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    Clinical Trial Results:
    A Phase IIIB, Multicenter, Randomized, Double-Blind, Placebo-Controlled, Clinical Efficacy Study of Baloxavir Marboxil for the Reduction of Direct Transmission of Influenza From Otherwise Healthy Patients to Household Contacts

    Summary
    EudraCT number
    		 2018-004056-37
    Trial protocol
    		 ES   GB   GR   HU   PL   FR   BG  
    Global end of trial date
    10 May 2024

    Results information
    Results version number
    		 v1(current)
    This version publication date
    15 Dec 2024
    First version publication date
    15 Dec 2024
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    MV40618
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03969212
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Hoffmann-La Roche
    Sponsor organisation address
    Grenzacherstrasse 124, Basel, Switzerland, CH-4058
    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)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    12 Aug 2024
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    10 May 2024
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this study was to evaluate the efficacy of a single, oral dose of baloxavir marboxil (BXM) compared with a placebo to prevent secondary within-household transmission of influenza A/B.
    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
    10 Oct 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
    Greece: 7
    Country: Number of subjects enrolled
    Hungary: 24
    Country: Number of subjects enrolled
    Israel: 148
    Country: Number of subjects enrolled
    Poland: 85
    Country: Number of subjects enrolled
    Spain: 15
    Country: Number of subjects enrolled
    Türkiye: 230
    Country: Number of subjects enrolled
    United States: 1310
    Country: Number of subjects enrolled
    Bulgaria: 1041
    Country: Number of subjects enrolled
    Costa Rica: 6
    Country: Number of subjects enrolled
    Mexico: 44
    Country: Number of subjects enrolled
    South Africa: 112
    Country: Number of subjects enrolled
    China: 441
    Country: Number of subjects enrolled
    Japan: 668
    Country: Number of subjects enrolled
    United Kingdom: 1
    Country: Number of subjects enrolled
    India: 2
    Worldwide total number of subjects
    4134
    EEA total number of subjects
    1172
    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)
    433
    Adolescents (12-17 years)
    495
    Adults (18-64 years)
    3063
    From 65 to 84 years
    132
    85 years and over
    11

    Subject disposition

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    Recruitment
    Recruitment details
    		 Participants with acute influenza infection (Index participants [IPs]) and their household contacts (HHCs) took part in the study across 142 investigative sites in 15 countries from 10 October 2019 to 10 May 2024. A total of 4138 participants, 1457 IPs, and 2681 HHCs, were included in the study.

    Pre-assignment
    Screening details
    		 IPs received baloxavir marboxil or placebo in a 1:1 ratio, and their evaluable HHCs were assessed for influenza symptoms. No treatment was administered to the HHCs. Of the 1345 HHCs enrolled in ‘Baloxavir Marboxil:HHCs’, 1305 completed the study. Baseline data was not collected for 4 HHCs, hence only 1341 HHCs are presented in the disposition.

    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, Monitor, Carer, Data analyst, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo: IPs
    Arm description
    		 IPs were randomized in this arm to receive a single dose of matching placebo orally as a tablet or oral suspension based on their weight and age.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Granules for oral suspension, Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Single, oral dose of matching placebo administered according to age and weight of IPs.

    Arm title
    		 Baloxavir Marboxil: IPs
    Arm description
    		 IPs were randomized in this arm to receive a single dose of baloxavir marboxil orally based on their weight and age.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Baloxavir Marboxil
    Investigational medicinal product code
    RO7191686
    Other name
    XOFLUZA
    Pharmaceutical forms
    Granules for oral suspension, Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Single, oral dose of baloxavir marboxil administered according to age and weight of IPs.

    Arm title
    		 Placebo: HHCs
    Arm description
    		 HHCs related to IPs randomized to the placebo arm were evaluated for influenza transmission (either virological or symptomatic) up to Day 9 of the observation period without any treatment being administered.
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    		 Baloxavir Marboxil: HHCs
    Arm description
    		 HHCs related to IPs randomized to the baloxavir marboxil arm were evaluated for influenza transmission (either virological or symptomatic) up to Day 9 of the observation period without any treatment being administered.
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 1
    		Placebo: IPs Baloxavir Marboxil: IPs Placebo: HHCs Baloxavir Marboxil: HHCs
    Started
    731
    726
    1336
    1341
    Treated
    726
    723
    0 [1]
    0 [2]
    Completed
    699
    688
    1300
    1301
    Not completed
    32
    38
    36
    40
         Consent withdrawn by subject
    7
    13
    5
    11
         Physician decision
    -
    -
    1
    -
         Adverse Event
    1
    -
    -
    -
         Other
    22
    23
    28
    26
         Lost to follow-up
    2
    2
    2
    2
         Protocol deviation
    -
    -
    -
    1
    Notes
    [1] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: HHCs were not treated in this study.
    [2] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: HHCs were not treated in this study.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo: IPs
    Reporting group description
    		 IPs were randomized in this arm to receive a single dose of matching placebo orally as a tablet or oral suspension based on their weight and age.

