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    Clinical Trial Results:
    A multi-center, phase III, non-controlled, open-label trial to evaluate the pharmacokinetics, safety, and efficacy of BAY 94-9027 for prophylaxis and treatment of bleeding in previously treated children (age <12 years) with severe hemophilia A

    Summary
    EudraCT number
    		 2012-004434-42
    Trial protocol
    		 GB   BE   IT   NL   LT   BG   Outside EU/EEA   PL   AT   NO   ES   GR  
    Global end of trial date
    19 Feb 2020

    Results information
    Results version number
    		 v3(current)
    This version publication date
    03 Sep 2020
    First version publication date
    17 Jul 2016
    Other versions
    		 v1 , v2
    Version creation reason

    Trial information

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    Trial identification
    Sponsor protocol code
    15912
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01775618
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Bayer AG
    Sponsor organisation address
    Kaiser-Wilhelm-Allee, D-51368 Leverkusen, Germany,
    Public contact
    Therapeutic Area Head, Bayer AG, clinical-trials-contact@bayer.com
    Scientific contact
    Therapeutic Area Head, Bayer AG, clinical-trials-contact@bayer.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    		 EMEA-001229-PIP01-11
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    26 Mar 2020
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    19 Feb 2020
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate pharmacokinetics (PK), safety, and efficacy of BAY94-9027 for prophylaxis and treatment of bleeding in previously treated patients (PTPs) with hemophilia A.
    Protection of trial subjects
    The conduct of this clinical study met all local legal and regulatory requirements. The study was conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki and the International Conference on Harmonization guideline E6: Good Clinical Practice. Before entering the study, the informed consent form was read by and explained to all subjects and/or their legally authorized representative. Participating subjects signed informed consent form and could withdraw from the study at any time without any disadvantage and without having to provide a reason for this decision. Only investigators qualified by training and experience were selected as appropriate experts to investigate the study drug.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    29 May 2013
    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
    Spain: 1
    Country: Number of subjects enrolled
    Greece: 1
    Country: Number of subjects enrolled
    Norway: 2
    Country: Number of subjects enrolled
    New Zealand: 3
    Country: Number of subjects enrolled
    Netherlands: 6
    Country: Number of subjects enrolled
    Poland: 3
    Country: Number of subjects enrolled
    Austria: 3
    Country: Number of subjects enrolled
    Belgium: 3
    Country: Number of subjects enrolled
    Bulgaria: 5
    Country: Number of subjects enrolled
    Italy: 7
    Country: Number of subjects enrolled
    Lithuania: 1
    Country: Number of subjects enrolled
    Canada: 3
    Country: Number of subjects enrolled
    Argentina: 1
    Country: Number of subjects enrolled
    Israel: 9
    Country: Number of subjects enrolled
    United States: 13
    Country: Number of subjects enrolled
    Romania: 4
    Country: Number of subjects enrolled
    United Kingdom: 8
    Worldwide total number of subjects
    73
    EEA total number of subjects
    44
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    73
    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
    		 The main study period was conducted at 31 centers; Part 2 of the study (expansion group) was conducted at 7 centers; and the extension study period was conducted at 32 centers. The entire study included subjects between 29 May 2013 (first subject first visit) and 19 February 2020 (last subject last visit).

    Pre-assignment
    Screening details
    		 Overall 65 subjects were screened in the main study, of them 61 subjects were allocated to treatment. A total of 13 subjects were screened for enrollment in Part 2 and 12 subjects completed screening. 59 subjects were transitioned from the the main study or from Part 2 into the extension study period.

    Period 1
    Period 1 title
    Main study and Part 2
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Main: Age group <6 years
    Arm description
    		 Subjects with age less than (<) 6 years were treated and prophylaxis administered with BAY94-9027 at a dose of 25-60 international units/kilogram (IU/kg) twice per week or 45-60 IU/kg every 5 days or 60 IU/kg every 7 days as an intravenous (IV) infusion as per clinical needs of each subject up to at least 50 exposure days (EDs) and a minimum of at least 6 months.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Recombinant Factor VIII
    Investigational medicinal product code
    BAY94-9027
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    25-60 IU/kg twice per week or 45-60 IU/kg every 5 days or 60 IU/kg every 7 days as an IV infusion as per clinical needs of each subject up to at least 50 EDs and a minimum of at least 6 months.

    Arm title
    		 Main: Age group 6 to <12 years
    Arm description
    		 Subjects with age 6 to <12 years were treated and prophylaxis administered with BAY94-9027 at a dose of 25-60 IU/kg twice per week or 45-60 IU/kg every 5 days or 60 IU/kg every 7 days as an IV infusion as per clinical needs of each subject up to at least 50 EDs and a minimum of at least 6 months.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Recombinant Factor VIII
    Investigational medicinal product code
    BAY94-9027
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    25-60 IU/kg/administration twice per week or 45-60 IU/kg every 5 days or 60 IU/kg every 7 days as an IV infusion as per clinical needs of each subject up to at least 50 EDs and a minimum of at least 6 months.

    Arm title
    		 Part 2: Expansion group <6 years
    Arm description
    		 Subjects with age <6 years were administered with BAY94-9027 at a dose of 25-60 IU/kg twice per week for prophylaxis for 12 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Recombinant Factor VIII
    Investigational medicinal product code
    BAY94-9027
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    25-60 IU/kg twice per week for prophylaxis for 12 weeks.

    Number of subjects in period 1
    		Main: Age group <6 years Main: Age group 6 to <12 years Part 2: Expansion group <6 years
    Started
    32
    29
    12
    Completed
    25
    28
    8
    Not completed
    7
    1
    4
         Adverse event, non-fatal
    6
    1
    4
         Withdrawal by parent/guardian
    1
    -
    -
    Period 2
    Period 2 title
    Extension study
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 Extension: Age group <12 years
    Arm description
    		 Subjects with age <12 years were treated and prophylaxis administered with BAY94-9027 at a dose of 25-60 IU/kg twice per week or 45-60 IU/kg every 5 days or 60 IU/kg every 7 days as an IV infusion as per clinical needs of each subject for at least 50 EDs or until marketing authorization of the drug.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Recombinant Factor VIII
    Investigational medicinal product code
    BAY94-9027
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    25-60 IU/kg twice per week or 45-60 IU/kg every 5 days or 60 IU/kg every 7 days as an IV infusion as per clinical needs of each subject for at least 50 EDs or until marketing authorization of the drug.

