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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

    Results information
    Results version number
    		 v2
    This version publication date
    19 Aug 2016
    First version publication date
    17 Jul 2016
    Other versions
    		 v1 , v3
    Version creation reason
    • New data added to full data set
    AE threshold changed

    Trial information

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    Trial identification
    Sponsor protocol code
    BAY94-9027/15912
    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
    Interim
    Date of interim/final analysis
    19 Mar 2015
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    19 Mar 2015
    Global end of trial reached?
    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
    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: 5
    Country: Number of subjects enrolled
    United States: 12
    Country: Number of subjects enrolled
    Romania: 4
    Country: Number of subjects enrolled
    United Kingdom: 8
    Worldwide total number of subjects
    61
    EEA total number of subjects
    40
    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)
    61
    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 study was conducted at 31 centers that enrolled subjects across 13 countries, between 29 May 2013 (first subject first visit) and 19 March 2015 (last subject last visit).

    Pre-assignment
    Screening details
    		 Overall 65 subjects were screened, of them 3 subjects initially failed screening but successfully re-screened and resulting in 68 subjects and 61 subjects were allocated to treatment.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Age group less than (<) 6 years
    Arm description
    		 Subjects with age group <6 years were treated and prophylaxis administered with BAY94-9027 at a dose of 25-60 international units/kilogram (IU/kg)/administration 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 (ED) and a minimum of at least 6 months.
    Arm type
    		 Experimental

    Investigational medicinal product name
    BAY94-9027
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects received a dose of 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 exposure days (ED) and a minimum of at least 6 months.

    Arm title
    		 Age group 6 to <12 years
    Arm description
    		 Subjects with age group 6 to <12 years were treated and prophylaxis administered with BAY94-9027 at a dose of 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 ED and a minimum of at least 6 months.
    Arm type
    		 Experimental

    Investigational medicinal product name
    BAY94-9027
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects received a dose of 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 exposure days (ED) and a minimum of at least 6 months.

    Number of subjects in period 1
    		Age group less than (<) 6 years Age group 6 to <12 years
    Started
    32
    29
    Completed
    25
    28
    Not completed
    7
    1
         Adverse event, non-fatal
    6
    1
         Withdrawal by parent/guardian
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Age group less than (<) 6 years
    Reporting group description
    		 Subjects with age group <6 years were treated and prophylaxis administered with BAY94-9027 at a dose of 25-60 international units/kilogram (IU/kg)/administration 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 (ED) and a minimum of at least 6 months.

    Reporting group title
    Age group 6 to <12 years
    Reporting group description
    		 Subjects with age group 6 to <12 years were treated and prophylaxis administered with BAY94-9027 at a dose of 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 ED and a minimum of at least 6 months.

    Reporting group values
    		 Age group less than (<) 6 years Age group 6 to <12 years Total
    Number of subjects
    		 32 29 61
    Age categorical
    Units: Subjects
        Children (2-11 years)
    		 32 29 61
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 3.5 ( 1 ) 8.6 ( 1.5 ) -
    Gender categorical
    Units: Subjects
        Female
    		 0 0 0
        Male
    		 32 29 61

    End points

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    End points reporting groups
    Reporting group title
    Age group less than (<) 6 years
    Reporting group description
    		 Subjects with age group <6 years were treated and prophylaxis administered with BAY94-9027 at a dose of 25-60 international units/kilogram (IU/kg)/administration 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 (ED) and a minimum of at least 6 months.

    Reporting group title
    Age group 6 to <12 years
    Reporting group description
    		 Subjects with age group 6 to <12 years were treated and prophylaxis administered with BAY94-9027 at a dose of 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 ED and a minimum of at least 6 months.

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

    Subject analysis set title
    Intent-to-treat (ITT)-Analysis set Main part
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    ITT included all safety subjects who had infusion/bleeding data from the Electronic Patient Diary (EPD).

    Subject analysis set title
    Pharmacokinetic (PK) Analysis Set (PKS)
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    All subjects with a valid profile of BAY94-9027 were included in the analysis of PK data.

