
    Description Participants assessed the severity of 7 influenza-associated symptoms on a 4-point scale (0 = no symptoms to 3 = severe). Time to improvement of cough, fatigue, and muscle/joint pain was defined as the time from the start of treatment to the time when each symptom was alleviated, maintained, or improved, as defined below, for at least 21.5 hours: Preexisting symptoms that were worse at baseline must have improved at least 1 point from baseline Preexisting symptoms not worse at baseline must have maintained baseline severity New symptoms must have alleviated, defined as a score of 0 (None) or 1 (Mild). Time to improvement of sore throat, headache, nasal congestion, and feverish/chills was defined as the time from the start of treatment to the time when the symptom was assessed as 0 (None) or 1 (Mild) for at least 21.5 hours. Time to improvement of symptoms was analyzed using KM methods; participants with no improvement of symptoms were censored at the last observation.
    Time Frame Initiation of study treatment up to Day 14

    Outcome Measure Data

    Analysis Population Description
    Participants in the intention-to-treat infected population; the analysis of each individual symptom includes participants with new or preexisting and worsened symptom scores of moderate (2) or severe (3) at baseline, and with available time to improvement of symptom data.
    Arm/Group Title Baloxavir Marboxil Placebo Oseltamivir
    Arm/Group Description Participants received either 40 mg or 80 mg of baloxavir marboxil orally on Day 1 based on body weight of < 80 kg or ≥ 80 kg at Screening, respectively. Participants also received placebo to oseltamivir orally twice a day (BID) on Days 1 to 5. Participants received placebo to baloxavir marboxil on Day 1 and placebo to oseltamivir orally twice a day on Days 1 to 5. Participants received 75 mg oseltamivir twice a day on Days 1 to 5 and placebo to baloxavir marboxil on Day 1.
    Measure Participants 388 386 389
    Cough
    47.3
    70.4
    47.5
    Sore Throat
    40.2
    46.5
    39.3
    Headache
    33.4
    43.9
    31.3
    Nasal Congestion
    45.6
    57.7
    44.0
    Feverishness or Chills
    28.3
    31.9
    29.1
    Muscle or Joint Pain
    37.2
    44.9
    33.2
    Fatigue
    41.3
    48.8
    43.2
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Baloxavir Marboxil, Placebo
    Comments Cough
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.0009
    Comments The p value was not adjusted for multiplicity, testing was conducted at the two-sided significance level of 0.05.
    Method Generalized Wilcoxon test
    Comments Peto-Prentice's generalized Wilcoxon test stratified by baseline composite symptom score, preexisting and worsened symptoms, and region.
    Method of Estimation Estimation Parameter Median Difference
    Estimated Value -23.1
    Confidence Interval () %
    to
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Baloxavir Marboxil, Oseltamivir
    Comments Cough
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.4074
    Comments The p value was not adjusted for multiplicity, testing was conducted at the two-sided significance level of 0.05.
    Method Generalized Wilcoxon test
    Comments Peto-Prentice's generalized Wilcoxon test stratified by baseline composite symptom score, preexisting and worsened symptoms, and region.
    Method of Estimation Estimation Parameter Median Difference
    Estimated Value -0.2
    Confidence Interval () %
    to
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 3
    Statistical Analysis Overview Comparison Group Selection Baloxavir Marboxil, Placebo
    Comments Sore Throat
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.2496
    Comments The p value was not adjusted for multiplicity, testing was conducted at the two-sided significance level of 0.05.
    Method Generalized Wilcoxon test
    Comments Peto-Prentice's generalized Wilcoxon test stratified by baseline composite symptom score, preexisting and worsened symptoms, and region.
    Method of Estimation Estimation Parameter Median Difference
    Estimated Value -6.3
    Confidence Interval () %
    to
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 4
    Statistical Analysis Overview Comparison Group Selection Baloxavir Marboxil, Oseltamivir
    Comments Sore Throat
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.2963
    Comments The p value was not adjusted for multiplicity, testing was conducted at the two-sided significance level of 0.05.
    Method Generalized Wilcoxon test
    Comments Peto-Prentice's generalized Wilcoxon test stratified by baseline composite symptom score, preexisting and worsened symptoms, and region.
    Method of Estimation Estimation Parameter Median Difference
    Estimated Value 0.9
    Confidence Interval () %
    to
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 5
    Statistical Analysis Overview Comparison Group Selection Baloxavir Marboxil, Placebo
    Comments Headache
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.0390
    Comments The p value was not adjusted for multiplicity, testing was conducted at the two-sided significance level of 0.05.
    Method Generalized Wilcoxon test
    Comments Peto-Prentice's generalized Wilcoxon test stratified by baseline composite symptom score, preexisting and worsened symptoms, and region.
    Method of Estimation Estimation Parameter Median Difference
    Estimated Value -10.6
    Confidence Interval () %
    to
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 6
    Statistical Analysis Overview Comparison Group Selection Baloxavir Marboxil, Oseltamivir
    Comments Headache
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.7877
    Comments The p value was not adjusted for multiplicity, testing was conducted at the two-sided significance level of 0.05.
    Method Generalized Wilcoxon test
    Comments Peto-Prentice's generalized Wilcoxon test stratified by baseline composite symptom score, preexisting and worsened symptoms, and region.
    Method of Estimation Estimation Parameter Median Difference
    Estimated Value 2.0
    Confidence Interval () %
    to
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 7
