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    Clinical Trial Results:
    A Phase III, Open-Label, Multicentre Study to Evaluate Efficacy, Pharmacokinetics, and Safety of Biostate® in Paediatric Subjects with Haemophilia A.

    Summary
    EudraCT number
    		 2009-015112-18
    Trial protocol
    		 BG  
    Global end of trial date
    01 Jul 2014

    Results information
    Results version number
    		 v1(current)
    This version publication date
    13 Jul 2016
    First version publication date
    06 Aug 2015
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CSLCT-BIO-08-53
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01229007
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    CSL Behring GmbH
    Sponsor organisation address
    Emil-von-Behring-Str 76, Marburg, Germany, 35041
    Public contact
    Clinical Trial Disclosure Manager, CSL Behring, clinicaltrials@cslbehring.com
    Scientific contact
    Clinical Trial Disclosure Manager, CSL Behring, clinicaltrials@cslbehring.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    		 EMEA-000312-PIP01-08
    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
    15 Aug 2014
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    01 Jul 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    1. To assess the efficacy of Biostate in paediatric subjects with haemophilia A. 2. To investigate the pharmacokinetics (PK) of Biostate in paediatric subjects with haemophilia A.
    Protection of trial subjects
    This study was carried out in accordance with the International Conference on Harmonisation (ICH) Good Clinical Practice guidelines, and standard operating procedures for clinical research and development at CSL Behring (CSLB). The study protocol and all amendments were approved by the Independent Ethics Committee(s) (IECs) / Institutional Review Board(s) (IRBs) of the participating centers. Before undergoing screening procedures for possible enrollment into the study, subjects were informed, in an understandable form, about the nature, scope, and possible consequences of the study. The investigator was responsible for obtaining a subject’s written informed consent to participate in the study. The investigator may cease study treatment and withdraw the subject, or the subject may withdraw himself from participation in the study at any time. If a subject is withdrawn from the study or further participation is declined, the subject will continue to have access to medical care and will be treated according to routine medical practice, but will no longer receive the investigational medicinal product (IMP).
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    17 Aug 2010
    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
    Ukraine: 4
    Country: Number of subjects enrolled
    Belarus: 7
    Country: Number of subjects enrolled
    Guatemala: 2
    Country: Number of subjects enrolled
    Mexico: 1
    Country: Number of subjects enrolled
    Georgia: 12
    Country: Number of subjects enrolled
    Lebanon: 9
    Worldwide total number of subjects
    35
    EEA total number of subjects
    0
    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)
    4
    Children (2-11 years)
    31
    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
    		 -

    Pre-assignment
    Screening details
    		 This study included a Screening period of up to 35 days.

    Period 1
    Period 1 title
    Pharmacokinetic (PK) Component
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 PK Component
    Arm description
    		 A single dose of 50 IU FVIII/kg body weight of Biostate on Day 1 by intravenous (IV) infusion.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Human coagulation Factor VIII / von Willebrand Factor
    Investigational medicinal product code
    Other name
    Biostate®, Voncento®
    Pharmaceutical forms
    Powder and solvent for solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    The PK infusion dose received was based on the actual FVIII concentration of the batch used for this infusion in order to dose accurately for the PK component.

    Number of subjects in period 1
    		PK Component
    Started
    35
    Completed
    35
    Period 2
    Period 2 title
    Efficacy Component
    Is this the baseline period?
    		 Yes [1]
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Prophylaxis Therapy Arm
    Arm description
    		 In the efficacy component, each subject received a dose of Biostate as determined by the investigator based on the subject’s clinical condition, previous FVIII concentrate requirements, previous response to therapy, weight, and reason for usage. Guidelines for prophylaxis therapy were 20-40 IU FVIII/kg body weight per day at intervals of 2 to 3 days. In some cases, especially in younger subjects, shorter dosage intervals or higher doses may have been necessary.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Human coagulation Factor VIII / von Willebrand Factor
    Investigational medicinal product code
    Other name
    Biostate®, Voncento®
    Pharmaceutical forms
    Powder and solvent for solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    The dose received for non-PK infusions was based on the nominal FVIII vial strength of the batch used for this infusion.

    Arm title
    		 On-Demand Therapy Arm
    Arm description
    		 In the efficacy component, each subject received a dose of Biostate as determined by the investigator based on the subject’s clinical condition, previous FVIII concentrate requirements, previous response to therapy, weight, and reason for usage.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Human coagulation Factor VIII / von Willebrand Factor
    Investigational medicinal product code
    Other name
    Biostate®, Voncento®
    Pharmaceutical forms
    Powder and solvent for solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    The dose received for non-PK infusions was based on the nominal FVIII vial strength of the batch used for this infusion.

    Notes
    [1] - Period 1 is not the baseline period. It is expected that period 1 will be the baseline period.
    Justification: Efficacy Component was chosen to present baseline characteristics by treatment arm.
    Number of subjects in period 2
    		Prophylaxis Therapy Arm On-Demand Therapy Arm
    Started
    18
    17
    Completed
    15
    13
    Not completed
    3
    4
         Consent withdrawn by subject
    -
    2
         FVIII inhibitor development
    -
    2
         Non-compliance with prophylaxis regimen
    1
    -
         Site closure
    2
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Prophylaxis Therapy Arm
    Reporting group description
    		 In the efficacy component, each subject received a dose of Biostate as determined by the investigator based on the subject’s clinical condition, previous FVIII concentrate requirements, previous response to therapy, weight, and reason for usage. Guidelines for prophylaxis therapy were 20-40 IU FVIII/kg body weight per day at intervals of 2 to 3 days. In some cases, especially in younger subjects, shorter dosage intervals or higher doses may have been necessary.

    Reporting group title
    On-Demand Therapy Arm
    Reporting group description
    		 In the efficacy component, each subject received a dose of Biostate as determined by the investigator based on the subject’s clinical condition, previous FVIII concentrate requirements, previous response to therapy, weight, and reason for usage.

