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    Clinical Trial Results:
    A Phase III, Randomized, Double-Blind Placebo-Controlled, Multicenter Study To Evaluate the Efficacy and Safety of Baloxavir Marboxil in Combination With Standard-of-Care Neuraminidase Inhibitor in Hospitalized Participants With Severe Influenza

    Summary
    EudraCT number
    		 2018-001416-30
    Trial protocol
    		 BG   EE   CZ   SE   BE   DE   FR   FI   HU   ES   RO  
    Global end of trial date
    16 Mar 2020

    Results information
    Results version number
    		 v1(current)
    This version publication date
    30 Sep 2020
    First version publication date
    30 Sep 2020
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CP40617
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03684044
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    F. Hoffmann-La Roche AG
    Sponsor organisation address
    Grenzacherstrasse 124, Basel, Switzerland, CH-4070
    Public contact
    F. Hoffmann-La Roche AG, F. Hoffmann-La Roche AG, 41 616878333,, global.trial_information@roche.com
    Scientific contact
    F. Hoffmann-La Roche AG,, F. Hoffmann-La Roche AG, 41 616878333, global.trial_information@roche.com
    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
    30 Jul 2020
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    16 Mar 2020
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the clinical efficacy of baloxavir marboxil plus a standard of care (SOC) neuraminidase inhibitor (NAI) compared with matching placebo plus a SOC NAI
    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
    08 Jan 2019
    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
    Argentina: 8
    Country: Number of subjects enrolled
    Australia: 1
    Country: Number of subjects enrolled
    Belgium: 4
    Country: Number of subjects enrolled
    Bulgaria: 71
    Country: Number of subjects enrolled
    Canada: 7
    Country: Number of subjects enrolled
    Czech Republic: 2
    Country: Number of subjects enrolled
    Germany: 6
    Country: Number of subjects enrolled
    Spain: 31
    Country: Number of subjects enrolled
    Estonia: 1
    Country: Number of subjects enrolled
    France: 13
    Country: Number of subjects enrolled
    Hong Kong: 2
    Country: Number of subjects enrolled
    Israel: 28
    Country: Number of subjects enrolled
    Japan: 41
    Country: Number of subjects enrolled
    Korea, Republic of: 13
    Country: Number of subjects enrolled
    Mexico: 20
    Country: Number of subjects enrolled
    Netherlands: 2
    Country: Number of subjects enrolled
    Peru: 4
    Country: Number of subjects enrolled
    Romania: 20
    Country: Number of subjects enrolled
    Singapore: 2
    Country: Number of subjects enrolled
    Serbia: 49
    Country: Number of subjects enrolled
    Sweden: 5
    Country: Number of subjects enrolled
    Turkey: 2
    Country: Number of subjects enrolled
    Ukraine: 10
    Country: Number of subjects enrolled
    United States: 21
    Worldwide total number of subjects
    363
    EEA total number of subjects
    155
    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)
    11
    Adults (18-64 years)
    191
    From 65 to 84 years
    129
    85 years and over
    32

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 366 participants enrolled into the study and 363 actually received any treatment. All patients who received any study treatment are included in the safety analysis. Patients that received at least one dose of study treatment and were centrally assessed RT-PCR positive for influenza at any time point where included in the efficacy analysis.

    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 at least two doses of baloxavir marboxil or its matching placebo on Day 1 and 4. A third dose of Baloxavir or its matching placebo will be given on Day 7 for participants who have not improved according to protocol defined criteria on Day 5 Study treatment will be given in combination with SOC NAI (i.e., oseltamivir, zanamivir, or peramivir) in accordance with local clinical practice. SOC NAI will be administered to cover a minimum of treatment exposure from Day 1 to Day 5
    Arm type
    		 Experimental

    Investigational medicinal product name
    Baloxavir marboxil
    Investigational medicinal product code
    Other name
    Xofluza
    Pharmaceutical forms
    Tablet, Granules for oral suspension
    Routes of administration
    Oral use
    Dosage and administration details
    Baloxavir marboxil will be administered as a weight-based dose on Days 1 and 4. A third dose of Baloxavir or its matching placebo will be given on Day 7 for participants who have not improved according to protocol defined criteria on Day 5

    Arm title
    		 Placebo
    Arm description
    		 Participants will be assigned in a 2:1 ratio to receive baloxavir marboxil or matching placebo. Study treatment will be given in combination with SOC NAI (i.e., oseltamivir, zanamivir, or peramivir) in accordance with local clinical practice. SOC NAI will be administered to cover a minimum of treatment exposure from Day 1 to Day 5
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet, Granules for oral suspension
    Routes of administration
    Oral use
    Dosage and administration details
    Participants will receive Baloxavir marboxil matching placebo.

