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    Clinical Trial Results:
    An Open-label Study to Assess the Safety, Tolerability, Pharmacokinetics, and Efficacy of Baloxavir Marboxil 2% Granules after Administration of a Single Dose to Otherwise Healthy Pediatric Patients with Influenza

    Summary
    EudraCT number
    2021-001026-22
    Trial protocol
    Outside EU/EEA  
    Global end of trial date
    17 Mar 2020

    Results information
    Results version number
    v1(current)
    This version publication date
    28 Mar 2021
    First version publication date
    28 Mar 2021
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    1813T0835
    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, 530-0012
    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
    17 Mar 2020
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    17 Mar 2020
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The main objective of this study was to assess the safety, tolerability, pharmacokinetics (PK), and efficacy of baloxavir marboxil 2% granules in otherwise healthy pediatric participants with influenza virus infection aged less than 12 years and weighing less than 20 kg at Screening.
    Protection of trial subjects
    All study participants were required to read and sign an Informed Consent Form (ICF).
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    25 Jan 2019
    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: 45
    Worldwide total number of subjects
    45
    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)
    13
    Children (2-11 years)
    32
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    0
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    Participants were enrolled at 15 study centers in Japan.

    Pre-assignment
    Screening details
    Participants with a clinical diagnosis of influenza A and/or B virus infection were enrolled in each arm of the study based on weight. Participants in the <10 kg arm received a 1 mg/kg or 2 mg/kg dose based on age. Participants aged <3 months were to receive a dose of 1 mg/kg. No participants in the study were <3 months of age.

    Period 1
    Period 1 title
    Overall Period
    Is this the baseline period?
    Yes
    Allocation method
    Not applicable
    Blinding used
    Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Baloxavir Marboxil (Participants’ weight <10 kg)
    Arm description
    Participants who weighed <10 kilograms (kg) and were greater than or equal to (≥) 3 months of age received a single oral dose of 2 milligram per kilogram (mg/kg) baloxavir marboxil 2% granules on Day 1.
    Arm type
    Experimental

    Investigational medicinal product name
    Baloxavir marboxil
    Investigational medicinal product code
    Other name
    S-033188, RO7191686, Xofluza
    Pharmaceutical forms
    Granules in sachet
    Routes of administration
    Oral use
    Dosage and administration details
    A single oral dose of 1 mg/kg or 2 mg/kg of baloxavir marboxil 2% granules was to be administered on Day 1 based on participants’ age and body weight at Screening. All partipants in this arm received 2 mg/kg of baloxavir marboxil 2% granules.

    Arm title
    Baloxavir Marboxil (Participants’ weight ≥10 kg to <20 kg)
    Arm description
    Participants who weighed between 10 to <20 kg received 20 mg of baloxavir marboxil 2% granules as a single oral dose on Day 1 irrespective of their age.
    Arm type
    Experimental

    Investigational medicinal product name
    Baloxavir marboxil
    Investigational medicinal product code
    Other name
    S-033188, RO7191686, Xofluza
    Pharmaceutical forms
    Granules in sachet
    Routes of administration
    Oral use
    Dosage and administration details
    A single oral dose of 20 mg of baloxavir marboxil 2% granules was administered on Day 1 based on participants’ age and body weight at Screening.

    Number of subjects in period 1
    Baloxavir Marboxil (Participants’ weight <10 kg) Baloxavir Marboxil (Participants’ weight ≥10 kg to <20 kg)
    Started
    9
    36
    Completed
    9
    36

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Baloxavir Marboxil (Participants’ weight <10 kg)
    Reporting group description
    Participants who weighed <10 kilograms (kg) and were greater than or equal to (≥) 3 months of age received a single oral dose of 2 milligram per kilogram (mg/kg) baloxavir marboxil 2% granules on Day 1.

    Reporting group title
    Baloxavir Marboxil (Participants’ weight ≥10 kg to <20 kg)
    Reporting group description
    Participants who weighed between 10 to <20 kg received 20 mg of baloxavir marboxil 2% granules as a single oral dose on Day 1 irrespective of their age.

