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    Clinical Trial Results:
    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.

    Summary
    EudraCT number
    2016-002688-32
    Trial protocol
    DE   LV   HU   GB   PL   BG   ES   BE  
    Global end of trial date
    20 Apr 2018

    Results information
    Results version number
    v1(current)
    This version publication date
    02 Nov 2018
    First version publication date
    02 Nov 2018
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    1602T0832
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02949011
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Shionogi Ltd. [Sponsor for Europe, Australia, New Zealand and South Africa)
    Sponsor organisation address
    5th floor, 33 Kingsway, London, United Kingdom, WC2B 6UF
    Public contact
    Shionogi Ltd., Shionogi Ltd., +44 0203 053 4200, shionogiclintrials-admin@shionogi.co.jp
    Scientific contact
    shionogiclintrials-admin@shionogi.co.jp, Shionogi Ltd., +44 0203 053 4200, shionogiclintrials-admin@shionogi.co.jp
    Sponsor organisation name
    Shionogi & Co., Ltd. [Sponsor for Japan and other Asian countries]
    Sponsor organisation address
    3-1-8, Doshomachi 3-chome, Chuo-ku, Osaka, Japan, 541-0045
    Public contact
    Shionogi & Co. Ltd., Shionogi & Co. Ltd., +81 662097885, shionogiclintrials-admin@shionogi.co.jp
    Scientific contact
    Shionogi & Co. Ltd., Shionogi & Co. Ltd., +81 662097885, shionogiclintrials-admin@shionogi.co.jp
    Sponsor organisation name
    Shionogi Inc. [Sponsor for North America]
    Sponsor organisation address
    300 Campus Drive, Florham Park, NJ, United States, 07932
    Public contact
    Shionogi Inc., Shionogi Inc., +1 8008499707, shionogiclintrials-admin@shionogi.co.jp
    Scientific contact
    Shionogi Inc., Shionogi Inc., +1 8008499707, shionogiclintrials-admin@shionogi.co.jp
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    25 Jun 2018
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    20 Apr 2018
    Global end of trial reached?
    Yes
    Global end of trial date
    20 Apr 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the efficacy of a single, oral dose of S-033188 (baloxavir marboxil), compared with placebo by measuring the time to improvement of influenza symptoms in patients with influenza. Eligible patients were randomized in a 1:1:1 ratio to receive baloxavir marboxil or oseltamivir or placebo.
    Protection of trial subjects
    The study was conducted in accordance with the protocol approved by the IRBs/IECs, all applicable regulatory requirements, the current Good Clinical Practice (GCP) guidelines, all applicable patient privacy requirements, and the ethical principles that are outlined in the Declaration of Helsinki (1996).
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    11 Jan 2017
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Romania: 15
    Country: Number of subjects enrolled
    New Zealand: 4
    Country: Number of subjects enrolled
    South Africa: 85
    Country: Number of subjects enrolled
    Philippines: 17
    Country: Number of subjects enrolled
    Korea, Republic of: 11
    Country: Number of subjects enrolled
    Taiwan: 10
    Country: Number of subjects enrolled
    Japan: 465
    Country: Number of subjects enrolled
    United States: 1302
    Country: Number of subjects enrolled
    Poland: 59
    Country: Number of subjects enrolled
    Spain: 11
    Country: Number of subjects enrolled
    United Kingdom: 11
    Country: Number of subjects enrolled
    Belgium: 13
    Country: Number of subjects enrolled
    Bulgaria: 117
    Country: Number of subjects enrolled
    Germany: 13
    Country: Number of subjects enrolled
    Hungary: 11
    Country: Number of subjects enrolled
    Latvia: 40
    Worldwide total number of subjects
    2184
    EEA total number of subjects
    290
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    59
    Adults (18-64 years)
    1523
    From 65 to 84 years
    588
    85 years and over
    14

    Subject disposition

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    Recruitment
    Recruitment details
    A multicentre study conducted at 551 sites: included in Europe, USA, Japan, Asia Pacific and South Africa. Number of patients Consented: 2592 and Randomized: 2184 (730 in the baloxavir marboxil, 725 in the oseltamivir and 729 in the placebo groups respectively).