    Reporting group title
    Baloxavir Marboxil: IPs
    Reporting group description
    		 IPs were randomized in this arm to receive a single dose of baloxavir marboxil orally based on their weight and age.

    Reporting group title
    Placebo: HHCs
    Reporting group description
    		 HHCs related to IPs randomized to the placebo arm were evaluated for influenza transmission (either virological or symptomatic) up to Day 9 of the observation period without any treatment being administered.

    Reporting group title
    Baloxavir Marboxil: HHCs
    Reporting group description
    		 HHCs related to IPs randomized to the baloxavir marboxil arm were evaluated for influenza transmission (either virological or symptomatic) up to Day 9 of the observation period without any treatment being administered.

    Reporting group values
    		 Placebo: IPs Baloxavir Marboxil: IPs Placebo: HHCs Baloxavir Marboxil: HHCs Total
    Number of subjects
    		 731 726 1336 1341 4134
    Age Categorical
    Units: Subjects
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 31.2 ( 15.8 ) 30.5 ( 15.2 ) 34.7 ( 18.4 ) 35.3 ( 18.6 ) -
    Gender Categorical
    Units: Subjects
        Female
    		 377 389 740 709 2215
        Male
    		 354 337 596 632 1919
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    		 83 83 169 153 488
        Not Hispanic or Latino
    		 646 633 1133 1145 3557
        Unknown or Not Reported
    		 2 10 34 43 89
    Race
    Units: Subjects
        American Indian or Alaska Native
    		 7 7 9 8 31
        Asian
    		 196 190 370 364 1120
        Black or African American
    		 28 19 47 46 140
        White
    		 483 495 817 871 2666
        Multiple Race
    		 3 0 9 5 17
        Unknown
    		 14 15 74 47 150
        Native Hawaiian or other Pacific Islander
    		 0 0 10 0 10

    End points

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    End points reporting groups
    Reporting group title
    Placebo: IPs
    Reporting group description
    		 IPs were randomized in this arm to receive a single dose of matching placebo orally as a tablet or oral suspension based on their weight and age.

    Reporting group title
    Baloxavir Marboxil: IPs
    Reporting group description
    		 IPs were randomized in this arm to receive a single dose of baloxavir marboxil orally based on their weight and age.

    Reporting group title
    Placebo: HHCs
    Reporting group description
    		 HHCs related to IPs randomized to the placebo arm were evaluated for influenza transmission (either virological or symptomatic) up to Day 9 of the observation period without any treatment being administered.

    Reporting group title
    Baloxavir Marboxil: HHCs
    Reporting group description
    		 HHCs related to IPs randomized to the baloxavir marboxil arm were evaluated for influenza transmission (either virological or symptomatic) up to Day 9 of the observation period without any treatment being administered.

    Subject analysis set title
    Placebo: Household
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    All households of randomized IPs who received matching placebo, with the IP being PCR positive at screening and with at least one HHC enrolled for the full study.

    Subject analysis set title
    Baloxavir Marboxil: Household
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    All households of randomized IPs who received baloxavir marboxil, with the IP being PCR positive at screening and with at least one HHC enrolled for the full study.