    Reporting group values
    Baloxavir Marboxil (Participants’ weight <10 kg) Baloxavir Marboxil (Participants’ weight ≥10 kg to <20 kg) Total
    Number of subjects
    9 36 45
    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)
    9 4 13
        Children (2-11 years)
    0 32 32
        Adolescents (12-17 years)
    0 0 0
        Adults (18-64 years)
    0 0 0
        From 65-84 years
    0 0 0
        85 years and over
    0 0 0
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    0.4 ± 0.5 3.4 ± 1.5 -
    Gender Categorical
    Units: Subjects
        Female
    3 17 20
        Male
    6 19 25

    End points

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    End points reporting groups
    Reporting group title
    Baloxavir Marboxil (Participants’ weight <10 kg)
    Reporting group description
    Participants who weighed <10 kilograms (kg) and were greater than or equal to (≥) 3 months of age received a single oral dose of 2 milligram per kilogram (mg/kg) baloxavir marboxil 2% granules on Day 1.

    Reporting group title
    Baloxavir Marboxil (Participants’ weight ≥10 kg to <20 kg)
    Reporting group description
    Participants who weighed between 10 to <20 kg received 20 mg of baloxavir marboxil 2% granules as a single oral dose on Day 1 irrespective of their age.

    Subject analysis set title
    Baloxavir marboxil 2 mg/kg dose
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    The PK concentration population consisted of all participants who received at least one dose of the study drug and had at least one evaluable PK assay result.

    Subject analysis set title
    Baloxavir marboxil 20 mg dose
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    The PK concentration population consisted of all participants who received at least one dose of the study drug and had at least one evaluable PK assay result.

    Primary: Time to Alleviation of Influenza Illness

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    End point title
    Time to Alleviation of Influenza Illness [1]
    End point description
    Time to alleviation of influenza illness was defined as time taken from the start of treatment to the point at which all of the following criteria were met, and these clinical conditions persisted for at least 21.5 hours (90% of 24 hours): i) In the participant diary, cough and nasal discharge/nasal congestion were both rated as 0=absent or 1=mild; ii) Axillary temperature was < 37.5 degree Celsius [°C]. Intent-to-treat infected (ITTI) population included all participants who received study drug with a confirmed diagnosis of influenza virus infection on Day 1 and complied with Good Clinical Practice (GCP).
    End point type
    Primary
    End point timeframe
    Day 1 up to Day 14
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analyses were planned for this endpoint.
    End point values
    Baloxavir Marboxil (Participants’ weight <10 kg) Baloxavir Marboxil (Participants’ weight ≥10 kg to <20 kg)
    Number of subjects analysed
    8
    35
    Units: hours
        median (confidence interval 95%)
    26.4 (12.1 to 51.6)
    42.1 (28.6 to 54.8)
    No statistical analyses for this end point

    Secondary: Influenza Virus Titer

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    End point title
    Influenza Virus Titer
    End point description
    Influenza virus titer is the quantity of influenza virus in a given volume within the samples obtained from nasopharyngeal swabs. A lower value indicates lower viral load. Influenza virus titer was reported in log-transformed units i.e. log₁₀ of the 50% tissue culture infective dose per millilitre (log₁₀[TCID₅₀/mL]). Participants with positive virus titer at baseline in the ITTI population were included in the analysis.
    End point type
    Secondary
    End point timeframe
    Predose on Day 1, Days 2, 3, 4 (one visit on either Day 3 or Day 4 was mandatory), 6, and 9
    End point values
    Baloxavir Marboxil (Participants’ weight <10 kg) Baloxavir Marboxil (Participants’ weight ≥10 kg to <20 kg)
    Number of subjects analysed
    8
    35
    Units: log₁₀[TCID₅₀/mL]
    arithmetic mean (standard deviation)
        Day 1 (n=8, 34)
    4.68 ± 1.05
    5.53 ± 1.73
        Day 2 (n=8, 34)
    0.70 ± 0.00
    1.03 ± 0.73
        Day 3 (n=6, 18)
    0.70 ± 0.00
    1.15 ± 1.18
        Day 4 (n=3, 23)
    0.70 ± 0.00
    1.30 ± 1.06
        Day 6 (n=8, 34)
    1.99 ± 1.36
    2.02 ± 1.69
        Day 9 (n=8, 34)
    0.70 ± 0.00
    1.24 ± 1.11
    No statistical analyses for this end point

    Secondary: Amount of Virus RNA Determined by Reverse Transcription Polymerase Chain Reaction (RT-PCR)

