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    Clinical Trial Results:
    A phase 3 randomized, double-blind, placebo-controlled study to confirm the efficacy of a single dose of baloxavir marboxil in the prevention of influenza virus infection

    Summary
    EudraCT number
    2020-000696-20
    Trial protocol
    Outside EU/EEA  
    Global end of trial date
    25 Mar 2019

    Results information
    Results version number
    v1(current)
    This version publication date
    12 Jul 2020
    First version publication date
    12 Jul 2020
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    1719T0834
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    -
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Shionogi & Co., Ltd.
    Sponsor organisation address
    12F, Hankyu Terminal Bldg., 1-4, Shibata 1-chome, Osaka, Japan,
    Public contact
    Corporate Communications Department, Shionogi & Co., Ltd., shionogiclintrials-admin@shionogi.co.jp
    Scientific contact
    Corporate Communications Department, Shionogi & Co., Ltd., shionogiclintrials-admin@shionogi.co.jp
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    EMEA-002440-PIP01-18
    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?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    09 Aug 2019
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    25 Mar 2019
    Global end of trial reached?
    Yes
    Global end of trial date
    25 Mar 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The main objective of this study was to evaluate the efficacy of a single oral dose of baloxavir marboxil compared with placebo in the prevention of influenza virus infection in subjects who were household members of influenza-infected patients
    Protection of trial subjects
    All study subjects were required to read and sign an Informed Consent Form
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    09 Nov 2018
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Japan: 749
    Worldwide total number of subjects
    749
    EEA total number of subjects
    0
    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)
    6
    Children (2-11 years)
    136
    Adolescents (12-17 years)
    33
    Adults (18-64 years)
    551
    From 65 to 84 years
    21
    85 years and over
    2

    Subject disposition

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    Recruitment
    Recruitment details
    -

    Pre-assignment
    Screening details
    752 subjects were randomized in this study but only 749 (374 in the baloxavir marboxil group and 375 in the placebo group) were included in the safety and efficacy analyses. 2 subjects were not dosed and 1 subject was discontinued due to non-compliance.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Baloxavir Marboxil
    Arm description
    Participants will receive a single oral dose of baloxavir marboxil on Day 1 (based on body weight)
    Arm type
    Experimental

    Investigational medicinal product name
    S-033188
    Investigational medicinal product code
    Other name
    Baloxavir Marboxil
    Pharmaceutical forms
    Granules, Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    S-033188 is available as 20-mg tablets or 2% granules (containing 20 mg of baloxavir marboxil per 1 g of granules). Subjects ≥12 years of age at screening were administered 40 mg if their body weight was < 80 kg or 80 mg if their body weight was ≥ 80 kg. Subjects < 12 years of age at screening were administered 1 mg/kg (weight < 10 kg) or 10 mg (Weight 10 to < 20 kg) or 20 mg (weight 20 to < 40 kg) or 40 mg (Weight ≥ 40 kg)

    Arm title
    Placebo
    Arm description
    Participants will receive a single oral dose of matching placebo
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Granules, Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo was available as tablets or granules. Subjects ≥12 years of age at screening were administered 2 placebo tablets if their body weight was < 80 kg or 4 placebo tablets if their body weight was ≥ 80 kg. Subjects < 12 years of age at screening were administered granules (50 mg/kg if weight < 10 kg) or 1 placebo granule packet (Weight 10 to < 20 kg) or 1 placebo tablet (weight 20 to < 40 kg) or 2 placebo tablets (Weight ≥ 40 kg).