    Primary: Percentage of HHCs With Virological Influenza Transmission by Day 5

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    End point title
    		 Percentage of HHCs With Virological Influenza Transmission by Day 5 [1]
    End point description
    The virological transmission was determined based on Polymerase Chain Reaction Positive (PCR+) influenza test results. Percentage of HHCs who tested PCR+ for influenza by Day 5 post IP randomization with virus subtype matching with that of the respective IP, irrespective of being symptomatic or asymptomatic are reported. The primary household contacts analysis set (PAS-HC) included unvaccinated HHCs who were linked to households where the IP was baseline PCR+ for influenza A or B, received the study drug, and where all contacts were PCR negative at baseline.
    End point type
    Primary
    End point timeframe
    Baseline (Day 1) to Day 5
    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: This endpoint was planned to only evaluate the HHCs associated with the IPs.
    End point values
    		 Placebo: HHCs Baloxavir Marboxil: HHCs
    Number of subjects analysed
    1098
    1118
    Units: percentage of HHCs
    number (confidence interval 95.38%)
        HHC with endpoint positive
    13.42 (10.66 to 16.76)
    9.50 (7.40 to 12.13)
    Statistical analysis title
    		 Baloxavir Marboxil vs Placebo
    Statistical analysis description
    The odds ratio (OR) shown represents the odds of Baloxavir Marboxil (BMX) versus the odds of Placebo.
    Comparison groups
    Placebo: HHCs v Baloxavir Marboxil: HHCs
    Number of subjects included in analysis
    2216
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.013
    Method
    		 Generalized estimating equation (GEE)
    Parameter type
    		 Adjusted OR (BMX vs Placebo)
    Point estimate
    0.68
    Confidence interval
         level
    		 95.38%
         sides
    2-sided
         lower limit
    		 0.5
         upper limit
    		 0.93

    Secondary: Percentage of HHCs With Symptomatic Influenza Transmission by Day 5

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    End point title
    		 Percentage of HHCs With Symptomatic Influenza Transmission by Day 5 [2]
    End point description
    Virological transmission was determined based on PCR+ influenza test results. Percentage of HHCs who were PCR+ for influenza by Day 5 post IP randomization with virus subtype matching with respective IP & develop symptoms at any time during the study are reported. HHCs ≥12 years old were symptomatic if 1. Presence of temperature ≥38.0 Celsius & 1 respiratory symptom or 2. Presence of one respiratory symptom & 1 general systemic symptom (headache, feverishness or chills, muscle or joint pain, fatigue), with /without a fever. HHCs ≥2 & <12 years old were symptomatic if the presence of temperature was ≥38.0 Celsius & upper respiratory tract infection signs or symptoms (cough, nasal congestion, or rhinorrhea). Symptoms must be either new, or have worsened versus baseline (BA) in HHC with BA symptoms due to a preexisting comorbidity. PAS-HC=unvaccinated HHCs who were linked to HHs where IP was BA PCR+ for influenza A/B, received study drug, & where all contacts were PCR negative at BA.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1) to Day 5
    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: This endpoint was planned to only evaluate the HHCs associated with the IPs.
    End point values
    		 Placebo: HHCs Baloxavir Marboxil: HHCs
    Number of subjects analysed
    1098
    1118
    Units: percentage of HHCs
        number (confidence interval 95.38%)
    7.61 (5.66 to 10.17)
    5.80 (4.10 to 8.15)
    Statistical analysis title
    		 Baloxavir Marboxil vs Placebo
    Statistical analysis description
    The OR shown represents the odds of BMX versus the odds of Placebo.
    Comparison groups
    Placebo: HHCs v Baloxavir Marboxil: HHCs
    Number of subjects included in analysis
    2216
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.155
    Method
    		 GEE model
    Parameter type
    		 Adjusted OR (BMX vs Placebo)
    Point estimate
    0.75
    Confidence interval
         level
    		 95.38%
         sides
    2-sided
         lower limit
    		 0.5
         upper limit
    		 1.12

    Secondary: Percentage of Households (HHs) With Virological Influenza Transmission at Household Level by Day 5