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    End point title
    Amount of Virus RNA Determined by Reverse Transcription Polymerase Chain Reaction (RT-PCR)
    End point description
    The amount of virus ribonucleic acid (RNA) observed at each time point including Baseline was reported in log-transformed units i.e. log₁₀ of viral particles per millilitre (log₁₀[vp/mL]). Participants in the ITTI population were included in the analysis.
    End point type
    Secondary
    End point timeframe
    Predose on Day 1, Days 2, 3, 4 (one visit on either Day 3 or Day 4 was mandatory), 6 and 9
    End point values
    Baloxavir Marboxil (Participants’ weight <10 kg) Baloxavir Marboxil (Participants’ weight ≥10 kg to <20 kg)
    Number of subjects analysed
    8
    35
    Units: log₁₀[vp/mL]
    arithmetic mean (standard deviation)
        Day 1 (n=8, 35)
    6.50 ± 0.80
    6.39 ± 0.94
        Day 2 (n=8, 35)
    4.57 ± 0.93
    5.26 ± 0.98
        Day 3 (n=6, 18)
    3.52 ± 0.76
    4.25 ± 1.22
        Day 4 (n=3, 24)
    2.57 ± 0.37
    4.15 ± 1.24
        Day 6 (n=8, 35)
    5.04 ± 1.55
    4.52 ± 1.37
        Day 9 (n=8, 35)
    2.75 ± 0.79
    3.66 ± 1.41
    No statistical analyses for this end point

    Secondary: Change From Baseline in Influenza Virus Titer

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    End point title
    Change From Baseline in Influenza Virus Titer
    End point description
    Influenza virus titer is the quantity of influenza virus in a given volume within the samples obtained from nasopharyngeal swabs. A lower value indicates a lower viral load. The change from Baseline in influenza virus titer at each time point was reported in log-transformed units i.e. log₁₀ of the 50% tissue culture infective dose per mL (log₁₀[TCID₅₀/mL]). Participants with positive virus titer at baseline in the ITTI population were included in the analysis.
    End point type
    Secondary
    End point timeframe
    Baseline and Days 2, 3, 4 (one visit on either Day 3 or Day 4 was mandatory), 6 and 9
    End point values
    Baloxavir Marboxil (Participants’ weight <10 kg) Baloxavir Marboxil (Participants’ weight ≥10 kg to <20 kg)
    Number of subjects analysed
    8
    34
    Units: log₁₀[TCID₅₀/mL]
    arithmetic mean (standard deviation)
        Change from Baseline at Day 2 (n=8, 34)
    -3.98 ± 1.05
    -4.51 ± 1.72
        Change from Baseline at Day 3 (n=6, 18)
    -3.83 ± 1.14
    -3.98 ± 1.91
        Change from Baseline at Day 4 (n=3, 23)
    -4.27 ± 0.64
    -4.11 ± 2.30
        Change from Baseline at Day 6 (n=8, 34)
    -2.69 ± 1.03
    -3.51 ± 2.46
        Change from Baseline at Day 9 (n=8, 34)
    -3.98 ± 1.05
    -4.29 ± 1.80
    No statistical analyses for this end point

    Secondary: Change From Baseline in the Amount of Virus RNA Determined by RT-PCR

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    End point title
    Change From Baseline in the Amount of Virus RNA Determined by RT-PCR
    End point description
    The change from Baseline in the amount of virus RNA at each time point was reported in log-transformed units i.e. log₁₀ of viral particles per mL (log₁₀[vp/mL]). Participants in the ITTI population were included in the analysis.
    End point type
    Secondary
    End point timeframe
    Baseline and Days 2, 3, 4 (one visit on either Day 3 or Day 4 was mandatory), 6 and 9
    End point values
    Baloxavir Marboxil (Participants’ weight <10 kg) Baloxavir Marboxil (Participants’ weight ≥10 kg to <20 kg)
    Number of subjects analysed
    8
    35
    Units: log₁₀[vp/mL]
    arithmetic mean (standard deviation)
        Change from Baseline at Day 2 (n=8, 35)
    -1.93 ± 0.56
    -1.13 ± 1.18
        Change from Baseline at Day 3 (n=6, 18)
    -3.12 ± 0.50
    -1.96 ± 1.42
        Change from Baseline at Day 4 (n=3, 24)
    -3.45 ± 0.87
    -2.19 ± 1.54
        Change from Baseline at Day 6 (n=8, 35)
    -1.46 ± 1.52
    -1.87 ± 1.63
        Change from Baseline at Day 9 (n=8, 35)
    -3.75 ± 1.24
    -2.73 ± 1.64
    No statistical analyses for this end point