    Number of subjects in period 1
    		Baloxavir Marboxil Placebo
    Started
    239
    124
    Completed
    217
    104
    Not completed
    22
    20
         Adverse event, serious fatal
    4
    7
         Physician decision
    1
    -
         Consent withdrawn by subject
    11
    9
         Adverse event, non-fatal
    3
    -
         Patient Not Available
    -
    2
         Lost to follow-up
    3
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Baloxavir Marboxil
    Reporting group description
    		 Participants will receive at least two doses of baloxavir marboxil or its matching placebo on Day 1 and 4. A third dose of Baloxavir or its matching placebo will be given on Day 7 for participants who have not improved according to protocol defined criteria on Day 5 Study treatment will be given in combination with SOC NAI (i.e., oseltamivir, zanamivir, or peramivir) in accordance with local clinical practice. SOC NAI will be administered to cover a minimum of treatment exposure from Day 1 to Day 5

    Reporting group title
    Placebo
    Reporting group description
    		 Participants will be assigned in a 2:1 ratio to receive baloxavir marboxil or matching placebo. Study treatment will be given in combination with SOC NAI (i.e., oseltamivir, zanamivir, or peramivir) in accordance with local clinical practice. SOC NAI will be administered to cover a minimum of treatment exposure from Day 1 to Day 5

    Reporting group values
    		 Baloxavir Marboxil Placebo Total
    Number of subjects
    		 239 124 363
    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)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 8 3 11
        Adults (18-64 years)
    		 134 57 191
        From 65-84 years
    		 79 50 129
        85 years and over
    		 18 14 32
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    		 58.0 ( 19.8 ) 61.6 ( 20.3 ) -
    Sex: Female, Male
    Units:
        Male
    		 122 68 190
        Female
    		 117 56 173

    End points

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    End points reporting groups
    Reporting group title
    Baloxavir Marboxil
    Reporting group description
    		 Participants will receive at least two doses of baloxavir marboxil or its matching placebo on Day 1 and 4. A third dose of Baloxavir or its matching placebo will be given on Day 7 for participants who have not improved according to protocol defined criteria on Day 5 Study treatment will be given in combination with SOC NAI (i.e., oseltamivir, zanamivir, or peramivir) in accordance with local clinical practice. SOC NAI will be administered to cover a minimum of treatment exposure from Day 1 to Day 5

    Reporting group title
    Placebo
    Reporting group description
    		 Participants will be assigned in a 2:1 ratio to receive baloxavir marboxil or matching placebo. Study treatment will be given in combination with SOC NAI (i.e., oseltamivir, zanamivir, or peramivir) in accordance with local clinical practice. SOC NAI will be administered to cover a minimum of treatment exposure from Day 1 to Day 5

    Primary: Time to Clinical Improvement

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    End point title
    		 Time to Clinical Improvement
    End point description
    Time to Clinical Improvement is defined as Time to Hospital Discharge OR Time to NEWS2 (National Early Warning Score 2) of ≤ 2 maintained for 24 hours.
    End point type
    Primary
    End point timeframe
    Up to Day 35
    End point values
    		 Baloxavir Marboxil Placebo
    Number of subjects analysed
    208
    114
    Units: hours
        median (confidence interval 95%)
    97.5 (75.9 to 117.2)
    100.2 (75.9 to 144.4)
    Statistical analysis title
    		 Baloxavir Marboxil vs. Placebo
    Comparison groups
    Baloxavir Marboxil v Placebo
    Number of subjects included in analysis
    322
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.4666
    Method
    		 Gehan Wilcoxon
    Parameter type
    		 Median difference (net)
    Point estimate
    -2.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -53.4
         upper limit
    		 25.9