    Pre-assignment
    Screening details
    The study population composed of Male and female patients ≥ 12 years old with influenza A and/or B infection at high risk of developing influenza complications within 48 hours of symptom onset. Definition of high risk patients was adapted from the Centers for Disease Control and Prevention (CDC) criteria.

    Pre-assignment period milestones
    Number of subjects started
    2592 [1]
    Number of subjects completed
    2184

    Pre-assignment subject non-completion reasons
    Reason: Number of subjects
    Other: 22
    Reason: Number of subjects
    Lost to follow up: 1
    Reason: Number of subjects
    Failure to meet I/E Criteria: 319
    Reason: Number of subjects
    Consent withdrawn by subject: 66
    Notes
    [1] - The number of subjects reported to have started the pre-assignment period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: The number of subjects reported to have 'started' the "pre-assignment" period is the number that signed the Informed Consent Form prior to randomization. The number reported to have 'completed' is the number of patients that were randomized and is therefore, lower. Thus, the world-wide number reported is equal to the number of randomised patients and not to the pre-assignment number.
    Period 1
    Period 1 title
    Treatment period (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator
    Blinding implementation details
    The study was conducted in a double-blind, double-dummy fashion by using placebo matching baloxavir marboxil and oseltamivir in appearance, labelling and packaging.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Treatment with baloxavir marboxil
    Arm description
    Patients randomized to baloxavir marboxil received a single oral dose of either 2 or 4 tablets of baloxavir marboxil 20 mg (based on body weight of < 80 kg or ≥ 80 kg at Screening, respectively) and oseltamivir placebo (1 capsule) BID on Day 1 followed by oseltamivir placebo (1 capsule) BID on Days 2 to 5.
    Arm type
    Experimental

    Investigational medicinal product name
    Bloxavir marboxil 20 mg tablets
    Investigational medicinal product code
    S-033188
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    A single dose of baloxavir marboxil on Day 1 + oseltamivir placebo BID on Days 1 to 5.

    Arm title
    Treatment with placebo
    Arm description
    Patients randomized to placebo received a single oral dose of either 2 or 4 tablets of baloxavir marboxil placebo (based on body weight of < 80 kg or ≥ 80 kg at Screening, respectively) on Day 1 and 1 capsule of oseltamivir placebo BID on Days 1 to 5.
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Placebo
    Other name
    Pharmaceutical forms
    Capsule, hard, Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    A single dose of baloxavir marboxil placebo on Day 1 + oseltamivir placebo BID on Days 1 to 5.

    Arm title
    Treatment with oseltamivir
    Arm description
    Patients randomized to oseltamivir received 1 capsule of oseltamivir 75 mg BID for 5 days (Day 1 to 5) and a single oral dose of either 2 or 4 tablets of baloxavir marboxil placebo (based on body weight of < 80 kg or ≥ 80 kg at Screening, respectively) on Day 1.
    Arm type
    Active comparator

    Investigational medicinal product name
    Oseltamivir
    Investigational medicinal product code
    Oseltamivir
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    A single dose of baloxavir marboxil placebo on Day 1 + oseltamivir BID on Days 1 to 5.

    Number of subjects in period 1
    Treatment with baloxavir marboxil Treatment with placebo Treatment with oseltamivir
    Started
    730
    729
    725
    Completed
    697
    695
    683
    Not completed
    33
    34
    42
         Death
    -
    -
    1
         Protocol deviation
    5
    3
    3
         Other
    2
    4
    6
         Lack of efficacy
    -
    2
    -
         Adverse event, non-fatal
    6
    7
    3
         Consent withdrawn by subject
    13
    13
    21
         Failure to meet I/E Criteria
    -
    -
    3
         Lost to follow-up
    7
    5
    5

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Treatment with baloxavir marboxil
    Reporting group description
    Patients randomized to baloxavir marboxil received a single oral dose of either 2 or 4 tablets of baloxavir marboxil 20 mg (based on body weight of < 80 kg or ≥ 80 kg at Screening, respectively) and oseltamivir placebo (1 capsule) BID on Day 1 followed by oseltamivir placebo (1 capsule) BID on Days 2 to 5.