    Number of subjects in period 1
    Baloxavir Marboxil Placebo
    Started
    374
    375
    Completed
    373
    375
    Not completed
    1
    0
         Consent withdrawn by subject
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Baloxavir Marboxil
    Reporting group description
    Participants will receive a single oral dose of baloxavir marboxil on Day 1 (based on body weight)

    Reporting group title
    Placebo
    Reporting group description
    Participants will receive a single oral dose of matching placebo

    Reporting group values
    Baloxavir Marboxil Placebo Total
    Number of subjects
    374 375 749
    Age Categorical
    Units: Subjects
        In utero
    0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    0 0 0
        Newborns (0-27 days)
    0 0 0
        Infants and toddlers (28 days-23 months)
    1 5 6
        Children (2-11 years)
    70 66 136
        Adolescents (12-17 years)
    12 21 33
        Adults (18-64 years)
    283 268 551
        From 65-84 years
    7 14 21
        85 years and over
    1 1 2
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    33.5 ± 15.8 33.6 ± 17.0 -
    Gender Categorical
    Units: Subjects
        Female
    297 290 587
        Male
    77 85 162

    End points

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    End points reporting groups
    Reporting group title
    Baloxavir Marboxil
    Reporting group description
    Participants will receive a single oral dose of baloxavir marboxil on Day 1 (based on body weight)

    Reporting group title
    Placebo
    Reporting group description
    Participants will receive a single oral dose of matching placebo

    Primary: Proportion of subjects who are infected with influenza virus (RT-PCR positive), and present with fever and at least one respiratory symptom

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    End point title
    Proportion of subjects who are infected with influenza virus (RT-PCR positive), and present with fever and at least one respiratory symptom
    End point description
    Influenza virus infection was confirmed through Reverse transcription polymerase chain reaction (RT-PCR positive). Fever was defined as subjects having a body temperature (axillary) of ≥37.5°C. Respiratory symptoms included having cough or nasal discharge/nasal congestion with a severity of 2: Moderate or 3: Severe as assessed in the subject diary.
    End point type
    Primary
    End point timeframe
    Day 1 to Day 10
    End point values
    Baloxavir Marboxil Placebo
    Number of subjects analysed
    374
    375
    Units: percentage of participants
        number (confidence interval 95%)
    1.9 (0.8 to 3.8)
    13.6 (10.3 to 17.5)
    Statistical analysis title
    Baloxavir versus Placebo
    Comparison groups
    Placebo v Baloxavir Marboxil
    Number of subjects included in analysis
    749
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    modified Poisson regression approach
    Parameter type
    Risk ratio (RR)
    Point estimate
    0.14
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.06
         upper limit
    0.3

    Secondary: Time from study treatment to the time when fever, at least one respiratory symptom, and influenza virus infection (RT-PCR) were observed

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    End point title
    Time from study treatment to the time when fever, at least one respiratory symptom, and influenza virus infection (RT-PCR) were observed
    End point description
    An influenza infection proportion curve based on the length of time from the study treatment to the first time point when fever, at least one respiratory symptom (cough and/or nasal discharge/nasal congestion), and influenza virus infection were all confirmed was plotted by treatment group, using the Kaplan-Meier method. Restricted mean survival time (RMST) up to Day 10 in each treatment group was estimated by integrating the Kaplan-Meier survival curve. If a subject had no positive test result for influenza virus or has no fever or any respiratory symptom (cough or nasal discharge/nasal congestion) at any time after the study treatment, the subject was handled as a censored case at the last observation time point.
    End point type
    Secondary
    End point timeframe
    Day 1 (baseline) to study end (approximately 15 days)
    End point values
    Baloxavir Marboxil Placebo
    Number of subjects analysed
    374
    375
    Units: Day
        number (confidence interval 95%)
    10.0 (9.9 to 10.0)
    9.1 (8.9 to 9.4)
    Statistical analysis title
    Difference in RMST up to day 10 (day)
    Comparison groups
    Baloxavir Marboxil v Placebo
    Number of subjects included in analysis
    749
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    t-test, 2-sided
    Parameter type
    RMST
    Point estimate
    0.8
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.6
         upper limit
    1

    Secondary: Proportion of subjects who are infected with influenza virus (RT-PCR positive), and present with fever or at least one influenza symptom