    Primary: Annualized Number of Total Bleeds

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    End point title
    		 Annualized Number of Total Bleeds [1]
    End point description
    The annualized number of total bleeds included sum of all spontaneous bleeds and traumatic bleeds during prophylactic treatment, assessment of PK, and assessment of response to treatment of bleeds. 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 outcome measure.
    End point values
    		 Age group less than (<) 6 years Age group 6 to <12 years
    Number of subjects analysed
    32 [2]
    28 [3]
    Units: Bleeds
    median (inter-quartile range (Q1-Q3))
        Overall Bleeds
    2.68 (1.08 to 6.79)
    2.92 (0 to 6.66)
    Notes
    [2] - ITT with evaluable subjects for this endpoint.
    [3] - ITT with evaluable subjects for this endpoint.
    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 [4]
    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
    [4] - 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 outcome measure.
    End point values
    		 Age group less than (<) 6 years Age group 6 to <12 years
    Number of subjects analysed
    15 [5]
    15 [6]
    Units: IU/dL
        geometric mean (standard deviation)
    110.9 ( 1.33 )
    127 ( 1.21 )
    Notes
    [5] - PKS with evaluable subjects for this endpoint.
    [6] - PKS 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 [7]
    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
    [7] - 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 outcome measure.
    End point values
    		 Age group less than (<) 6 years Age group 6 to <12 years
    Number of subjects analysed
    16 [8]
    16 [9]
    Units: hour
        geometric mean (standard deviation)
    14.1 ( 1.39 )
    15.8 ( 1.25 )
    Notes
    [8] - PKS with evaluable subjects for this endpoint.
    [9] - PKS 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 [10]
    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
    [10] - 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 outcome measure.
    End point values
    		 Age group less than (<) 6 years Age group 6 to <12 years
    Number of subjects analysed
    15 [11]
    13 [12]
    Units: IU*h/dL
        geometric mean (standard deviation)
    1804.3 ( 1.94 )
    2837.03 ( 1.21 )
    Notes
    [11] - PKS with evaluable subjects for this endpoint.
    [12] - PKS 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 [13]
    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
    [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 outcome measure.
    End point values
    		 Age group less than (<) 6 years Age group 6 to <12 years
    Number of subjects analysed
    16 [14]
    14 [15]
    Units: hour
        geometric mean (standard deviation)
    19.1 ( 1.42 )
    23.7 ( 1.25 )
    Notes
    [14] - PKS with evaluable subjects for this endpoint.
    [15] - PKS 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 [16]
    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
    [16] - 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 outcome measure.
    End point values
    		 Age group less than (<) 6 years Age group 6 to <12 years
    Number of subjects analysed
    16 [17]
    14 [18]
    Units: Deciliter per kilogram (dL/kg)
        geometric mean (standard deviation)
    0.62 ( 1.48 )
    0.49 ( 1.2 )
    Notes
    [17] - PKS with evaluable subjects for this endpoint.
    [18] - PKS 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 [19]
    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
    [19] - 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 outcome measure.
    End point values
    		 Age group less than (<) 6 years Age group 6 to <12 years
    Number of subjects analysed
    16 [20]
    14 [21]
    Units: Deciliter per hour per kilogram[dL/h/kg)
        geometric mean (standard deviation)
    0.032 ( 1.94 )
    0.021 ( 1.22 )
    Notes
    [20] - PKS with evaluable subjects for this endpoint.
    [21] - PKS 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 [22]
    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
    [22] - 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 outcome measure.
    End point values
    		 Age group less than (<) 6 years Age group 6 to <12 years
    Number of subjects analysed
    32 [23]
    28 [24]
    Units: Number of bleed
        Excellent
    29
    26
        Good
    34
    31
        Moderate
    6
    9
        Poor
    3
    2
    Notes
    [23] - ITT
    [24] - ITT
    No statistical analyses for this end point

    Primary: Number of Subjects With Development of Clinically Significant Levels of Inhibitory Antibodies to FVIII

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    End point title
    		 Number of Subjects With Development of Clinically Significant Levels of Inhibitory Antibodies to FVIII [25]
    End point description
    Subjects were monitored for the development of inhibitory antibodies to FVIII.
    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 outcome measure.
    End point values
    		 Age group less than (<) 6 years Age group 6 to <12 years
    Number of subjects analysed
    0 [26]
    0 [27]
    Units: Subjects
    Notes
    [26] - Data was not available since the expansion phase of study is ongoing.
    [27] - Data was not available since the expansion phase of study is ongoing.
    No statistical analyses for this end point

