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    Clinical Trial Results:
    A Phase 3 Open-label, Multicenter Study of the Safety, Efficacy, and Pharmacokinetics of Intravenous Recombinant Coagulation Factor VIII Fc-von Willebrand Factor-XTEN Fusion Protein (rFVIIIFc-VWF-XTEN; BIVV001) in Previously Treated Pediatric Patients <12 Years of Age With Severe Hemophilia A

    Summary
    EudraCT number
    		 2020-000769-18
    Trial protocol
    		 DE   FR   IE   GB   BE   SE   HU   NL   IT   Outside EU/EEA  
    Global end of trial date
    18 Jan 2023

    Results information
    Results version number
    		 v2(current)
    This version publication date
    19 Apr 2024
    First version publication date
    30 Jul 2023
    Other versions
    		 v1
    Version creation reason

    Trial information

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    Trial identification
    Sponsor protocol code
    EFC16295
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT04759131
    WHO universal trial number (UTN)
    		 U1111-1244-0558
    Other trial identifiers
    		 IND: 017464
    Sponsors
    Sponsor organisation name
    Bioverativ, a Sanofi Company
    Sponsor organisation address
    225 Second Avenue, Waltham, Massachusetts, United States, 02451
    Public contact
    Trial Transparency Team, Sanofi aventis recherche & développement, Contact-US@sanofi.com
    Scientific contact
    Trial Transparency Team, Sanofi aventis recherche & développement, Contact-US@sanofi.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    		 EMEA-002501-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?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    08 Feb 2023
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    18 Jan 2023
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    - To evaluate the safety of BIVV001 in previously treated pediatric subjects with hemophilia A.
    Protection of trial subjects
    The study was conducted by investigators experienced in the treatment of paediatric patients. The parent(s) or guardian(s) as well as the children were fully informed of all pertinent aspects of the clinical trial as well as the possibility to discontinue at any time. In addition to the consent form for the parent(s)/guardian(s), an assent form in child-appropriate language was provided and explained to the child. Repeated invasive procedures were minimised. The number of blood samples as well as the amount of blood drawn were adjusted according to age and weight. A topical anesthesia may have been used to minimise distress and discomfort.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    19 Feb 2021
    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
    Sweden: 1
    Country: Number of subjects enrolled
    United Kingdom: 2
    Country: Number of subjects enrolled
    France: 6
    Country: Number of subjects enrolled
    Germany: 2
    Country: Number of subjects enrolled
    Hungary: 1
    Country: Number of subjects enrolled
    Netherlands: 3
    Country: Number of subjects enrolled
    Ireland: 2
    Country: Number of subjects enrolled
    Italy: 2
    Country: Number of subjects enrolled
    Canada: 9
    Country: Number of subjects enrolled
    Australia: 4
    Country: Number of subjects enrolled
    Taiwan: 7
    Country: Number of subjects enrolled
    United States: 19
    Country: Number of subjects enrolled
    Spain: 5
    Country: Number of subjects enrolled
    Türkiye: 8
    Country: Number of subjects enrolled
    Switzerland: 3
    Worldwide total number of subjects
    74
    EEA total number of subjects
    22
    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)
    2
    Children (2-11 years)
    72
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    0
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Study was conducted at 40 active sites in 15 countries. A total of 79 pediatric subjects were screened between 19 February 2021 to 09 February 2022, of which 5 subjects had screen failure due to not meeting the eligibility criteria.

    Pre-assignment
    Screening details
    		 The study comprised of 2 age cohorts of children with severe hemophilia A: less than (<) 6 years and 6 to <12 years. A total of 74 subjects were enrolled in this study.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 BIVV001: Subjects aged <6 Years
    Arm description
    		 Subjects aged <6 years received BIVV001 at a dose of 50 international units per kilogram (IU/kg) intravenous (IV) injection once-weekly (QW) prophylaxis for 52 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Efanesoctocog alfa
    Investigational medicinal product code
    BIVV001
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    BIVV001 50 IU/kg, IV injection QW for up to 52 weeks.

    Arm title
    		 BIVV001: Subjects aged 6 to <12 Years
    Arm description
    		 Subjects aged 6 to <12 years received BIVV001 at a dose of 50 IU/kg IV injection QW prophylaxis for 52 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Efanesoctocog alfa
    Investigational medicinal product code
    BIVV001
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    BIVV001 50 IU/kg, IV injection QW for up to 52 weeks.

    Number of subjects in period 1
    		BIVV001: Subjects aged <6 Years BIVV001: Subjects aged 6 to <12 Years
    Started
    38
    36
    Completed
    36
    36
    Not completed
    2
    0
         Investigator’s discretion
    1
    -
         Subject withdrawal
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    BIVV001: Subjects aged <6 Years
    Reporting group description
    		 Subjects aged <6 years received BIVV001 at a dose of 50 international units per kilogram (IU/kg) intravenous (IV) injection once-weekly (QW) prophylaxis for 52 weeks.

    Reporting group title
    BIVV001: Subjects aged 6 to <12 Years
    Reporting group description
    		 Subjects aged 6 to <12 years received BIVV001 at a dose of 50 IU/kg IV injection QW prophylaxis for 52 weeks.

    Reporting group values
    		 BIVV001: Subjects aged <6 Years BIVV001: Subjects aged 6 to <12 Years Total
    Number of subjects
    		 38 36 74
    Age categorical
    Baseline characteristics analysis was performed on full analysis set (FAS) which included all subjects who took at least 1 dose of study intervention.
    Units: Subjects
        Children (1 to 5 years)
    		 38 0 38
        Children (>=6 to 11 years))
    		 0 36 36
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 3.69 ± 1.21 8.42 ± 2.08 -
    Gender categorical
    Units: Subjects
        Female
    		 0 0 0
        Male
    		 38 36 74
    Race
    Units: Subjects
        White
    		 30 25 55
        Black or African American
    		 1 2 3
        Asian
    		 4 4 8
        Other or Not Reported
    		 3 5 8

    End points

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    End points reporting groups
    Reporting group title
    BIVV001: Subjects aged <6 Years
    Reporting group description
    		 Subjects aged <6 years received BIVV001 at a dose of 50 international units per kilogram (IU/kg) intravenous (IV) injection once-weekly (QW) prophylaxis for 52 weeks.

    Reporting group title
    BIVV001: Subjects aged 6 to <12 Years
    Reporting group description
    		 Subjects aged 6 to <12 years received BIVV001 at a dose of 50 IU/kg IV injection QW prophylaxis for 52 weeks.

    Subject analysis set title
    Subjects With Major Surgery
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subjects from any arm (BIVV001: subjects aged <6 Years or BIVV001: subjects aged 6 to <12 Years) who had at least 6 days of exposure to BIVV001 and a negative inhibitor test within 4 weeks prior to surgery and underwent major surgery (defined as any invasive operative procedure that required any of the following: opening into a major body cavity [e.g., abdomen, thorax, skull]; operation on a joint; removal of an organ; dental extraction of any molar teeth or greater than or equal to (>=) 3 non-molar teeth; operative alteration of normal anatomy; crossing of a mesenchymal barrier [e.g., pleura, peritoneum, dura]) after the first dose of study drug during the study.

    Subject analysis set title
    BIVV001 (Efanesoctocog Alfa)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    All subjects who were enrolled in study and received BIVV001 in either Arm 'BIVV001: subjects aged <6 years' or 'BIVV001: subjects aged 6 to <12 years'.

    Primary: Number of Subjects With Neutralising Antibodies (Development of Inhibitors) Directed Against Factor VIII

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    End point title
    		 Number of Subjects With Neutralising Antibodies (Development of Inhibitors) Directed Against Factor VIII [1]
    End point description
    Inhibitor development was defined as an inhibitor result of greater than or equal to (>=0.6) Bethesda units (BU/mL) that was confirmed by a second test result from a separate sample, drawn 2 to 4 weeks following the date when the original sample was drawn. Both tests must have been performed by the central laboratory using the Nijmegen modified Bethesda assay. Analysis was performed on safety analysis set which included all subjects who took at least 1 dose of study intervention.
    End point type
    Primary
    End point timeframe
    Baseline up to Week 52
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: As the endpoint was descriptive in nature, no statistical analysis was provided.
    End point values
    		 BIVV001: Subjects aged <6 Years BIVV001: Subjects aged 6 to <12 Years
    Number of subjects analysed
    38
    36
    Units: subjects
    0
    0
    No statistical analyses for this end point

    Secondary: Annualised Bleeding Rate (ABR): For Treated Bleeds

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    End point title
    		 Annualised Bleeding Rate (ABR): For Treated Bleeds
    End point description
    ABR: annualised number of treated bleeding episodes (BE) per subject per year. ABR=number of treated BE during efficacy period (EP)/total number of days during EP*365.25. Treated BE: any occurrence of hemorrhage required administration of BIVV001. It started from 1st sign of bleed and ended no more than 72 hours after last injection to treat BE, any subsequent bleeding at same location/injections administered less than or equal to (<=) 72 hours apart from previous injection were considered same BE. Any injection after >72 hours post preceding one=considered 1st injection to treat new BE in same location. Any bleed at different location: considered as separate BE, regardless of time from last injection. EP=sum of all intervals of time during which subjects were treated with BIVV001 according to study arms and treatment regimens. ABR: by negative binomial model with total number of treated BE during EP as response variable and log-transformed EP duration (years) as offset variable. FAS.
    End point type
    Secondary
    End point timeframe
    Baseline up to Week 52
    End point values
    		 BIVV001: Subjects aged <6 Years BIVV001: Subjects aged 6 to <12 Years
    Number of subjects analysed
    38
    36
    Units: episodes per subject per year
        arithmetic mean (confidence interval 95%)
    0.48 (0.30 to 0.77)
    1.33 (0.64 to 2.76)
    No statistical analyses for this end point