    Secondary: Percentage of Participants Positive For Influenza Virus Titer

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    End point title
    Percentage of Participants Positive For Influenza Virus Titer
    End point description
    Influenza virus titer is the quantity of influenza virus in a given volume within the samples obtained from nasopharyngeal swabs. A lower value indicates lower viral load. Positive influenza virus titer was defined as virus titer not less than the lower limit of quantification among those assessed for virus titer on Days 2, 3, 4, 6, and 9. Participants positive for influenza virus titer at Baseline in the ITTI population were included in the analyses.
    End point type
    Secondary
    End point timeframe
    Days 2, 3, 4 (one visit on either Day 3 or Day 4 was mandatory), 6, and 9
    End point values
    Baloxavir Marboxil (Participants’ weight <10 kg) Baloxavir Marboxil (Participants’ weight ≥10 kg to <20 kg)
    Number of subjects analysed
    8
    34
    Units: percentage of participants
    number (confidence interval 95%)
        Day 2 (n=8, 34)
    0.0 (0.0 to 36.9)
    29.4 (15.1 to 47.5)
        Day 3 (n=6, 18)
    0.0 (0.0 to 45.9)
    22.2 (6.4 to 47.6)
        Day 4 (n=3, 23)
    0.0 (0.0 to 70.8)
    34.8 (16.4 to 57.3)
        Day 6 (n=8, 34)
    62.5 (24.5 to 91.5)
    58.8 (40.7 to 75.4)
        Day 9 (n=8, 34)
    12.5 (0.3 to 52.7)
    32.4 (17.4 to 50.5)
    No statistical analyses for this end point

    Secondary: Percentage of Participants Positive For Influenza Virus by RT-PCR

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    End point title
    Percentage of Participants Positive For Influenza Virus by RT-PCR
    End point description
    The percentage of participants positive for influenza virus by RT-PCR on Days 2, 3, 4, 6, and 9 and not less than the lower limit of detection among the participants with detectable amounts of virus RNA at Baseline was analysed.
    End point type
    Secondary
    End point timeframe
    Days 2, 3, 4 (one visit on either Day 3 or Day 4 was mandatory), 6, and 9
    End point values
    Baloxavir Marboxil (Participants’ weight <10 kg) Baloxavir Marboxil (Participants’ weight ≥10 kg to <20 kg)
    Number of subjects analysed
    8
    35
    Units: percentage of participants
    number (confidence interval 95%)
        Day 2 (n=8, 35)
    100.0 (63.1 to 100.0)
    100.0 (90.0 to 100.0)
        Day 3 (n=6, 18)
    100.0 (54.1 to 100.0)
    94.4 (72.7 to 99.9)
        Day 4 (n=3, 24)
    100.0 (29.2 to 100.0)
    95.8 (78.9 to 99.9)
        Day 6 (n=8, 35)
    100.0 (63.1 to 100.0)
    97.1 (85.1 to 99.9)
        Day 9 (n=8, 35)
    75.0 (34.9 to 96.8)
    77.1 (59.9 to 89.6)
    No statistical analyses for this end point

    Secondary: Area Under the Curve (AUC) in Virus Titer

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    End point title
    Area Under the Curve (AUC) in Virus Titer
    End point description
    The AUC in virus titer was calculated using the trapezoidal method. Participants in the ITTI population were included in the analysis.
    End point type
    Secondary
    End point timeframe
    Baseline up to Day 9
    End point values
    Baloxavir Marboxil (Participants’ weight <10 kg) Baloxavir Marboxil (Participants’ weight ≥10 kg to <20 kg)
    Number of subjects analysed
    8
    34
    Units: log₁₀[TCID₅₀/mL]*hours
        arithmetic mean (standard deviation)
    -659.1 ± 190.5
    -711.4 ± 357.0
    No statistical analyses for this end point

    Secondary: Area Under the Curve (AUC) in the Amount of Virus RNA Determined by RT-PCR

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    End point title
    Area Under the Curve (AUC) in the Amount of Virus RNA Determined by RT-PCR
    End point description
    The AUC in the amount of virus RNA determined by RT-PCR was calculated using the trapezoidal method. Participants in the ITTI population were included in the analysis.
    End point type
    Secondary
    End point timeframe
    Baseline up to Day 9
    End point values
    Baloxavir Marboxil (Participants’ weight <10 kg) Baloxavir Marboxil (Participants’ weight ≥10 kg to <20 kg)
    Number of subjects analysed
    8
    35
    Units: log₁₀[vp/mL]*hours
        arithmetic mean (standard deviation)
    -478.4 ± 165.0
    -357.9 ± 226.7
    No statistical analyses for this end point