    Secondary: Response Rates of the 6-Point Ordinal Scale at Day 7

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    End point title
    		 Response Rates of the 6-Point Ordinal Scale at Day 7
    End point description
    The ordinal scale categories are: Category 1) Discharged (or “ready for discharge”) Category 2) Non-ICU hospital ward (or “ready for hospital ward”) not requiring supplemental oxygen/non-invasive ventilation Category 3) Non-ICU hospital ward (or “ready for hospital ward”) requiring supplemental oxygen/non-invasive ventilation Category 4) ICU without mechanical (invasive) ventilation (or “ready for ICU admission”) Category 5) Mechanical (invasive) ventilation Category 6) Death
    End point type
    Secondary
    End point timeframe
    Day 7
    End point values
    		 Baloxavir Marboxil Placebo
    Number of subjects analysed
    199
    108
    Units: percentage of participants
    number (not applicable)
        Category 1
    49.2
    45.4
        Category 2
    22.6
    24.1
        Category 3
    20.1
    22.2
        Category 4
    4.0
    1.9
        Category 5
    3.5
    4.6
        Category 6
    0.5
    1.9
    Statistical analysis title
    		 Baloxavir Marboxil vs. Placebo
    Comparison groups
    Baloxavir Marboxil v Placebo
    Number of subjects included in analysis
    307
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.6326
    Method
    		 Cochran-Mantel-Haenszel
    Confidence interval

    Secondary: Time to Clinical Response

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    End point title
    		 Time to Clinical Response
    End point description
    Time to Clinical Response is based on temperature ranges, oxygen saturation, respiratory status, heart rate, and hospitalization status.
    End point type
    Secondary
    End point timeframe
    Up to Day 35
    End point values
    		 Baloxavir Marboxil Placebo
    Number of subjects analysed
    208
    114
    Units: hours
        median (confidence interval 95%)
    138.3 (120.0 to 161.1)
    145.1 (128.0 to 187.2)
    Statistical analysis title
    		 Baloxavir Marboxil vs. Placebo
    Comparison groups
    Baloxavir Marboxil v Placebo
    Number of subjects included in analysis
    322
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.3272
    Method
    		 Gehan Wilcoxon
    Parameter type
    		 Mean difference (net)
    Point estimate
    -6.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -50.9
         upper limit
    		 17.7

    Secondary: Percentage of Participants on Mechanical Ventilation

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    End point title
    		 Percentage of Participants on Mechanical Ventilation
    End point description
    End point type
    Secondary
    End point timeframe
    Up to Day 35
    End point values
    		 Baloxavir Marboxil Placebo
    Number of subjects analysed
    208
    114
    Units: percentage of participants
        number (not applicable)
    5.3
    6.1
    No statistical analyses for this end point

    Secondary: Duration of Mechanical Ventilation

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    End point title
    		 Duration of Mechanical Ventilation
    End point description
    End point type
    Secondary
    End point timeframe
    Up to Day 35
    End point values
    		 Baloxavir Marboxil Placebo
    Number of subjects analysed
    208
    114
    Units: hours
        median (full range (min-max))
    150.25 (18.0 to 465.0)
    91.00 (24.0 to 407.0)
    No statistical analyses for this end point

    Secondary: Percentage of Participants Requiring ICU Stay

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    End point title
    		 Percentage of Participants Requiring ICU Stay
    End point description
    End point type
    Secondary
    End point timeframe
    Up to Day 35
    End point values
    		 Baloxavir Marboxil Placebo
    Number of subjects analysed
    208
    114
    Units: percentage of participants
        number (not applicable)
    4.3
    3.5
    No statistical analyses for this end point

    Secondary: Duration of ICU Stay

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    End point title
    		 Duration of ICU Stay
    End point description
    End point type
    Secondary
    End point timeframe
    Up to Day 35
    End point values
    		 Baloxavir Marboxil Placebo
    Number of subjects analysed
    208
    114
    Units: hours
        median (full range (min-max))
    138.55 (23.7 to 362.0)
    71.78 (18.7 to 139.4)
    No statistical analyses for this end point

    Secondary: Time to Clinical Failure

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    End point title
    		 Time to Clinical Failure
    End point description
    Time to clinical failure, defined as the time to death, mechanical ventilation, or ICU admission, corresponding to ordinal scale categories 6, 5, and 4, respectively, from baseline. Here 99999 represents data that was not available as very few patients experienced a clinical failure event and the median time to clinical failure could not be estimated
    End point type
    Secondary
    End point timeframe
    Up to Day 35
    End point values
    		 Baloxavir Marboxil Placebo
    Number of subjects analysed
    208
    114
    Units: hours
        median (confidence interval 95%)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    No statistical analyses for this end point

    Secondary: Time to Hospital Discharge

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    End point title
    		 Time to Hospital Discharge
    End point description
    End point type
    Secondary
    End point timeframe
    Up to Day 35
    End point values
    		 Baloxavir Marboxil Placebo
    Number of subjects analysed
    208
    114
    Units: hours
        median (confidence interval 95%)
    166.7 (144.7 to 190.7)
    167.3 (146.4 to 211.1)
    No statistical analyses for this end point

    Secondary: Percentage of Participants with Post-Treatment Influenza-Related Complications