    Secondary: Sensitivity Analysis: Annualised Bleeding Rate: For Treated Bleeds

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    End point title
    		 Sensitivity Analysis: Annualised Bleeding Rate: For Treated Bleeds
    End point description
    ABR: annualised number of treated BE per subject per year. ABR = number of treated BE during EP/total number of days during EP*365.25. Treated BE: any occurrence of hemorrhage that required administration of BIVV001. It started from 1st sign of bleed and ended no more than 72 hours after last injection to treat BE, any subsequent bleeding at same location/injections administered <=72 hours apart from previous injection were considered same BE. Any injection to treat bleed, taken >72 hours after preceding one, was considered 1st injection to treat new bleeding episode in same location. Any bleed at different location: considered as separate BE, regardless of time from last injection. EP reflects sum of all intervals of time during which subjects were treated with BIVV001 according to study arms and treatment regimens. ABR: using NB model with total number of treated BE during EP as response variable and log-transformed EP duration (years) as offset variable. FAS population.
    End point type
    Secondary
    End point timeframe
    Baseline up to Week 52
    End point values
    		 BIVV001: Subjects aged <6 Years BIVV001: Subjects aged 6 to <12 Years
    Number of subjects analysed
    38
    35 [2]
    Units: episodes per subject per year
        arithmetic mean (confidence interval 95%)
    0.48 (0.30 to 0.77)
    0.75 (0.41 to 1.40)
    Notes
    [2] - Excluded 1 subject who did not receive weekly prophylaxis treatment for an extended period of time.
    No statistical analyses for this end point

    Secondary: Sensitivity Analysis: Annualised Bleeding Rate for All Bleeding Episodes

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    End point title
    		 Sensitivity Analysis: Annualised Bleeding Rate for All Bleeding Episodes
    End point description
    ABR: annualised number of all BE (treated & untreated)/subject/year. ABR=number of all BE during EP/total number of days during EP*365.25. BE: any hemorrhage occurrence required administration of BIVV001. It started from 1st sign of bleed & ended no more than 72 hours after last injection to treat BE, any subsequent bleeding at same location/injections administered <=72 hours apart from previous injection were considered same BE. Any bleed at different location: considered as separate BE, regardless of time from last injection. EP: sum of all intervals of time during which subjects treated with BIVV001 according to study arms and treatment regimens. ABR: estimated by NB model with total number of treated BE during EP as response variable and log-transformed EP duration (years) as offset variable. Spontaneous: bleeding without contributing factor (definite trauma/antecedent strenuous activity). Traumatic: bleeding with known/believed reason. FAS population.
    End point type
    Secondary
    End point timeframe
    Baseline up to Week 52
    End point values
    		 BIVV001: Subjects aged <6 Years BIVV001: Subjects aged 6 to <12 Years
    Number of subjects analysed
    38
    35 [3]
    Units: episodes per subject per year
        arithmetic mean (confidence interval 95%)
    2.78 (1.39 to 5.58)
    2.32 (1.30 to 4.13)
    Notes
    [3] - Excluded 1 subject who did not receive weekly prophylaxis treatment for an extended period of time.
    No statistical analyses for this end point

    Secondary: Annualised Bleeding Rate for All Bleeding Episodes

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    End point title
    		 Annualised Bleeding Rate for All Bleeding Episodes
    End point description
    ABR:annualised number of all BE (treated and untreated)/subject/year. ABR=number of all BE during EP/total number of days during EP*365.25. BE:any occurrence of hemorrhage required administration of BIVV001. It started from 1st sign of bleed and ended no more than 72 hours after last injection to treat BE, any subsequent bleeding at same location/injections administered <=72 hours apart from previous injection were considered same BE. Any injection after >72 hours post preceding one=considered 1st injection to treat new BE in same location. Any bleed at different location: considered as separate BE, regardless of time from last injection. EP:sum of all intervals of time during which subjects treated with BIVV001 according to study arms & treatment regimens. ABR:NB model with total number of treated BE during EP as response variable and log-transformed EP duration (years) as offset variable. Spontaneous:bleeding without contributing factor, Traumatic:bleeding with known reason. FAS.
    End point type
    Secondary
    End point timeframe
    Baseline up to Week 52
    End point values
    		 BIVV001: Subjects aged <6 Years BIVV001: Subjects aged 6 to <12 Years
    Number of subjects analysed
    38
    36
    Units: episodes per subject per year
        arithmetic mean (confidence interval 95%)
    2.78 (1.39 to 5.58)
    2.85 (1.59 to 5.12)
    No statistical analyses for this end point

    Secondary: Annualised Bleeding Rate by Type of Bleed (Spontaneous, Traumatic and Unknown Type)

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    End point title
    		 Annualised Bleeding Rate by Type of Bleed (Spontaneous, Traumatic and Unknown Type)
    End point description
    ABR: annualised number of treated bleeding episodes per subject per year. ABR = number of all BE during EP/total number of days during EP*365.25. EP reflects sum of all intervals of time during which subjects were treated with BIVV001 according to study arms and treatment regimens. Treated BE: episode that started from 1st sign of bleed and ended no more than 72 hours after last injection to treat bleeding episode, any subsequent bleeding at same location/injections administered <=72 hours apart from previous injection were considered same bleeding episode. Any injection to treat bleed, taken >72 hours after preceding one was considered 1st injection to treat new BE in same location. Any bleed at different location was considered as separate bleeding episode, regardless of time from last injection. Spontaneous bleeding: BE without contributing factor (definite trauma/antecedent "strenuous" activity). Traumatic bleeding: BE with known/believed reason for bleed. Analysed on FAS.
    End point type
    Secondary
    End point timeframe
    Baseline up to Week 52
    End point values
    		 BIVV001: Subjects aged <6 Years BIVV001: Subjects aged 6 to <12 Years
    Number of subjects analysed
    38
    36
    Units: episodes per subject per year
    arithmetic mean (confidence interval 95%)
        Spontaneous
    0.17 (0.08 to 0.38)
    0.14 (0.04 to 0.53)
        Traumatic
    0.28 (0.14 to 0.55)
    0.59 (0.31 to 1.14)
        Unknown type
    0.03 (0.00 to 0.20)
    0.59 (0.12 to 3.02)
    No statistical analyses for this end point

    Secondary: Sensitivity Analysis: Annualised Bleeding Rate by Type of Bleed (Spontaneous, Traumatic and Unknown Type)

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    End point title
    		 Sensitivity Analysis: Annualised Bleeding Rate by Type of Bleed (Spontaneous, Traumatic and Unknown Type)
    End point description
    ABR: annualised number of treated bleeding episodes per subject per year. ABR = number of all BE during EP/total number of days during EP*365.25. EP reflects sum of all intervals of time during which subjects were treated with BIVV001 according to study arms and treatment regimens. Treated BE: episode that started from 1st sign of bleed and ended no more than 72 hours after last injection to treat bleeding episode, any subsequent bleeding at same location/injections administered <=72 hours apart from previous injection were considered same bleeding episode. Any injection to treat bleed, taken >72 hours after preceding one, was considered 1st injection to treat new BE in same location. Any bleed at different location was considered as separate bleeding episode, regardless of time from last injection. Spontaneous bleeding: BE without contributing factor (definite trauma/antecedent "strenuous" activity). Traumatic bleeding: BE with known/believed reason for bleed. Analysed on FAS.
    End point type
    Secondary
    End point timeframe
    Baseline up to Week 52
    End point values
    		 BIVV001: Subjects aged <6 Years BIVV001: Subjects aged 6 to <12 Years
    Number of subjects analysed
    38
    35 [4]
    Units: episodes per subject per year
    arithmetic mean (confidence interval 95%)
        Spontaneous
    0.17 (0.08 to 0.38)
    0.15 (0.04 to 0.55)
        Traumatic
    0.28 (0.14 to 0.55)
    0.52 (0.26 to 1.04)
        Unknown type
    0.03 (0.00 to 0.20)
    0.09 (0.03 to 0.27)
    Notes
    [4] - Excluded 1 subject who did not receive weekly prophylaxis treatment for an extended period of time.
    No statistical analyses for this end point

    Secondary: Annualised Bleeding Rate by Location of Bleed (Joint, Muscle, Internal and Skin/Mucosa)

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    End point title
    		 Annualised Bleeding Rate by Location of Bleed (Joint, Muscle, Internal and Skin/Mucosa)
    End point description
    ABR: annualised number of treated bleeding episodes per subject per year. ABR = number of all BE during EP/total number of days during EP*365.25. Efficacy period reflects sum of all intervals of time during which subjects were treated with BIVV001 according to study arms and treatment regimens. Treated bleeding episode: episode that started from 1st sign of bleed and ended no more than 72 hours after last injection to treat bleeding episode, any subsequent bleeding at same location/injections administered <=72 hours apart from previous injection were considered same bleeding episode. Any injection >72 hours after preceding one, was considered 1st injection to treat new BE in same location. Any bleed at different location was considered as separate bleeding episode, regardless of time from last injection. Spontaneous bleeding: BE without contributing factor (definite trauma/antecedent "strenuous" activity). Traumatic bleeding: BE with known/believed reason for bleed. Analysed on FAS.
    End point type
    Secondary
    End point timeframe
    Baseline up to Week 52
    End point values
    		 BIVV001: Subjects aged <6 Years BIVV001: Subjects aged 6 to <12 Years
    Number of subjects analysed
    38
    36
    Units: episodes per subject per year
    arithmetic mean (standard deviation)
        Joint
    0.19 ± 0.63
    0.99 ± 3.62
        Muscle
    0.03 ± 0.16
    0.17 ± 0.51
        Internal
    0.08 ± 0.28
    0.06 ± 0.35
        Skin/mucosa
    0.16 ± 0.38
    0.25 ± 0.60
    No statistical analyses for this end point