    Reporting group title
    Treatment with placebo
    Reporting group description
    Patients randomized to placebo received a single oral dose of either 2 or 4 tablets of baloxavir marboxil placebo (based on body weight of < 80 kg or ≥ 80 kg at Screening, respectively) on Day 1 and 1 capsule of oseltamivir placebo BID on Days 1 to 5.

    Reporting group title
    Treatment with oseltamivir
    Reporting group description
    Patients randomized to oseltamivir received 1 capsule of oseltamivir 75 mg BID for 5 days (Day 1 to 5) and a single oral dose of either 2 or 4 tablets of baloxavir marboxil placebo (based on body weight of < 80 kg or ≥ 80 kg at Screening, respectively) on Day 1.

    Reporting group values
    Treatment with baloxavir marboxil Treatment with placebo Treatment with oseltamivir Total
    Number of subjects
    730 729 725 2184
    Age categorical
    Overall,
    Units: Subjects
        Adolescents (12-17 years)
    21 17 21 59
        Adults (18-64 years)
    500 509 514 1523
        From 65-84 years
    207 199 182 588
        85 years and over
    2 4 8 14
    Age continuous
    Units: years
        arithmetic mean (full range (min-max))
    51.7 (12 to 86) 52.0 (12 to 92) 51.1 (12 to 93) -
    Gender categorical
    Units: Subjects
        Female
    401 417 424 1242
        Male
    329 312 301 942

    End points

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    End points reporting groups
    Reporting group title
    Treatment with baloxavir marboxil
    Reporting group description
    Patients randomized to baloxavir marboxil received a single oral dose of either 2 or 4 tablets of baloxavir marboxil 20 mg (based on body weight of < 80 kg or ≥ 80 kg at Screening, respectively) and oseltamivir placebo (1 capsule) BID on Day 1 followed by oseltamivir placebo (1 capsule) BID on Days 2 to 5.

    Reporting group title
    Treatment with placebo
    Reporting group description
    Patients randomized to placebo received a single oral dose of either 2 or 4 tablets of baloxavir marboxil placebo (based on body weight of < 80 kg or ≥ 80 kg at Screening, respectively) on Day 1 and 1 capsule of oseltamivir placebo BID on Days 1 to 5.

    Reporting group title
    Treatment with oseltamivir
    Reporting group description
    Patients randomized to oseltamivir received 1 capsule of oseltamivir 75 mg BID for 5 days (Day 1 to 5) and a single oral dose of either 2 or 4 tablets of baloxavir marboxil placebo (based on body weight of < 80 kg or ≥ 80 kg at Screening, respectively) on Day 1.

    Primary: Time to Improvement of Influenza Symptoms Primary Analysis in the Intention to Treat Infection (ITTI) Population

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    End point title
    Time to Improvement of Influenza Symptoms Primary Analysis in the Intention to Treat Infection (ITTI) Population
    End point description
    End point type
    Primary
    End point timeframe
    The assessment of influenza symptoms was carried out from Day 1 to Day 14.
    End point values
    Treatment with baloxavir marboxil Treatment with placebo Treatment with oseltamivir
    Number of subjects analysed
    385
    385
    388
    Units: Hours
        median (confidence interval 95%)
    73.2 (67.2 to 85.1)
    102.3 (92.7 to 113.1)
    81.0 (69.4 to 91.5)
    Statistical analysis title
    baloxavir marboxil comparison with placebo
    Comparison groups
    Treatment with baloxavir marboxil v Treatment with placebo
    Number of subjects included in analysis
    770
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    Peto-Prentice's generalized Wilcoxon
    Parameter type
    Median difference (net)
    Point estimate
    -29.1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -42.8
         upper limit
    -14.6
    Statistical analysis title
    baloxavir marboxil comparison with oseltamivir
    Comparison groups
    Treatment with oseltamivir v Treatment with baloxavir marboxil
    Number of subjects included in analysis
    773
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.8347
    Method
    Peto-Prentice's generalized Wilcoxon
    Parameter type
    Median difference (net)
    Point estimate
    -7.7
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -22.7
         upper limit
    7.9

    Primary: Time to Improvement of Influenza Symptoms Sensitivity Analysis in the ITTI Population