    Secondary: Time to Cessation of Viral Shedding by Virus Titer

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    End point title
    Time to Cessation of Viral Shedding by Virus Titer
    End point description
    Time to cessation of viral shedding by influenza virus titer was defined as the time from initiation of the study treatment until the virus titer was for the first time less than the lower limit of quantification. Participants in the ITTI population were included in the analysis. '0.9999' or '99999' means the limit of confidence interval was not calculated because there was no observation value corresponding the limit of confidence interval to ensure the 95% confidence coefficient.
    End point type
    Secondary
    End point timeframe
    Day 1 up to Day 9
    End point values
    Baloxavir Marboxil (Participants’ weight <10 kg) Baloxavir Marboxil (Participants’ weight ≥10 kg to <20 kg)
    Number of subjects analysed
    8
    34
    Units: hours
        median (confidence interval 95%)
    24 (0.9999 to 99999)
    24 (0.9999 to 99999)
    No statistical analyses for this end point

    Secondary: Time to Cessation of Viral Shedding by RT-PCR

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    End point title
    Time to Cessation of Viral Shedding by RT-PCR
    End point description
    Time to cessation of viral shedding by RT-PCR was defined as the time from initiation of the study treatment until the amount of virus RNA was for the first time less than the lower limit of detection. Participants in the ITTI population were included in the analysis. '0.9999' or '99999' means the limit of confidence interval was not calculated because there was no observation value corresponding the limit of confidence interval to ensure the 95% confidence coefficient.
    End point type
    Secondary
    End point timeframe
    Day 1 up to Day 9
    End point values
    Baloxavir Marboxil (Participants’ weight <10 kg) Baloxavir Marboxil (Participants’ weight ≥10 kg to <20 kg)
    Number of subjects analysed
    8
    35
    Units: hours
        median (confidence interval 95%)
    300.0 (216.0 to 384.0)
    240.0 (216.0 to 99999)
    No statistical analyses for this end point

    Secondary: Time to Resolution of Fever

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    End point title
    Time to Resolution of Fever
    End point description
    Time to resolution of fever was defined as the time from the initiation of the study treatment until first experience of fever resolution. Resolution of fever was defined as the time point when the participant’s self-measured axillary temperature had become less than 37.5ºC and remained below 37.5ºC for at least 12 hours. Participants in the ITTI population were included in the analysis.
    End point type
    Secondary
    End point timeframe
    Day 1 up to Day 14
    End point values
    Baloxavir Marboxil (Participants’ weight <10 kg) Baloxavir Marboxil (Participants’ weight ≥10 kg to <20 kg)
    Number of subjects analysed
    8
    35
    Units: hours
        median (confidence interval 95%)
    22.3 (12.1 to 32.8)
    22.0 (20.2 to 29.1)
    No statistical analyses for this end point

    Secondary: Percentage of Participants Who Reported Normal Body Temperature

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    End point title
    Percentage of Participants Who Reported Normal Body Temperature
    End point description
    Percentage of participants whose axillary temperature was below 37.5ºC in the ITTI population at each time point were analysed.
    End point type
    Secondary
    End point timeframe
    Postdose: 12 hours (h), 24 h, 36 h, 48 h, 72 h, 76 h, 120 h, 144 h, 168 h, 192 h and 216 h (up to Day 10)
    End point values
    Baloxavir Marboxil (Participants’ weight <10 kg) Baloxavir Marboxil (Participants’ weight ≥10 kg to <20 kg)
    Number of subjects analysed
    8
    35
    Units: percentage of participants
    number (confidence interval 95%)
        12 h postdose (n=8, 35)
    50.0 (15.7 to 84.3)
    22.9 (10.4 to 40.1)
        24 h postdose (n=8, 35)
    87.5 (47.3 to 99.7)
    65.7 (47.8 to 80.9)
        36 h postdose (n=8, 34)
    87.5 (47.3 to 99.7)
    85.3 (68.9 to 95.0)
        48 h postdose (n=8, 35)
    100.0 (63.1 to 100.0)
    100.0 (90.0 to 100.0)
        72 h postdose (n=8, 35)
    100.0 (63.1 to 100.0)
    100.0 (90.0 to 100.0)
        96 h postdose (n=8, 35)
    87.5 (47.3 to 99.7)
    91.4 (76.9 to 98.2)
        120 h postdose (n=8, 34)
    87.5 (47.3 to 99.7)
    94.1 (80.3 to 99.3)
        144 h postdose (n=8, 35)
    62.5 (24.5 to 91.5)
    97.1 (85.1 to 99.9)
        168 h postdose (n=8, 33)
    87.5 (47.3 to 99.7)
    97.0 (84.2 to 99.9)
        192 h postdose (n=8, 34)
    75.0 (34.9 to 96.8)
    97.1 (84.7 to 99.9)
        216 h postdose (n=8, 35)
    87.5 (47.3 to 99.7)
    100.0 (90.0 to 100.0)
    No statistical analyses for this end point