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    End point title
    		 Percentage of Participants with Post-Treatment Influenza-Related Complications
    End point description
    Influenza-related complications included pneumonia, myositis or rhabdomyolysis, encephalitis or encephalopathy, myocarditis and/or pericarditis, otitis media, sinusitis, exacerbation of COPD/asthma, sepsis, acute lung injury or acute respiratory distress syndrome.
    End point type
    Secondary
    End point timeframe
    Up to Day 35
    End point values
    		 Baloxavir Marboxil Placebo
    Number of subjects analysed
    208
    114
    Units: percentage of participants
        number (not applicable)
    10.6
    14.0
    No statistical analyses for this end point

    Secondary: Mortality Rate at Day 7

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    End point title
    		 Mortality Rate at Day 7
    End point description
    End point type
    Secondary
    End point timeframe
    Up to Day 7
    End point values
    		 Baloxavir Marboxil Placebo
    Number of subjects analysed
    208
    114
    Units: percentage of participants
        number (confidence interval 95%)
    0.5 (0.01 to 2.65)
    2.6 (0.55 to 7.50)
    No statistical analyses for this end point

    Secondary: Mortality Rate at Day 28

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    End point title
    		 Mortality Rate at Day 28
    End point description
    End point type
    Secondary
    End point timeframe
    Up to Day 28
    End point values
    		 Baloxavir Marboxil Placebo
    Number of subjects analysed
    208
    114
    Units: percentage of participants
        number (confidence interval 95%)
    1.9 (0.53 to 4.85)
    5.3 (1.96 to 11.10)
    No statistical analyses for this end point

    Secondary: Time to NEWS2 of ≤ 2 maintained for 24 hours

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    End point title
    		 Time to NEWS2 of ≤ 2 maintained for 24 hours
    End point description
    A score of 0 (Range 0 - 3) indicates normal health conditions.
    End point type
    Secondary
    End point timeframe
    Up to Day 35
    End point values
    		 Baloxavir Marboxil Placebo
    Number of subjects analysed
    208
    114
    Units: hours
        median (confidence interval 95%)
    106.3 (88.3 to 138.3)
    127.2 (77.4 to 156.3)
    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 virus titer is defined as the time, in hours, between the initiation of study treatment and first time when the influenza virus titer is below the limit of detection (0.75 log10 TCID50/mL)
    End point type
    Secondary
    End point timeframe
    Screening (baseline) and on Days 2, 3, 4, 5, 7, and 10
    End point values
    		 Baloxavir Marboxil Placebo
    Number of subjects analysed
    159
    78
    Units: hours
        median (confidence interval 95%)
    23.9 (23.2 to 24.5)
    63.7 (46.4 to 68.1)
    No statistical analyses for this end point

    Secondary: Change from Baseline in Influenza Virus Titer at Each Timepoint

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    End point title
    		 Change from Baseline in Influenza Virus Titer at Each Timepoint
    End point description
    Influenza virus titer is the quantity of influenza virus in a given volume within the samples obtained from nasal swabs. If influenza virus titer was less than the lower limit of quantification, the virus titer was imputed as 0.749 (log10TCID50/mL). A lower value indicates lower viral titer.
    End point type
    Secondary
    End point timeframe
    Days 2, 3, 4, 5, 7, and 10
    End point values
    		 Baloxavir Marboxil Placebo
    Number of subjects analysed
    159
    78
    Units: log10 TCID50/ml
    number (not applicable)
        Day 2
    -2.36
    -1.00
        Day 3
    -2.70
    -1.93
        Day 4
    -2.88
    -2.50
        Day 5
    -3.01
    -2.81
        Day 7
    -3.00
    -2.95
        Day 10
    -3.02
    -3.06
    No statistical analyses for this end point

    Secondary: Percentage of Participants with Positive Influenza Virus Titer at Each Timepoint

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    End point title
    		 Percentage of Participants with Positive Influenza Virus Titer at Each Timepoint
    End point description
    Influenza virus titer is the quantity of influenza virus in a given volume within the samples obtained from nasal swabs. If influenza virus titer was less than the lower limit of quantification, the virus titer was imputed as 0.749 (log10 TCID50/mL). A lower value indicates lower viral titer.
    End point type
    Secondary
    End point timeframe
    Days 2, 3, 4, 5, 7, and 10
    End point values
    		 Baloxavir Marboxil Placebo
    Number of subjects analysed
    159
    78
    Units: percentage of participants
    number (not applicable)
        Day 2
    37.7
    80.3
        Day 3
    18.6
    53.4
        Day 4
    7.9
    26.7
        Day 5
    1.3
    20.8
        Day 7
    2.7
    5.8
        Day 10
    1.4
    1.4
    No statistical analyses for this end point