    Statistical Analysis Overview Comparison Group Selection Baloxavir Marboxil, Placebo
    Comments Nasal Congestion
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.0017
    Comments The p value was not adjusted for multiplicity, testing was conducted at the two-sided significance level of 0.05.
    Method Generalized Wilcoxon test
    Comments Peto-Prentice's generalized Wilcoxon test stratified by baseline composite symptom score, preexisting and worsened symptoms, and region.
    Method of Estimation Estimation Parameter Median Difference
    Estimated Value -12.1
    Confidence Interval () %
    to
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 8
    Statistical Analysis Overview Comparison Group Selection Baloxavir Marboxil, Oseltamivir
    Comments Nasal Congestion
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.8119
    Comments The p value was not adjusted for multiplicity, testing was conducted at the two-sided significance level of 0.05.
    Method Generalized Wilcoxon test
    Comments Peto-Prentice's generalized Wilcoxon test stratified by baseline composite symptom score, preexisting and worsened symptoms, and region.
    Method of Estimation Estimation Parameter Median Difference
    Estimated Value 1.5
    Confidence Interval () %
    to
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 9
    Statistical Analysis Overview Comparison Group Selection Baloxavir Marboxil, Placebo
    Comments Feverishness or Chills
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.0070
    Comments The p value was not adjusted for multiplicity, testing was conducted at the two-sided significance level of 0.05.
    Method Generalized Wilcoxon test
    Comments Peto-Prentice's generalized Wilcoxon test stratified by baseline composite symptom score, preexisting and worsened symptoms, and region.
    Method of Estimation Estimation Parameter Median Difference
    Estimated Value -3.6
    Confidence Interval () %
    to
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 10
    Statistical Analysis Overview Comparison Group Selection Baloxavir Marboxil, Oseltamivir
    Comments Feverishness or Chills
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.9191
    Comments The p value was not adjusted for multiplicity, testing was conducted at the two-sided significance level of 0.05.
    Method Generalized Wilcoxon test
    Comments Peto-Prentice's generalized Wilcoxon test stratified by baseline composite symptom score, preexisting and worsened symptoms, and region.
    Method of Estimation Estimation Parameter Median Difference
    Estimated Value -0.7
    Confidence Interval () %
    to
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 11
    Statistical Analysis Overview Comparison Group Selection Baloxavir Marboxil, Placebo
    Comments Muscle or Joint Pain
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.0232
    Comments The p value was not adjusted for multiplicity, testing was conducted at the two-sided significance level of 0.05.
    Method Generalized Wilcoxon test
    Comments Peto-Prentice's generalized Wilcoxon test stratified by baseline composite symptom score, preexisting and worsened symptoms, and region.
    Method of Estimation Estimation Parameter Median Difference
    Estimated Value -7.7
    Confidence Interval () %
    to
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 12
    Statistical Analysis Overview Comparison Group Selection Baloxavir Marboxil, Oseltamivir
    Comments Muscle or Joint Pain
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.5436
    Comments The p value was not adjusted for multiplicity, testing was conducted at the two-sided significance level of 0.05.
    Method Generalized Wilcoxon test
    Comments Peto-Prentice's generalized Wilcoxon test stratified by baseline composite symptom score, preexisting and worsened symptoms, and region.
    Method of Estimation Estimation Parameter Median Difference
    Estimated Value 4.0
    Confidence Interval () %
    to
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 13
    Statistical Analysis Overview Comparison Group Selection Baloxavir Marboxil, Placebo
    Comments Fatigue
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.0207
    Comments The p value was not adjusted for multiplicity, testing was conducted at the two-sided significance level of 0.05.
    Method Generalized Wilcoxon test
    Comments Peto-Prentice's generalized Wilcoxon test stratified by baseline composite symptom score, preexisting and worsened symptoms, and region.
    Method of Estimation Estimation Parameter Median Difference
    Estimated Value -7.5
    Confidence Interval () %
    to
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 14
    Statistical Analysis Overview Comparison Group Selection Baloxavir Marboxil, Oseltamivir
    Comments Fatigue
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.3710
    Comments The p value was not adjusted for multiplicity, testing was conducted at the two-sided significance level of 0.05.
    Method Generalized Wilcoxon test
    Comments Peto-Prentice's generalized Wilcoxon test stratified by baseline composite symptom score, preexisting and worsened symptoms, and region.
    Method of Estimation Estimation Parameter Median Difference
    Estimated Value -1.9
    Confidence Interval () %
    to
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    18. Secondary Outcome
    Title Time to Return to Preinfluenza Health Status
    Description Participants were asked to record their preinfluenza health status on a scale from 0 (worst possible health) to 10 (normal health [for someone your age and condition]), and their health status at baseline and every day after initiation of study treatment on the same scale. Return to preinfluenza health status was defined as time from the initiation of the study treatment to the first time when the health status score was equal to or higher than the preinfluenza health status score. Time to return to preinfluenza health status was analyzed using KM methods; participants with a smaller number on the scale for health status by the last observation time point were censored at that time point.
    Time Frame Baseline to Day 14