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    End point title
    Time to Improvement of Influenza Symptoms Sensitivity Analysis in the ITTI Population
    End point description
    End point type
    Primary
    End point timeframe
    The assessment of influenza symptoms was carried out from Day 1 to Day 14.
    End point values
    Treatment with baloxavir marboxil Treatment with placebo Treatment with oseltamivir
    Number of subjects analysed
    385
    385
    388
    Units: Hours
        median (confidence interval 95%)
    73.2 (67.2 to 85.1)
    102.3 (92.7 to 113.1)
    81.0 (69.4 to 91.5)
    Statistical analysis title
    baloxavir marboxil comparison with placebo
    Comparison groups
    Treatment with baloxavir marboxil v Treatment with placebo
    Number of subjects included in analysis
    770
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0008
    Method
    Stratified log-rank test
    Parameter type
    Median difference (net)
    Point estimate
    -29.1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -42.8
         upper limit
    -14.6
    Statistical analysis title
    baloxavir marboxil comparison with oseltamivir
    Comparison groups
    Treatment with baloxavir marboxil v Treatment with oseltamivir
    Number of subjects included in analysis
    773
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.8449
    Method
    Stratified log-rank test
    Parameter type
    Median difference (net)
    Point estimate
    -7.7
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -22.7
         upper limit
    7.9

    Primary: Time to Improvement of Influenza Symptoms by Influenza Vaccination Status in the ITTI Population who had received an Influenza Vaccine

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    End point title
    Time to Improvement of Influenza Symptoms by Influenza Vaccination Status in the ITTI Population who had received an Influenza Vaccine
    End point description
    End point type
    Primary
    End point timeframe
    The assessment of influenza symptoms was carried out from Day 1 to Day 14.
    End point values
    Treatment with baloxavir marboxil Treatment with placebo Treatment with oseltamivir
    Number of subjects analysed
    91
    99
    104
    Units: Hours
        median (confidence interval 95%)
    65.4 (52.6 to 85.1)
    92.7 (76.1 to 110.6)
    90.0 (70.4 to 103.7)
    Statistical analysis title
    baloxavir marboxil comparison with placebo
    Comparison groups
    Treatment with baloxavir marboxil v Treatment with placebo
    Number of subjects included in analysis
    190
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.1042
    Method
    Wilcoxon generalized test
    Parameter type
    Median difference (net)
    Point estimate
    -27.3
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -49.9
         upper limit
    -0.2
    Statistical analysis title
    baloxavir marboxil comparison with oseltamivir
    Comparison groups
    Treatment with oseltamivir v Treatment with baloxavir marboxil
    Number of subjects included in analysis
    195
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.4069
    Method
    Wilcoxon generalized test
    Parameter type
    Median difference (net)
    Point estimate
    -24.6
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -43
         upper limit
    2.6

    Primary: Time to Improvement of Influenza Symptoms by Influenza Vaccination Status in the ITTI Population who had Not received an Influenza Vaccine

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    End point title
    Time to Improvement of Influenza Symptoms by Influenza Vaccination Status in the ITTI Population who had Not received an Influenza Vaccine
    End point description
    End point type
    Primary
    End point timeframe
    The assessment of influenza symptoms was carried out from Day 1 to Day 14.
    End point values
    Treatment with baloxavir marboxil Treatment with placebo Treatment with oseltamivir
    Number of subjects analysed
    294
    286
    284
    Units: Hours
        median (confidence interval 95%)
    76.9 (68.4 to 90.2)
    103.1 (93.2 to 117.3)
    77.0 (66.8 to 94.8)
    Statistical analysis title
    baloxavir marboxil comparison with placebo
    Comparison groups
    Treatment with baloxavir marboxil v Treatment with placebo
    Number of subjects included in analysis
    580
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0003
    Method
    Wilcoxon generalized test
    Parameter type
    Median difference (net)
    Point estimate
    -26.2
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -45.8
         upper limit
    -11.5
    Statistical analysis title
    baloxavir marboxil comparison with oseltamivir
    Comparison groups
    Treatment with baloxavir marboxil v Treatment with oseltamivir
    Number of subjects included in analysis
    578
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.8998
    Method
    Wilcoxon generalized test
    Parameter type
    Median difference (net)
    Point estimate
    -0.1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -22.5
         upper limit
    18.2