    Secondary: Area Under the Curve in Virus Titer

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    End point title
    		 Area Under the Curve in Virus Titer
    End point description
    End point type
    Secondary
    End point timeframe
    Days 1, 2, 3, 4, 5, 7, and 10
    End point values
    		 Baloxavir Marboxil Placebo
    Number of subjects analysed
    159
    77
    Units: log10 TCID50/mL*hours
        arithmetic mean (standard deviation)
    291.68 ( 176.68 )
    332.04 ( 183.63 )
    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, in hours, is defined as the time between the initiation of study treatment and first time when the virus RNA by RT-PCR is below the limit of detection (2.05 for flu A and 2.83 for flu B log10 virus particles/mL). Here 999999 represents data that were not estimable due to low number of events.
    End point type
    Secondary
    End point timeframe
    Screening (baseline) and on Days 2, 3, 4, 5, 7, and 10
    End point values
    		 Baloxavir Marboxil Placebo
    Number of subjects analysed
    205
    111
    Units: hours
        median (confidence interval 95%)
    216.3 (211.3 to 239.8)
    261.1 (236.4 to 999999)
    No statistical analyses for this end point

    Secondary: Change from Baseline in the Amount of Virus RNA (RT-PCR) at Each Timepoint

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    End point title
    		 Change from Baseline in the Amount of Virus RNA (RT-PCR) at Each Timepoint
    End point description
    If the amount of virus RNA was less than the lower limit of quantification, the amount of virus RNA was imputed as 2.18 for flu A and 2.93 for flu B (log10 virus particles/mL)
    End point type
    Secondary
    End point timeframe
    Days 2, 3, 4, 5, 7, and 10
    End point values
    		 Baloxavir Marboxil Placebo
    Number of subjects analysed
    205
    111
    Units: log10 virus particles/mL
    number (not applicable)
        Day 2
    -0.98
    -0.66
        Day 3
    -1.54
    -1.19
        Day 4
    -2.35
    -1.84
        Day 5
    -2.91
    -2.39
        Day 7
    -3.15
    -2.96
        Day 10
    -3.69
    -3.21
    No statistical analyses for this end point

    Secondary: Percentage of Participants Positive by RT-PCR at Each Timepoint

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    End point title
    		 Percentage of Participants Positive by RT-PCR at Each Timepoint
    End point description
    If the amount of virus RNA was less than the lower limit of quantification, the amount of virus RNA was imputed as 2.18 for flu A and 2.93 for flu B (log10 virus particles/mL)
    End point type
    Secondary
    End point timeframe
    Days 2, 3, 4, 5, 7, and 10
    End point values
    		 Baloxavir Marboxil Placebo
    Number of subjects analysed
    205
    111
    Units: percentage of participants
    number (not applicable)
        Day 2
    95.6
    96.3
        Day 3
    90.0
    93.3
        Day 4
    88.1
    87.9
        Day 5
    79.9
    85.4
        Day 7
    69.6
    68.0
        Day 10
    46.7
    50.5
    No statistical analyses for this end point

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

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    End point title
    		 Area Under the Curve in the Amount of Virus RNA (RT-PCR)
    End point description
    End point type
    Secondary
    End point timeframe
    Days 1, 2, 3, 4, 5, 7, and 10
    End point values
    		 Baloxavir Marboxil Placebo
    Number of subjects analysed
    197
    106
    Units: log10 virus particles/mL
        arithmetic mean (standard deviation)
    676.40 ( 371.72 )
    740.15 ( 484.07 )
    No statistical analyses for this end point

    Secondary: Percentage of Participants with Adverse Events (AEs) and Serious Adverse Events (SAEs)

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    End point title
    		 Percentage of Participants with Adverse Events (AEs) and Serious Adverse Events (SAEs)
    End point description
    An adverse event (AE) is any untoward medical occurrence in a participant or clinical investigation participant administered a pharmaceutical product and that does not necessarily have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not considered related to the medicinal (investigational) product. A serious adverse event (SAE) is any significant hazard, contraindication, side effect that is fatal or life-threatening, requires hospitalization or prolongation of an existing hospitalization, results in persistent or significant disability/ incapacity, is a congenital anomaly/ birth defect, is medically significant or requires intervention to prevent one or other of the outcomes listed above.
    End point type
    Secondary
    End point timeframe
    Up to Day 35
    End point values
    		 Baloxavir Marboxil Placebo
    Number of subjects analysed
    239
    124
    Units: percentage of participants
    number (not applicable)
        AEs
    45.2
    50.0
        SAEs
    12.1
    15.3
    No statistical analyses for this end point