    Reporting group values
    		 Prophylaxis Therapy Arm On-Demand Therapy Arm Total
    Number of subjects
    		 18 17 35
    Age categorical
    Units: Subjects
        0 to < 2 years
    		 0 4 4
        2 to < 6 years
    		 4 8 12
        6 to < 12 years
    		 14 5 19
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 7.3 ( 2.68 ) 4.9 ( 3.43 ) -
    Gender categorical
    Units: Subjects
        Female
    		 0 0 0
        Male
    		 18 17 35

    End points

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    End points reporting groups
    Reporting group title
    PK Component
    Reporting group description
    		 A single dose of 50 IU FVIII/kg body weight of Biostate on Day 1 by intravenous (IV) infusion.
    Reporting group title
    Prophylaxis Therapy Arm
    Reporting group description
    		 In the efficacy component, each subject received a dose of Biostate as determined by the investigator based on the subject’s clinical condition, previous FVIII concentrate requirements, previous response to therapy, weight, and reason for usage. Guidelines for prophylaxis therapy were 20-40 IU FVIII/kg body weight per day at intervals of 2 to 3 days. In some cases, especially in younger subjects, shorter dosage intervals or higher doses may have been necessary.

    Reporting group title
    On-Demand Therapy Arm
    Reporting group description
    		 In the efficacy component, each subject received a dose of Biostate as determined by the investigator based on the subject’s clinical condition, previous FVIII concentrate requirements, previous response to therapy, weight, and reason for usage.

    Subject analysis set title
    PK Population: Overall
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    The PK population used for the PK evaluation following the infusion of Biostate included 33 subjects in total (17 of the prophylaxis arm and 16 of the on-demand arm). One prophylaxis subject (no PK concentrations available) and 1 on-demand subject (pre-existing FVIII inhibitors) were excluded from the PK population.

    Subject analysis set title
    PK Population: 0 to < 6 Years
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subjects in the PK population who were < 6 years old.

    Subject analysis set title
    PK Population: 6 to < 12 Years
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subjects in the PK population who were 6 to < 12 years old.

    Subject analysis set title
    Efficacy Population: Prophylaxis
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    All treated subjects in the Prophylaxis Therapy arm who participated in the efficacy component of the study with an available haemostatic efficacy assessment.

    Subject analysis set title
    Efficacy Population: On-demand
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    All treated subjects in the On-demand Therapy arm who participated in the efficacy component of the study with an available haemostatic efficacy assessment.

    Subject analysis set title
    Safety Population: Prophylaxis
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    All subjects in the Prophylaxis Therapy arm who received at least 1 dose of Biostate.

    Subject analysis set title
    Safety Population: On-demand
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    All subjects in the On-demand Therapy arm who received at least 1 dose of Biostate.

    Primary: FVIII:C PK Parameter: Incremental Recovery (IR)

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    End point title
    		 FVIII:C PK Parameter: Incremental Recovery (IR) [1]
    End point description
    PK parameters were calculated by a non-compartmental infusion model. FVIII:C concentrations were used as measured for the derivation of the PK parameters without baseline adjustment.
    End point type
    Primary
    End point timeframe
    Pre-infusion (up to 5 hours prior to start of infusion); 30 minutes (+5 minutes), 4 hours (±15 minutes), 8 hours (±30 minutes), 24 hours (±2 hours), and 48 hours (±2 hours) after the end of infusion.
    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: PK parameters were summarised by descriptive statistics.
    End point values
    		 PK Population: Overall PK Population: 0 to < 6 Years PK Population: 6 to < 12 Years
    Number of subjects analysed
    33
    15
    18
    Units: (IU/mL)/(IU/kg)
        geometric mean (geometric coefficient of variation)
    0.015 ( 27.1 )
    0.014 ( 19 )
    0.015 ( 32 )
    No statistical analyses for this end point

    Primary: FVIII:C PK Parameter: Half-life (t1/2)

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    End point title
    		 FVIII:C PK Parameter: Half-life (t1/2) [2]
    End point description
    PK parameters were calculated by a non-compartmental infusion model. FVIII:C concentrations were used as measured for the derivation of the PK parameters without baseline adjustment.
    End point type
    Primary
    End point timeframe
    Pre-infusion (up to 5 hours prior to start of infusion); 30 minutes (+5 minutes), 4 hours (±15 minutes), 8 hours (±30 minutes), 24 hours (±2 hours), and 48 hours (±2 hours) after the end of infusion.
    Notes
    [2] - 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: PK parameters were summarised by descriptive statistics.
    End point values
    		 PK Population: Overall PK Population: 0 to < 6 Years PK Population: 6 to < 12 Years
    Number of subjects analysed
    32 [3]
    15
    17 [4]
    Units: hours
        geometric mean (geometric coefficient of variation)
    10.4 ( 24.9 )
    10 ( 25.6 )
    10.8 ( 24.7 )
    Notes
    [3] - subjects with evaluable data
    [4] - subjects with evaluable data
    No statistical analyses for this end point

    Primary: FVIII:C PK Parameter: Maximum Plasma Concentration (Cmax)

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    End point title
    		 FVIII:C PK Parameter: Maximum Plasma Concentration (Cmax) [5]
    End point description
    PK parameters were calculated by a non-compartmental infusion model. FVIII:C concentrations were used as measured for the derivation of the PK parameters without baseline adjustment.
    End point type
    Primary
    End point timeframe
    Pre-infusion (up to 5 hours prior to start of infusion); 30 minutes (+5 minutes), 4 hours (±15 minutes), 8 hours (±30 minutes), 24 hours (±2 hours), and 48 hours (±2 hours) after the end of infusion.
    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: PK parameters were summarised by descriptive statistics.
    End point values
    		 PK Population: Overall PK Population: 0 to < 6 Years PK Population: 6 to < 12 Years
    Number of subjects analysed
    33
    15
    18
    Units: IU/mL
        geometric mean (geometric coefficient of variation)
    0.71 ( 29.5 )
    0.72 ( 19.1 )
    0.69 ( 35.9 )
    No statistical analyses for this end point