    Number of subjects in period 2 [1]
    		Extension: Age group <12 years
    Started
    59
    Completed
    57
    Not completed
    2
         Adverse event, non-fatal
    1
         Other
    1
    Notes
    [1] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: Optional participation of the extension study were offered to subjects completing the main study or Part 2.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Main: Age group <6 years
    Reporting group description
    		 Subjects with age less than (<) 6 years were treated and prophylaxis administered with BAY94-9027 at a dose of 25-60 international units/kilogram (IU/kg) twice per week or 45-60 IU/kg every 5 days or 60 IU/kg every 7 days as an intravenous (IV) infusion as per clinical needs of each subject up to at least 50 exposure days (EDs) and a minimum of at least 6 months.

    Reporting group title
    Main: Age group 6 to <12 years
    Reporting group description
    		 Subjects with age 6 to <12 years were treated and prophylaxis administered with BAY94-9027 at a dose of 25-60 IU/kg twice per week or 45-60 IU/kg every 5 days or 60 IU/kg every 7 days as an IV infusion as per clinical needs of each subject up to at least 50 EDs and a minimum of at least 6 months.

    Reporting group title
    Part 2: Expansion group <6 years
    Reporting group description
    		 Subjects with age <6 years were administered with BAY94-9027 at a dose of 25-60 IU/kg twice per week for prophylaxis for 12 weeks.

    Reporting group values
    		 Main: Age group <6 years Main: Age group 6 to <12 years Part 2: Expansion group <6 years Total
    Number of subjects
    		 32 29 12 73
    Age categorical
    Units: Subjects
        Children (2-11 years)
    		 32 29 12 73
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 3.5 ( 1.0 ) 8.6 ( 1.5 ) 3.5 ( 1.24 ) -
    Gender categorical
    Units: Subjects
        Female
    		 0 0 0 0
        Male
    		 32 29 12 73

    End points

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    End points reporting groups
    Reporting group title
    Main: Age group <6 years
    Reporting group description
    		 Subjects with age less than (<) 6 years were treated and prophylaxis administered with BAY94-9027 at a dose of 25-60 international units/kilogram (IU/kg) twice per week or 45-60 IU/kg every 5 days or 60 IU/kg every 7 days as an intravenous (IV) infusion as per clinical needs of each subject up to at least 50 exposure days (EDs) and a minimum of at least 6 months.

    Reporting group title
    Main: Age group 6 to <12 years
    Reporting group description
    		 Subjects with age 6 to <12 years were treated and prophylaxis administered with BAY94-9027 at a dose of 25-60 IU/kg twice per week or 45-60 IU/kg every 5 days or 60 IU/kg every 7 days as an IV infusion as per clinical needs of each subject up to at least 50 EDs and a minimum of at least 6 months.

    Reporting group title
    Part 2: Expansion group <6 years
    Reporting group description
    		 Subjects with age <6 years were administered with BAY94-9027 at a dose of 25-60 IU/kg twice per week for prophylaxis for 12 weeks.
    Reporting group title
    Extension: Age group <12 years
    Reporting group description
    		 Subjects with age <12 years were treated and prophylaxis administered with BAY94-9027 at a dose of 25-60 IU/kg twice per week or 45-60 IU/kg every 5 days or 60 IU/kg every 7 days as an IV infusion as per clinical needs of each subject for at least 50 EDs or until marketing authorization of the drug.

    Subject analysis set title
    Safety Analysis Set (SAF) - Main study
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    All subjects enrolled into the main study who received at least one dose of study medication.

    Subject analysis set title
    Intent-to-treat (ITT) Analysis set - Main study
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All safety subjects enrolled into the main study who had infusion/bleeding data from the Electronic Patient Diary (EPD).

    Subject analysis set title
    Pharmacokinetic (PK) Analysis Set (PKS) - Main study
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    All subjects enrolled into the main study with a valid profile of BAY94-9027 were included in the analysis of PK data.

    Subject analysis set title
    Safety Analysis Set (SAF) - Part 2
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    All subjects enrolled into the Part 2 of the study (expansion group) who received at least one dose of study medication.

    Subject analysis set title
    Safety Analysis Set (SAF) - Extension study
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    All subjects enrolled into the extension study who received at least one dose of study medication in the extension study period.

    Primary: Annualized number of total bleeds in main study

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    End point title
    		 Annualized number of total bleeds in main study [1] [2]
    End point description
    The annualized number of total bleeds included sum of all spontaneous bleeds and traumatic bleeds during prophylactic treatment. An exposure day defined as a calendar day during which at least one infusion was taken by the subject.
    End point type
    Primary
    End point timeframe
    Baseline up to 50 exposure days (ED) over 6 months
    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: Only descriptive summary statistics were planned for this endpoint.
    [2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The primary objective of Part 2 and extension study was to evaluate the safety of BAY94-9027.
    End point values
    		 Main: Age group <6 years Main: Age group 6 to <12 years
    Number of subjects analysed
    32 [3]
    28 [4]
    Units: Bleeds
    median (inter-quartile range (Q1-Q3))
        Overall Bleeds
    2.68 (1.08 to 6.79)
    2.92 (0 to 6.66)
    Notes
    [3] - ITT - Main study
    [4] - ITT - Main study
    No statistical analyses for this end point