    Secondary: Sensitivity Analysis: Annualised Bleeding Rate by Location of Bleed (Joint, Muscle, Internal and Skin/Mucosa)

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    End point title
    		 Sensitivity Analysis: Annualised Bleeding Rate by Location of Bleed (Joint, Muscle, Internal and Skin/Mucosa)
    End point description
    ABR: annualised number of treated bleeding episodes per subject per year. ABR = number of all BE during EP/total number of days during EP*365.25. EP reflects sum of all intervals of time during which subjects were treated with BIVV001 according to study arms & treatment regimens. Treated BE: episode that started from 1st sign of bleed and ended no more than 72 hours after last injection to treat bleeding episode any subsequent bleeding at same location/injections administered <=72 hours apart from previous injection were considered same bleeding episode. Any injection to treat bleed, taken >72 hours after preceding one, was considered 1st injection to treat new BE in same location. Any bleed at different location was considered as separate bleeding episode, regardless of time from last injection. Spontaneous bleeding: BE without contributing factor (definite trauma/antecedent "strenuous" activity). Traumatic bleeding: BE with known/believed reason for bleed. Analysed on FAS.
    End point type
    Secondary
    End point timeframe
    Baseline up to Week 52
    End point values
    		 BIVV001: Subjects aged <6 Years BIVV001: Subjects aged 6 to <12 Years
    Number of subjects analysed
    38
    35 [5]
    Units: episodes per subject per year
    arithmetic mean (standard deviation)
        Joint
    0.19 ± 0.63
    0.40 ± 0.93
        Muscle
    0.03 ± 0.16
    0.17 ± 0.52
        Internal
    0.08 ± 0.28
    0.06 ± 0.35
        Skin/mucosa
    0.16 ± 0.38
    0.26 ± 0.61
    Notes
    [5] - Excluded 1 subject who did not receive weekly prophylaxis treatment for an extended period of time.
    No statistical analyses for this end point

    Secondary: Percentage of Subjects Achieving FVIII Activity Levels Above 1%, 3%, 5%, 10%, 15%, and 20%

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    End point title
    		 Percentage of Subjects Achieving FVIII Activity Levels Above 1%, 3%, 5%, 10%, 15%, and 20%
    End point description
    FVIII activity level was measured using activated partial thromboplastin time (aPTT)-based one stage clotting assay. Percentage of subjects who achieved steady-state trough FVIII activity levels above (>) 1%, 3%, 5%, 10%, 15%, and 20% were reported in this endpoint. Subjects were counted in more than one category, as applicable. Analysis was performed on full analysis set (FAS) which included all subjects who took at least 1 dose of study intervention. Here, 'number of subjects analysed = subjects with available data for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline up to Week 52
    End point values
    		 BIVV001: Subjects aged <6 Years BIVV001: Subjects aged 6 to <12 Years
    Number of subjects analysed
    32
    29
    Units: percentage of subjects
    number (not applicable)
        >1%
    100
    100
        >3%
    100
    100
        >5%
    75.0
    100
        >10%
    18.8
    51.7
        >15%
    9.4
    6.9
        >20%
    3.1
    6.9
    No statistical analyses for this end point

    Secondary: Sensitivity Analysis: Number of Injections of BIVV001 Required to Treat a Bleeding Episode

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    End point title
    		 Sensitivity Analysis: Number of Injections of BIVV001 Required to Treat a Bleeding Episode
    End point description
    A bleeding episode was defined as an episode that started from 1st sign of bleed and ended no more than 72 hours after last injection to treat bleeding episode, any subsequent bleeding at same location or injections administered <=72 hours apart from previous injection were considered same bleeding episode. Any injection to treat bleed, taken >72 hours after preceding one, was considered 1st injection to treat new BE in same location. Any bleed at different location: considered as separate BE, regardless of time from last injection. Analysis was performed on FAS excluding 1 subject who did not receive weekly prophylaxis treatment for an extended period of time.
    End point type
    Secondary
    End point timeframe
    Baseline up to Week 52
    End point values
    		 BIVV001: Subjects aged <6 Years BIVV001: Subjects aged 6 to <12 Years
    Number of subjects analysed
    38 [6]
    35 [7]
    Units: injections per bleeding episode
        arithmetic mean (standard deviation)
    1.12 ± 0.33
    1.00 ± 0.00
    Notes
    [6] - 17 = total number of treated bleeding episodes in 'BIVV001: Subjects Aged <6 Years'.
    [7] - 26 = total number of treated bleeding episodes in 'BIVV001: Subjects Aged 6 to <12 Years'.
    No statistical analyses for this end point

    Secondary: Number of Injections of BIVV001 Required to Treat a Bleeding Episode

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    End point title
    		 Number of Injections of BIVV001 Required to Treat a Bleeding Episode
    End point description
    A bleeding episode was defined as an episode that started from 1st sign of bleed and ended no more than 72 hours after last injection to treat bleeding episode, any subsequent bleeding at same location or injections administered <=72 hours apart from previous injection were considered same bleeding episode. Any injection to treat bleed, taken >72 hours after preceding one, was considered 1st injection to treat new BE in same location. Any bleed at different location was considered as separate bleeding episode, regardless of time from last injection. Analysis was performed on FAS.
    End point type
    Secondary
    End point timeframe
    Baseline up to Week 52
    End point values
    		 BIVV001: Subjects aged <6 Years BIVV001: Subjects aged 6 to <12 Years
    Number of subjects analysed
    38 [8]
    36 [9]
    Units: injections per bleeding episode
        arithmetic mean (standard deviation)
    1.12 ± 0.33
    1.30 ± 0.69
    Notes
    [8] - 17 = total number of treated bleeding episodes in 'BIVV001: Subjects Aged <6 Years'.
    [9] - 47 = total number of treated bleeding episodes in 'BIVV001: Subjects Aged 6 to <12 Years'.
    No statistical analyses for this end point

    Secondary: Sensitivity Analysis: Percentage of Bleeding Episodes Treated With a Single Injection of BIVV001

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    End point title
    		 Sensitivity Analysis: Percentage of Bleeding Episodes Treated With a Single Injection of BIVV001
    End point description
    A bleeding episode was defined as an episode that started from 1st sign of bleed and ended no more than 72 hours after last injection to treat bleeding episode, any subsequent bleeding at same location or injections administered <=72 hours apart from previous injection were considered same bleeding episode. Any injection to treat bleed, taken >72 hours after preceding one, was considered 1st injection to treat new BE in same location. Any bleed at different location: considered as separate BE, regardless of time from last injection. Percentage of bleeding episodes (of all bleeding episodes occurred) which were treated with single injection was reported in this endpoint. Analysis was performed on FAS, excluding the subject who did not receive the weekly prophylaxis treatment as per protocol for an extended period of time.
    End point type
    Secondary
    End point timeframe
    Baseline up to Week 52
    End point values
    		 BIVV001: Subjects aged <6 Years BIVV001: Subjects aged 6 to <12 Years
    Number of subjects analysed
    38 [10]
    25 [11]
    Units: percentage of bleeding episodes
        number (not applicable)
    88.2
    100
    Notes
    [10] - 17 = total number of treated bleeding episodes in 'BIVV001: Subjects Aged <6 Years'.
    [11] - 26 = total number of treated bleeding episodes in 'BIVV001: Subjects Aged 6 to <12 Years'.
    No statistical analyses for this end point

    Secondary: Percentage of Bleeding Episodes Treated With a Single Injection of BIVV001

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    End point title
    		 Percentage of Bleeding Episodes Treated With a Single Injection of BIVV001
    End point description
    A bleeding episode was defined as an episode that started from 1st sign of bleed and ended no more than 72 hours after last injection to treat bleeding episode, any subsequent bleeding at same location or injections administered <=72 hours apart from previous injection were considered same bleeding episode. Any injection to treat bleed, taken >72 hours after preceding one, was considered 1st injection to treat new BE in same location. Any bleed at different location: considered as separate BE, regardless of time from last injection. Percentage of bleeding episodes (of all bleeding episodes occurred) which were treated with single injection was reported in this endpoint. Analysis was performed on FAS.
    End point type
    Secondary
    End point timeframe
    Baseline up to Week 52
    End point values
    		 BIVV001: Subjects aged <6 Years BIVV001: Subjects aged 6 to <12 Years
    Number of subjects analysed
    38 [12]
    36 [13]
    Units: percentage of bleeding episodes
        number (not applicable)
    88.2
    78.7
    Notes
    [12] - 17 = total number of treated bleeding episodes in 'BIVV001: Subjects Aged <6 Years'.
    [13] - 47 = total number of treated bleeding episodes in 'BIVV001: Subjects Aged 6 to <12 Years'.
    No statistical analyses for this end point

    Secondary: Physicians' Global Assessment (PGA) of Subject's Response to BIVV001 Treatment Based on a 4-point Response Scale