    Secondary: Body Temperature at Each Timepoint

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    End point title
    Body Temperature at Each Timepoint
    End point description
    Body temperature observed at each time point including Baseline was evaluated. Participants in the ITTI population were included in the analysis.
    End point type
    Secondary
    End point timeframe
    Baseline (0h, Day 1) and postdose 12 h, 24 h, 36 h, 48 h, 72 h, 96 h, 120 h, 144 h, 168 h, 192 h, and 216 h (up to Day 10)
    End point values
    Baloxavir Marboxil (Participants’ weight <10 kg) Baloxavir Marboxil (Participants’ weight ≥10 kg to <20 kg)
    Number of subjects analysed
    8
    35
    Units: degree Celsius (°C)
    arithmetic mean (standard deviation)
        Baseline (n=8, 35)
    39.06 ± 0.77
    38.59 ± 0.60
        12 h postdose (n=8, 35)
    37.78 ± 1.20
    38.16 ± 1.03
        24 h postdose (n=8, 35)
    36.99 ± 0.55
    37.32 ± 0.93
        36 h postdose (n=8, 34)
    36.86 ± 0.79
    36.85 ± 0.72
        48 h postdose (n=8, 35)
    36.61 ± 0.22
    36.51 ± 0.42
        72 h postdose (n=8, 35)
    36.64 ± 0.41
    36.40 ± 0.52
        96 h postdose (n=8, 35)
    36.84 ± 0.53
    36.63 ± 0.66
        120 h postdose (n=8, 34)
    36.98 ± 0.85
    36.56 ± 0.45
        144 h postdose (n=8, 35)
    36.99 ± 0.70
    36.49 ± 0.42
        168 h postdose (n=8, 33)
    36.96 ± 0.81
    36.47 ± 0.46
        192 h postdose (n=8, 34)
    36.98 ± 0.43
    36.57 ± 0.38
        216 h postdose (n=8, 35)
    36.86 ± 0.49
    36.49 ± 0.33
    No statistical analyses for this end point

    Secondary: Time to Alleviation of Cough Symptoms

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    End point title
    Time to Alleviation of Cough Symptoms
    End point description
    Time to alleviation of cough symptoms was defined as the time from initiation of the study treatment until the alleviation of cough symptoms. The alleviation of a symptom was defined as the time point when a symptom was assessed as 0=absent or 1=mild, for at least 21.5 hours (90% of 24 hours). Participants in the ITTI population, whose symptom scores at baseline were moderate or severe, were included in the analysis. '0.9999' or '99999' means the limit of confidence interval was not calculated because there was no observation value corresponding the limit of confidence interval to ensure the 95% confidence coefficient.
    End point type
    Secondary
    End point timeframe
    Day 1 up to Day 14
    End point values
    Baloxavir Marboxil (Participants’ weight <10 kg) Baloxavir Marboxil (Participants’ weight ≥10 kg to <20 kg)
    Number of subjects analysed
    1
    10
    Units: hours
        median (confidence interval 95%)
    30.8 (0.9999 to 99999)
    3.8 (0.3 to 6.7)
    No statistical analyses for this end point