    Outcome Measure Data

    Analysis Population Description
    Participants in the intention-to-treat infected population whose health status score at baseline was lower than the preinfluenza health status score and with available time to return to preinfluenza health status data.
    Arm/Group Title Baloxavir Marboxil Placebo Oseltamivir
    Arm/Group Description Participants received either 40 mg or 80 mg of baloxavir marboxil orally on Day 1 based on body weight of < 80 kg or ≥ 80 kg at Screening, respectively. Participants also received placebo to oseltamivir orally twice a day (BID) on Days 1 to 5. Participants received placebo to baloxavir marboxil on Day 1 and placebo to oseltamivir orally twice a day on Days 1 to 5. Participants received 75 mg oseltamivir twice a day on Days 1 to 5 and placebo to baloxavir marboxil on Day 1.
    Measure Participants 274 274 286
    Median (95% Confidence Interval) [hours]
    126.4
    149.8
    126.9
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Baloxavir Marboxil, Placebo
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.4634
    Comments The p value was not adjusted for multiplicity, testing was conducted at the two-sided significance level of 0.05.
    Method Generalized Wilcoxon test
    Comments Peto-Prentice's generalized Wilcoxon test stratified by baseline composite symptom score, preexisting and worsened symptoms, and region.
    Method of Estimation Estimation Parameter Median Difference
    Estimated Value -23.4
    Confidence Interval () %
    to
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Baloxavir Marboxil, Oseltamivir
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.6386
    Comments The p value was not adjusted for multiplicity, testing was conducted at the two-sided significance level of 0.05.
    Method Generalized Wilcoxon test
    Comments Peto-Prentice's generalized Wilcoxon test stratified by baseline composite symptom score, preexisting and worsened symptoms, and region.
    Method of Estimation Estimation Parameter Median Difference
    Estimated Value -0.6
    Confidence Interval () %
    to
    Parameter Dispersion Type:
    Value:
    Estimation Comments
    19. Secondary Outcome
    Title Percentage of Participants Requiring Systemic Antibiotics for Infections Secondary to Influenza Infection
    Description The percentage of participants who received systemic antibiotics for any of the predefined complications (sinusitis, otitis media, bronchitis and pneumonia).
    Time Frame Day 2 to Day 22