    Primary: Maximum observed drug concentration (Cmax) in plasma of BAY94-9027

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    End point title
    		 Maximum observed drug concentration (Cmax) in plasma of BAY94-9027 [5] [6]
    End point description
    Maximum observed drug concentration, directly taken from analytical data. Geometric mean and geometric standard deviation (Geom SD) were reported.
    End point type
    Primary
    End point timeframe
    Pre-dose to 72 hours post-dose
    Notes
    [5] - 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: Only descriptive summary statistics were planned for this endpoint.
    [6] - 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: The primary objective of Part 2 and extension study was to evaluate the safety of BAY94-9027.
    End point values
    		 Main: Age group <6 years Main: Age group 6 to <12 years
    Number of subjects analysed
    15 [7]
    15 [8]
    Units: International units/deciliter (IU/dL)
        geometric mean (standard deviation)
    110.9 ( 1.33 )
    127 ( 1.21 )
    Notes
    [7] - PKS - Main study with evaluable subjects for this endpoint.
    [8] - PKS - Main study with evaluable subjects for this endpoint.
    No statistical analyses for this end point

    Primary: Half-life associated with the terminal slope (t1/2) in plasma of BAY94-9027

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    End point title
    		 Half-life associated with the terminal slope (t1/2) in plasma of BAY94-9027 [9] [10]
    End point description
    Half-life associated with the terminal slope. Geometric mean and geometric standard deviation (Geo SD) were reported.
    End point type
    Primary
    End point timeframe
    Pre-dose to 72 hours post-dose
    Notes
    [9] - 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: Only descriptive summary statistics were planned for this endpoint.
    [10] - 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: The primary objective of Part 2 and extension study was to evaluate the safety of BAY94-9027.
    End point values
    		 Main: Age group <6 years Main: Age group 6 to <12 years
    Number of subjects analysed
    16 [11]
    16 [12]
    Units: Hours
        geometric mean (standard deviation)
    14.1 ( 1.39 )
    15.8 ( 1.25 )
    Notes
    [11] - PKS - Main study with evaluable subjects for this endpoint.
    [12] - PKS - Main study with evaluable subjects for this endpoint.
    No statistical analyses for this end point

    Primary: Area under the concentration versus time curve from zero to infinity (AUC) in plasma of BAY94-9027

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    End point title
    		 Area under the concentration versus time curve from zero to infinity (AUC) in plasma of BAY94-9027 [13] [14]
    End point description
    Area under the concentration versus time curve from zero to infinity after single (first) dose. Geometric mean and geometric standard deviation (Geo SD) were reported.
    End point type
    Primary
    End point timeframe
    Pre-dose to 72 hours post-dose
    Notes
    [13] - 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: Only descriptive summary statistics were planned for this endpoint.
    [14] - 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: The primary objective of Part 2 and extension study was to evaluate the safety of BAY94-9027.
    End point values
    		 Main: Age group <6 years Main: Age group 6 to <12 years
    Number of subjects analysed
    15 [15]
    13 [16]
    Units: IU*hours/deciliter (IU*h/dL)
        geometric mean (standard deviation)
    1804.3 ( 1.94 )
    2837.03 ( 1.21 )
    Notes
    [15] - PKS - Main study with evaluable subjects for this endpoint.
    [16] - PKS - Main study with evaluable subjects for this endpoint.
    No statistical analyses for this end point

    Primary: Mean residence time (MRT) of BAY94-9027

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    End point title
    		 Mean residence time (MRT) of BAY94-9027 [17] [18]
    End point description
    Mean residence time after intravenous infusion was reported. Geometric mean and geometric standard deviation (Geo SD) were reported.
    End point type
    Primary
    End point timeframe
    Pre-dose to 72 hours post-dose
    Notes
    [17] - 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: Only descriptive summary statistics were planned for this endpoint.
    [18] - 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: The primary objective of Part 2 and extension study was to evaluate the safety of BAY94-9027.
    End point values
    		 Main: Age group <6 years Main: Age group 6 to <12 years
    Number of subjects analysed
    16 [19]
    14 [20]
    Units: Hours
        geometric mean (standard deviation)
    19.1 ( 1.42 )
    23.7 ( 1.25 )
    Notes
    [19] - PKS - Main study with evaluable subjects for this endpoint.
    [20] - PKS - Main study with evaluable subjects for this endpoint
    No statistical analyses for this end point

    Primary: Apparent volume of distribution at steady state after intravascular administration (Vss) of BAY94-9027

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    End point title
    		 Apparent volume of distribution at steady state after intravascular administration (Vss) of BAY94-9027 [21] [22]
    End point description
    Apparent volume of distribution at steady state after intravascular administration (Vss) of BAY949027. Geometric mean and geometric standard deviation (Geo SD) were reported.
    End point type
    Primary
    End point timeframe
    Pre-dose to 72 hours post-dose
    Notes
    [21] - 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: Only descriptive summary statistics were planned for this endpoint.
    [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: The primary objective of Part 2 and extension study was to evaluate the safety of BAY94-9027.
    End point values
    		 Main: Age group <6 years Main: Age group 6 to <12 years
    Number of subjects analysed
    16 [23]
    14 [24]
    Units: Deciliter per kilogram (dL/kg)
        geometric mean (standard deviation)
    0.62 ( 1.48 )
    0.49 ( 1.2 )
    Notes
    [23] - PKS - Main study with evaluable subjects for this endpoint.
    [24] - PKS - Main study with evaluable subjects for this endpoint.
    No statistical analyses for this end point

    Primary: Systemic clearance (CL) of BAY94-9027

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    End point title
    		 Systemic clearance (CL) of BAY94-9027 [25] [26]
    End point description
    Total body clearance of drug in the measured matrix (volume/time) or (volume/time/body weight) calculated after intravenous application (expression by qualifier or matrix). Geometric mean and geometric standard deviation (Geo SD) were reported.
    End point type
    Primary
    End point timeframe
    Pre-dose to 72 hours post-dose
    Notes
    [25] - 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: Only descriptive summary statistics were planned for this endpoint.
    [26] - 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: The primary objective of Part 2 and extension study was to evaluate the safety of BAY94-9027.
    End point values
    		 Main: Age group <6 years Main: Age group 6 to <12 years
    Number of subjects analysed
    16 [27]
    14 [28]
    Units: Deciliter per hour per kilogram[dL/h/kg)
        geometric mean (standard deviation)
    0.032 ( 1.94 )
    0.021 ( 1.22 )
    Notes
    [27] - PKS - Main study with evaluable subjects for this endpoint.
    [28] - PKS - Main study with evaluable subjects for this endpoint.
    No statistical analyses for this end point