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    End point title
    		 Physicians' Global Assessment (PGA) of Subject's Response to BIVV001 Treatment Based on a 4-point Response Scale
    End point description
    Physicians assessed subject's response to BIVV001 treatment using 4-point response scale categorised as: Excellent= BE responded to fewer than/usual number of injections/less than/usual dose of FVIII/rate of breakthrough bleeding during prophylaxis was <= that usually observed; Effective = most BE responded to same number of injections and dose, but some required more injections/higher doses/there was minor increase in rate of breakthrough bleeding; partially effective = BE most often required more injections and/or higher doses than expected/adequate breakthrough bleeding prevention during prophylaxis required more frequent injections and/or higher doses; Ineffective = routine failure to control hemostasis or hemostatic control required additional agents. Analysis was performed on FAS. Here, 'number of subjects analysed' = subjects with available data for this endpoint.
    End point type
    Secondary
    End point timeframe
    Week 13 and Week 52/End of study (EOS)/Early termination (ET)
    End point values
    		 BIVV001: Subjects aged <6 Years BIVV001: Subjects aged 6 to <12 Years
    Number of subjects analysed
    37
    36
    Units: subjects
        Week 13: Excellent
    37
    34
        Week 13: Effective
    0
    2
        Week 13: Partially effective
    0
    0
        Week 13: Ineffective
    0
    0
        Week 52/EOS/ET: Excellent
    37
    36
        Week 52/EOS/ET: Effective
    0
    0
        Week 52/EOS/ET: Partially effective
    0
    0
        Week 52/EOS/ET: Ineffective
    0
    0
    No statistical analyses for this end point

    Secondary: Sensitivity Analysis: Total Dose of BIVV001 Required to Treat Bleeding Episode

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    End point title
    		 Sensitivity Analysis: Total Dose of BIVV001 Required to Treat Bleeding Episode
    End point description
    A bleeding episode was defined as an episode that started from 1st sign of bleed and ended no more than 72 hours after last injection to treat bleeding episode, any subsequent bleeding at same location or injections administered <=72 hours apart from previous injection were considered same bleeding episode. Any injection to treat bleed, taken >72 hours after preceding one, was considered 1st injection to treat new BE in same location. Any injection after >72 hours post preceding one, was considered 1st injection to treat new BE in same location. Any bleed at different location: considered as separate BE, regardless of time from last injection. Total dose was expressed in unit: IU/kg. Analysis was performed on FAS, excluding 1 subject who did not receive weekly prophylaxis treatment for an extended period of time.
    End point type
    Secondary
    End point timeframe
    Baseline up to Week 52
    End point values
    		 BIVV001: Subjects aged <6 Years BIVV001: Subjects aged 6 to <12 Years
    Number of subjects analysed
    38 [14]
    35 [15]
    Units: IU/kg
        arithmetic mean (standard deviation)
    52.29 ± 15.84
    50.39 ± 6.71
    Notes
    [14] - 17 = total number of treated bleeding episodes in 'BIVV001: Subjects Aged <6 Years'.
    [15] - 26 = total number of treated bleeding episodes in 'BIVV001: Subjects Aged 6 to <12 Years'.
    No statistical analyses for this end point

    Secondary: Total Dose of BIVV001 Required to Treat Bleeding Episode

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    End point title
    		 Total Dose of BIVV001 Required to Treat Bleeding Episode
    End point description
    A bleeding episode was defined as an episode that started from 1st sign of bleed and ended no more than 72 hours after last injection to treat bleeding episode, any subsequent bleeding at same location or injections administered <=72 hours apart from previous injection were considered same bleeding episode. Any injection to treat bleed, taken >72 hours after preceding one, was considered 1st injection to treat new BE in same location. Any bleed at different location: considered as separate BE, regardless of time from last injection. Total dose was expressed in unit: International units per kilogram (IU/kg). Analysis was performed on FAS.
    End point type
    Secondary
    End point timeframe
    Baseline up to Week 52
    End point values
    		 BIVV001: Subjects aged <6 Years BIVV001: Subjects aged 6 to <12 Years
    Number of subjects analysed
    38 [16]
    36 [17]
    Units: IU/kg
        arithmetic mean (standard deviation)
    52.29 ± 15.84
    66.90 ± 37.01
    Notes
    [16] - 17 = total number of treated bleeding episodes in 'BIVV001: Subjects Aged <6 Years'.
    [17] - 47 = total number of treated bleeding episodes in 'BIVV001: Subjects Aged 6 to <12 Years'.
    No statistical analyses for this end point

    Secondary: Subject's Response to BIVV001 Treatment Based on the International Society on Thrombosis and Haemostasis (ISTH) 4-point Response Scale

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    End point title
    		 Subject's Response to BIVV001 Treatment Based on the International Society on Thrombosis and Haemostasis (ISTH) 4-point Response Scale
    End point description
    Subject's response to 1st injection of BIVV001 treatment for treating bleed was evaluated by ISTH 4-point response scale categorised as: Excellent (complete pain relief [PR]/complete resolution of signs of bleeding [SoB]), Good (significant PR/improvement in SoB), Moderate (modest PR/improvement in SoB) and none (no or minimal improvement/condition worsened). Assessed approximately 72 hours after initial treatment for BE. Bleeding episode: an episode that started from 1st sign of bleed and ended no more than 72 hours after last treatment for bleed, within which any symptoms of bleeding at same location/injections <=72 hours apart were considered same BE. Any injection after >72 hours post preceding one=considered 1st injection to treat new BE in same location. Any bleed at different location: considered as separate BE, regardless of time from last injection. Subjects were counted in more than one category, as applicable. Analysed on FAS.
    End point type
    Secondary
    End point timeframe
    Baseline up to Week 52
    End point values
    		 BIVV001: Subjects aged <6 Years BIVV001: Subjects aged 6 to <12 Years
    Number of subjects analysed
    38 [18]
    36 [19]
    Units: Injections with a response
        Excellent
    14
    22
        Good
    1
    2
        Moderate
    1
    0
        None
    0
    0
    Notes
    [18] - 16 = number of injections with a response.
    [19] - 24 = number of injections with a response.
    No statistical analyses for this end point

    Secondary: Total Annualised BIVV001 Consumption Per Subject

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    End point title
    		 Total Annualised BIVV001 Consumption Per Subject
    End point description
    Total annualised BIVV001 consumption (in IU/kg) was calculated for each subject as: Total IU/kg of BIVV001 during EP divided by total number of days during EP*365.25. EP reflects the sum of all intervals of time during which subjects were treated with BIVV001 according to the study arms and treatment regimens. Analysis was performed on FAS.
    End point type
    Secondary
    End point timeframe
    Baseline up to Week 52
    End point values
    		 BIVV001: Subjects aged <6 Years BIVV001: Subjects aged 6 to <12 Years
    Number of subjects analysed
    38
    36
    Units: IU/kg per subject per year
        arithmetic mean (standard deviation)
    3115.57 ± 488.64
    2884.67 ± 207.88
    No statistical analyses for this end point

    Secondary: Annualised Joint Bleeding Rate (AJBR)

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    End point title
    		 Annualised Joint Bleeding Rate (AJBR)
    End point description
    AJBR: annualised number of joint bleeding/subject/year. ABR = number of treated joint BE during EP divided by total number of days during EP*365.25. Joint BE: unusual sensation in joint ('aura') along with 1) increasing swelling/warmth over skin, joint; 2) increasing pain or 3) progressive loss of range of motion/difficulty in using limb compared to Baseline. BE: episode started from 1st sign of bleed & ended no more than 72 hours after last treatment for bleed, within which any symptoms of bleeding at same location/injections <=72 hours apart considered same BE. Any injection after >72 hours post preceding one=1st injection to treat new BE in same location. Any bleed at different location=separate BE, regardless of time from last injection. EP: sum of all intervals of time during which subjects treated with BIVV001 per study arms and treatment regimens. ABR: NB model with total number of treated BE during EP (response variable) & log-transformed EP duration (offset variable). FAS.
    End point type
    Secondary
    End point timeframe
    Baseline up to Week 52
    End point values
    		 BIVV001: Subjects aged <6 Years BIVV001: Subjects aged 6 to <12 Years
    Number of subjects analysed
    38
    36
    Units: joint BE per subject per year
        arithmetic mean (confidence interval 95%)
    0.19 (0.06 to 0.62)
    0.99 (0.38 to 2.60)
    No statistical analyses for this end point

    Secondary: Change From Baseline in Hemophilia Joint Health Score Domain Score at Week 52

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    End point title
    		 Change From Baseline in Hemophilia Joint Health Score Domain Score at Week 52
    End point description
    HJHS is a validated 11-item scoring tool developed for the assessment of joint health in subjects with hemophilia. Following domains were assessed for elbows, knee and ankle joints: swelling (score 0 = no swelling to 3=severe), duration of swelling (score 0 = no swelling and 1 = >=6 months), muscle atrophy (score 0 = none to 2 = severe), crepitus on motion (score 0 = none to 2=severe), flexion loss (score 0 = <5' to 3 = >20'), extension loss (score 0 = <5' to 3 = >20'), joint pain (score 0 = no pain through active range of motion to 2 = pain through active range) and strength (score 0 = holds test position with maximum resistance to 4 = trace/no muscle contraction), for each item 0 = no damage and higher score = severe damage. Analysis was performed on FAS. Here, 'n' = subjects with available data for each specified category.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 52
    End point values
    		 BIVV001: Subjects aged <6 Years BIVV001: Subjects aged 6 to <12 Years
    Number of subjects analysed
    38
    36
    Units: score on a scale
    arithmetic mean (standard deviation)
        Swelling (n = 19, 35)
    0.0 ± 0.0
    -0.1 ± 0.6
        Duration Of Swelling (n = 19, 35)
    0.1 ± 0.2
    -0.0 ± 0.2
        Muscle Atrophy (n = 19, 35)
    0.0 ± 0.0
    -0.1 ± 0.4
        Crepitus On Motion (n = 19, 35)
    0.1 ± 0.2
    -0.1 ± 0.5
        Flexion Loss (n = 19, 35)
    -0.9 ± 4.1
    -0.1 ± 0.6
        Extension Loss (n = 19, 35)
    -0.2 ± 1.0
    0.2 ± 0.9
        Joint Pain (n = 19, 35)
    0.0 ± 0.0
    0.0 ± 0.4
        Strength (n = 18, 33)
    1.3 ± 10.0
    -0.8 ± 4.2
    No statistical analyses for this end point