    Primary: Primary: FVIII:C PK Parameter: Area Under the Plasma Concentration-time Curve From Time Point 0 to Last Quantifiable Time Point (AUC[0-t])

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    End point title
    		 Primary: FVIII:C PK Parameter: Area Under the Plasma Concentration-time Curve From Time Point 0 to Last Quantifiable Time Point (AUC[0-t]) [6]
    End point description
    PK parameters were calculated by a non-compartmental infusion model. FVIII:C concentrations were used as measured for the derivation of the PK parameters without baseline adjustment.
    End point type
    Primary
    End point timeframe
    Pre-infusion (up to 5 hours prior to start of infusion); 30 minutes (+5 minutes), 4 hours (±15 minutes), 8 hours (±30 minutes), 24 hours (±2 hours), and 48 hours (±2 hours) after the end of infusion.
    Notes
    [6] - 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: PK parameters were summarised by descriptive statistics.
    End point values
    		 PK Population: Overall PK Population: 0 to < 6 Years PK Population: 6 to < 12 Years
    Number of subjects analysed
    33
    15
    18
    Units: h*IU/mL
        geometric mean (geometric coefficient of variation)
    7.86 ( 35.1 )
    7.79 ( 23.2 )
    7.92 ( 41.2 )
    No statistical analyses for this end point

    Primary: FVIII:C PK Parameter: Area Under the Plasma Concentration-time Curve From Time 0 to Infinite Time (AUC[0-∞])

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    End point title
    		 FVIII:C PK Parameter: Area Under the Plasma Concentration-time Curve From Time 0 to Infinite Time (AUC[0-∞]) [7]
    End point description
    PK parameters were calculated by a non-compartmental infusion model. FVIII:C concentrations were used as measured for the derivation of the PK parameters without baseline adjustment.
    End point type
    Primary
    End point timeframe
    Pre-infusion (up to 5 hours prior to start of infusion); 30 minutes (+5 minutes), 4 hours (±15 minutes), 8 hours (±30 minutes), 24 hours (±2 hours), and 48 hours (±2 hours) after the end of infusion.
    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: PK parameters were summarised by descriptive statistics.
    End point values
    		 PK Population: Overall PK Population: 0 to < 6 Years PK Population: 6 to < 12 Years
    Number of subjects analysed
    32 [8]
    15
    17 [9]
    Units: h*IU/mL
        geometric mean (geometric coefficient of variation)
    8.68 ( 31.9 )
    8.12 ( 23.7 )
    9.21 ( 34.9 )
    Notes
    [8] - subjects with evaluable data
    [9] - subjects with evaluable data
    No statistical analyses for this end point

    Primary: FVIII:C PK Parameter: Total Clearance (CL)

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    End point title
    		 FVIII:C PK Parameter: Total Clearance (CL) [10]
    End point description
    PK parameters were calculated by a non-compartmental infusion model. FVIII:C concentrations were used as measured for the derivation of the PK parameters without baseline adjustment.
    End point type
    Primary
    End point timeframe
    Pre-infusion (up to 5 hours prior to start of infusion); 30 minutes (+5 minutes), 4 hours (±15 minutes), 8 hours (±30 minutes), 24 hours (±2 hours), and 48 hours (±2 hours) after the end of infusion.
    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: PK parameters were summarised by descriptive statistics.
    End point values
    		 PK Population: Overall PK Population: 0 to < 6 Years PK Population: 6 to < 12 Years
    Number of subjects analysed
    32 [11]
    15
    17
    Units: mL/h/kg
        geometric mean (geometric coefficient of variation)
    5.71 ( 35.6 )
    6.2 ( 28.3 )
    5.32 ( 42.3 )
    Notes
    [11] - subjects with evaluable data
    No statistical analyses for this end point

    Primary: FVIII:C PK Parameter: Volume of Distribution at Steady State (Vss)

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    End point title
    		 FVIII:C PK Parameter: Volume of Distribution at Steady State (Vss) [12]
    End point description
    PK parameters were calculated by a non-compartmental infusion model. FVIII:C concentrations were used as measured for the derivation of the PK parameters without baseline adjustment.
    End point type
    Primary
    End point timeframe
    Pre-infusion (up to 5 hours prior to start of infusion); 30 minutes (+5 minutes), 4 hours (±15 minutes), 8 hours (±30 minutes), 24 hours (±2 hours), and 48 hours (±2 hours) after the end of infusion.
    Notes
    [12] - 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: PK parameters were summarised by descriptive statistics.
    End point values
    		 PK Population: Overall PK Population: 0 to < 6 Years PK Population: 6 to < 12 Years
    Number of subjects analysed
    32 [13]
    15
    17 [14]
    Units: mL/kg
        geometric mean (geometric coefficient of variation)
    79.9 ( 61.3 )
    81.5 ( 39.1 )
    78.5 ( 75.8 )
    Notes
    [13] - subjects with evaluable data
    [14] - subjects with evaluable data
    No statistical analyses for this end point

    Primary: FVIII:C PK Parameter: Mean Residence Time to Infinite Time (MRTinf)

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    End point title
    		 FVIII:C PK Parameter: Mean Residence Time to Infinite Time (MRTinf) [15]
    End point description
    PK parameters were calculated by a non-compartmental infusion model. FVIII:C concentrations were used as measured for the derivation of the PK parameters without baseline adjustment.
    End point type
    Primary
    End point timeframe
    Pre-infusion (up to 5 hours prior to start of infusion); 30 minutes (+5 minutes), 4 hours (±15 minutes), 8 hours (±30 minutes), 24 hours (±2 hours), and 48 hours (±2 hours) after the end of infusion.
    Notes
    [15] - 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: PK parameters were summarised by descriptive statistics.
    End point values
    		 PK Population: Overall PK Population: 0 to < 6 Years PK Population: 6 to < 12 Years
    Number of subjects analysed
    32 [16]
    15
    17 [17]
    Units: hours
        geometric mean (geometric coefficient of variation)
    13.9828 ( 21.1 )
    13.1497 ( 19.5 )
    14.7617 ( 21.4 )
    Notes
    [16] - subjects with evaluable data
    [17] - subjects with available data
    No statistical analyses for this end point