    Primary: Number of subjects with assessment of adequacy of hemostasis for treatment of bleeds

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    End point title
    		 Number of subjects with assessment of adequacy of hemostasis for treatment of bleeds [29] [30]
    End point description
    Subjects/caregivers' assessment for adequacy of hemostasis (stopping bleeding) for each bleed was reported using 4 point scale as 'excellent', 'good', 'moderate', and 'poor'; where, Excellent: Abrupt pain relief and /or improvement in signs of bleeding with no additional infusion administered, Good: Definite pain relief and/or improvement in signs of bleeding, but possibly requiring more than one infusion for complete resolution, Moderate: Probable or slight improvement in signs of bleeding, with at least one additional infusion for complete resolution, Poor: No improvement or condition worsened.
    End point type
    Primary
    End point timeframe
    Pre-dose to 72 hours post-dose
    Notes
    [29] - 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: Only descriptive summary statistics were planned for this endpoint.
    [30] - 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: The primary objective of Part 2 and extension study was to evaluate the safety of BAY94-9027.
    End point values
    		 Main: Age group <6 years Main: Age group 6 to <12 years
    Number of subjects analysed
    32 [31]
    28 [32]
    Units: Bleeds
        Excellent
    29
    26
        Good
    34
    31
        Moderate
    6
    9
        Poor
    3
    2
    Notes
    [31] - ITT - Main study
    [32] - ITT - Main study
    No statistical analyses for this end point

    Primary: Number of subjects with events of special interest in Part 2

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    End point title
    		 Number of subjects with events of special interest in Part 2 [33] [34]
    End point description
    Hypersensitivity reactions to the study drug and loss of efficacy of the drug product were defined in the study as events of special interest.
    End point type
    Primary
    End point timeframe
    12 weeks
    Notes
    [33] - 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: Only descriptive summary statistics were planned for this endpoint.
    [34] - 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: Characterization of the potential immune response was defined as primary endpoint only for Part 2.
    End point values
    		 Part 2: Expansion group <6 years
    Number of subjects analysed
    12 [35]
    Units: Subjects
    4
    Notes
    [35] - SAF - Part 2
    No statistical analyses for this end point

    Primary: Number of subjects with any anti-drug antibody development in Part 2

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    End point title
    		 Number of subjects with any anti-drug antibody development in Part 2 [36] [37]
    End point description
    Number of subjects in Part 2 with any antibody in plasma, not present before, but developed after first infusion of study drug was reported.
    End point type
    Primary
    End point timeframe
    12 weeks
    Notes
    [36] - 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: Only descriptive summary statistics were planned for this endpoint.
    [37] - 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: Characterization of the potential immune response was defined as primary endpoint only for Part 2.
    End point values
    		 Part 2: Expansion group <6 years
    Number of subjects analysed
    6 [38]
    Units: Subjects
    2
    Notes
    [38] - Subjects in SAF - Part 2 with no positive baseline assessments for any antibody
    No statistical analyses for this end point

    Primary: Number of subjects with events of special interest and any anti-drug antibody development in Part 2

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    End point title
    		 Number of subjects with events of special interest and any anti-drug antibody development in Part 2 [39] [40]
    End point description
    Number of subjects in Part 2 with with events of special interest and any antibody in plasma, not present before, but developed after first infusion of study drug was reported.
    End point type
    Primary
    End point timeframe
    12 weeks
    Notes
    [39] - 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: Only descriptive summary statistics were planned for this endpoint.
    [40] - 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: Characterization of the potential immune response was defined as primary endpoint only for Part 2.
    End point values
    		 Part 2: Expansion group <6 years
    Number of subjects analysed
    4 [41]
    Units: Subjects
    3
    Notes
    [41] - Subjects in SAF - Part 2 with events of special interest
    No statistical analyses for this end point

    Primary: Number of subjects with inhibitor development in Part 2

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    End point title
    		 Number of subjects with inhibitor development in Part 2 [42] [43]
    End point description
    Subject in Part 2 were evaluated for positive FVIII inhibitor level (>=0.6 BU/mL, using Nijmegen modified Bethesda assay).
    End point type
    Primary
    End point timeframe
    12 weeks
    Notes
    [42] - 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: Only descriptive summary statistics were planned for this endpoint.
    [43] - 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: Inhibitor development in main study and extension study was reported as separate endpoints.
    End point values
    		 Part 2: Expansion group <6 years
    Number of subjects analysed
    12 [44]
    Units: Subjects
    0
    Notes
    [44] - SAF - Part 2
    No statistical analyses for this end point

    Primary: Number of subjects with inhibitor development in extension study

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    End point title
    		 Number of subjects with inhibitor development in extension study [45]
    End point description
    Subject in Part 2 were evaluated for positive FVIII inhibitor level (>=0.6 BU/mL, using Nijmegen modified Bethesda assay).
    End point type
    Primary
    End point timeframe
    Up to the final visit of the extension study
    Notes
    [45] - 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: Only descriptive summary statistics were planned for this endpoint. None of the inhibitors was confirmed in a second sample.
    End point values
    		 Extension: Age group <12 years
    Number of subjects analysed
    59 [46]
    Units: Subjects
    3
    Notes
    [46] - SAF - Extension study
    No statistical analyses for this end point

    Secondary: Number of subjects with inhibitor development in main study

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    End point title
    		 Number of subjects with inhibitor development in main study [47]
    End point description
    Subject were evaluated for positive FVIII inhibitor level (>=0.6 BU/mL, using Nijmegen modified Bethesda assay).
    End point type
    Secondary
    End point timeframe
    After 10 to 15 and 50 exposure days over 6 months.
    Notes
    [47] - 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: Inhibitor development in Part 2 and extension study was reported as separate endpoints.
    End point values
    		 Main: Age group <6 years Main: Age group 6 to <12 years
    Number of subjects analysed
    32 [48]
    29 [49]
    Units: Subjects
    0
    0
    Notes
    [48] - SAF - Main study
    [49] - SAF - Main study
    No statistical analyses for this end point