    Secondary: Sensitivity Analysis: Annualised Joint Bleeding Rate (AJBR)

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    End point title
    		 Sensitivity Analysis: Annualised Joint Bleeding Rate (AJBR)
    End point description
    AJBR: annualised number of joint bleeding/subject/year. ABR = number of treated joint BE during EP divided by total number of days during EP*365.25. Joint BE: unusual sensation in joint ('aura') along with 1) increasing swelling/warmth over skin, joint; 2) increasing pain or 3) progressive loss of range of motion/difficulty in using limb compared to Baseline. BE: episode started from 1st sign of bleed & ended no more than 72 hours after last treatment for bleed, within which any symptoms of bleeding at same location/injections <=72 hours apart considered same BE. Any injection after >72 hours post preceding one=1st injection to treat new BE in same location. Any bleed at different location=separate BE, regardless of time from last injection. EP: sum of all intervals of time during which subjects treated with BIVV001 per study arms and treatment regimens. ABR: NB model with total number of treated BE during EP (response variable) & log-transformed EP duration (offset variable). FAS.
    End point type
    Secondary
    End point timeframe
    Baseline up to Week 52
    End point values
    		 BIVV001: Subjects aged <6 Years BIVV001: Subjects aged 6 to <12 Years
    Number of subjects analysed
    38
    35 [20]
    Units: joint BE per subject per year
        arithmetic mean (confidence interval 95%)
    0.19 (0.06 to 0.62)
    0.41 (0.19 to 0.89)
    Notes
    [20] - Excluded 1 subject who did not receive weekly prophylaxis treatment for an extended period of time.
    No statistical analyses for this end point

    Secondary: Change From Baseline in Hemophilia Quality of Life Questionnaire (Haemo-QoL) Kids Short Version Total Score at Week 52 for Children Subjects (Aged 4 to 7 and 8 to <12 Years)

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    End point title
    		 Change From Baseline in Hemophilia Quality of Life Questionnaire (Haemo-QoL) Kids Short Version Total Score at Week 52 for Children Subjects (Aged 4 to 7 and 8 to <12 Years)
    End point description
    Haemo-QoL kids short version: used to measure physical and emotional impacts on quality of life in children & adolescent with hemophilia. It was administered to children & their caregivers. Short version for children containing 16 items (4 to 7 years) and 35 items (8 to <12 years) were selected in this study. This version covers 9 dimensions relevant for children's HRQoL (physical health, feelings, view of yourself, family, friends, other people, sports and school, dealing with hemophilia & treatment). Items were rated along 5 response options: never, seldom, sometimes, often and always, higher scores=greater impairment. Raw score for each domain were transformed to scale ranged between 0 to 100, where lower score=better HRQoL. Haem-A-QoL total Score=average of all domain scores and ranged from 0 to 100, where lower scores=better QoL. FAS. n=subjects with available data, n=0 signifies that no subjects were aged 8 to <12 years in 1st arm. 99999=space filler, no subjects were evaluable.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 52
    End point values
    		 BIVV001: Subjects aged <6 Years BIVV001: Subjects aged 6 to <12 Years
    Number of subjects analysed
    10
    14
    Units: score on a scale
    arithmetic mean (standard deviation)
        4 to 7 years (n = 10, 4)
    -5.31 ± 10.83
    4.69 ± 5.41
        8 to <12 years (n = 0, 10)
    99999 ± 99999
    -9.79 ± 12.18
    No statistical analyses for this end point

    Secondary: Change From Baseline in Hemophilia Quality of Life Questionnaire Parent Proxy Short Version Total Score at Week 52 for Children Subjects (Aged 4 to 7 and 8 to <12 Years): Parent's Evaluation

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    End point title
    		 Change From Baseline in Hemophilia Quality of Life Questionnaire Parent Proxy Short Version Total Score at Week 52 for Children Subjects (Aged 4 to 7 and 8 to <12 Years): Parent's Evaluation
    End point description
    Haemo-QoL parent proxy short version: used to measure physical and emotional impacts on quality of life in children and adolescent with hemophilia. It was administered to children & their caregivers. Short version for children's caregivers containing 16 items (subjects 4 to 7 years) and 35 items (subjects 8 to <12 years) were selected in this study. This version covers 9 dimensions relevant for children's HRQoL (physical health, feelings, view of yourself, family, friends, other people, sports and school, dealing with hemophilia and treatment). Items are rated along 5 response options: never, seldom, sometimes, often and always, higher scores=greater impairment. Raw score for each domain: transformed to scale ranged between 0 to 100, lower score=better HRQoL. Haem-A-QoL total Score=average of all domain scores and ranged from 0 to 100, lower scores=better quality of life. FAS. n=subjects with available data for each specified category, n=0 signifies that no subjects were evaluable.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 52
    End point values
    		 BIVV001: Subjects aged <6 Years BIVV001: Subjects aged 6 to <12 Years
    Number of subjects analysed
    19 [21]
    13
    Units: score on a scale
    arithmetic mean (standard deviation)
        4 to 7 years (n = 19, 4)
    -3.21 ± 12.23
    -1.17 ± 11.08
        8 to <12 years (n = 0, 9)
    99999 ± 99999
    -4.05 ± 10.77
    Notes
    [21] - 99999 = space filler which signifies that no subjects were evaluable.
    No statistical analyses for this end point

    Secondary: Change From Baseline in Hemophilia Quality of Life Questionnaire Parent Proxy Short Version Physical Health Domain Score at Week 52 for Children Subjects (Aged 8 to <12 years): Parent's Evaluation

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    End point title
    		 Change From Baseline in Hemophilia Quality of Life Questionnaire Parent Proxy Short Version Physical Health Domain Score at Week 52 for Children Subjects (Aged 8 to <12 years): Parent's Evaluation [22]
    End point description
    Haemo-QoL parent proxy short version: used to measure physical & emotional impacts on quality of life in children & adolescent with hemophilia. It was administered to children & their caregivers. Short version for children's caregivers containing 35 items (subjects 8 to <12 years) were selected and it covers 9 dimensions relevant for children's HRQoL (physical health, feelings, view of yourself, family, friends, other people, sports and school, dealing with hemophilia & treatment). Items are rated along 5 response options:never, seldom, sometimes, often and always, higher scores=greater impairment. Raw score for physical health domain were transformed to scale ranged between 0 and 100; lower score=better HRQoL. FAS. Number of subjects analysed=subjects with available data. Change from baseline in physical Health domain score per parent's evaluation was reported in this endpoint. Data for this endpoint was not planned to be collected & analysed for arm 'BIVV001:Subjects aged <6 years'.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 52
    Notes
    [22] - 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: Data were planned to be collected and analysed for specified arm only.
    End point values
    		 BIVV001: Subjects aged 6 to <12 Years
    Number of subjects analysed
    9
    Units: score on a scale
        arithmetic mean (standard deviation)
    -7.64 ± 11.60
    No statistical analyses for this end point

    Secondary: Change From Baseline in Hemophilia Quality of Life Questionnaire Kids Short Version Physical Health Domain Score at Week 52 for Children Subjects (Aged 8 to <12 years)

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    End point title
    		 Change From Baseline in Hemophilia Quality of Life Questionnaire Kids Short Version Physical Health Domain Score at Week 52 for Children Subjects (Aged 8 to <12 years) [23]
    End point description
    Haemo-QoL kids short version: used to measure physical & emotional impacts on quality of life in children & adolescent with hemophilia. It was administered to children & their caregivers. Short version for children containing 35 items (8 to <12 years) were selected in this study. This version covers 9 dimensions considered relevant for children's HRQoL (physical health, feelings, view of yourself, family, friends, other people, sports and school, dealing with hemophilia and treatment). Items are rated along 5 response options: never, seldom, sometimes, often and always, higher scores=greater impairment. Raw score for physical health domain were transformed to scale ranged between 0 to 100, where lower score=better HRQoL. FAS. Number of subjects analysed=subjects with available data this endpoint. Change from baseline in physical Health domain score was reported in this endpoint. Data for this endpoint was not planned to be collected and analysed for 'BIVV001: Subjects aged <6 years'.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 52
    Notes
    [23] - 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: Data were planned to be collected and analysed for specified arm only.
    End point values
    		 BIVV001: Subjects aged 6 to <12 Years
    Number of subjects analysed
    10
    Units: score on a scale
        arithmetic mean (standard deviation)
    -10.63 ± 14.75
    No statistical analyses for this end point

    Secondary: Total Number of Target Joints Resolved in Subjects at Week 52

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    End point title
    		 Total Number of Target Joints Resolved in Subjects at Week 52
    End point description
    A target joint at baseline was defined as a major joint with >=3 spontaneous bleeding episodes in a consecutive 6 month period prior to entry to the study, captured at Baseline. A target joint resolved was defined as <=2 spontaneous bleeds into that joint during 12 months of continuous exposure (defined as treatment regimen period >=52 weeks). Total number of target joints resolved at Week 52 were reported. Analysis was performed on FAS population. Here, 'number of subjects analysed' = subjects with available data for this endpoint and had at least 12 months of continuous exposure.
    End point type
    Secondary
    End point timeframe
    Week 52
    End point values
    		 BIVV001: Subjects aged <6 Years BIVV001: Subjects aged 6 to <12 Years
    Number of subjects analysed
    0 [24]
    1 [25]
    Units: Target joints resolved
        number (not applicable)
    2
    Notes
    [24] - None of the subject had at least 12 months of continuous exposure.
    [25] - 2=Total number of target joints (Baseline) from subjects with at least 12 months continuous exposure
    No statistical analyses for this end point