    Outcome Measure Data

    Analysis Population Description
    Intention-to-treat infected population
    Arm/Group Title Baloxavir Marboxil Placebo Oseltamivir
    Arm/Group Description Participants received either 40 mg or 80 mg of baloxavir marboxil orally on Day 1 based on body weight of < 80 kg or ≥ 80 kg at Screening, respectively. Participants also received placebo to oseltamivir orally twice a day (BID) on Days 1 to 5. Participants received placebo to baloxavir marboxil on Day 1 and placebo to oseltamivir orally twice a day on Days 1 to 5. Participants received 75 mg oseltamivir twice a day on Days 1 to 5 and placebo to baloxavir marboxil on Day 1.
    Measure Participants 388 386 389
    Number (95% Confidence Interval) [percentage of participants]
    3.4
    0.9%
    7.5
    1.9%
    3.9
    1%
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Baloxavir Marboxil, Placebo
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.0112
    Comments The p value was not adjusted for multiplicity, testing was conducted at the two-sided significance level of 0.05.
    Method Fisher Exact
    Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Baloxavir Marboxil, Oseltamivir
    Comments
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.8478
    Comments The p value was not adjusted for multiplicity, testing was conducted at the two-sided significance level of 0.05.
    Method Fisher Exact
    Comments
    20. Secondary Outcome
    Title Percentage of Participants With Influenza-related Complications
    Description Defined as the percentage of patients who experience each influenza-related complication (hospitalization, death, sinusitis, otitis media, bronchitis, and radiologically-confirmed pneumonia) as an adverse event after the initiation of study treatment.
    Time Frame Day 1 to Day 22

    Outcome Measure Data

    Analysis Population Description
    Intention-to-treat population
    Arm/Group Title Baloxavir Marboxil Placebo Oseltamivir
    Arm/Group Description Participants received either 40 mg or 80 mg of baloxavir marboxil orally on Day 1 based on body weight of < 80 kg or ≥ 80 kg at Screening, respectively. Participants also received placebo to oseltamivir orally twice a day (BID) on Days 1 to 5. Participants received placebo to baloxavir marboxil on Day 1 and placebo to oseltamivir orally twice a day on Days 1 to 5. Participants received 75 mg oseltamivir twice a day on Days 1 to 5 and placebo to baloxavir marboxil on Day 1.
    Measure Participants 388 386 389
    Any Complications
    2.8
    0.7%
    10.4
    2.7%
    4.6
    1.2%
    Death
    0.0
    0%
    0.0
    0%
    0.3
    0.1%
    Hospitalization
    0.8
    0.2%
    1.3
    0.3%
    1.0
    0.3%
    Sinusitis
    0.3
    0.1%
    2.1
    0.5%
    0.5
    0.1%
    Otitis media
    0.0
    0%
    0.8
    0.2%
    0.3
    0.1%
    Bronchitis
    1.8
    0.5%
    6.0
    1.6%
    2.3
    0.6%
    Pneumonia
    0.0
    0%
    0.8
    0.2%
    0.5
    0.1%
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Baloxavir Marboxil, Placebo
    Comments Any Complications
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value <0.0001
    Comments The p value was not adjusted for multiplicity, testing was conducted at the two-sided significance level of 0.05.
    Method Fisher Exact
    Comments
    Statistical Analysis 2
    Statistical Analysis Overview Comparison Group Selection Baloxavir Marboxil, Oseltamivir
    Comments Any Complications
    Type of Statistical Test Superiority
    Comments
    Statistical Test of Hypothesis p-Value 0.2558
    Comments The p value was not adjusted for multiplicity, testing was conducted at the two-sided significance level of 0.05.
    Method Fisher Exact
    Comments
    21. Secondary Outcome
    Title Percentage of Participants With Adverse Events (AEs)
    Description
    Time Frame From first dose of study drug to Day 22