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    End point title
    		 Percentage of Households (HHs) With Virological Influenza Transmission at Household Level by Day 5
    End point description
    Percentage of households with at least one HHC who met the primary endpoint of virological transmission by Day 5 are reported. Primary Households Analysis Set (PAS-HH) included all households of randomized IPs that were PCR+ at screening and with at least one HHC enrolled for the full study. The IPs should be a part of the Primary Index Patients Analysis Set (PAS-IP) which includes all randomized IPs with at least one HHC in the PAS-HC. PAS-HC included unvaccinated HHCs who were linked to households where the IP was baseline PCR+ for influenza A or B, received the study drug, and where all contacts were PCR negative at baseline.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1) to Day 5
    End point values
    		 Placebo: Household Baloxavir Marboxil: Household
    Number of subjects analysed
    544 [3]
    548 [4]
    Units: percentage of HHs
        number (not applicable)
    19.5
    15.5
    Notes
    [3] - Number analyzed represents the number of households analyzed for this endpoint.
    [4] - Number analyzed represents the number of households analyzed for this endpoint.
    Statistical analysis title
    		 Baloxavir Marboxil vs Placebo
    Statistical analysis description
    The OR shown represents the odds of BMX versus the odds of Placebo.
    Comparison groups
    Placebo: Household v Baloxavir Marboxil: Household
    Number of subjects included in analysis
    1092
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Odds Ratio (BMX vs Placebo)
    Point estimate
    0.76
    Confidence interval
         level
    		 95.38%
         sides
    2-sided
         lower limit
    		 0.55
         upper limit
    		 1.06

    Secondary: Percentage of Households With Symptomatic Influenza Transmission at Household Level by Day 5

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    End point title
    		 Percentage of Households With Symptomatic Influenza Transmission at Household Level by Day 5
    End point description
    Percentage of households with at least one HHC who meets the symptomatic transmission by Day 5 endpoint are reported. PAS-HH included all households of randomized IPs that were PCR+ at screening and with at least one HHC enrolled for the full study. The IPs should be a part of the PAS-IP which includes all randomized IPs with at least one HHC in the PAS-HC. PAS-HC included unvaccinated HHCs who were linked to households where the IP was baseline PCR+ for influenza A or B, received the study drug, and where all contacts were PCR negative at baseline.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1) to Day 5
    End point values
    		 Placebo: Household Baloxavir Marboxil: Household
    Number of subjects analysed
    544 [5]
    548 [6]
    Units: percentage of HHs
        number (not applicable)
    11.9
    8.6
    Notes
    [5] - Number analyzed represents the number of households analyzed for this endpoint.
    [6] - Number analyzed represents the number of households analyzed for this endpoint.
    Statistical analysis title
    		 Baloxavir Marboxil vs Placebo
    Statistical analysis description
    The OR shown represents the odds of BMX versus the odds of Placebo.
    Comparison groups
    Placebo: Household v Baloxavir Marboxil: Household
    Number of subjects included in analysis
    1092
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Odds Ratio (BMX vs Placebo)
    Point estimate
    0.69
    Confidence interval
         level
    		 95.38%
         sides
    2-sided
         lower limit
    		 0.46
         upper limit
    		 1.04

    Secondary: Percentage of HHCs With Virological Influenza Transmission by Day 9

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    End point title
    		 Percentage of HHCs With Virological Influenza Transmission by Day 9 [7]
    End point description
    Virological transmission was determined based on PCR+ influenza test results. Data are reported for percentage of HHCs who tested PCR+ for influenza by Day 9 post IP randomization with virus subtype matching with the respective IP, irrespective of being symptomatic/asymptomatic including: 1. all HHC meeting primary endpoint, AND 2. all HHC cases detected after Day 5 meeting following criteria: 2a. included HHC case was in an HH where another HHC had already met the primary endpoint OR 2b. included HHC case was PCR+ bearing an amino acid substitution of isoleucine for another amino acid at position 38 (I38X) in the polymerase acidic (PA) protein (PA/I38X substitution) or amino acid substitution of threonine to lysine at position 20 in the PA protein for influenza B only (PA/T20K), indicating transmission of virus with reduced susceptibility. PAS-HC analysis set used for this endpoint. Overall number analyzed=number of HHCs with data available for analysis.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1) to Day 9
    Notes
    [7] - 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: This endpoint was planned to only evaluate the HHCs associated with the IPs.
    End point values
    		 Placebo: HHCs Baloxavir Marboxil: HHCs
    Number of subjects analysed
    1038
    1081
    Units: percentage of HHCs
        number (confidence interval 95.38%)
    15.40 (12.20 to 19.27)
    10.77 (8.41 to 13.71)
    Statistical analysis title
    		 Baloxavir Marboxil vs Placebo
    Statistical analysis description
    The OR shown represents the odds of BMX versus the odds of Placebo.
    Comparison groups
    Placebo: HHCs v Baloxavir Marboxil: HHCs
    Number of subjects included in analysis
    2119
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Adjusted OR (BMX vs Placebo)
    Point estimate
    0.66
    Confidence interval
         level
    		 95.38%
         sides
    2-sided
         lower limit
    		 0.48
         upper limit
    		 0.91