    Primary: FVIII:C PK Parameter: Time the Maximum Concentration Occurs (Tmax)

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    End point title
    		 FVIII:C PK Parameter: Time the Maximum Concentration Occurs (Tmax) [18]
    End point description
    PK parameters were calculated by a non-compartmental infusion model. FVIII:C concentrations were used as measured for the derivation of the PK parameters without baseline adjustment.
    End point type
    Primary
    End point timeframe
    Pre-infusion (up to 5 hours prior to start of infusion); 30 minutes (+5 minutes), 4 hours (±15 minutes), 8 hours (±30 minutes), 24 hours (±2 hours), and 48 hours (±2 hours) after the end of infusion.
    Notes
    [18] - 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: PK parameters were summarised by descriptive statistics.
    End point values
    		 PK Population: Overall PK Population: 0 to < 6 Years PK Population: 6 to < 12 Years
    Number of subjects analysed
    33
    15
    18
    Units: hours
        geometric mean (geometric coefficient of variation)
    0.5876 ( 14.7 )
    0.5753 ( 3.1 )
    0.598 ( 19.2 )
    No statistical analyses for this end point

    Primary: FVIII:C PK Parameter: Minimum Plasma Concentration (Cmin)

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    End point title
    		 FVIII:C PK Parameter: Minimum Plasma Concentration (Cmin) [19]
    End point description
    PK parameters were calculated by a non-compartmental infusion model. FVIII:C concentrations were used as measured for the derivation of the PK parameters without baseline adjustment. Any values below the lower limit of quantification (LLOQ) for FVIII:C (LLOQ < 0.008 IU/mL) were set to zero.
    End point type
    Primary
    End point timeframe
    Pre-infusion (up to 5 hours prior to start of infusion).
    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: PK parameters were summarised by descriptive statistics.
    End point values
    		 PK Population: Overall PK Population: 0 to < 6 Years PK Population: 6 to < 12 Years
    Number of subjects analysed
    33
    15
    18
    Units: IU/mL
        arithmetic mean (standard deviation)
    0.0066 ( 0.187 )
    0.0107 ( 0.269 )
    0.0032 ( 0.0063 )
    No statistical analyses for this end point

    Primary: Investigator's Monthly Assessment of Haemostatic Efficacy

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    End point title
    		 Investigator's Monthly Assessment of Haemostatic Efficacy [20]
    End point description
    For each month of the study, haemostatic efficacy was assessed by the Investigator for subjects with a bleeding event. The efficacy grading scale was as follows: excellent=haemostasis achieved/cessation of bleeding; good=slight oozing/partial but adequate control of bleeding, does not require additional product for unplanned treatment; moderate=moderate bleeding/moderate control of bleeding, required additional product for unplanned treatment; none=severe uncontrolled bleeding. Subjects who did not have any bleeding events are included in this table. Bleeding events for which no Biostate treatment was needed are not included in this table.
    End point type
    Primary
    End point timeframe
    Months 1 through 12
    Notes
    [20] - 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: All efficacy variables were descriptively summarised by treatment arm and overall. No formal statistical tests were performed.
    End point values
    		 Efficacy Population: Prophylaxis Efficacy Population: On-demand
    Number of subjects analysed
    18 [21]
    16 [22]
    Units: subjects
        Month 1: Excellent; n=7, 15
    5
    2
        Month 1: Good; n=7, 15
    2
    13
        Month 1: Moderate; n=7, 15
    0
    0
        Month 1: None; n=7, 15
    0
    0
        Month 2: Excellent; n=10, 10
    8
    0
        Month 2: Good; n=10, 10
    2
    10
        Month 2: Moderate; n=10, 10
    0
    0
        Month 2: None; n=10, 10
    0
    0
        Month 3: Excellent; n=7, 9
    7
    0
        Month 3: Good; n=7, 9
    0
    9
        Month 3: Moderate; n=7, 9
    0
    0
        Month 3: None; n=7, 9
    0
    0
        Month 4: Excellent; n=8, 11
    5
    0
        Month 4: Good; n=8, 11
    3
    11
        Month 4: Moderate; n=8, 11
    0
    0
        Month 4: None; n=8, 11
    0
    0
        Month 5: Excellent; n=7, 11
    7
    2
        Month 5: Good; n=7, 11
    0
    9
        Month 5: Moderate; n=7, 11
    0
    0
        Month 5: None; n=7, 11
    0
    0
        Month 6: Excellent; n=7, 12
    5
    2
        Month 6: Good; n=7, 12
    2
    10
        Month 6: Moderate; n=7, 12
    0
    0
        Month 6: None; n=7, 12
    0
    0
        Month 7: Excellent; n=7, 11
    6
    0
        Month 7: Good; n=7, 11
    1
    11
        Month 7: Moderate; n=7, 11
    0
    0
        Month 7: None; n=7, 11
    0
    0
        Month 8: Excellent; n=4, 8
    4
    0
        Month 8: Good; n=4, 8
    0
    8
        Month 8: Moderate; n=4, 8
    0
    0
        Month 8: None; n=4, 8
    0
    0
        Month 9: Excellent; n=5, 7
    5
    0
        Month 9: Good; n=5, 7
    0
    7
        Month 9: Moderate; n=5, 7
    0
    0
        Month 9: None; n=5, 7
    0
    0
        Month 10: Excellent; n=5, 8
    4
    1
        Month 10: Good; n=5, 8
    1
    7
        Month 10: Moderate; n=5, 8
    0
    0
        Month 10: None; n=5, 8
    0
    0
        Month 11: Excellent; n=4, 10
    4
    1
        Month 11: Good; n=4, 10
    0
    9
        Month 11: Moderate; n=4, 10
    0
    0
        Month 11: None; n=4, 10
    0
    0
        Month 12: Excellent; n=1, 11
    1
    1
        Month 12: Good; n=1, 11
    0
    10
        Month 12: Moderate; n=1, 11
    0
    0
        Month 12: None; n=1, 11
    0
    0
    Notes
    [21] - n=subjects with an assessment at given time point
    [22] - n=subjects with an assessment at given time point
    No statistical analyses for this end point