    Secondary: Assessment of incremental recovery in main study

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    End point title
    		 Assessment of incremental recovery in main study [50]
    End point description
    Incremental recovery was determined by collecting a sample for FVIII level before the scheduled infusion, and a second sample collected 20-30 minutes after end of the infusion. The exact sampling times before and after infusion were documented in the CRF.
    End point type
    Secondary
    End point timeframe
    Baseline to the final visit of the main study
    Notes
    [50] - 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: Incremental recovery was defined as secondary endpoint only for main study.
    End point values
    		 Main: Age group <6 years Main: Age group 6 to <12 years
    Number of subjects analysed
    32 [51]
    28 [52]
    Units: Kilogram/deciliter (kg/dL)
    arithmetic mean (standard deviation)
        Baseline (N= 32, 28)
    1.698 ( 0.58 )
    1.941 ( 0.53 )
        Month 1 (N= 1, 3)
    2.326 ( 99999 )
    6.416 ( 7.85 )
        Month 2 (N= 1, 1)
    1.991 ( 99999 )
    2.261 ( 99999 )
        Month 3 (N= 22, 26)
    1.843 ( 0.53 )
    2.277 ( 0.7 )
        Month 6 (N= 22, 27)
    2.227 ( 0.58 )
    2.33 ( 0.67 )
    Notes
    [51] - ITT - Main study
    [52] - ITT - Main study
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From the start of study treatment up to 7 days after the last dose.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    22.1
    Reporting groups
    Reporting group title
    Main: Age group <6 years
    Reporting group description
    		 Subjects with age less than (<) 6 years were treated and prophylaxis administered with BAY94-9027 at a dose of 25-60 international units/kilogram (IU/kg) twice per week or 45-60 IU/kg every 5 days or 60 IU/kg every 7 days as an intravenous (IV) infusion as per clinical needs of each subject up to at least 50 exposure days (EDs) and a minimum of at least 6 months

    Reporting group title
    Main: Age group 6 to <12 years
    Reporting group description
    		 Subjects with age 6 to <12 years were treated and prophylaxis administered with BAY94-9027 at a dose of 25-60 IU/kg twice per week or 45-60 IU/kg every 5 days or 60 IU/kg every 7 days as an IV infusion as per clinical needs of each subject up to at least 50 EDs and a minimum of at least 6 months

    Reporting group title
    Part 2: Expansion group <6 years
    Reporting group description
    		 Subjects with age <6 years were administered with BAY94-9027 at a dose of 25-60 IU/kg twice per week for prophylaxis for 12 weeks

    Reporting group title
    Extension: Age group <12 years
    Reporting group description
    		 Subjects with age <12 years were treated and prophylaxis administered with BAY94-9027 at a dose of 25-60 IU/kg twice per week or 45-60 IU/kg every 5 days or 60 IU/kg every 7 days as an IV infusion as per clinical needs of each subject for at least 50 EDs or until marketing authorization of the drug