    Secondary: Percentage of Participants with AEs and SAEs Leading to Discontinuation from Treatment

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    End point title
    		 Percentage of Participants with AEs and SAEs Leading to Discontinuation from Treatment
    End point description
    Discontinuation from study treatment.
    End point type
    Secondary
    End point timeframe
    Up to Day 35
    End point values
    		 Baloxavir Marboxil Placebo
    Number of subjects analysed
    239
    124
    Units: percentage of participants
    number (not applicable)
        AEs
    1.3
    3.2
        SAEs
    0.8
    1.6
    No statistical analyses for this end point

    Secondary: Percentage of Participants with Any Post-Treatment ALT and AST Above Baseline and >3 × ULN, >5 × ULN, >10 × ULN

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    End point title
    		 Percentage of Participants with Any Post-Treatment ALT and AST Above Baseline and >3 × ULN, >5 × ULN, >10 × ULN
    End point description
    ALT = alanine aminotransferase AST = aspartate transaminase
    End point type
    Secondary
    End point timeframe
    Up to Day 35
    End point values
    		 Baloxavir Marboxil Placebo
    Number of subjects analysed
    239
    124
    Units: percentage of participants
    number (not applicable)
        AST(U/L) or ALT (U/L) >3 x ULN
    4.6
    8.9
        AST(U/L) or ALT (U/L) >5 x ULN
    0.8
    3.2
        AST(U/L) or ALT (U/L) >10 x ULN
    0
    1.6
    No statistical analyses for this end point

    Secondary: Plasma Concentration of Baloxavir (Active Metabolite) at Specified Time Points

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    End point title
    		 Plasma Concentration of Baloxavir (Active Metabolite) at Specified Time Points [1]
    End point description
    Here 999999 represents data that were not estimable.
    End point type
    Secondary
    End point timeframe
    Day 1, 2, 4, 5, 7 and 8
    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: PK parameters were not estimated for the Placebo arm.
    End point values
    		 Baloxavir Marboxil
    Number of subjects analysed
    8
    Units: ng/mL
    arithmetic mean (standard deviation)
        Day 1 - 30 minutes postdose
    37.82 ( 23.61 )
        Day 1 - 2 hours postdose
    75.06 ( 52.16 )
        Day 1 - 4 hours postdose
    95.85 ( 58.36 )
        Day 1 - 10 hours postdose
    64.47 ( 39.47 )
        Day 2 - 24 hours postdose
    53.36 ( 37.42 )
        Day 4 - Predose
    24.26 ( 15.87 )
        Day 4 - 30 minutes postdose
    49.16 ( 52.07 )
        Day 4 - 2 hours postdose
    109.66 ( 95.22 )
        Day 4 - 4 hours postdose
    117.69 ( 60.54 )
        Day 4 - 10 hours postdose
    94.08 ( 49.71 )
        Day 5 - 24 hours postdose
    77.98 ( 42.89 )
        Day 7 - predose
    23.31 ( 25.87 )
        Day 8 - 24 hours postdose
    105.00 ( 999999 )
        Visit 8
    28.37 ( 61.61 )
    No statistical analyses for this end point

    Secondary: Area Under the Concentration to Time Curve From Time 0 to 72 hours (AUC0-72) of Baloxavir

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    End point title
    		 Area Under the Concentration to Time Curve From Time 0 to 72 hours (AUC0-72) of Baloxavir [2]
    End point description
    End point type
    Secondary
    End point timeframe
    Day 1, 2, 4, 5, 7 and 8
    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: PK parameters were not estimated for the Placebo arm.
    End point values
    		 Baloxavir Marboxil
    Number of subjects analysed
    8
    Units: Hours(h)*nanogram(ng)/milliliter (mL)
    geometric mean (geometric coefficient of variation)
        Visit 1 (Day 1)
    2820 ( 70.5 )
        Visit 4 (Day 4)
    3170 ( 53.5 )
    No statistical analyses for this end point

    Secondary: Maximum Plasma Concentration (Cmax) of Baloxavir

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    End point title
    		 Maximum Plasma Concentration (Cmax) of Baloxavir [3]
    End point description
    End point type
    Secondary
    End point timeframe
    Day 1, 2, 4, 5, 7 and 8
    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: PK parameters were not estimated for the Placebo arm.
    End point values
    		 Baloxavir Marboxil
    Number of subjects analysed
    8
    Units: ng/mL
    geometric mean (geometric coefficient of variation)
        Visit 1 (Day 1)
    86.3 ( 64.6 )
        Visit 4 (Day 4)
    123 ( 51.7 )
    No statistical analyses for this end point