    Primary: Investigator’s Assessment of Haemostatic Efficacy per Non-surgical Bleeding (NSB) Event

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    End point title
    		 Investigator’s Assessment of Haemostatic Efficacy per Non-surgical Bleeding (NSB) Event [23]
    End point description
    Clinical assessments of haemostatic efficacy for all non-surgical bleeding events were done by the investigator in conjunction with the subject (or legal guardian) throughout the efficacy component of the study. The efficacy grading scale was as follows: excellent=haemostasis achieved/cessation of bleeding; good=slight oozing/partial but adequate control of bleeding, does not require additional product for unplanned treatment; moderate=moderate bleeding/moderate control of bleeding, required additional product for unplanned treatment; none=severe uncontrolled bleeding. Bleeding events with missing Investigator’s assessment for efficacy, or events for which no Biostate treatment was needed, were not considered for this table. Major bleeding event=one that involves any bleeding into a joint, muscle, or mucosal bleeds of the gastro-intestinal tract (excluding nasal or oral bleeding). All other bleeding events were classified as minor unless the Investigator assessment noted otherwise.
    End point type
    Primary
    End point timeframe
    up to month 12
    Notes
    [23] - 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: All efficacy variables were descriptively summarised by treatment arm and overall. No formal statistical tests were performed.
    End point values
    		 Efficacy Population: Prophylaxis Efficacy Population: On-demand
    Number of subjects analysed
    18 [24]
    16 [25]
    Units: events
        All NSB Events: Excellent; n=172, 318
    148
    77
        All NSB Events: Good; n=172, 318
    23
    241
        All NSB Events: Moderate; n=172, 318
    1
    0
        All NSB Events: None; n=172, 318
    0
    0
        Spontaneous Events: Excellent; n=54, 123
    42
    26
        Spontaneous Events: Good; n=54, 123
    11
    97
        Spontaneous Events: Moderate; n=54, 123
    1
    0
        Spontaneous Events: None; n=54, 123
    0
    0
        Trauma Events: Excellent; n=118, 194
    106
    51
        Trauma Events: Good; n=118, 194
    12
    143
        Trauma Events: Moderate; n=118, 194
    0
    0
        Trauma Events: None; n=118, 194
    0
    0
        Post-surgery Events: Excellent; n=0, 1
    0
    0
        Post-surgery Events: Good; n=0, 1
    0
    1
        Post-surgery Events: Moderate; n=0, 1
    0
    0
        Post-surgery Events: None; n=0, 1
    0
    0
        Major Events: Excellent; n=85, 98
    70
    4
        Major Events: Good; n=85, 98
    15
    94
        Major Events: Moderate; n=85, 98
    0
    0
        Major Events: None; n=85, 98
    0
    0
        Minor Events: Excellent; n=87, 220
    78
    73
        Minor Events: Good; n=87, 220
    8
    147
        Minor Events: Moderate; n=87, 220
    1
    0
        Minor Events: None; n=87, 220
    0
    0
        Joint Events: Excellent; n=143, 176
    122
    31
        Joint Events: Good; n=143, 176
    20
    145
        Joint Events: Moderate; n=143, 176
    1
    0
        Joint Events: None; n=143, 176
    0
    0
        Mucosal Events: Excellent; n=13, 73
    12
    24
        Mucosal Events: Good; n=13, 73
    1
    49
        Mucosal Events: Moderate; n=13, 73
    0
    0
        Mucosal Events: None; n=13, 73
    0
    0
        Muscle Events: Excellent; n=14, 67
    12
    21
        Muscle Events: Good; n=14, 67
    2
    46
        Muscle Events: Moderate; n=14, 67
    0
    0
        Muscle Events: None; n=14, 67
    0
    0
        Other Events: Excellent; n=2, 2
    2
    1
        Other Events: Good; n=2, 2
    0
    1
        Other Events: Moderate; n=2, 2
    0
    0
        Other Events: None; n=2, 2
    0
    0
    Notes
    [24] - n=NSB events treated with Biostate and with a haemostatic efficacy assessment.
    [25] - n=NSB events treated with Biostate and with a haemostatic efficacy assessment.
    No statistical analyses for this end point

    Primary: Subject’s Assessment of Haemostatic Efficacy per Day of Nonsurgical Bleeding Event