    Secondary: Number of Subjects With Inhibitor Development After 10 to 15 and 50 Exposure Days

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    End point title
    		 Number of Subjects With Inhibitor Development After 10 to 15 and 50 Exposure Days
    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.
    End point values
    		 Age group less than (<) 6 years Age group 6 to <12 years
    Number of subjects analysed
    32
    29
    Units: Subjects
    0
    0
    No statistical analyses for this end point

    Secondary: Assessment of Incremental Recovery

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    End point title
    		 Assessment of Incremental Recovery
    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 final visit of the extension study, (a minimum total of 100 ED)
    End point values
    		 Age group less than (<) 6 years Age group 6 to <12 years
    Number of subjects analysed
    32 [28]
    28 [29]
    Units: Recovery values
    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
    [28] - ITT
    [29] - ITT
    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.
    Adverse event reporting additional description
    Actually the investigator suspected that the subject has anti FVIII inhibitor development, without any lab test support. The test came back to show that the antibody is negative.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    17.1
    Reporting groups
    Reporting group title
    Age group 6 to <12 years
    Reporting group description
    		 Subjects with age group 6 to <12 years were treated and prophylaxis administered with BAY94-9027 at a dose of 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 ED and a minimum of at least 6 months.

    Reporting group title
    Age group Less than [<] 6 years
    Reporting group description
    		 Subjects with age group < 6 years were treated and prophylaxis administered with BAY94-9027 at a dose of 25-60 international units/kilogram (IU/kg)/administration 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 (ED) and a minimum of at least 6 months.