    Secondary: Change From Baseline in Hemophilia Joint Health Score (HJHS) Total Score at Week 52

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    End point title
    		 Change From Baseline in Hemophilia Joint Health Score (HJHS) Total Score at Week 52
    End point description
    HJHS is a validated 11-item scoring tool developed for the assessment of joint health in subjects with hemophilia. It comprised an evaluation of the elbows, knee and ankle joints: swelling (0 to 3), duration of swelling (0 to 1), muscle atrophy (0 to 2), crepitus on motion (0 to 2), flexion loss (0 to 3), extension loss (0 to 3), joint pain (0 to 2) and strength (0 to 4), in each item 0 = none and higher score = severe damage and global gait (walking, stairs, running, hopping on 1 leg) scored on scale ranged from 0 to 4, where 0 = all skills in normal limit and 4 = no skills within normal limits). Total HJHS score = sum of joint totals (0 to 120) + general gait (1 to 4) and ranged from 0 (no joint damage) to 124 (severe joint damage), where higher score indicated severe joint damage. Analysis was performed on FAS. Here, 'number of subjects analysed' = subjects with available data for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 52
    End point values
    		 BIVV001: Subjects aged <6 Years BIVV001: Subjects aged 6 to <12 Years
    Number of subjects analysed
    18
    33
    Units: score on a scale
        arithmetic mean (standard deviation)
    0.2 ± 8.3
    -1.1 ± 4.3
    No statistical analyses for this end point

    Secondary: Investigators' or Surgeons' Assessment of Subject's Hemostatic Response to BIVV001 Treatment

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    End point title
    		 Investigators' or Surgeons' Assessment of Subject's Hemostatic Response to BIVV001 Treatment
    End point description
    The Investigators/Surgeons who complete the surgical procedures assess the subject's response to surgery with BIVV001 treatment using a 4-point scale, where responses were categorised as: 1 = Excellent, 2 = Good, 3 = Fair, and 4 = Poor/none. Higher score indicated worst response. This assessment was performed 24 hours after the surgery. A surgery can be counted in more than one response category. Analysed on a surgery subgroup population which included all subjects who had undergone major surgery after the 1st dose of study drug. Here, number of subjects analysed' = subjects with major surgeries during the specified period (defined as the date and time of the first dose of study drug up to the last dose of study drug).
    End point type
    Secondary
    End point timeframe
    Baseline up to Week 52
    End point values
    		 Subjects With Major Surgery
    Number of subjects analysed
    2 [26]
    Units: major surgeries
    number (not applicable)
        Excellent or Good
    2
        Excellent
    2
        Good
    0
        Fair
    0
        Poor/none
    0
    Notes
    [26] - Number of major surgeries during the specified period occurred in subjects analysed = 2.
    No statistical analyses for this end point

    Secondary: Number of Injections Per Surgery Required to Maintain Hemostasis During Perioperative Period for Major Surgery

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    End point title
    		 Number of Injections Per Surgery Required to Maintain Hemostasis During Perioperative Period for Major Surgery
    End point description
    Perioperative period was time lapse surrounding the surgical act which was divided into 3 stages: preoperative (4 weeks prior to surgery), operative (during the surgery) and post-operative (24-hour post-surgery). The number of injections to maintain hemostasis (process to prevent and stop bleeding from blood vessel) per surgery included all injections from loading dose (i.e., the preoperative injection, administered either on the day of surgery or one day prior to the surgery), to end of surgery. Major surgery: defined as any invasive operative procedure that required any of the following: opening into major body cavity (e.g., abdomen, thorax, skull); operation on a joint; removal of an organ; dental extraction of any molar teeth or >=3 non-molar teeth; operative alteration of normal anatomy; crossing of a mesenchymal barrier (e.g., pleura, peritoneum, dura). Analysed on surgery subgroup population. Number of subjects analysed = subjects with major surgeries during specified period.
    End point type
    Secondary
    End point timeframe
    During the perioperative period (any time during Baseline up to Week 52)
    End point values
    		 Subjects With Major Surgery
    Number of subjects analysed
    2 [27]
    Units: Major surgeries
        One injection
    2
        Two injection
    0
        Three injection
    0
        Four injection
    0
        >Four injection
    0
    Notes
    [27] - Number of major surgeries during the specified period occurred in subjects analysed = 2.
    No statistical analyses for this end point

    Secondary: Number of Blood Component Transfusions Used During Perioperative Period for Major Surgery

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    End point title
    		 Number of Blood Component Transfusions Used During Perioperative Period for Major Surgery
    End point description
    The perioperative period was the time lapse surrounding the surgical act which was divided into 3 stages: preoperative (4 weeks prior to surgery), operative (during the surgery) and post-operative (24-hour post-surgery). The number of blood component transfusions used during perioperative period were summarised categorically (0, 1, 2, 3 and >3) for all major surgeries for the surgery subgroup. Major surgery: defined as any invasive operative procedure that required any of the following: opening into major body cavity (e.g., abdomen, thorax, skull); operation on a joint; removal of an organ; dental extraction of any molar teeth or >=3 non-molar teeth; operative alteration of normal anatomy; crossing of a mesenchymal barrier (e.g., pleura, peritoneum, dura). Analysis was performed on surgery subgroup population. Number of subjects analysed = subjects with major surgeries during specified period.
    End point type
    Secondary
    End point timeframe
    During the perioperative period (any time during Baseline up to Week 52)
    End point values
    		 Subjects With Major Surgery
    Number of subjects analysed
    2 [28]
    Units: Major surgeries
        Zero
    2
        One
    0
        Two
    0
        Three
    0
        >Three
    0
    Notes
    [28] - Number of major surgeries during the specified period occurred in subjects analysed = 2.
    No statistical analyses for this end point

    Secondary: Total BIVV001 Consumption From Day -1 to 14 During Perioperative Period for Major Surgery

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    End point title
    		 Total BIVV001 Consumption From Day -1 to 14 During Perioperative Period for Major Surgery
    End point description
    Perioperative period: time lapse surrounding surgical act which was divided into 3 stages: preoperative (4 weeks prior to surgery), operative (during the surgery) and post-operative (24-hour post-surgery). Total BIVV001 consumption were summarised from the loading dose (the day before surgery, i.e., on Day -1) up to 2 weeks following the surgery (i.e., Day 14) and were reported in this endpoint. Analysis was performed on surgery subgroup population. Here, Number of subjects analysed = subjects with major surgeries during specified period.
    End point type
    Secondary
    End point timeframe
    Day -1 to Day 14
    End point values
    		 Subjects With Major Surgery
    Number of subjects analysed
    2 [29]
    Units: IU/kg per major surgery
        arithmetic mean (standard deviation)
    201.97 ± 29.42
    Notes
    [29] - Number of major surgeries with BIVV001 administration within Day -1 to Day 14 = 2
    No statistical analyses for this end point

    Secondary: Type of Blood Component Transfusions Used During Perioperative Period for Major Surgery

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    End point title
    		 Type of Blood Component Transfusions Used During Perioperative Period for Major Surgery
    End point description
    The perioperative period was the time lapse surrounding the surgical act which was divided into 3 stages: preoperative (4 weeks prior to surgery), operative (during the surgery) and post-operative (24-hour post-surgery). The type of blood component (Red blood cell, platelet, fresh frozen plasma, whole blood and other) transfusions used were summarised for all major surgeries. Post-operative referred to the day following the end of surgery to the date of hospital discharge. Major surgery: defined as any invasive operative procedure that required any of the following: opening into major body cavity (e.g., abdomen, thorax, skull); operation on a joint; removal of an organ; dental extraction of any molar teeth or >=3 non-molar teeth; operative alteration of normal anatomy; crossing of a mesenchymal barrier (e.g., pleura, peritoneum, dura). Analysis was performed on surgery subgroup population. Number of subjects analysed = subjects with major surgeries during specified period.
    End point type
    Secondary
    End point timeframe
    During the perioperative period (any time during Baseline up to Week 52)
    End point values
    		 Subjects With Major Surgery
    Number of subjects analysed
    2 [30]
    Units: Major surgeries
        Red Blood Cell
    0
        Platelet
    0
        Fresh Frozen Plasma
    0
        Whole Blood
    0
        Other
    0
    Notes
    [30] - Number of major surgeries during the specified period occurred in subjects analysed = 2.
    No statistical analyses for this end point

    Secondary: Estimated Blood Loss During Major Surgery

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    End point title
    		 Estimated Blood Loss During Major Surgery
    End point description
    The estimated total blood loss (in millilitres) during major surgeries were summarised. Major surgery: defined as any invasive operative procedure that required any of the following: opening into major body cavity (e.g., abdomen, thorax, skull); operation on a joint; removal of an organ; dental extraction of any molar teeth or >=3 non-molar teeth; operative alteration of normal anatomy; crossing of a mesenchymal barrier (e.g., pleura, peritoneum, dura). Analysis was performed on surgery subgroup population. Here, number of subjects analysed = subjects with reported blood loss during major surgery.
    End point type
    Secondary
    End point timeframe
    Day 0 (i.e., day of surgery)
    End point values
    		 Subjects With Major Surgery
    Number of subjects analysed
    2 [31]
    Units: millilitres
        arithmetic mean (standard deviation)
    25.00 ± 35.36
    Notes
    [31] - Major surgeries with blood loss report during treatment regimen occurred in subjects analysed = 2
    No statistical analyses for this end point