    Secondary: Apparent Half-Life (T1/2) of Baloxavir

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    End point title
    		 Apparent Half-Life (T1/2) of Baloxavir [4]
    End point description
    Here 999999 represents data that were not estimable.
    End point type
    Secondary
    End point timeframe
    Day 1, 2, 4, 5, 7 and 8
    Notes
    [4] - 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: PK parameters were not estimated for the Placebo arm.
    End point values
    		 Baloxavir Marboxil
    Number of subjects analysed
    8
    Units: Hours (h)
    geometric mean (geometric coefficient of variation)
        Visit 1 (Day 1)
    18.9 ( 999999 )
        Visit 4 (Day 4)
    23.4 ( 12.8 )
    No statistical analyses for this end point

    Secondary: Concentration at 24 hours (C24) of Baloxavir

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    End point title
    		 Concentration at 24 hours (C24) of Baloxavir [5]
    End point description
    Here 999999 represents data that were not estimable.
    End point type
    Secondary
    End point timeframe
    Day 1, 2, 4, 5, 7 and 8
    Notes
    [5] - 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: PK parameters were not estimated for the Placebo arm.
    End point values
    		 Baloxavir Marboxil
    Number of subjects analysed
    8
    Units: ng/mL
    geometric mean (geometric coefficient of variation)
        Visit 1 (Day 1)
    43.9 ( 74.4 )
        Visit 4 (Day 4)
    67.1 ( 66.8 )
        Visit 6 (Day 7)
    105 ( 999999 )
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Baseline up to Day 35
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    18
    Reporting groups
    Reporting group title
    Baloxavir Marboxil
    Reporting group description
    		 Participants will receive at least two doses of baloxavir marboxil or its matching placebo on Day 1 and 4. A third dose of Baloxavir or its matching placebo will be given on Day 7 for participants who have not improved according to protocol defined criteria on Day 5 Study treatment will be given in combination with SOC NAI (i.e., oseltamivir, zanamivir, or peramivir) in accordance with local clinical practice. SOC NAI will be administered to cover a minimum of treatment exposure from Day 1 to Day 5

    Reporting group title
    Placebo
    Reporting group description
    		 Participants will be assigned in a 2:1 ratio to receive baloxavir marboxil or matching placebo. Study treatment will be given in combination with SOC NAI (i.e., oseltamivir, zanamivir, or peramivir) in accordance with local clinical practice. SOC NAI will be administered to cover a minimum of treatment exposure from Day 1 to Day 5