    Primary: Time to Improvement of Influenza Symptoms by Influenza Virus Subtype A/H3 in the ITTI Population

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    End point title
    Time to Improvement of Influenza Symptoms by Influenza Virus Subtype A/H3 in the ITTI Population
    End point description
    End point type
    Primary
    End point timeframe
    The assessment of influenza symptoms was carried out from Day 1 to Day 14.
    End point values
    Treatment with baloxavir marboxil Treatment with placebo Treatment with oseltamivir
    Number of subjects analysed
    180
    185
    190
    Units: Hours
        median (confidence interval 95%)
    75.4 (62.4 to 91.6)
    100.4 (88.4 to 113.4)
    68.2 (53.9 to 81.0)
    Statistical analysis title
    baloxavir marboxil comparison with placebo
    Comparison groups
    Treatment with baloxavir marboxil v Treatment with placebo
    Number of subjects included in analysis
    365
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0141
    Method
    Peto-Prentice's generalized Wilcoxon
    Confidence interval
    Statistical analysis title
    baloxavir marboxil comparison with oseltamivir
    Comparison groups
    Treatment with baloxavir marboxil v Treatment with oseltamivir
    Number of subjects included in analysis
    370
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.1433
    Method
    Peto-Prentice's generalized Wilcoxon
    Confidence interval

    Primary: Time to Improvement of Influenza Symptoms by Influenza Virus Subtype B in the ITTI Population

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    End point title
    Time to Improvement of Influenza Symptoms by Influenza Virus Subtype B in the ITTI Population
    End point description
    End point type
    Primary
    End point timeframe
    The assessment of influenza symptoms was carried out from Day 1 to Day 14.
    End point values
    Treatment with baloxavir marboxil Treatment with placebo Treatment with oseltamivir
    Number of subjects analysed
    166
    167
    148
    Units: Hours
        median (confidence interval 95%)
    74.6 (67.4 to 90.2)
    100.6 (82.8 to 115.8)
    101.6 (90.5 to 114.9)
    Statistical analysis title
    baloxavir marboxil comparison with placebo
    Comparison groups
    Treatment with baloxavir marboxil v Treatment with placebo
    Number of subjects included in analysis
    333
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0138
    Method
    Peto-Prentice's generalized Wilcoxon
    Confidence interval
    Statistical analysis title
    baloxavir marboxil comparison with oseltamivir
    Comparison groups
    Treatment with baloxavir marboxil v Treatment with oseltamivir
    Number of subjects included in analysis
    314
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0251
    Method
    Peto-Prentice's generalized Wilcoxon
    Confidence interval

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    All Adverse Events (AEs) were collected from the time of informed consent through Visit 7 (Day 22). If a patient withdrew early from the study, the Investigator or sub-investigator made effort to collect AEs for 21 days after the last dose of study drug.
    Adverse event reporting additional description
    Adverse events were classified by System Organ Class (SOC) and Preferred Term (PT) using Medical Dictionary for Regulatory Activities (MedDRA). Adverse events reported after the initial dose of study drug were used for safety analyses. All AEs, including those occurring prior to the initiation of the study treatment, were listed.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    19.1
    Reporting groups
    Reporting group title
    Baloxavir marboxil
    Reporting group description
    -

    Reporting group title
    Treatment with Placebo
    Reporting group description
    -

    Reporting group title
    Treatment with Oseltamivir
    Reporting group description
    -