    Secondary: Time to Alleviation of Nasal Discharge/Nasal Congestion Symptoms

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    End point title
    Time to Alleviation of Nasal Discharge/Nasal Congestion Symptoms
    End point description
    Time to alleviation of nasal discharge/ nasal congestion symptoms was defined as the time from initiation of the study treatment until the alleviation of nasal discharge/nasal congestion symptoms. The alleviation of a symptom was defined as the time point when a symptom was assessed as 0=absent or 1=mild, for at least 21.5 hours (90% of 24 hours). Participants in the ITTI population, whose symptom scores at baseline were moderate or severe, were included in the analysis.
    End point type
    Secondary
    End point timeframe
    Day 1 up to Day 14
    End point values
    Baloxavir Marboxil (Participants’ weight <10 kg) Baloxavir Marboxil (Participants’ weight ≥10 kg to <20 kg)
    Number of subjects analysed
    3
    16
    Units: hours
        median (confidence interval 95%)
    30.8 (2.0 to 246.0)
    30.3 (3.7 to 68.0)
    No statistical analyses for this end point

    Secondary: Time to Resumption of Normal Activity

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    End point title
    Time to Resumption of Normal Activity
    End point description
    Time to resumption of normal activity was defined as the time from initiation of the study treatment until the time when the participant’s guardian assessed the participant’s daily activities as 10. The participant’s ability to perform daily activities was assessed by the participant’s guardian on a scale of 0 (Unable to perform daily activities at all) to 10 (Able to perform all daily activities as usual). Participants in the ITTI population whose usual activity at Baseline was not 10 were included in the analyses.
    End point type
    Secondary
    End point timeframe
    Day 1 up to Day 14
    End point values
    Baloxavir Marboxil (Participants’ weight <10 kg) Baloxavir Marboxil (Participants’ weight ≥10 kg to <20 kg)
    Number of subjects analysed
    8
    35
    Units: hours
        median (confidence interval 95%)
    78.9 (48.8 to 194.0)
    81.4 (55.3 to 105.2)
    No statistical analyses for this end point

    Secondary: Percentage of Participants With Influenza-related Complications

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    End point title
    Percentage of Participants With Influenza-related Complications
    End point description
    The percentage of participants who developed influenza-related complications such as death, hospitalization, radiologically confirmed pneumonia, bronchitis, sinusitis, and otitis media after initiation of the study treatment was analysed. Participants in the ITTI population were included in the analysis.
    End point type
    Secondary
    End point timeframe
    Day 1 up to Day 22
    End point values
    Baloxavir Marboxil (Participants’ weight <10 kg) Baloxavir Marboxil (Participants’ weight ≥10 kg to <20 kg)
    Number of subjects analysed
    8
    35
    Units: percentage of participants
    number (confidence interval 95%)
        Any Influenza-related Complication
    0 (0.0 to 36.9)
    8.6 (1.8 to 23.1)
        Death
    0 (0.0 to 36.9)
    0 (0.0 to 10.0)
        Hospitalization
    0 (0.0 to 36.9)
    0 (0.0 to 10.0)
        Pneumonia
    0 (0.0 to 36.9)
    0 (0.0 to 10.0)
        Bronchitis
    0 (0.0 to 36.9)
    5.7 (0.7 to 19.2)
        Sinusitis
    0 (0.0 to 36.9)
    0 (0.0 to 10.0)
        Otitis media
    0 (0.0 to 36.9)
    2.9 (0.1 to 14.9)
    No statistical analyses for this end point

    Secondary: Percentage of Participants With Influenza-related Complications Particularly Seen in the Pediatric Population

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    End point title
    Percentage of Participants With Influenza-related Complications Particularly Seen in the Pediatric Population
    End point description
    The percentage of participants who developed influenza-related complications particularly seen in the pediatric population such as influenza-associated encephalitis or encephalopathy, febrile seizures, and myositis was analysed. Participants in the ITTI population were included in the analysis.
    End point type
    Secondary
    End point timeframe
    Day 1 up to Day 22
    End point values
    Baloxavir Marboxil (Participants’ weight <10 kg) Baloxavir Marboxil (Participants’ weight ≥10 kg to <20 kg)
    Number of subjects analysed
    8
    35
    Units: percentage of participants
    number (confidence interval 95%)
        Any pediatric influenza- related complication
    0 (0.0 to 36.9)
    0 (0.0 to 10.0)
        Influenza associated encephalitis / encephalopathy
    0 (0.0 to 36.9)
    0 (0.0 to 10.0)
        Febrile seizure
    0 (0.0 to 36.9)
    0 (0.0 to 10.0)
        Myositis
    0 (0.0 to 36.9)
    0 (0.0 to 10.0)
    No statistical analyses for this end point