    Outcome Measure Data

    Analysis Population Description
    All participants who received at least 1 dose of study drug
    Arm/Group Title Baloxavir Marboxil Placebo Oseltamivir
    Arm/Group Description Participants received either 40 mg or 80 mg of baloxavir marboxil orally on Day 1 based on body weight of < 80 kg or ≥ 80 kg at Screening, respectively. Participants also received placebo to oseltamivir orally twice a day (BID) on Days 1 to 5. Participants received placebo to baloxavir marboxil on Day 1 and placebo to oseltamivir orally twice a day on Days 1 to 5. Participants received 75 mg oseltamivir twice a day on Days 1 to 5 and placebo to baloxavir marboxil on Day 1.
    Measure Participants 730 727 721
    Any adverse event (AE)
    25.1
    6.5%
    29.7
    7.7%
    28.0
    7.2%
    Fatal adverse events
    0.0
    0%
    0.0
    0%
    0.1
    0%
    Serious adverse events
    0.7
    0.2%
    1.2
    0.3%
    1.1
    0.3%
    AEs leading to withdrawal of study drug
    0.7
    0.2%
    0.7
    0.2%
    0.6
    0.2%
    Treatment-related adverse events (TRAEs)
    5.6
    1.4%
    8.3
    2.2%
    7.9
    2%
    Fatal treatment-related adverse events
    0.0
    0%
    0.0
    0%
    0.0
    0%
    Treatment-related serious adverse events
    0.0
    0%
    0.3
    0.1%
    0.3
    0.1%
    TRAEs leading to withdrawal of study drug
    0.3
    0.1%
    0.3
    0.1%
    0.4
    0.1%