    Serious adverse events
    Baloxavir marboxil Treatment with Placebo Treatment with Oseltamivir
    Total subjects affected by serious adverse events
         subjects affected / exposed
    5 / 730 (0.68%)
    9 / 727 (1.24%)
    8 / 721 (1.11%)
         number of deaths (all causes)
    0
    0
    1
         number of deaths resulting from adverse events
    0
    0
    1
    Vascular disorders
    Hypotension
         subjects affected / exposed
    0 / 730 (0.00%)
    1 / 727 (0.14%)
    1 / 721 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Liver function test increased
         subjects affected / exposed
    0 / 730 (0.00%)
    0 / 727 (0.00%)
    1 / 721 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Liver function test abnormal
         subjects affected / exposed
    0 / 730 (0.00%)
    0 / 727 (0.00%)
    1 / 721 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Cardiac failure
         subjects affected / exposed
    0 / 730 (0.00%)
    0 / 727 (0.00%)
    1 / 721 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pneumothorax
         subjects affected / exposed
    1 / 730 (0.14%)
    0 / 727 (0.00%)
    1 / 721 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Acute respiratory distress syndrome
         subjects affected / exposed
    0 / 730 (0.00%)
    0 / 727 (0.00%)
    1 / 721 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Interstitial lung disease
         subjects affected / exposed
    0 / 730 (0.00%)
    0 / 727 (0.00%)
    1 / 721 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia aspiration
         subjects affected / exposed
    0 / 730 (0.00%)
    0 / 727 (0.00%)
    1 / 721 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Transient ischaemic attack
         subjects affected / exposed
    0 / 730 (0.00%)
    1 / 727 (0.14%)
    0 / 721 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    0 / 730 (0.00%)
    1 / 727 (0.14%)
    0 / 721 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Arachnoid cyst
         subjects affected / exposed
    0 / 730 (0.00%)
    0 / 727 (0.00%)
    1 / 721 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cerebral infarction
         subjects affected / exposed
    0 / 730 (0.00%)
    0 / 727 (0.00%)
    1 / 721 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    0 / 730 (0.00%)
    1 / 727 (0.14%)
    0 / 721 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Urinary retention
         subjects affected / exposed
    0 / 730 (0.00%)
    1 / 727 (0.14%)
    0 / 721 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ureterolithiasis
         subjects affected / exposed
    0 / 730 (0.00%)
    1 / 727 (0.14%)
    0 / 721 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Acute kidney injury
         subjects affected / exposed
    0 / 730 (0.00%)
    0 / 727 (0.00%)
    1 / 721 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholelithiasis
         subjects affected / exposed
    2 / 730 (0.27%)
    0 / 727 (0.00%)
    0 / 721 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bile duct stone
         subjects affected / exposed
    1 / 730 (0.14%)
    0 / 727 (0.00%)
    0 / 721 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hyperbilirubinaemia
         subjects affected / exposed
    0 / 730 (0.00%)
    1 / 727 (0.14%)
    0 / 721 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cholecystitis acute
         subjects affected / exposed
    1 / 730 (0.14%)
    0 / 727 (0.00%)
    0 / 721 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hyperglycaemia
         subjects affected / exposed
    0 / 730 (0.00%)
    1 / 727 (0.14%)
    0 / 721 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diabetes mellitus inadequate control
         subjects affected / exposed
    0 / 730 (0.00%)
    0 / 727 (0.00%)
    1 / 721 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Pneumonia influenzal
         subjects affected / exposed
    1 / 730 (0.14%)
    0 / 727 (0.00%)
    0 / 721 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 730 (0.14%)
    1 / 727 (0.14%)
    1 / 721 (0.14%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Vulval abscess
         subjects affected / exposed
    0 / 730 (0.00%)
    0 / 727 (0.00%)
    1 / 721 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Staphylococcal infection
         subjects affected / exposed
    0 / 730 (0.00%)
    0 / 727 (0.00%)
    1 / 721 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    0 / 730 (0.00%)
    0 / 727 (0.00%)
    1 / 721 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 2%
    Non-serious adverse events
    Baloxavir marboxil Treatment with Placebo Treatment with Oseltamivir
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    183 / 730 (25.07%)
    216 / 727 (29.71%)
    202 / 721 (28.02%)
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    20 / 730 (2.74%)
    21 / 727 (2.89%)
    23 / 721 (3.19%)
         occurrences all number
    20
    24
    27
    Nausea
         subjects affected / exposed
    20 / 730 (2.74%)
    28 / 727 (3.85%)
    34 / 721 (4.72%)
         occurrences all number
    20
    29
    36
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    21 / 730 (2.88%)
    33 / 727 (4.54%)
    30 / 721 (4.16%)
         occurrences all number
    21
    33
    30
    Sinusitis
         subjects affected / exposed
    14 / 730 (1.92%)
    21 / 727 (2.89%)
    22 / 721 (3.05%)
         occurrences all number
    14
    21
    22

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? No

    Interruptions (globally)

    Were there any global interruptions to the trial? No

    Limitations and caveats

    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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