    Secondary: Total Dose Required to Maintain Hemostasis From Day -1 to Day 0 During Perioperative Period for Major Surgery

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    End point title
    		 Total Dose Required to Maintain Hemostasis From Day -1 to Day 0 During Perioperative Period for Major Surgery
    End point description
    Perioperative period was time lapse surrounding surgical act which was divided into 3 stages: preoperative (4 weeks prior to surgery), operative (during surgery) and post-operative (24-hour post-surgery). Total dose (IU/kg) was sum across all injections per major surgery (including loading dose) needed to maintain hemostasis (process to prevent and stop bleeding from blood vessel) during surgery. Major surgery: any invasive operative procedure that required any of following: opening into major body cavity (e.g., abdomen, thorax, skull); operation on joint; removal of organ; dental extraction of any molar teeth or >=3 non-molar teeth; operative alteration of normal anatomy; crossing of mesenchymal barrier (e.g., pleura, peritoneum, dura). Day 0=surgery day. Loading dose for given surgery was preoperative injection, administered either on day of surgery or one day prior to surgery (i.e., Day -1). Surgery subgroup population. Number of subjects analysed=subjects with major surgeries.
    End point type
    Secondary
    End point timeframe
    Day -1 to Day 0 (day of surgery)
    End point values
    		 Subjects With Major Surgery
    Number of subjects analysed
    2 [32]
    Units: IU/kg
        arithmetic mean (standard deviation)
    61.13 ± 1.06
    Notes
    [32] - Number of major surgeries with loading dose given on day of surgery/1 day prior to surgery (Day -1).
    No statistical analyses for this end point

    Secondary: Number of Subjects With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse (TESAEs)

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    End point title
    		 Number of Subjects With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse (TESAEs)
    End point description
    An adverse event (AE) was defined as any untoward medical occurrence in a subject who received study drug which did not necessarily have a causal relationship with the treatment. A serious AE (SAE) was defined as any untoward medical occurrence that at any dose: resulted in death, was life-threatening, required inpatient hospitalisation or prolongation of existing hospitalisation, resulted in persistent or significant disability or incapacity, was a congenital anomaly or birth defect, or was a medically important event. Treatment-emergent AEs were AEs that developed, worsened or became serious from Baseline (Day 1) up to 3 weeks post last dose. Analysis was performed on safety analysis set.
    End point type
    Secondary
    End point timeframe
    From Baseline (Day 1) up to 3 weeks post last dose of BIVV001 (i.e., up to Week 55)
    End point values
    		 BIVV001: Subjects aged <6 Years BIVV001: Subjects aged 6 to <12 Years
    Number of subjects analysed
    38
    36
    Units: subjects
        TEAE
    33
    29
        TESAE
    5
    4
    No statistical analyses for this end point

    Secondary: Number of Subjects With Occurrence of Embolic and Thrombotic Events

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    End point title
    		 Number of Subjects With Occurrence of Embolic and Thrombotic Events
    End point description
    Embolic and thrombotic events were defined as arterial or venous thrombosis, confirmed by imaging. Analysis was performed on safety analysis set.
    End point type
    Secondary
    End point timeframe
    Baseline up to Week 52
    End point values
    		 BIVV001: Subjects aged <6 Years BIVV001: Subjects aged 6 to <12 Years
    Number of subjects analysed
    38
    36
    Units: subjects
    0
    0
    No statistical analyses for this end point

    Secondary: Pharmacokinetics: Elimination Half-life (t1/2z)

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    End point title
    		 Pharmacokinetics: Elimination Half-life (t1/2z)
    End point description
    Plasma t1/2z was the time measured for the plasma concentration of drug to decrease by one half. Analysis was performed on PK analysis set. Here, 'number of subjects analysed = subjects with available data for this endpoint. Data was planned to be collected and analysed for combined population of both arm groups with the available PK data.
    End point type
    Secondary
    End point timeframe
    pre-dose, 0.25, 3, 24, 72, and 168 hours post-dose on Day 1
    End point values
    		 BIVV001 (Efanesoctocog Alfa)
    Number of subjects analysed
    36
    Units: hours
        arithmetic mean (standard deviation)
    40.2 ± 4.29
    No statistical analyses for this end point

    Secondary: Pharmacokinetics (PK): Maximum FVIII Activity (Cmax)

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    End point title
    		 Pharmacokinetics (PK): Maximum FVIII Activity (Cmax)
    End point description
    Cmax was defined as the maximum observed plasma FVIII Activity. Analysis was performed on PK population which included all subjects who had completed adequate blood sample collection to assess key PK parameters. Data was planned to be collected and analysed for combined population of both arm groups with the available PK data.
    End point type
    Secondary
    End point timeframe
    Pre-dose, 0.25, 3, 24, 72, and 168 hours post-dose on Day 1
    End point values
    		 BIVV001 (Efanesoctocog Alfa)
    Number of subjects analysed
    37
    Units: IU per decilitre
        arithmetic mean (standard deviation)
    128 ± 46.4
    No statistical analyses for this end point

    Secondary: Pharmacokinetics: Clearance (CL)

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    End point title
    		 Pharmacokinetics: Clearance (CL)
    End point description
    CL is defined as the rate at which the drug is removed from the body. Analysis was performed on PK analysis set. Here, 'number of subjects analysed = subjects with available data for this endpoint. Data was planned to be collected and analysed for combined population of both arm groups with the available PK data.
    End point type
    Secondary
    End point timeframe
    pre-dose, 0.25, 3, 24, 72, and 168 hours post-dose on Day 1
    End point values
    		 BIVV001 (Efanesoctocog Alfa)
    Number of subjects analysed
    36
    Units: millilitres per hour per kilogram
        arithmetic mean (standard deviation)
    0.711 ± 0.132
    No statistical analyses for this end point

    Secondary: Pharmacokinetics: Volume of Distribution at Steady State (Vss)

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    End point title
    		 Pharmacokinetics: Volume of Distribution at Steady State (Vss)
    End point description
    Volume of distribution (Vd) is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug. Vss is the apparent volume of distribution at steady-state. Analysis was performed on PK analysis set. Here, 'number of subjects analysed = subjects with available data for this endpoint. Data was planned to be collected and analysed for combined population of both arm groups with the available PK data.
    End point type
    Secondary
    End point timeframe
    pre-dose, 0.25, 3, 24, 72, and 168 hours post-dose on Day 1
    End point values
    		 BIVV001 (Efanesoctocog Alfa)
    Number of subjects analysed
    36
    Units: millilitres per kilogram
        arithmetic mean (standard deviation)
    37.3 ± 6.19
    No statistical analyses for this end point

    Secondary: Pharmacokinetics: Area Under the Plasma FVIII Activity Versus Time Curve (AUC0-tau)

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    End point title
    		 Pharmacokinetics: Area Under the Plasma FVIII Activity Versus Time Curve (AUC0-tau)
    End point description
    AUC0-tau was defined as area under the plasma concentration-time profile from time zero (pre-dose) to dosing interval. Analysis was performed on PK analysis set. Here, 'number of subjects analysed = subjects with available data for this endpoint. Data was planned to be collected and analysed for combined population of both arm groups with the available PK data.
    End point type
    Secondary
    End point timeframe
    pre-dose, 0.25, 3, 24, 72, and 168 hours post-dose on Day 1
    End point values
    		 BIVV001 (Efanesoctocog Alfa)
    Number of subjects analysed
    35
    Units: hour*IU per decilitre
        arithmetic mean (standard deviation)
    7000 ± 1300
    No statistical analyses for this end point

    Secondary: Pharmacokinetics: Total Clearance at Steady State (CLss)

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    End point title
    		 Pharmacokinetics: Total Clearance at Steady State (CLss)
    End point description
    CLss is defined as the rate at which the drug is removed from the body at steady state. Data for this endpoint is not reported because samples were not collected to estimate CLss.
    End point type
    Secondary
    End point timeframe
    0 hour - 168 hour at week 26, 39 or 52
    End point values
    		 BIVV001 (Efanesoctocog Alfa)
    Number of subjects analysed
    0 [33]
    Units: millilitres per hour per kilogram
        arithmetic mean (standard deviation)
    ±
    Notes
    [33] - No data available.
    No statistical analyses for this end point

    Secondary: Time Above Predefined (10% and 40%) FVIII Activity Levels

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    End point title
    		 Time Above Predefined (10% and 40%) FVIII Activity Levels
    End point description
    Time above predefined (10% and 40%) FVIII activity levels mean time which BIVV001 maintains above 10 IU/dL and 40 IU/dL with single doses of 50 IU/kg. Analysis was performed on PK analysis set. Here, n=subjects with available data for each specified category. Data was planned to be collected and analysed for combined population of both arm groups with the available PK data.
    End point type
    Secondary
    End point timeframe
    pre-dose, 0.25, 3, 24, 72, and 168 hours post-dose on Day 1
    End point values
    		 BIVV001 (Efanesoctocog Alfa)
    Number of subjects analysed
    37
    Units: hours
    arithmetic mean (standard deviation)
        Time to 10 IU/dL
    160 ± 18.7
        Time to 40 IU/dL
    72.2 ± 12.5
    No statistical analyses for this end point

    Secondary: Pharmacokinetics: Incremental Recovery (IR)