    Secondary: Percentage of HHCs With Symptomatic Influenza Transmission by Day 9

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    End point title
    		 Percentage of HHCs With Symptomatic Influenza Transmission by Day 9 [8]
    End point description
    Data are reported for the percentage of HHCs who met the virological transmission by Day 9 endpoint and developed symptoms at any time during the study. HHCs ≥12 years were symptomatic if they had 1. temperature ≥38.0°C & one respiratory symptom or 2. one respiratory and one systemic symptom, with/without fever. HHCs ≥2 & <12 years were symptomatic if with a temperature ≥38.0°C and upper respiratory symptoms. Symptoms must be either new, or have worsened versus baseline in HHC with baseline symptoms due to a preexisting comorbidity. PAS-HC included unvaccinated HHCs who were linked to households where IP was baseline PCR+ for influenza A or B, received study drug, and where all contacts were PCR negative at baseline. Overall number analyzed is the number of participants with data available for analysis.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1) to Day 9
    Notes
    [8] - 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: This endpoint was planned to only evaluate the HHCs associated with the IPs.
    End point values
    		 Placebo: HHCs Baloxavir Marboxil: HHCs
    Number of subjects analysed
    1037
    1079
    Units: percentage of HHCs
        number (confidence interval 95.38%)
    8.26 (6.10 to 11.09)
    6.15 (4.37 to 8.58)
    Statistical analysis title
    		 Baloxavir Marboxil vs Placebo
    Statistical analysis description
    The OR shown represents the odds of BMX versus the odds of Placebo.
    Comparison groups
    Placebo: HHCs v Baloxavir Marboxil: HHCs
    Number of subjects included in analysis
    2116
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Adjusted OR (BMX vs Placebo)
    Point estimate
    0.73
    Confidence interval
         level
    		 95.38%
         sides
    2-sided
         lower limit
    		 0.48
         upper limit
    		 1.09

    Secondary: Percentage of Households With Any Virological Infection at Household Level by Day 9

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    End point title
    		 Percentage of Households With Any Virological Infection at Household Level by Day 9
    End point description
    Virological infection at HH level were defined as the HHs with at least one HHC who met the endpoint of any virological infection by Day 9. PAS-HH included all households of randomized IPs that were PCR+ at screening and with at least one HHC enrolled for the full study. The IPs should be a part of the PAS-IP which includes all randomized IPs with at least one HHC in the PAS-HC. PAS-HC included unvaccinated HHCs who were linked to households where the IP was baseline PCR+ for influenza A or B, received the study drug, and where all contacts were PCR negative at baseline.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1) to Day 9
    End point values
    		 Placebo: Household Baloxavir Marboxil: Household
    Number of subjects analysed
    544 [9]
    548 [10]
    Units: percentage of HHs
        number (not applicable)
    24.3
    20.1
    Notes
    [9] - Number analyzed represents the number of households analyzed for this endpoint.
    [10] - Number analyzed represents the number of households analyzed for this endpoint.
    Statistical analysis title
    		 Baloxavir Marboxil vs Placebo
    Statistical analysis description
    The OR shown represents the odds of BMX versus the odds of Placebo.
    Comparison groups
    Placebo: Household v Baloxavir Marboxil: Household
    Number of subjects included in analysis
    1092
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Odds Ratio (BMX vs Placebo)
    Point estimate
    0.79
    Confidence interval
         level
    		 95.38%
         sides
    2-sided
         lower limit
    		 0.59
         upper limit
    		 1.06