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    End point title
    		 Subject’s Assessment of Haemostatic Efficacy per Day of Nonsurgical Bleeding Event [26]
    End point description
    Assessments of haemostatic efficacy were done by the subject (or legal guardian) throughout the efficacy component of the study. The efficacy grading scale was as follows: excellent=haemostasis achieved/cessation of bleeding; good=slight oozing/partial but adequate control of bleeding, does not require additional product for unplanned treatment; moderate=moderate bleeding/moderate control of bleeding, required additional product for unplanned treatment; none=severe uncontrolled bleeding. Bleeding events with missing subject's assessment for efficacy or events for which no Biostate treatment was needed are not included in this table.
    End point type
    Primary
    End point timeframe
    up to Month 12
    Notes
    [26] - 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: All efficacy variables were descriptively summarised by treatment arm and overall. No formal statistical tests were performed.
    End point values
    		 Efficacy Population: Prophylaxis Efficacy Population: On-demand
    Number of subjects analysed
    18 [27]
    16 [28]
    Units: days
        All Days: Excellent; n=182, 363
    132
    83
        All Days: Good; n=182, 363
    37
    209
        All Days: Moderate; n=182, 363
    13
    71
        All Days: None; n=182, 363
    0
    0
        Day 1: Excellent; n=162, 225
    124
    69
        Day 1: Good; n=162, 225
    26
    110
        Day 1: Moderate; n=162, 225
    12
    46
        Day 1: None; n=162, 225
    0
    0
        Day 2: Excellent; n=19, 89
    8
    13
        Day 2: Good; n=19, 89
    10
    57
        Day 2: Moderate; n=19, 89
    1
    19
        Day 2: None; n=19, 89
    0
    0
        Day 3: Excellent; n=1, 31
    0
    1
        Day 3: Good; n=1, 31
    1
    26
        Day 3: Moderate; n=1, 31
    0
    4
        Day 3: None; n=1, 31
    0
    0
        Day 4: Excellent; n=0, 10
    0
    0
        Day 4: Good; n=0, 10
    0
    9
        Day 4: Moderate; n=0, 10
    0
    1
        Day 4: None; n=0, 10
    0
    0
        Day 5: Excellent; n=0, 5
    0
    0
        Day 5: Good; n=0, 5
    0
    4
        Day 5: Moderate; n=0, 5
    0
    1
        Day 5: None; n=0, 5
    0
    0
        Day 7: Excellent; n=0, 2
    0
    0
        Day 7: Good; n=0, 2
    0
    2
        Day 7: Moderate; n=0, 2
    0
    0
        Day 7: None; n=0, 2
    0
    0
        Day 10: Excellent; n=0, 1
    0
    0
        Day 10: Good; n=0, 1
    0
    1
        Day 10: Moderate; n=0, 1
    0
    0
        Day 10: None; n=0, 1
    0
    0
    Notes
    [27] - n=total number of days due to bleeds with available subject's assessment.
    [28] - n=total number of days due to bleeds with available subject's assessment.
    No statistical analyses for this end point

    Primary: Investigator's Assessment of Haemostatic Efficacy During Surgeries per In-house Day

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    End point title
    		 Investigator's Assessment of Haemostatic Efficacy During Surgeries per In-house Day [29]
    End point description
    Clinical assessments of haemostatic efficacy were done by the investigator in conjunction with the subject (or legal guardian) throughout the efficacy component of the study. The efficacy grading scale was as follows: excellent=haemostasis achieved/cessation of bleeding; good=slight oozing/partial but adequate control of bleeding, does not require additional product for unplanned treatment; moderate=moderate bleeding/moderate control of bleeding, required additional product for unplanned treatment; none=severe uncontrolled bleeding. Surgeries with missing investigator's assessment for efficacy are not included.
    End point type
    Primary
    End point timeframe
    up to 12 months
    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: All efficacy variables were descriptively summarised by treatment arm and overall. No formal statistical tests were performed.
    End point values
    		 Efficacy Population: Prophylaxis Efficacy Population: On-demand
    Number of subjects analysed
    18 [30]
    16 [31]
    Units: in-house days due to surgeries
        All Days: Excellent; n=4, 3
    4
    0
        All Days: Good; n=4, 3
    0
    3
        All Days: Moderate; n=4, 3
    0
    0
        All Days: None; n=4, 3
    0
    0
        Day 1: Excellent; n=2, 3
    2
    0
        Day 1: Good; n=2, 3
    0
    3
        Day 1: Moderate; n=2, 3
    0
    0
        Day 1: None; n=2, 3
    0
    0
        Day 2: Excellent; n=1, 0
    1
    0
        Day 2: Good; n=1, 0
    0
    0
        Day 2: Moderate; n=1, 0
    0
    0
        Day 2: None; n=1, 0
    0
    0
        Day 3: Excellent; n=1, 0
    1
    0
        Day 3: Good; n=1, 0
    0
    0
        Day 3: Moderate; n=1, 0
    0
    0
        Day 3: None; n=1, 0
    0
    0
    Notes
    [30] - n=in-house days due to surgeries with available investigator's assessment.
    [31] - n=in-house days due to surgeries with available investigator's assessment.
    No statistical analyses for this end point

    Primary: Investigator's Assessment of Haemostatic Efficacy During Surgeries at Discharge

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    End point title
    		 Investigator's Assessment of Haemostatic Efficacy During Surgeries at Discharge [32]
    End point description
    Clinical assessments of haemostatic efficacy were done by the investigator in conjunction with the subject (or legal guardian) throughout the efficacy component of the study. The efficacy grading scale was as follows: excellent=haemostasis achieved/cessation of bleeding; good=slight oozing/partial but adequate control of bleeding, does not require additional product for unplanned treatment; moderate=moderate bleeding/moderate control of bleeding, required additional product for unplanned treatment; none=severe uncontrolled bleeding. Surgeries with missing investigator's assessment for efficacy are not included. Major surgery included surgery involving a risk to the life of the subject; minor surgery included surgery involving little risk to the life of the subject.
    End point type
    Primary
    End point timeframe
    up to 12 months
    Notes
    [32] - 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: All efficacy variables were descriptively summarised by treatment arm and overall. No formal statistical tests were performed.
    End point values
    		 Efficacy Population: Prophylaxis Efficacy Population: On-demand
    Number of subjects analysed
    18 [33]
    16 [34]
    Units: surgeries
        All Surgeries: Excellent; n=2, 3
    2
    0
        All Surgeries: Good; n=2, 3
    0
    3
        All Surgeries: Moderate; n=2, 3
    0
    0
        All Surgeries: None; n=2, 3
    0
    0
        Major Surgeries: Excellent; n=0, 2
    0
    0
        Major Surgeries: Good; n=0, 2
    0
    2
        Major Surgeries: Moderate; n=0, 2
    0
    0
        Major Surgeries: None; n=0, 2
    0
    0
        Minor Surgeries: Excellent; n=2, 1
    2
    0
        Minor Surgeries: Good; n=2, 1
    0
    1
        Minor Surgeries: Moderate; n=2, 1
    0
    0
        Minor Surgeries: None; n=2, 1
    0
    0
    Notes
    [33] - n=number of surgeries of given type with available investigator's assessment.
    [34] - n=number of surgeries of given type with available investigator's assessment.
    No statistical analyses for this end point