    Serious adverse events
    		 Baloxavir Marboxil Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    29 / 239 (12.13%)
    19 / 124 (15.32%)
         number of deaths (all causes)
    4
    7
         number of deaths resulting from adverse events
    Vascular disorders
    Aortic aneurysm rupture
         subjects affected / exposed
    1 / 239 (0.42%)
    0 / 124 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    1 / 239 (0.42%)
    0 / 124 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Orthostatic hypotension
         subjects affected / exposed
    0 / 239 (0.00%)
    1 / 124 (0.81%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral ischaemia
         subjects affected / exposed
    1 / 239 (0.42%)
    0 / 124 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Multiple organ dysfunction syndrome
         subjects affected / exposed
    2 / 239 (0.84%)
    0 / 124 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    Immune system disorders
    Graft versus host disease
         subjects affected / exposed
    0 / 239 (0.00%)
    1 / 124 (0.81%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory failure
         subjects affected / exposed
    2 / 239 (0.84%)
    1 / 124 (0.81%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Asthma
         subjects affected / exposed
    1 / 239 (0.42%)
    0 / 124 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchospasm
         subjects affected / exposed
    1 / 239 (0.42%)
    0 / 124 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    3 / 239 (1.26%)
    0 / 124 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    1 / 239 (0.42%)
    0 / 124 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Interstitial lung disease
         subjects affected / exposed
    0 / 239 (0.00%)
    2 / 124 (1.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Respiratory failure
         subjects affected / exposed
    1 / 239 (0.42%)
    1 / 124 (0.81%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Product issues
    Device malfunction
         subjects affected / exposed
    1 / 239 (0.42%)
    0 / 124 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Hepatic enzyme increased
         subjects affected / exposed
    0 / 239 (0.00%)
    1 / 124 (0.81%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Ankle fracture
         subjects affected / exposed
    1 / 239 (0.42%)
    0 / 124 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fall
         subjects affected / exposed
    0 / 239 (0.00%)
    1 / 124 (0.81%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal compression fracture
         subjects affected / exposed
    0 / 239 (0.00%)
    1 / 124 (0.81%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    1 / 239 (0.42%)
    0 / 124 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    1 / 239 (0.42%)
    0 / 124 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bradycardia
         subjects affected / exposed
    1 / 239 (0.42%)
    0 / 124 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    1 / 239 (0.42%)
    1 / 124 (0.81%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Congestive cardiomyopathy
         subjects affected / exposed
    0 / 239 (0.00%)
    1 / 124 (0.81%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial ischaemia
         subjects affected / exposed
    1 / 239 (0.42%)
    0 / 124 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Supraventricular tachycardia
         subjects affected / exposed
    1 / 239 (0.42%)
    0 / 124 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebral artery embolism
         subjects affected / exposed
    1 / 239 (0.42%)
    0 / 124 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Encephalopathy
         subjects affected / exposed
    0 / 239 (0.00%)
    1 / 124 (0.81%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Blood and lymphatic system disorders
    Febrile neutropenia
         subjects affected / exposed
    1 / 239 (0.42%)
    0 / 124 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    0 / 239 (0.00%)
    1 / 124 (0.81%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rectal haemorrhage
         subjects affected / exposed
    0 / 239 (0.00%)
    1 / 124 (0.81%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    0 / 239 (0.00%)
    1 / 124 (0.81%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    0 / 239 (0.00%)
    1 / 124 (0.81%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Infections and infestations
    Asymptomatic bacteriuria
         subjects affected / exposed
    1 / 239 (0.42%)
    0 / 124 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    1 / 239 (0.42%)
    0 / 124 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    0 / 239 (0.00%)
    1 / 124 (0.81%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Clostridium difficile colitis
         subjects affected / exposed
    1 / 239 (0.42%)
    0 / 124 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device related infection
         subjects affected / exposed
    0 / 239 (0.00%)
    1 / 124 (0.81%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocarditis
         subjects affected / exposed
    1 / 239 (0.42%)
    0 / 124 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower respiratory tract infection viral
         subjects affected / exposed
    1 / 239 (0.42%)
    0 / 124 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    7 / 239 (2.93%)
    5 / 124 (4.03%)
         occurrences causally related to treatment / all
    0 / 7
    0 / 5
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Pneumonia bacterial
         subjects affected / exposed
    2 / 239 (0.84%)
    1 / 124 (0.81%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia viral
         subjects affected / exposed
    1 / 239 (0.42%)
    0 / 124 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    0 / 239 (0.00%)
    1 / 124 (0.81%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Septic shock
         subjects affected / exposed
    1 / 239 (0.42%)
    0 / 124 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Superinfection viral
         subjects affected / exposed
    1 / 239 (0.42%)
    0 / 124 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Metabolism and nutrition disorders
    Gout
         subjects affected / exposed
    0 / 239 (0.00%)
    1 / 124 (0.81%)
         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: 3%
    Non-serious adverse events
    		 Baloxavir Marboxil Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    44 / 239 (18.41%)
    27 / 124 (21.77%)
    Investigations
    Hepatic enzyme increased
         subjects affected / exposed
    6 / 239 (2.51%)
    5 / 124 (4.03%)
         occurrences all number
    7
    5
    Nervous system disorders
    Headache
         subjects affected / exposed
    9 / 239 (3.77%)
    2 / 124 (1.61%)
         occurrences all number
    11
    2
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    10 / 239 (4.18%)
    6 / 124 (4.84%)
         occurrences all number
    10
    6
    Diarrhoea
         subjects affected / exposed
    8 / 239 (3.35%)
    6 / 124 (4.84%)
         occurrences all number
    8
    7
    Nausea
         subjects affected / exposed
    7 / 239 (2.93%)
    4 / 124 (3.23%)
         occurrences all number
    9
    4
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    5 / 239 (2.09%)
    4 / 124 (3.23%)
         occurrences all number
    6
    4
    Metabolism and nutrition disorders
    Hypokalaemia
         subjects affected / exposed
    9 / 239 (3.77%)
    5 / 124 (4.03%)
         occurrences all number
    9
    5

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    30 May 2019
    Major updates included the change from study sample size from approximately 240 to approximately 366, the endpoint “time to clinical response” was moved from an exploratory endpoint to secondary endpoint, and section was added to summarize post-marketing safety data that identified hypersensitivity reactions.

    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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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
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