    Secondary: Percentage of HHCs With Any Virological Infection by Day 9

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    End point title
    		 Percentage of HHCs With Any Virological Infection by Day 9 [11]
    End point description
    Virological infection was defined as HHCs who tested PCR+ for influenza by Day 9 post IP randomization based on PCR influenza test results. PAS-HC included unvaccinated HHCs who were linked to households where the IP was baseline PCR+ for influenza A or B and received study drug and where all contacts were PCR negative at baseline. Overall number analyzed is the number of participants with data available for analysis.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1) to Day 9
    Notes
    [11] - 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: This endpoint was planned to only evaluate the HHCs associated with the IPs.
    End point values
    		 Placebo: HHCs Baloxavir Marboxil: HHCs
    Number of subjects analysed
    1040
    1071
    Units: percentage of HHCs
        number (confidence interval 95.38%)
    18.68 (15.36 to 22.53)
    13.98 (11.31 to 17.16)
    Statistical analysis title
    		 Baloxavir Marboxil vs Placebo
    Statistical analysis description
    The OR shown represents the odds of BMX versus the odds of Placebo.
    Comparison groups
    Placebo: HHCs v Baloxavir Marboxil: HHCs
    Number of subjects included in analysis
    2111
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Adjusted OR (BMX vs Placebo)
    Point estimate
    0.71
    Confidence interval
         level
    		 95.38%
         sides
    2-sided
         lower limit
    		 0.53
         upper limit
    		 0.94

    Secondary: Percentage of HHCs With Any Symptomatic Infection by Day 9

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    End point title
    		 Percentage of HHCs With Any Symptomatic Infection by Day 9 [12]
    End point description
    Percentage of HHCs who tested PCR+ for influenza by Day 9 post IP randomization and develop symptoms at any time during the study are reported. HHCs ≥12 years were symptomatic if they had (1) a temperature ≥38.0°C and one respiratory symptom (cough, sore throat, nasal congestion) or (2) one respiratory & one systemic symptom (headache, chills, muscle/joint pain, fatigue), with/without fever. HHCs ≥2 and <12 years were symptomatic with a temperature ≥38.0°C and upper respiratory symptoms (cough, nasal congestion, rhinorrhea). Symptoms must be either new, or have worsened versus baseline in HHC with baseline symptoms due to a preexisting comorbidity. PAS-HC included unvaccinated HHCs who were linked to households where the IP was baseline PCR+ for influenza A or B and received study drug and where all contacts were PCR negative at baseline. Overall number analyzed is the number of participants with data available for analysis.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1) to Day 9
    Notes
    [12] - 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: This endpoint was planned to only evaluate the HHCs associated with the IPs.
    End point values
    		 Placebo: HHCs Baloxavir Marboxil: HHCs
    Number of subjects analysed
    1039
    1069
    Units: percentage of HHCs
        number (confidence interval 95.38%)
    8.71 (6.49 to 11.60)
    6.43 (4.61 to 8.91)
    Statistical analysis title
    		 Baloxavir Marboxil vs Placebo
    Statistical analysis description
    The OR shown represents the odds of BMX versus the odds of Placebo.
    Comparison groups
    Placebo: HHCs v Baloxavir Marboxil: HHCs
    Number of subjects included in analysis
    2108
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Adjusted OR (BMX vs Placebo)
    Point estimate
    0.72
    Confidence interval
         level
    		 95.38%
         sides
    2-sided
         lower limit
    		 0.49
         upper limit
    		 1.07

    Secondary: Percentage of Households With Any Symptomatic Infection at HH Level by Day 9

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    End point title
    		 Percentage of Households With Any Symptomatic Infection at HH Level by Day 9
    End point description
    Percentage of HHs with at least one HHC who meets the endpoint of any symptomatic infection by Day 9 are reported. HHCs ≥12 years were symptomatic if they had (1) a temperature ≥38.0°C and one respiratory symptom (cough, sore throat, nasal congestion) or (2) one respiratory & one systemic symptom (headache, chills, muscle/joint pain, fatigue), with/without fever. HHCs ≥2 & <12 years were symptomatic with a temperature ≥38.0°C &upper respiratory symptoms (cough, nasal congestion, rhinorrhea). PAS-HH included all households of randomized IPs that were PCR+ at screening and with at least one HHC enrolled for the full study. The IPs should be a part of the PAS-IP which includes all randomized IPs with at least one HHC in the PAS-HC. PAS-HC included unvaccinated HHCs who were linked to households where the IP was baseline PCR+ for influenza A or B, received the study drug, and where all contacts were PCR negative at baseline.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1) to Day 9
    End point values
    		 Placebo: Household Baloxavir Marboxil: Household
    Number of subjects analysed
    544 [13]
    548 [14]
    Units: percentage of HHs
        number (not applicable)
    12.9
    9.5
    Notes
    [13] - Number analyzed represents the number of households analyzed for this endpoint.
    [14] - Number analyzed represents the number of households analyzed for this endpoint.
    Statistical analysis title
    		 Placebo vs Baloxavir Marboxil
    Statistical analysis description
    The OR shown represents the odds of BMX versus the odds of Placebo.
    Comparison groups
    Placebo: Household v Baloxavir Marboxil: Household
    Number of subjects included in analysis
    1092
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Odds Ratio (BMX vs Placebo)
    Point estimate
    0.71
    Confidence interval
         level
    		 95.38%
         sides
    2-sided
         lower limit
    		 0.48
         upper limit
    		 1.04