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    End point title
    Proportion of subjects who are infected with influenza virus (RT-PCR positive), and present with fever or at least one influenza symptom
    End point description
    Influenza symptoms could be a respiratory symptom (cough or nasal discharge/nasal congestion) or a systemic symptom (headache, feverishness or chills, muscle or joint pain, fatigue).
    End point type
    Secondary
    End point timeframe
    Day 1 (baseline) to Day 10
    End point values
    Baloxavir Marboxil Placebo
    Number of subjects analysed
    374
    375
    Units: percentage of participants
        number (confidence interval 95%)
    5.3 (3.3 to 8.1)
    22.4 (18.3 to 27.0)
    Statistical analysis title
    Baloxavir Marboxil vs. Placebo
    Comparison groups
    Baloxavir Marboxil v Placebo
    Number of subjects included in analysis
    749
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    modified Poisson regression approach
    Parameter type
    Risk ratio (RR)
    Point estimate
    0.24
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.15
         upper limit
    0.38

    Secondary: Time from study treatment to the time when fever or at least one influenza symptom, and influenza virus infection (RT-PCR) are observed.

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    End point title
    Time from study treatment to the time when fever or at least one influenza symptom, and influenza virus infection (RT-PCR) are observed.
    End point description
    Restricted mean survival time (RMST) up to Day 10 in each treatment group was estimated by integrating the Kaplan-Meier survival curve.
    End point type
    Secondary
    End point timeframe
    Day 1 (baseline) to study end (approximately 15 days)
    End point values
    Baloxavir Marboxil Placebo
    Number of subjects analysed
    374
    375
    Units: Days
        number (confidence interval 95%)
    9.8 (9.7 to 9.9)
    8.5 (8.2 to 8.8)
    Statistical analysis title
    Difference in RMST up to Day 10
    Comparison groups
    Baloxavir Marboxil v Placebo
    Number of subjects included in analysis
    749
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    t-test, 2-sided
    Parameter type
    RMST
    Point estimate
    1.3
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1
         upper limit
    1.6

    Secondary: Proportion of asymptomatic influenza-infected (RT-PCR positive) subjects

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    End point title
    Proportion of asymptomatic influenza-infected (RT-PCR positive) subjects
    End point description
    End point type
    Secondary
    End point timeframe
    Day 1 (baseline) to Day 10
    End point values
    Baloxavir Marboxil Placebo
    Number of subjects analysed
    374
    375
    Units: percentage of participants
        number (confidence interval 95%)
    7.8 (5.3 to 10.9)
    7.7 (5.2 to 10.9)
    Statistical analysis title
    Baloxavir Marboxil vs. Placebo
    Comparison groups
    Baloxavir Marboxil v Placebo
    Number of subjects included in analysis
    749
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.9917
    Method
    modified Poisson regression approach
    Parameter type
    Risk ratio (RR)
    Point estimate
    1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.61
         upper limit
    1.64

    Secondary: Proportion of subjects with influenza virus infection (RT-PCR positive)

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    End point title
    Proportion of subjects with influenza virus infection (RT-PCR positive)
    End point description
    The proportion of subjects with influenza virus infection (RT-PCR positive) regardless of symptoms
    End point type
    Secondary
    End point timeframe
    Day 1 (baseline) to Day 10
    End point values
    Baloxavir Marboxil Placebo
    Number of subjects analysed
    374
    375
    Units: percentage of participants
        number (confidence interval 95%)
    13.1 (9.9 to 16.9)
    30.4 (25.8 to 35.3)
    Statistical analysis title
    Baloxavir Marboxil vs. Placebo
    Comparison groups
    Baloxavir Marboxil v Placebo
    Number of subjects included in analysis
    749
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    modified Poisson regression approach
    Parameter type
    Risk ratio (RR)
    Point estimate
    0.43
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.32
         upper limit
    0.58

    Secondary: Proportion of subjects with Adverse Events (AEs)

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    End point title
    Proportion of subjects with Adverse Events (AEs)
    End point description
    End point type
    Secondary
    End point timeframe
    Day 1 (baseline) to study end (approximately 15 days)
    End point values
    Baloxavir Marboxil Placebo
    Number of subjects analysed
    374
    375
    Units: percentage of participants
    number (confidence interval 95%)
        Adverse Events
    22.2 (18.1 to 26.7)
    20.5 (16.6 to 25.0)
        Deaths
    0 (0 to 1.0)
    0 (0 to 1.0)
        Other Serious Adverse Events
    0 (0 to 1.0)
    0.3 (0.0 to 1.5)
    No statistical analyses for this end point