    Serious adverse events
    		 Age group 6 to <12 years Age group Less than [<] 6 years
    Total subjects affected by serious adverse events
         subjects affected / exposed
    3 / 29 (10.34%)
    8 / 32 (25.00%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Investigations
    Anti factor VIII antibody positive
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 32 (3.13%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Drug specific antibody present
         subjects affected / exposed
    0 / 29 (0.00%)
    3 / 32 (9.38%)
         occurrences causally related to treatment / all
    0 / 0
    5 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Red blood cells CSF positive
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Subcutaneous haematoma
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 32 (3.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Surgical and medical procedures
    Catheter management
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 32 (3.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Central venous catheterisation
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 32 (3.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Haemorrhage intracranial
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 32 (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
    Catheter site swelling
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 32 (3.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device connection issue
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Drug hypersensitivity
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 32 (3.13%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypersensitivity
         subjects affected / exposed
    1 / 29 (3.45%)
    1 / 32 (3.13%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Photophobia
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Gastroenteritis
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Staphylococcal infection
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 32 (3.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Age group 6 to <12 years Age group Less than [<] 6 years
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    18 / 29 (62.07%)
    24 / 32 (75.00%)
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    2 / 29 (6.90%)
    6 / 32 (18.75%)
         occurrences all number
    2
    6
    Arthropod bite
         subjects affected / exposed
    0 / 29 (0.00%)
    2 / 32 (6.25%)
         occurrences all number
    0
    2
    Fall
         subjects affected / exposed
    0 / 29 (0.00%)
    3 / 32 (9.38%)
         occurrences all number
    0
    3
    Post-traumatic pain
         subjects affected / exposed
    0 / 29 (0.00%)
    2 / 32 (6.25%)
         occurrences all number
    0
    2
    Ligament sprain
         subjects affected / exposed
    0 / 29 (0.00%)
    2 / 32 (6.25%)
         occurrences all number
    0
    2
    Head injury
         subjects affected / exposed
    0 / 29 (0.00%)
    2 / 32 (6.25%)
         occurrences all number
    0
    4
    Subcutaneous haematoma
         subjects affected / exposed
    0 / 29 (0.00%)
    2 / 32 (6.25%)
         occurrences all number
    0
    12
    Wound
         subjects affected / exposed
    0 / 29 (0.00%)
    2 / 32 (6.25%)
         occurrences all number
    0
    2
    Vascular disorders
    Haematoma
         subjects affected / exposed
    0 / 29 (0.00%)
    2 / 32 (6.25%)
         occurrences all number
    0
    16
    Nervous system disorders
    Headache
         subjects affected / exposed
    6 / 29 (20.69%)
    2 / 32 (6.25%)
         occurrences all number
    8
    2
    General disorders and administration site conditions
    Mass
         subjects affected / exposed
    0 / 29 (0.00%)
    2 / 32 (6.25%)
         occurrences all number
    0
    2
    Pyrexia
         subjects affected / exposed
    2 / 29 (6.90%)
    7 / 32 (21.88%)
         occurrences all number
    4
    9
    Gastrointestinal disorders
    Vomiting
         subjects affected / exposed
    3 / 29 (10.34%)
    2 / 32 (6.25%)
         occurrences all number
    3
    2
    Diarrhoea
         subjects affected / exposed
    2 / 29 (6.90%)
    4 / 32 (12.50%)
         occurrences all number
    2
    4
    Abdominal pain upper
         subjects affected / exposed
    3 / 29 (10.34%)
    0 / 32 (0.00%)
         occurrences all number
    3
    0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    1 / 29 (3.45%)
    5 / 32 (15.63%)
         occurrences all number
    1
    5
    Epistaxis
         subjects affected / exposed
    4 / 29 (13.79%)
    3 / 32 (9.38%)
         occurrences all number
    9
    5
    Oropharyngeal pain
         subjects affected / exposed
    5 / 29 (17.24%)
    1 / 32 (3.13%)
         occurrences all number
    5
    1
    Skin and subcutaneous tissue disorders
    Ecchymosis
         subjects affected / exposed
    1 / 29 (3.45%)
    2 / 32 (6.25%)
         occurrences all number
    1
    2
    Rash
         subjects affected / exposed
    1 / 29 (3.45%)
    3 / 32 (9.38%)
         occurrences all number
    2
    4
    Skin irritation
         subjects affected / exposed
    0 / 29 (0.00%)
    2 / 32 (6.25%)
         occurrences all number
    0
    2
    Musculoskeletal and connective tissue disorders
    Pain in extremity
         subjects affected / exposed
    3 / 29 (10.34%)
    3 / 32 (9.38%)
         occurrences all number
    4
    3
    Arthralgia
         subjects affected / exposed
    3 / 29 (10.34%)
    1 / 32 (3.13%)
         occurrences all number
    3
    1
    Infections and infestations
    Gastroenteritis
         subjects affected / exposed
    3 / 29 (10.34%)
    2 / 32 (6.25%)
         occurrences all number
    3
    2
    Nasopharyngitis
         subjects affected / exposed
    1 / 29 (3.45%)
    5 / 32 (15.63%)
         occurrences all number
    1
    8
    Rhinitis
         subjects affected / exposed
    0 / 29 (0.00%)
    3 / 32 (9.38%)
         occurrences all number
    0
    3
    Tonsillitis
         subjects affected / exposed
    2 / 29 (6.90%)
    0 / 32 (0.00%)
         occurrences all number
    2
    0
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 29 (3.45%)
    6 / 32 (18.75%)
         occurrences all number
    1
    6
    Varicella
         subjects affected / exposed
    1 / 29 (3.45%)
    2 / 32 (6.25%)
         occurrences all number
    1
    2
    Viral infection
         subjects affected / exposed
    3 / 29 (10.34%)
    1 / 32 (3.13%)
         occurrences all number
    3
    1

    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
    The main purpose of this amendment was the addition of a more structured approach to increasing the dose or dose frequency if breakthrough bleeds occurred and a visit window of plus or minus 1 week was added to the extension visits. In addition, the following clarifications were made: references to incremental recovery were removed when they were redundant; the amount of time after reconstitution that the drug product must be used was corrected; the timing of collection of one of the Work Productivity and Activity Impairment (WPAI) assessments was corrected; the protocol for inhibitor testing was clarified; a reference to an integrated subject/parent information sheet and informed consent form was corrected. Finally, editorial changes, correction of typographical errors, and minor revisions of language were made to ensure clarity and consistency throughout the document.
    12 Aug 2014
    The primary purpose of this Amendment was to update the protocol in response to adverse events that have been observed in study performance.

    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.
    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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