    Adverse Events

    Time Frame All-cause mortality data are reported from Day 1 though Day 22. Adverse events are reported from the first dose of study drug through Day 22 (i.e. treatment-emergent adverse events).
    Adverse Event Reporting Description One participant randomized to placebo and one participant randomized to oseltamivir received baloxavir marboxil in error, and are counted in the baloxavir marboxil, treatment group for safety analyses. One participant died after a myocardial infarction that occurred prior to receiving any study drug; although this death is included in the all-cause mortality table this death was not considered treatment-emergent.
    Arm/Group Title Baloxavir Marboxil Placebo Oseltamivir
    Arm/Group Description Participants received either 40 mg or 80 mg of baloxavir marboxil orally on Day 1 based on body weight of < 80 kg or ≥ 80 kg at Screening, respectively. Participants also received placebo to oseltamivir orally twice a day (BID) on Days 1 to 5. Participants received placebo to baloxavir marboxil on Day 1 and placebo to oseltamivir orally twice a day on Days 1 to 5. Participants received 75 mg oseltamivir twice a day on Days 1 to 5 and placebo to baloxavir marboxil on Day 1.
    All Cause Mortality
    Baloxavir Marboxil Placebo Oseltamivir
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 1/730 (0.1%) 0/727 (0%) 1/721 (0.1%)
    Serious Adverse Events
    Baloxavir Marboxil Placebo Oseltamivir
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 5/730 (0.7%) 9/727 (1.2%) 8/721 (1.1%)
    Cardiac disorders
    Cardiac failure 0/730 (0%) 0/727 (0%) 1/721 (0.1%)
    Gastrointestinal disorders
    Nausea 0/730 (0%) 1/727 (0.1%) 0/721 (0%)
    Hepatobiliary disorders
    Cholelithiasis 2/730 (0.3%) 0/727 (0%) 0/721 (0%)
    Bile duct stone 1/730 (0.1%) 0/727 (0%) 0/721 (0%)
    Cholecystitis acute 1/730 (0.1%) 0/727 (0%) 0/721 (0%)
    Hyperbilirubinaemia 0/730 (0%) 1/727 (0.1%) 0/721 (0%)
    Infections and infestations
    Pneumonia 1/730 (0.1%) 1/727 (0.1%) 1/721 (0.1%)
    Pneumonia influenzal 1/730 (0.1%) 0/727 (0%) 0/721 (0%)
    Septic shock 0/730 (0%) 0/727 (0%) 1/721 (0.1%)
    Vulval abscess 0/730 (0%) 0/727 (0%) 1/721 (0.1%)
    Staphylococcal infection 0/730 (0%) 0/727 (0%) 1/721 (0.1%)
    Investigations
    Liver function test abnormal 0/730 (0%) 0/727 (0%) 1/721 (0.1%)
    Liver function test increased 0/730 (0%) 0/727 (0%) 1/721 (0.1%)
    Metabolism and nutrition disorders
    Diabetes mellitus inadequate control 0/730 (0%) 0/727 (0%) 1/721 (0.1%)
    Hyperglycaemia 0/730 (0%) 1/727 (0.1%) 0/721 (0%)
    Nervous system disorders
    Cerebral infarction 0/730 (0%) 0/727 (0%) 1/721 (0.1%)
    Headache 0/730 (0%) 1/727 (0.1%) 0/721 (0%)
    Transient ischaemic attack 0/730 (0%) 1/727 (0.1%) 0/721 (0%)
    Arachnoid cyst 0/730 (0%) 0/727 (0%) 1/721 (0.1%)
    Renal and urinary disorders
    Urinary retention 0/730 (0%) 1/727 (0.1%) 0/721 (0%)
    Acute kidney injury 0/730 (0%) 0/727 (0%) 1/721 (0.1%)
    Ureterolithiasis 0/730 (0%) 1/727 (0.1%) 0/721 (0%)
    Respiratory, thoracic and mediastinal disorders
    Pneumothorax 1/730 (0.1%) 0/727 (0%) 1/721 (0.1%)
    Acute respiratory distress syndrome 0/730 (0%) 0/727 (0%) 1/721 (0.1%)
    Interstitial lung disease 0/730 (0%) 0/727 (0%) 1/721 (0.1%)
    Pneumonia aspiration 0/730 (0%) 0/727 (0%) 1/721 (0.1%)
    Vascular disorders
    Hypotension 0/730 (0%) 1/727 (0.1%) 1/721 (0.1%)
    Other (Not Including Serious) Adverse Events
    Baloxavir Marboxil Placebo Oseltamivir
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 70/730 (9.6%) 92/727 (12.7%) 90/721 (12.5%)
    Gastrointestinal disorders
    Diarrhoea 20/730 (2.7%) 21/727 (2.9%) 23/721 (3.2%)
    Nausea 20/730 (2.7%) 28/727 (3.9%) 34/721 (4.7%)
    Infections and infestations
    Bronchitis 21/730 (2.9%) 33/727 (4.5%) 30/721 (4.2%)
    Sinusitis 14/730 (1.9%) 21/727 (2.9%) 22/721 (3.1%)

    Limitations/Caveats

    [Not Specified]

    More Information

    Certain Agreements

    Principal Investigators are NOT employed by the organization sponsoring the study.

    The sponsor can embargo results from a PI's center until the combined results from the completed study have been published in full or the sponsor confirms there will be no multicenter study publication. Results communications must be provided to the sponsor for review at least 60 days before submission for publication. By written request, the sponsor can extend the embargo up to an additional 60 days. The sponsor cannot require changes to scientific content and cannot further extend the embargo.

    Results Point of Contact

    Name/Title Shionogi Clinical Trials Administrator
    Organization Shionogi Inc.
    Phone 800-849-9707
    Email shionogiclintrials-admin@shionogi.co.jp
    Responsible Party:
    Shionogi
    ClinicalTrials.gov Identifier:
    NCT02949011
    Other Study ID Numbers:
    • 1602T0832
    • 2016-002688-32
    First Posted:
    Oct 31, 2016
    Last Update Posted:
    Nov 19, 2019
    Last Verified:
    Nov 1, 2019