    Secondary: Maximum plasma concentration (Cmax) of S-033447

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    End point title
    Maximum plasma concentration (Cmax) of S-033447 [1]
    End point description
    I = Influenza-infected subjects with fever and at least one respiratory symptom; and O = The other subjects.
    End point type
    Secondary
    End point timeframe
    Day 1 (baseline) to study end (approximately 15 days)
    Notes
    [1] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: S-033447 concentrations were only measured in the Baloxavir Marboxil arm.
    End point values
    Baloxavir Marboxil
    Number of subjects analysed
    369
    Units: ng/mL
    geometric mean (geometric coefficient of variation)
        ≥ 12 years I (n=4)
    95.3 ± 54.1
        ≥ 12 years O (n=297)
    91.0 ± 32.4
        < 12 years I (n=3)
    85.2 ± 10.5
        < 12 years O (n=65)
    93.5 ± 17.6
    No statistical analyses for this end point

    Secondary: Area under the plasma concentration-time curve extrapolated from time zero to infinity (AUC0-inf) of S-033447

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    End point title
    Area under the plasma concentration-time curve extrapolated from time zero to infinity (AUC0-inf) of S-033447 [2]
    End point description
    I = Influenza-infected subjects with fever and at least one respiratory symptom; and O = The other subjects.
    End point type
    Secondary
    End point timeframe
    Day 1 (baseline) to study end (approximately 15 days)
    Notes
    [2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: S-033447 concentrations were only measured in the Baloxavir Marboxil arm.
    End point values
    Baloxavir Marboxil
    Number of subjects analysed
    369
    Units: ng.hr/mL
    geometric mean (geometric coefficient of variation)
        ≥ 12 years I (n=4)
    6895 ± 63.1
        ≥ 12 years O (n=297)
    6178 ± 30.8
        < 12 years I (n=3)
    4001 ± 12.3
        < 12 years O (n=65)
    4218 ± 25.6
    No statistical analyses for this end point

    Secondary: Plasma concentration 24 hours post-dose (C24) of S-033447

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    End point title
    Plasma concentration 24 hours post-dose (C24) of S-033447 [3]
    End point description
    I = Influenza-infected subjects with fever and at least one respiratory symptom; and O = The other subjects.
    End point type
    Secondary
    End point timeframe
    Day 1 (baseline) to 24 hours post-dose
    Notes
    [3] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: S-033447 concentrations were only measured in the Baloxavir Marboxil arm.
    End point values
    Baloxavir Marboxil
    Number of subjects analysed
    369
    Units: ng/mL
    geometric mean (geometric coefficient of variation)
        ≥ 12 years I (n=4)
    51.8 ± 25.7
        ≥ 12 years O (n=297)
    52.7 ± 25.1
        < 12 years I (n=3)
    48.9 ± 11.1
        < 12 years O (n=65)
    51.9 ± 20.3
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Day 1 (baseline) to study end (approximately 15 days)
    Assessment type
    Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    21.0
    Reporting groups
    Reporting group title
    Baloxavir Marboxil
    Reporting group description
    Participants will receive a single oral dose of baloxavir marboxil on Day 1 (based on body weight)

    Reporting group title
    Placebo
    Reporting group description
    Participants will receive a single oral dose of matching placebo

    Serious adverse events
    Baloxavir Marboxil Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 374 (0.00%)
    1 / 375 (0.27%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Psychiatric disorders
    Psychotic disorders
         subjects affected / exposed
    0 / 374 (0.00%)
    1 / 375 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Baloxavir Marboxil Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    24 / 374 (6.42%)
    25 / 375 (6.67%)
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    24 / 374 (6.42%)
    25 / 375 (6.67%)
         occurrences all number
    24
    25

    More information

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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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