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    End point title
    		 Pharmacokinetics: Incremental Recovery (IR)
    End point description
    IR was calculated as (Peak activity [in IU/dL] - Trough activity [in IU/dL])/Actual Dose (in IU/kg), and peak activity at each visit was the highest activity level after the dosing, and trough activity at each visit was the activity level prior to the dosing. Analysis was performed on PK analysis set. Data was planned to be collected and analysed for combined population of both arm groups with the available PK data.
    End point type
    Secondary
    End point timeframe
    pre-dose, 0.25, 3, 24, 72, and 168 hours post-dose on Day 1
    End point values
    		 BIVV001 (Efanesoctocog Alfa)
    Number of subjects analysed
    37
    Units: IU/dL per IU/kg
        arithmetic mean (standard deviation)
    2.53 ± 0.880
    No statistical analyses for this end point

    Secondary: Pharmacokinetics: Trough Concentration for BIVV001 (Ctrough)

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    End point title
    		 Pharmacokinetics: Trough Concentration for BIVV001 (Ctrough)
    End point description
    Ctrough is the pre-dose concentration of a drug. Ctrough was measured by apTT-Baseline-OSC assay. Analysis was performed on FAS. Here, 'n' = subjects with available data for each specified category. Data was planned to be collected and analysed for combined population of both arm groups with the available PK data.
    End point type
    Secondary
    End point timeframe
    Pre-dose at Baseline (Day 1) and Week 52
    End point values
    		 BIVV001 (Efanesoctocog Alfa)
    Number of subjects analysed
    74
    Units: IU/dL
    arithmetic mean (standard deviation)
        Baseline (n = 69)
    0.00 ± 0.00
        Week 52 (n = 72)
    13.68 ± 21.84
    No statistical analyses for this end point

    Secondary: Pharmacokinetics: Mean Residence Time (MRT)

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    End point title
    		 Pharmacokinetics: Mean Residence Time (MRT)
    End point description
    MRT is the average total time a drug molecule spends in the body. Analysis was performed on PK analysis set. Here, 'number of subjects analysed = subjects with available data for this endpoint. Data was planned to be collected and analysed for combined population of both arm groups with the available PK data.
    End point type
    Secondary
    End point timeframe
    pre-dose, 0.25, 3, 24, 72, and 168 hours post-dose on Day 1
    End point values
    		 BIVV001 (Efanesoctocog Alfa)
    Number of subjects analysed
    36
    Units: hours
        arithmetic mean (standard deviation)
    53.0 ± 6.22
    No statistical analyses for this end point

    Secondary: Pharmacokinetics: Dose-normalised Area Under the Activity-time Curve (DNAUC0-tau)

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    End point title
    		 Pharmacokinetics: Dose-normalised Area Under the Activity-time Curve (DNAUC0-tau)
    End point description
    AUC0-tau was defined as the area under the activity-time curve over the dosing interval. AUC was normalised by dose. Analysis was performed on PK analysis set. Here, 'number of subjects analysed = subjects with available data for this endpoint. Data was planned to be collected and analysed for combined population of both arm groups with the available PK data.
    End point type
    Secondary
    End point timeframe
    pre-dose, 0.25, 3, 24, 72, and 168 hours post-dose on Day 1
    End point values
    		 BIVV001 (Efanesoctocog Alfa)
    Number of subjects analysed
    35
    Units: hour*kilogram*IU/decilitre/IU
        arithmetic mean (standard deviation)
    139 ± 25.2
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From Baseline (Day 1) up to 3 weeks post last dose of BIVV001 (i.e., up to Week 55)
    Adverse event reporting additional description
    Analysis was performed on safety analysis set.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    25.1
    Reporting groups
    Reporting group title
    BIVV001: Subjects aged <6 years
    Reporting group description
    		 Subjects aged <6 years received BIVV001 at a dose of 50 IU/kg IV injection QW prophylaxis for 52 weeks.

    Reporting group title
    BIVV001: Subjects aged 6 to <12 years
    Reporting group description
    		 Subjects aged 6 to <12 years received BIVV001 at a dose of 50 IU/kg IV injection QW prophylaxis for 52 weeks.

    Serious adverse events
    		 BIVV001: Subjects aged <6 years BIVV001: Subjects aged 6 to <12 years
    Total subjects affected by serious adverse events
         subjects affected / exposed
    5 / 38 (13.16%)
    4 / 36 (11.11%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    Injury, poisoning and procedural complications
    Head Injury
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Surgical and medical procedures
    Circumcision
         subjects affected / exposed
    1 / 38 (2.63%)
    0 / 36 (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
    Vascular Device Occlusion
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Eosinophilic Oesophagitis
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    1 / 38 (2.63%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Product issues
    Device Malfunction
         subjects affected / exposed
    0 / 38 (0.00%)
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Bacteraemia
         subjects affected / exposed
    1 / 38 (2.63%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular Device Infection
         subjects affected / exposed
    2 / 38 (5.26%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    1 / 38 (2.63%)
    0 / 36 (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
    		 BIVV001: Subjects aged <6 years BIVV001: Subjects aged 6 to <12 years
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    31 / 38 (81.58%)
    28 / 36 (77.78%)
    Investigations
    Alanine Aminotransferase Increased
         subjects affected / exposed
    2 / 38 (5.26%)
    0 / 36 (0.00%)
         occurrences all number
    2
    0
    Sars-Cov-2 Test Positive
         subjects affected / exposed
    7 / 38 (18.42%)
    4 / 36 (11.11%)
         occurrences all number
    7
    6
    Injury, poisoning and procedural complications
    Joint Injury
         subjects affected / exposed
    0 / 38 (0.00%)
    2 / 36 (5.56%)
         occurrences all number
    0
    2
    Limb Injury
         subjects affected / exposed
    0 / 38 (0.00%)
    2 / 36 (5.56%)
         occurrences all number
    0
    3
    Contusion
         subjects affected / exposed
    1 / 38 (2.63%)
    3 / 36 (8.33%)
         occurrences all number
    1
    3
    Head Injury
         subjects affected / exposed
    1 / 38 (2.63%)
    4 / 36 (11.11%)
         occurrences all number
    1
    4
    Nervous system disorders
    Headache
         subjects affected / exposed
    2 / 38 (5.26%)
    1 / 36 (2.78%)
         occurrences all number
    2
    2
    Blood and lymphatic system disorders
    Neutropenia
         subjects affected / exposed
    3 / 38 (7.89%)
    0 / 36 (0.00%)
         occurrences all number
    3
    0
    Iron Deficiency Anaemia
         subjects affected / exposed
    2 / 38 (5.26%)
    0 / 36 (0.00%)
         occurrences all number
    2
    0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    8 / 38 (21.05%)
    1 / 36 (2.78%)
         occurrences all number
    17
    1
    Peripheral Swelling
         subjects affected / exposed
    2 / 38 (5.26%)
    0 / 36 (0.00%)
         occurrences all number
    2
    0
    Immune system disorders
    Seasonal Allergy
         subjects affected / exposed
    1 / 38 (2.63%)
    2 / 36 (5.56%)
         occurrences all number
    1
    2
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    1 / 38 (2.63%)
    2 / 36 (5.56%)
         occurrences all number
    1
    2
    Diarrhoea
         subjects affected / exposed
    3 / 38 (7.89%)
    1 / 36 (2.78%)
         occurrences all number
    3
    1
    Vomiting
         subjects affected / exposed
    4 / 38 (10.53%)
    1 / 36 (2.78%)
         occurrences all number
    4
    1
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    2 / 38 (5.26%)
    1 / 36 (2.78%)
         occurrences all number
    2
    1
    Oropharyngeal Pain
         subjects affected / exposed
    2 / 38 (5.26%)
    0 / 36 (0.00%)
         occurrences all number
    5
    0
    Skin and subcutaneous tissue disorders
    Eczema
         subjects affected / exposed
    3 / 38 (7.89%)
    0 / 36 (0.00%)
         occurrences all number
    3
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 38 (0.00%)
    5 / 36 (13.89%)
         occurrences all number
    0
    7
    Pain In Extremity
         subjects affected / exposed
    2 / 38 (5.26%)
    3 / 36 (8.33%)
         occurrences all number
    2
    4
    Infections and infestations
    Upper Respiratory Tract Infection
         subjects affected / exposed
    6 / 38 (15.79%)
    5 / 36 (13.89%)
         occurrences all number
    7
    7
    Respiratory Tract Infection Viral
         subjects affected / exposed
    2 / 38 (5.26%)
    0 / 36 (0.00%)
         occurrences all number
    3
    0
    Pharyngitis
         subjects affected / exposed
    0 / 38 (0.00%)
    2 / 36 (5.56%)
         occurrences all number
    0
    2
    Nasopharyngitis
         subjects affected / exposed
    3 / 38 (7.89%)
    3 / 36 (8.33%)
         occurrences all number
    6
    3
    Influenza
         subjects affected / exposed
    0 / 38 (0.00%)
    2 / 36 (5.56%)
         occurrences all number
    0
    2
    Gastroenteritis Viral
         subjects affected / exposed
    5 / 38 (13.16%)
    1 / 36 (2.78%)
         occurrences all number
    6
    2
    Ear Infection
         subjects affected / exposed
    1 / 38 (2.63%)
    2 / 36 (5.56%)
         occurrences all number
    1
    2
    Covid-19
         subjects affected / exposed
    1 / 38 (2.63%)
    2 / 36 (5.56%)
         occurrences all number
    1
    2
    Viral Infection
         subjects affected / exposed
    3 / 38 (7.89%)
    1 / 36 (2.78%)
         occurrences all number
    4
    1
    Viral Upper Respiratory Tract Infection
         subjects affected / exposed
    3 / 38 (7.89%)
    1 / 36 (2.78%)
         occurrences all number
    4
    2
    Asymptomatic Covid-19
         subjects affected / exposed
    2 / 38 (5.26%)
    5 / 36 (13.89%)
         occurrences all number
    2
    5

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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