    Serious adverse events
    		 Main: Age group <6 years Main: Age group 6 to <12 years Part 2: Expansion group <6 years Extension: Age group <12 years
    Total subjects affected by serious adverse events
         subjects affected / exposed
    8 / 32 (25.00%)
    3 / 29 (10.34%)
    2 / 12 (16.67%)
    20 / 59 (33.90%)
         number of deaths (all causes)
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    Surgical and medical procedures
    Catheter management
         subjects affected / exposed
    1 / 32 (3.13%)
    0 / 29 (0.00%)
    0 / 12 (0.00%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Central venous catheter removal
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 29 (0.00%)
    0 / 12 (0.00%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Central venous catheterisation
         subjects affected / exposed
    1 / 32 (3.13%)
    0 / 29 (0.00%)
    0 / 12 (0.00%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Synoviorthesis
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 29 (0.00%)
    0 / 12 (0.00%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Catheter site swelling
         subjects affected / exposed
    1 / 32 (3.13%)
    0 / 29 (0.00%)
    0 / 12 (0.00%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Drug ineffective
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 29 (0.00%)
    1 / 12 (8.33%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Immune system disorders
    Drug hypersensitivity
         subjects affected / exposed
    1 / 32 (3.13%)
    0 / 29 (0.00%)
    0 / 12 (0.00%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypersensitivity
         subjects affected / exposed
    1 / 32 (3.13%)
    1 / 29 (3.45%)
    1 / 12 (8.33%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Social circumstances
    Physical assault
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 29 (0.00%)
    0 / 12 (0.00%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pharyngeal haemorrhage
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 29 (0.00%)
    0 / 12 (0.00%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tonsillar inflammation
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 29 (0.00%)
    0 / 12 (0.00%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Product issues
    Device connection issue
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 29 (3.45%)
    0 / 12 (0.00%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Device occlusion
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 29 (0.00%)
    0 / 12 (0.00%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Anti factor VIII antibody positive
         subjects affected / exposed
    1 / 32 (3.13%)
    0 / 29 (0.00%)
    0 / 12 (0.00%)
    2 / 59 (3.39%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Drug specific antibody present
         subjects affected / exposed
    3 / 32 (9.38%)
    0 / 29 (0.00%)
    0 / 12 (0.00%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    5 / 5
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Concussion
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 29 (0.00%)
    0 / 12 (0.00%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Fibula fracture
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 29 (0.00%)
    0 / 12 (0.00%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Head injury
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 29 (0.00%)
    0 / 12 (0.00%)
    3 / 59 (5.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin laceration
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 29 (0.00%)
    0 / 12 (0.00%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Subcutaneous haematoma
         subjects affected / exposed
    1 / 32 (3.13%)
    0 / 29 (0.00%)
    0 / 12 (0.00%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Congenital, familial and genetic disorders
    Cryptorchism
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 29 (0.00%)
    0 / 12 (0.00%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Cardiomyopathy
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 29 (0.00%)
    0 / 12 (0.00%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Haemorrhage intracranial
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 29 (3.45%)
    0 / 12 (0.00%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 29 (3.45%)
    0 / 12 (0.00%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Somnolence
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 29 (0.00%)
    0 / 12 (0.00%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Subarachnoid haemorrhage
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 29 (3.45%)
    0 / 12 (0.00%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 29 (0.00%)
    0 / 12 (0.00%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Diplopia
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 29 (0.00%)
    0 / 12 (0.00%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Photophobia
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 29 (3.45%)
    0 / 12 (0.00%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 29 (0.00%)
    0 / 12 (0.00%)
    2 / 59 (3.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Abdominal wall haematoma
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 29 (0.00%)
    0 / 12 (0.00%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Crohn's disease
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 29 (0.00%)
    0 / 12 (0.00%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastritis
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 29 (0.00%)
    0 / 12 (0.00%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Inguinal hernia
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 29 (0.00%)
    0 / 12 (0.00%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 29 (3.45%)
    0 / 12 (0.00%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Haemarthrosis
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 29 (0.00%)
    0 / 12 (0.00%)
    5 / 59 (8.47%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Appendicitis
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 29 (0.00%)
    0 / 12 (0.00%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Device related sepsis
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 29 (0.00%)
    0 / 12 (0.00%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 29 (3.45%)
    0 / 12 (0.00%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Otitis media
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 29 (0.00%)
    0 / 12 (0.00%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 29 (0.00%)
    0 / 12 (0.00%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Staphylococcal infection
         subjects affected / exposed
    1 / 32 (3.13%)
    0 / 29 (0.00%)
    0 / 12 (0.00%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Viral infection
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 29 (0.00%)
    0 / 12 (0.00%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Main: Age group <6 years Main: Age group 6 to <12 years Part 2: Expansion group <6 years Extension: Age group <12 years
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    24 / 32 (75.00%)
    19 / 29 (65.52%)
    10 / 12 (83.33%)
    53 / 59 (89.83%)
    Injury, poisoning and procedural complications
    Arthropod bite
         subjects affected / exposed
    2 / 32 (6.25%)
    0 / 29 (0.00%)
    0 / 12 (0.00%)
    1 / 59 (1.69%)
         occurrences all number
    2
    0
    0
    2
    Contusion
         subjects affected / exposed
    5 / 32 (15.63%)
    2 / 29 (6.90%)
    3 / 12 (25.00%)
    10 / 59 (16.95%)
         occurrences all number
    5
    2
    3
    13
    Fall
         subjects affected / exposed
    3 / 32 (9.38%)
    0 / 29 (0.00%)
    2 / 12 (16.67%)
    7 / 59 (11.86%)
         occurrences all number
    3
    0
    3
    9
    Hand fracture
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 29 (0.00%)
    0 / 12 (0.00%)
    3 / 59 (5.08%)
         occurrences all number
    0
    0
    0
    3
    Head injury
         subjects affected / exposed
    2 / 32 (6.25%)
    0 / 29 (0.00%)
    0 / 12 (0.00%)
    12 / 59 (20.34%)
         occurrences all number
    4
    0
    0
    17
    Joint injury
         subjects affected / exposed
    1 / 32 (3.13%)
    0 / 29 (0.00%)
    1 / 12 (8.33%)
    10 / 59 (16.95%)
         occurrences all number
    1
    0
    1
    12
    Ligament sprain
         subjects affected / exposed
    2 / 32 (6.25%)
    0 / 29 (0.00%)
    0 / 12 (0.00%)
    7 / 59 (11.86%)
         occurrences all number
    2
    0
    0
    10
    Limb injury
         subjects affected / exposed
    1 / 32 (3.13%)
    0 / 29 (0.00%)
    0 / 12 (0.00%)
    10 / 59 (16.95%)
         occurrences all number
    1
    0
    0
    16
    Lip injury
         subjects affected / exposed
    2 / 32 (6.25%)
    0 / 29 (0.00%)
    0 / 12 (0.00%)
    0 / 59 (0.00%)
         occurrences all number
    2
    0
    0
    0
    Mouth injury
         subjects affected / exposed
    2 / 32 (6.25%)
    0 / 29 (0.00%)
    0 / 12 (0.00%)
    0 / 59 (0.00%)
         occurrences all number
    2
    0
    0
    0
    Post-traumatic pain
         subjects affected / exposed
    2 / 32 (6.25%)
    0 / 29 (0.00%)
    0 / 12 (0.00%)
    7 / 59 (11.86%)
         occurrences all number
    2
    0
    0
    11
    Skin abrasion
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 29 (0.00%)
    0 / 12 (0.00%)
    3 / 59 (5.08%)
         occurrences all number
    0
    0
    0
    7
    Skin injury
         subjects affected / exposed
    1 / 32 (3.13%)
    0 / 29 (0.00%)
    1 / 12 (8.33%)
    0 / 59 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Skin laceration
         subjects affected / exposed
    1 / 32 (3.13%)
    0 / 29 (0.00%)
    0 / 12 (0.00%)
    3 / 59 (5.08%)
         occurrences all number
    1
    0
    0
    4
    Subcutaneous haematoma
         subjects affected / exposed
    2 / 32 (6.25%)
    0 / 29 (0.00%)
    1 / 12 (8.33%)
    5 / 59 (8.47%)
         occurrences all number
    12
    0