    Primary: Subject's Daily Post-Surgery Assessment of Haemostatic Efficacy at Home

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    End point title
    		 Subject's Daily Post-Surgery Assessment of Haemostatic Efficacy at Home [35]
    End point description
    Assessments of haemostatic efficacy were done by the subject (or legal guardian) throughout the efficacy component of the study. The efficacy grading scale was as follows: excellent=haemostasis achieved/cessation of bleeding; good=slight oozing/partial but adequate control of bleeding, does not require additional product for unplanned treatment; moderate=moderate bleeding/moderate control of bleeding, required additional product for unplanned treatment; none=severe uncontrolled bleeding. Surgeries with missing subject's assessment for efficacy are not included.
    End point type
    Primary
    End point timeframe
    up to 12 months
    Notes
    [35] - 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: All efficacy variables were descriptively summarised by treatment arm and overall. No formal statistical tests were performed.
    End point values
    		 Efficacy Population: Prophylaxis Efficacy Population: On-demand
    Number of subjects analysed
    18 [36]
    16 [37]
    Units: post-surgery days
        All Days: Excellent; n=1, 2
    1
    0
        All Days: Good; n=1, 2
    0
    2
        All Days: Moderate; n=1, 2
    0
    0
        All Days: None; n=1, 2
    0
    0
        Day 1: Excellent; n=1, 2
    1
    0
        Day 1: Good; n=1, 2
    0
    2
        Day 1: Moderate; n=1, 2
    0
    0
        Day 1: None; n=1, 2
    0
    0
    Notes
    [36] - n=total post-surgery days at home with available subject's assessment.
    [37] - n=total post-surgery days at home with available subject's assessment.
    No statistical analyses for this end point

    Primary: Assessment of Blood Loss During Surgeries By Type of Surgery

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    End point title
    		 Assessment of Blood Loss During Surgeries By Type of Surgery [38]
    End point description
    In the case of any surgical procedures, the surgical team provided an assessment at the time of the procedure of the extent of blood loss for each specific surgical procedure performed on a subject. The blood loss was compared to the expected blood loss from a subject without a bleeding disorder undergoing the same procedure. The following grading scale was used: less than expected loss, equivalent to expected loss, more than expected loss. Major surgery included surgery involving a risk to the life of the subject; minor surgery included surgery involving little risk to the life of the subject.
    End point type
    Primary
    End point timeframe
    up to Month 12
    Notes
    [38] - 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: All efficacy variables were descriptively summarised by treatment arm and overall. No formal statistical tests were performed.
    End point values
    		 Efficacy Population: Prophylaxis Efficacy Population: On-demand
    Number of subjects analysed
    18 [39]
    16 [40]
    Units: surgeries
        All Surgeries: Less Than Expected; n=2, 3
    1
    1
        All Surgeries: Equivalent To Expected; n=2, 3
    1
    2
        All Surgeries: More Than Expected; n=2, 3
    0
    0
        Major Surgeries: Less Than Expected; n=0, 2
    0
    0
        Major Surgeries: Equivalent To Expected; n=0, 2
    0
    2
        Major Surgeries: More Than Expected; n=0, 2
    0
    0
        Minor Surgeries: Less Than Expected; n=2, 1
    1
    1
        Minor Surgeries: Equivalent To Expected; n=2, 1
    1
    0
        Minor Surgeries: More Than Expected; n=2, 1
    0
    0
    Notes
    [39] - n=number of surgeries of given type.
    [40] - n=number of surgeries of given type.
    No statistical analyses for this end point

    Primary: Number of Subjects Requiring Surgery-Related Blood Product Transfusions

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    End point title
    		 Number of Subjects Requiring Surgery-Related Blood Product Transfusions [41]
    End point description
    End point type
    Primary
    End point timeframe
    up to 12 months
    Notes
    [41] - 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: All efficacy variables were descriptively summarised by treatment arm and overall. No formal statistical tests were performed.
    End point values
    		 Efficacy Population: Prophylaxis Efficacy Population: On-demand
    Number of subjects analysed
    18
    16
    Units: subjects
    0
    0
    No statistical analyses for this end point

    Secondary: Overview of Treatment Emergent Adverse Events (TEAEs)

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    End point title
    		 Overview of Treatment Emergent Adverse Events (TEAEs)
    End point description
    An adverse event (AE) is any untoward medical occurrence that does not necessarily have a causal relationship to the study product. A serious AE (SAE) was defined as any untoward medical occurrence that at any dose: results in death; is life-threatening; requires inpatient hospitalisation or prolongation of existing hospitalisation; results in persistent or significant disability/incapacity; is a congenital anomaly/birth defect; is another medically important condition. The intensity/severity of AEs was categorized as mild, moderate, or severe. The relationship of the AE to the study product was categorized as not related, unlikely, possibly, probably or definitely. AEs occurring after the first dose of study medication were considered treatment-emergent. Serious TEAEs category include subjects who had a FVIII inhibitor reported. Discontinuation category refers to "drug interrupted" being ticked on the case report form.
    End point type
    Secondary
    End point timeframe
    From first administration of the IMP until Final Visit or up to ± 7 days (for AEs) or 30 days (for SAEs) after the last IMP administration (up to 12 months). Events considered related to a study procedure were recorded from the point of informed consent.
    End point values
    		 Safety Population: Prophylaxis Safety Population: On-demand
    Number of subjects analysed
    18
    17
    Units: subjects
        At Least 1 TEAE
    12
    11
        At Least 1 Severe TEAE
    3
    3
        At Least 1 Serious TEAE
    2
    3
        At Least 1 TEAE Leading to Discontinuation
    2
    0
    No statistical analyses for this end point

    Secondary: Factor VIII Inhibitors

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    End point title
    		 Factor VIII Inhibitors
    End point description
    End point type
    Secondary
    End point timeframe
    Screening, PK Day 2 (24 hours post-dose), Months 1, 3, 6, 9, 12, Final Visit (up to 12 months ± 7 days)
    End point values
    		 Safety Population: Prophylaxis Safety Population: On-demand
    Number of subjects analysed
    18
    17
    Units: subjects
        Screening
    0
    0
        PK Day 2 (24 hours post-dose)
    0
    1
        Month 1
    1
    1
        Month 3
    2
    0
        Month 6
    0
    1
        Month 9
    0
    0
        Month 12
    0
    0
        Final Visit
    1
    2
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From first administration of the IMP until Final Visit or up to ± 7 days (for AEs) or 30 days (for SAEs) after the last IMP administration (up to 12 months). Events considered related to a study procedure were recorded from the point of informed consent.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    13.0
    Reporting groups
    Reporting group title
    Safety Population: Prophylaxis
    Reporting group description
    		 The safety population included all subjects who received at least 1 dose of Biostate.