    Secondary: Plasma Concentration of S-033447

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    End point title
    Plasma Concentration of S-033447
    End point description
    S-033447 or baloxavir is the active metabolite of baloxavir marboxil. The observed plasma concentration of baloxavir at 24 hours postdose (C24) was analysed. The PK concentration population consisted of all participants who received at least one dose of the study drug and had at least one evaluable PK assay result.
    End point type
    Secondary
    End point timeframe
    0.5 to 2 hours postdose at Day 1, Day 2, at one time point during the period from Day 6 to 22, and at Day 3 and/or Day 4 as needed
    End point values
    Baloxavir marboxil 2 mg/kg dose Baloxavir marboxil 20 mg dose
    Number of subjects analysed
    7
    26
    Units: nanogram/mL (ng/mL)
        geometric mean (geometric coefficient of variation)
    100 ± 43.4
    87.7 ± 44.0
    No statistical analyses for this end point

    Secondary: Percentage of Participants With Adverse Events (AEs)

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    End point title
    Percentage of Participants With Adverse Events (AEs)
    End point description
    An adverse event (AE) was defined as any untoward medical occurrence in a participant who was administered a pharmaceutical product (including an investigational drug) during the course of a clinical investigation. An AE could therefore be any unfavorable and unintended sign (including abnormal laboratory findings), symptom, or disease that was temporally associated with the use of the investigational product, regardless of whether it was considered to be related to the investigational product or not. The safety population consisted of all participants who received at least one dose of the study drug and complied with GCP.
    End point type
    Secondary
    End point timeframe
    Day 1 up to Day 22
    End point values
    Baloxavir Marboxil (Participants’ weight <10 kg) Baloxavir Marboxil (Participants’ weight ≥10 kg to <20 kg)
    Number of subjects analysed
    9
    36
    Units: percentage of participants
        number (confidence interval 95%)
    55.6 (21.2 to 86.3)
    52.8 (35.5 to 69.6)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From the time of informed consent up to Day 22
    Adverse event reporting additional description
    The safety population consisted of all participants who received at least one dose of the study drug and complied with GCP.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    21.1
    Reporting groups
    Reporting group title
    Baloxavir Marboxil (Participants’ weight <10 kg)
    Reporting group description
    Participants who weighed <10 kg and were greater than or equal to (≥) 3 months of age received a single oral dose of 2 mg/kg baloxavir marboxil 2% granules on Day 1.

    Reporting group title
    Baloxavir Marboxil (Participants’ weight ≥ 10 kg to < 20 kg)
    Reporting group description
    Participants who weighed between 10 to < 20 kg received 20 mg of baloxavir marboxil 2% granules as a single oral dose on Day 1 irrespective of their age.

    Serious adverse events
    Baloxavir Marboxil (Participants’ weight <10 kg) Baloxavir Marboxil (Participants’ weight ≥ 10 kg to < 20 kg)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 36 (0.00%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Baloxavir Marboxil (Participants’ weight <10 kg) Baloxavir Marboxil (Participants’ weight ≥ 10 kg to < 20 kg)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    5 / 9 (55.56%)
    13 / 36 (36.11%)
    Respiratory, thoracic and mediastinal disorders
    Rhinorrhoea
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 36 (0.00%)
         occurrences all number
    1
    0
    Upper respiratory tract inflammation
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 36 (0.00%)
         occurrences all number
    1
    0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    0 / 9 (0.00%)
    5 / 36 (13.89%)
         occurrences all number
    0
    5
    Skin and subcutaneous tissue disorders
    Skin fissures
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 36 (0.00%)
         occurrences all number
    1
    0
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    0 / 9 (0.00%)
    2 / 36 (5.56%)
         occurrences all number
    0
    2
    Influenza
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 36 (0.00%)
         occurrences all number
    1
    0
    Nasopharyngitis
         subjects affected / exposed
    2 / 9 (22.22%)
    6 / 36 (16.67%)
         occurrences all number
    2
    6
    Rotavirus infection
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 36 (0.00%)
         occurrences all number
    1
    0
    Enterocolitis viral
         subjects affected / exposed
    1 / 9 (11.11%)
    1 / 36 (2.78%)
         occurrences all number
    1
    1
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 9 (11.11%)
    2 / 36 (5.56%)
         occurrences all number
    1
    2

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    16 Apr 2019
    The original study protocol was amended as follows: 1) The planned duration of the study was increased by one year; 2) Shionogi & Co., Ltd. Was added to the Study Monitoring section.

    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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