    1
    6
    Vascular disorders
    Haematoma
         subjects affected / exposed
    3 / 32 (9.38%)
    0 / 29 (0.00%)
    1 / 12 (8.33%)
    6 / 59 (10.17%)
         occurrences all number
    18
    0
    1
    9
    Nervous system disorders
    Headache
         subjects affected / exposed
    2 / 32 (6.25%)
    6 / 29 (20.69%)
    0 / 12 (0.00%)
    16 / 59 (27.12%)
         occurrences all number
    2
    8
    0
    36
    Presyncope
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 29 (0.00%)
    1 / 12 (8.33%)
    0 / 59 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Blood and lymphatic system disorders
    Lymphadenopathy
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 29 (0.00%)
    0 / 12 (0.00%)
    4 / 59 (6.78%)
         occurrences all number
    0
    0
    0
    4
    General disorders and administration site conditions
    Drug ineffective
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 29 (0.00%)
    2 / 12 (16.67%)
    0 / 59 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Injection site pruritus
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 29 (0.00%)
    1 / 12 (8.33%)
    0 / 59 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Malaise
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 29 (0.00%)
    0 / 12 (0.00%)
    3 / 59 (5.08%)
         occurrences all number
    0
    0
    0
    7
    Mass
         subjects affected / exposed
    2 / 32 (6.25%)
    0 / 29 (0.00%)
    0 / 12 (0.00%)
    3 / 59 (5.08%)
         occurrences all number
    2
    0
    0
    3
    Pain
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 29 (3.45%)
    0 / 12 (0.00%)
    5 / 59 (8.47%)
         occurrences all number
    0
    1
    0
    7
    Peripheral swelling
         subjects affected / exposed
    1 / 32 (3.13%)
    0 / 29 (0.00%)
    0 / 12 (0.00%)
    3 / 59 (5.08%)
         occurrences all number
    1
    0
    0
    3
    Pyrexia
         subjects affected / exposed
    7 / 32 (21.88%)
    2 / 29 (6.90%)
    3 / 12 (25.00%)
    24 / 59 (40.68%)
         occurrences all number
    9
    4
    3
    63
    Ear and labyrinth disorders
    Ear pain
         subjects affected / exposed
    1 / 32 (3.13%)
    0 / 29 (0.00%)
    0 / 12 (0.00%)
    4 / 59 (6.78%)
         occurrences all number
    3
    0
    0
    6
    Immune system disorders
    Seasonal allergy
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 29 (3.45%)
    0 / 12 (0.00%)
    4 / 59 (6.78%)
         occurrences all number
    0
    1
    0
    4
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 29 (3.45%)
    0 / 12 (0.00%)
    8 / 59 (13.56%)
         occurrences all number
    0
    1
    0
    13
    Abdominal pain upper
         subjects affected / exposed
    0 / 32 (0.00%)
    3 / 29 (10.34%)
    0 / 12 (0.00%)
    3 / 59 (5.08%)
         occurrences all number
    0
    3
    0
    4
    Dental caries
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 29 (0.00%)
    0 / 12 (0.00%)
    3 / 59 (5.08%)
         occurrences all number
    0
    0
    0
    4
    Diarrhoea
         subjects affected / exposed
    4 / 32 (12.50%)
    2 / 29 (6.90%)
    0 / 12 (0.00%)
    7 / 59 (11.86%)
         occurrences all number
    4
    2
    0
    14
    Gingival bleeding
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 29 (0.00%)
    0 / 12 (0.00%)
    5 / 59 (8.47%)
         occurrences all number
    0
    0
    0
    7
    Loose tooth
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 29 (0.00%)
    0 / 12 (0.00%)
    3 / 59 (5.08%)
         occurrences all number
    0
    0
    0
    4
    Nausea
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 29 (0.00%)
    0 / 12 (0.00%)
    7 / 59 (11.86%)
         occurrences all number
    0
    0
    0
    9
    Vomiting
         subjects affected / exposed
    2 / 32 (6.25%)
    3 / 29 (10.34%)
    0 / 12 (0.00%)
    12 / 59 (20.34%)
         occurrences all number
    2
    3
    0
    21
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    5 / 32 (15.63%)
    1 / 29 (3.45%)
    2 / 12 (16.67%)
    16 / 59 (27.12%)
         occurrences all number
    5
    1
    3
    30
    Epistaxis
         subjects affected / exposed
    3 / 32 (9.38%)
    4 / 29 (13.79%)
    2 / 12 (16.67%)
    16 / 59 (27.12%)
         occurrences all number
    5
    9
    2
    41
    Nasal congestion
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 29 (0.00%)
    0 / 12 (0.00%)
    3 / 59 (5.08%)
         occurrences all number
    0
    0
    0
    3
    Oropharyngeal pain
         subjects affected / exposed
    1 / 32 (3.13%)
    5 / 29 (17.24%)
    0 / 12 (0.00%)
    14 / 59 (23.73%)
         occurrences all number
    1
    5
    0
    20
    Rhinorrhoea
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 29 (0.00%)
    0 / 12 (0.00%)
    3 / 59 (5.08%)
         occurrences all number
    0
    0
    0
    5
    Skin and subcutaneous tissue disorders
    Dermatitis contact
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 29 (0.00%)
    0 / 12 (0.00%)
    3 / 59 (5.08%)
         occurrences all number
    0
    0
    0
    4
    Rash
         subjects affected / exposed
    3 / 32 (9.38%)
    1 / 29 (3.45%)
    1 / 12 (8.33%)
    4 / 59 (6.78%)
         occurrences all number
    4
    2
    1
    4
    Urticaria
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 29 (0.00%)
    0 / 12 (0.00%)
    3 / 59 (5.08%)
         occurrences all number
    0
    0
    0
    3
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    1 / 32 (3.13%)
    3 / 29 (10.34%)
    1 / 12 (8.33%)
    11 / 59 (18.64%)
         occurrences all number
    1
    3
    1
    16
    Back pain
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 29 (0.00%)
    0 / 12 (0.00%)
    4 / 59 (6.78%)
         occurrences all number
    0
    0
    0
    8
    Haemarthrosis
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 29 (3.45%)
    1 / 12 (8.33%)
    2 / 59 (3.39%)
         occurrences all number
    0
    1
    1
    4
    Joint swelling
         subjects affected / exposed
    1 / 32 (3.13%)
    0 / 29 (0.00%)
    0 / 12 (0.00%)
    3 / 59 (5.08%)
         occurrences all number
    1
    0
    0
    4
    Pain in extremity
         subjects affected / exposed
    3 / 32 (9.38%)
    3 / 29 (10.34%)
    2 / 12 (16.67%)
    14 / 59 (23.73%)
         occurrences all number
    3
    4
    2
    20
    Synovitis
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 29 (0.00%)
    0 / 12 (0.00%)
    4 / 59 (6.78%)
         occurrences all number
    0
    0
    0
    5
    Tendonitis
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 29 (0.00%)
    0 / 12 (0.00%)
    6 / 59 (10.17%)
         occurrences all number
    0
    0
    0
    7
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    1 / 32 (3.13%)
    0 / 29 (0.00%)
    0 / 12 (0.00%)
    4 / 59 (6.78%)
         occurrences all number
    1
    0
    0
    12
    Conjunctivitis
         subjects affected / exposed
    1 / 32 (3.13%)
    0 / 29 (0.00%)
    0 / 12 (0.00%)
    3 / 59 (5.08%)
         occurrences all number
    1
    0
    0
    4
    Ear infection
         subjects affected / exposed
    1 / 32 (3.13%)
    1 / 29 (3.45%)
    1 / 12 (8.33%)
    5 / 59 (8.47%)
         occurrences all number
    2
    1
    1
    8
    Gastroenteritis
         subjects affected / exposed
    2 / 32 (6.25%)
    3 / 29 (10.34%)
    0 / 12 (0.00%)
    7 / 59 (11.86%)
         occurrences all number
    2
    3
    0
    7
    Impetigo
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 29 (0.00%)
    0 / 12 (0.00%)
    3 / 59 (5.08%)
         occurrences all number
    0
    0
    0
    6
    Influenza
         subjects affected / exposed
    1 / 32 (3.13%)
    0 / 29 (0.00%)
    0 / 12 (0.00%)
    10 / 59 (16.95%)
         occurrences all number
    1
    0
    0
    12
    Nasopharyngitis
         subjects affected / exposed
    5 / 32 (15.63%)
    1 / 29 (3.45%)
    0 / 12 (0.00%)
    19 / 59 (32.20%)
         occurrences all number
    8
    1
    0
    34
    Otitis externa
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 29 (0.00%)
    0 / 12 (0.00%)
    3 / 59 (5.08%)
         occurrences all number
    0
    0
    0
    6
    Otitis media
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 29 (0.00%)
    0 / 12 (0.00%)
    4 / 59 (6.78%)
         occurrences all number
    0
    0
    0
    5
    Pharyngitis
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 29 (0.00%)
    0 / 12 (0.00%)
    5 / 59 (8.47%)
         occurrences all number
    0
    0
    0
    7
    Pharyngitis streptococcal
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 29 (3.45%)
    0 / 12 (0.00%)
    5 / 59 (8.47%)
         occurrences all number
    0
    1
    0
    7
    Pneumonia
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 29 (0.00%)
    0 / 12 (0.00%)
    4 / 59 (6.78%)
         occurrences all number
    0
    0
    0
    4
    Rhinitis
         subjects affected / exposed
    3 / 32 (9.38%)
    0 / 29 (0.00%)
    0 / 12 (0.00%)
    9 / 59 (15.25%)
         occurrences all number
    3
    0
    0
    11
    Sinusitis
         subjects affected / exposed
    1 / 32 (3.13%)
    1 / 29 (3.45%)
    0 / 12 (0.00%)
    5 / 59 (8.47%)
         occurrences all number
    2
    1
    0
    13
    Tonsillitis
         subjects affected / exposed
    0 / 32 (0.00%)
    2 / 29 (6.90%)
    0 / 12 (0.00%)
    7 / 59 (11.86%)
         occurrences all number
    0
    2
    0
    9
    Upper respiratory tract infection
         subjects affected / exposed
    6 / 32 (18.75%)
    1 / 29 (3.45%)
    1 / 12 (8.33%)
    9 / 59 (15.25%)
         occurrences all number
    6
    1
    1
    16
    Varicella
         subjects affected / exposed
    2 / 32 (6.25%)
    1 / 29 (3.45%)
    0 / 12 (0.00%)
    4 / 59 (6.78%)
         occurrences all number
    2
    1
    0
    4
    Viral infection
         subjects affected / exposed
    1 / 32 (3.13%)
    3 / 29 (10.34%)
    0 / 12 (0.00%)
    4 / 59 (6.78%)
         occurrences all number
    1
    3
    0
    5