    Reporting group title
    Safety Population: On-demand
    Reporting group description
    		 The safety population included all subjects who received at least 1 dose of Biostate.

    Serious adverse events
    		 Safety Population: Prophylaxis Safety Population: On-demand
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 18 (11.11%)
    3 / 17 (17.65%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Injury, poisoning and procedural complications
    Tibia fracture
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 17 (5.88%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Factor VIII inhibition
         subjects affected / exposed
    2 / 18 (11.11%)
    2 / 17 (11.76%)
         occurrences causally related to treatment / all
    2 / 2
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Safety Population: Prophylaxis Safety Population: On-demand
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    11 / 18 (61.11%)
    9 / 17 (52.94%)
    Injury, poisoning and procedural complications
    Arthropod bite
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 17 (0.00%)
         occurrences all number
    1
    0
    Femur fracture
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    0
    1
    Vascular disorders
    Hypotension
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 17 (0.00%)
         occurrences all number
    1
    0
    Nervous system disorders
    Headache
         subjects affected / exposed
    2 / 18 (11.11%)
    0 / 17 (0.00%)
         occurrences all number
    3
    0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 18 (0.00%)
    2 / 17 (11.76%)
         occurrences all number
    0
    2
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    4 / 18 (22.22%)
    2 / 17 (11.76%)
         occurrences all number
    7
    2
    Eye disorders
    Corneal oedema
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 17 (0.00%)
         occurrences all number
    2
    0
    Gastrointestinal disorders
    Toothache
         subjects affected / exposed
    1 / 18 (5.56%)
    2 / 17 (11.76%)
         occurrences all number
    1
    4
    Diarrhoea
         subjects affected / exposed
    2 / 18 (11.11%)
    0 / 17 (0.00%)
         occurrences all number
    2
    0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    3 / 18 (16.67%)
    5 / 17 (29.41%)
         occurrences all number
    4
    6
    Upper airway obstruction
         subjects affected / exposed
    3 / 18 (16.67%)
    0 / 17 (0.00%)
         occurrences all number
    4
    0
    Asthma
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 17 (0.00%)
         occurrences all number
    1
    0
    Bronchospasm
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 17 (0.00%)
         occurrences all number
    1
    0
    Dyspnoea
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 17 (0.00%)
         occurrences all number
    1
    0
    Tonsillar hypertrophy
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 17 (0.00%)
         occurrences all number
    1
    0
    Hepatobiliary disorders
    Hepatosplenomegaly
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    0
    1
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    4 / 18 (22.22%)
    0 / 17 (0.00%)
         occurrences all number
    6
    0
    Dermatitis allergic
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    0
    1
    Dermatosis
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 17 (0.00%)
         occurrences all number
    1
    0
    Eczema
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 17 (0.00%)
         occurrences all number
    1
    0
    Pruritus
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 17 (0.00%)
         occurrences all number
    1
    0
    Skin hypopigmentation
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 17 (0.00%)
         occurrences all number
    1
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    2 / 18 (11.11%)
    0 / 17 (0.00%)
         occurrences all number
    2
    0
    Haemarthrosis
         subjects affected / exposed
    0 / 18 (0.00%)
    2 / 17 (11.76%)
         occurrences all number
    0
    4
    Pain in extremity
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 17 (0.00%)
         occurrences all number
    1
    0
    Infections and infestations
    Rhinitis
         subjects affected / exposed
    4 / 18 (22.22%)
    0 / 17 (0.00%)
         occurrences all number
    10
    0
    Influenza
         subjects affected / exposed
    2 / 18 (11.11%)
    1 / 17 (5.88%)
         occurrences all number
    2
    1
    Acute tonsillitis
         subjects affected / exposed
    2 / 18 (11.11%)
    0 / 17 (0.00%)
         occurrences all number
    3
    0
    Bronchitis
         subjects affected / exposed
    0 / 18 (0.00%)
    2 / 17 (11.76%)
         occurrences all number
    0
    2
    Gastroenteritis
         subjects affected / exposed
    2 / 18 (11.11%)
    0 / 17 (0.00%)
         occurrences all number
    2
    0
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 18 (0.00%)
    2 / 17 (11.76%)
         occurrences all number
    0
    2
    Adenoiditis
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 17 (0.00%)
         occurrences all number
    1
    0
    Bronchitis viral
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    0
    1
    Helminthic infection
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 17 (0.00%)
         occurrences all number
    1
    0
    Nasopharyngitis
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    0
    1
    Pharyngitis
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    0
    1
    Pulpitis dental
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    0
    1
    Tonsilitis
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 17 (0.00%)
         occurrences all number
    1
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    20 Sep 2010
    The following main changes were included: - Data recording by electronic case report form (eCRF). - Modification of inclusion criterion 3 because no hepatitis A virus vaccine was available for children aged <1 year. - Change of central laboratory. - Correction of blood volumes collected for PK and efficacy component. - Clarification of Biostate dosing during the PK component. - Explanation of use of patient card.
    24 May 2012
    The following main changes were included: - Extension of treatment added to in total 100 exposure days, but no longer than 12 months. - The allowance of continuation of treatment at the discretion of the principle investigator and Independent Monitoring Committee when a clinically insignificant FVIII inhibitor was determined.

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

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

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