    Secondary: Number of IPs With Adverse Events (AEs)

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    End point title
    		 Number of IPs With Adverse Events (AEs) [15]
    End point description
    An AE is any untoward medical occurrence in a participant administered a pharmaceutical product and regardless of 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. Safety IP Set included all randomized participants who received at least one dose of study treatment.
    End point type
    Secondary
    End point timeframe
    Baseline up to Day 9 (for IPs ≥12 years old) and Day 21 (for IPs <12 years old)
    Notes
    [15] - 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: Safety data was collected only for the IPs enrolled in the study.
    End point values
    		 Placebo: IPs Baloxavir Marboxil: IPs
    Number of subjects analysed
    726
    723
    Units: participants
    51
    33
    No statistical analyses for this end point

    Secondary: Number of IPs With Serious Adverse Events (SAEs)

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    End point title
    		 Number of IPs With Serious Adverse Events (SAEs) [16]
    End point description
    A 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 or incapacity, is a congenital anomaly or birth defect, is medically significant or requires intervention to prevent one or other of the outcomes listed above. Safety IP Set included all randomized participants who received at least one dose of study treatment.
    End point type
    Secondary
    End point timeframe
    Baseline up to Day 9 (for IPs ≥12 years old) and Day 21 (for IPs <12 years old)
    Notes
    [16] - 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: Safety data was collected only for the IPs enrolled in the study.
    End point values
    		 Placebo: IPs Baloxavir Marboxil: IPs
    Number of subjects analysed
    726
    723
    Units: participants
    2
    1
    No statistical analyses for this end point

    Adverse events

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    Adverse events information [1]
    Timeframe for reporting adverse events
    Baseline up to Day 9 (IPs ≥12 years old) Baseline up to Day 21 (IPs <12 years old)
    Adverse event reporting additional description
    Safety IP Set included all randomized participants who received at least one dose of study treatment. Safety data was collected only for IPs as no treatment was administered to the HHCs in this study.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    27.0
    Reporting groups
    Reporting group title
    Placebo: IPs
    Reporting group description
    		 IPs were randomized in this arm to receive a single dose of matching placebo orally as a tablet or oral suspension based on their weight and age.

    Reporting group title
    Baloxavir Marboxil: IPs
    Reporting group description
    		 IPs received a single dose of baloxavir marboxil orally based on their weight and age.

    Notes
    [1] - There are no non-serious adverse events recorded for these results. It is expected that there will be at least one non-serious adverse event reported.
    Justification: There were no Non-serious adverse events at a 5% threshold in this study.
    Serious adverse events
    		 Placebo: IPs Baloxavir Marboxil: IPs
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 726 (0.28%)
    1 / 723 (0.14%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Pregnancy, puerperium and perinatal conditions
    Abortion spontaneous
         subjects affected / exposed
    0 / 726 (0.00%)
    1 / 723 (0.14%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    1 / 726 (0.14%)
    0 / 723 (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
    1 / 726 (0.14%)
    0 / 723 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hyponatraemia
         subjects affected / exposed
    1 / 726 (0.14%)
    0 / 723 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Placebo: IPs Baloxavir Marboxil: IPs
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    0 / 726 (0.00%)
    0 / 723 (0.00%)

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    11 Jun 2019
    Protocol amended primarily to update safety information.
    10 Aug 2020
    Protocol amended primarily to expand the pediatric IP population to include IPs 5 to 11 years old, to add SARS-CoV-2 testing at screening and during the study as applicable, and to exclude and/or withdraw IPs and households who test positive for SARS-CoV-2 during the study.
    29 Mar 2022
    Protocol amended to reduce the requirement from 2 or more HHCs to 1 or more HHCs to participate in the entire duration of the study and who had not received the influenza vaccine within 6 months prior to screening. In addition, IPs who are <12 years old who had received the oral suspension were asked to answer a questionnaire regarding the palatability and acceptability of the study drug.

    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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