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    18 Jun 2013
    Amendment 1, primarily revised the protocol by adding a more structured approach to increasing the dose or dose frequency if breakthrough bleeds occur. Also, in order to make the extension consistent with the main study, a visit window of +/- 1 week was added to the extension visits.
    12 Aug 2014
    Amendment 2, updated the protocol in response to adverse events that were observed in study performance. Both hypersensitivity reactions and potential loss of efficacy of the drug product had also been reported and may had been suspected to be associated with the development of antibodies to BAY 94-9027. These events were now to be identified in this studydefined as adverse events of special interest and required study observations and the timeline required for obtaining these observations were defined listed in more detail. Additionally, the protocol was modified to allow doses up to 60 IU/kg in the 2x/week treatment group, if clinically indicated. Also, major surgeries were now to be allowed.
    18 Jun 2015
    Amendment 3, provided primarily the addition of an expansion group (Part 2) of the protocol to enroll a minimum of 8-10 subjects in the age group <6 years, for a period of 12 weeks of therapy with twice weekly dosing. The primary objective of the expansion arm was safety, with an aim to characterize the potential immune response to BAY 94-9027. The goal was to better characterize the adverse events of special interest (hypersensitivity to the infused study drug or loss of efficacy).
    13 Jun 2017
    Amendment 4, included clarification of the objective for the extension study to assess the long term safety of BAY 94-9027 over at least 100 accumulated ED. The measurement of body height, documentation of body height at all past study visits, the renal safety assessment using serum biomarkers and urinary biomarkers, and standard assessment of neurological examination including vision and fundus examination were added to the extension study visits. The guidelines for neurological examination were provided in the Appendices.

    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.
    Occurrence of "±” in relation with geometric SD is autogenerated and cannot be deleted. '99999' indicates that standard deviation was not estimable because only 1 subject was evaluable for this timepoint.

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/32212300
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    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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