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    Clinical Trial Results:
    A Phase III Open-label, Multi-centre Study to Assess the Pharmacokinetics, Efficacy, and Safety of Biostate® in Paediatric Subjects With von Willebrand Disease

    Summary
    EudraCT number
    		 2009-017753-34
    Trial protocol
    		 DE   BG  
    Global end of trial date
    27 Aug 2013

    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-08-52
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    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
    23 Oct 2013
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    27 Aug 2013
    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 von Willebrand disease (VWD). 2. To investigate the pharmacokinetics (PK) profile of Biostate in paediatric subjects with VWD.
    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
    29 Jul 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
    Germany: 3
    Country: Number of subjects enrolled
    Ukraine: 3
    Country: Number of subjects enrolled
    Belarus: 2
    Country: Number of subjects enrolled
    Guatemala: 1
    Country: Number of subjects enrolled
    Georgia: 2
    Country: Number of subjects enrolled
    Lebanon: 6
    Worldwide total number of subjects
    17
    EEA total number of subjects
    3
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    2
    Children (2-11 years)
    15
    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 bolus intravenous (i.v.) infusion of 80 IU/kg von Willebrand factor: ristocetin cofactor (VWF RCo) on Day 1 (for the initial PK assessment) and on Day 180 (Month 6) for the repeat PK assessment (in type 3 VWD subjects only).
    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
    Biostate was administered at a maximum of 6 mL/min as tolerated by the subject.

    Number of subjects in period 1
    		PK Component
    Started
    17
    Repeat PK (Type 3 VWD PK Subjects Only)
    9 [1]
    Completed
    17
    Notes
    [1] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: 9 subjects with VWD Type 3 participated in the repeat PK assessment, which occurred after the treatment period of the study had started. These subjects continued in the treatment period until the end of the study along with the other subjects.
    Period 2
    Period 2 title
    Treatment Period (Efficacy Component)
    Is this the baseline period?
    		 Yes [2]
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Arm 1: Prophylaxis Therapy
    Arm description
    		 Subjects who were treated on a set prophylaxis regimen with a VWF product at the time of study entry were enrolled into the prophylaxis arm to receive Biostate as a pre-defined prophylaxis regimen determined by the Investigator according to the severity of their disease for a period of 12 months.
    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
    Biostate was administered at a maximum of 6 mL/min as tolerated by the subject.

    Arm title
    		 Arm 2: On-Demand Therapy
    Arm description
    		 Subjects who were not treated on a set prophylaxis regimen with a VWF product at the time of study entry and who required a VWF product for the treatment of non-surgical bleeding (NSB) events (control during surgery, or spontaneous, or trauma induced) were enrolled to start Biostate treatment of NSB events (on-demand therapy). If Biostate was used for irregular prevention of bleedings, this was considered as “on demand” therapy. Subjects who had been on an on-demand therapy previously were allowed to switch to prophylaxis therapy at the beginning of the efficacy component.
    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
    Biostate was administered at a maximum of 6 mL/min as tolerated by the subject.

    Notes
    [2] - Period 1 is not the baseline period. It is expected that period 1 will be the baseline period.
    Justification: The PK component ran concurrently with the Treatment period, which presents data by arm and was therefore chosen to present subject disposition.
    Number of subjects in period 2
    		Arm 1: Prophylaxis Therapy Arm 2: On-Demand Therapy
    Started
    4
    13
    Completed
    4
    13

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Arm 1: Prophylaxis Therapy
    Reporting group description
    		 Subjects who were treated on a set prophylaxis regimen with a VWF product at the time of study entry were enrolled into the prophylaxis arm to receive Biostate as a pre-defined prophylaxis regimen determined by the Investigator according to the severity of their disease for a period of 12 months.

    Reporting group title
    Arm 2: On-Demand Therapy
    Reporting group description
    		 Subjects who were not treated on a set prophylaxis regimen with a VWF product at the time of study entry and who required a VWF product for the treatment of non-surgical bleeding (NSB) events (control during surgery, or spontaneous, or trauma induced) were enrolled to start Biostate treatment of NSB events (on-demand therapy). If Biostate was used for irregular prevention of bleedings, this was considered as “on demand” therapy. Subjects who had been on an on-demand therapy previously were allowed to switch to prophylaxis therapy at the beginning of the efficacy component.

    Reporting group values
    		 Arm 1: Prophylaxis Therapy Arm 2: On-Demand Therapy Total
    Number of subjects
    		 4 13 17
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 2 2
        Children (2-11 years)
    		 4 11 15
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 0 0 0
        From 65-84 years
    		 0 0 0
        85 years and over
    		 0 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 5 ± 2.5 5.3 ± 3.7 -
    Gender categorical
    Units: Subjects
        Female
    		 0 10 10
        Male
    		 4 3 7

    End points

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    End points reporting groups
    Reporting group title
    PK Component
    Reporting group description
    		 A single bolus intravenous (i.v.) infusion of 80 IU/kg von Willebrand factor: ristocetin cofactor (VWF RCo) on Day 1 (for the initial PK assessment) and on Day 180 (Month 6) for the repeat PK assessment (in type 3 VWD subjects only).
    Reporting group title
    Arm 1: Prophylaxis Therapy
    Reporting group description
    		 Subjects who were treated on a set prophylaxis regimen with a VWF product at the time of study entry were enrolled into the prophylaxis arm to receive Biostate as a pre-defined prophylaxis regimen determined by the Investigator according to the severity of their disease for a period of 12 months.

    Reporting group title
    Arm 2: On-Demand Therapy
    Reporting group description
    		 Subjects who were not treated on a set prophylaxis regimen with a VWF product at the time of study entry and who required a VWF product for the treatment of non-surgical bleeding (NSB) events (control during surgery, or spontaneous, or trauma induced) were enrolled to start Biostate treatment of NSB events (on-demand therapy). If Biostate was used for irregular prevention of bleedings, this was considered as “on demand” therapy. Subjects who had been on an on-demand therapy previously were allowed to switch to prophylaxis therapy at the beginning of the efficacy component.

    Primary: Investigator’s 3-Monthly Assessment of Haemostatic Efficacy

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    End point title
    		 Investigator’s 3-Monthly Assessment of Haemostatic Efficacy [1]
    End point description
    For each 3-month interval 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 3, 6, 9, 12
    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: All efficacy variables were descriptively summarised by treatment arm and overall. No formal statistical tests were performed.
    End point values
    		 Arm 1: Prophylaxis Therapy Arm 2: On-Demand Therapy
    Number of subjects analysed
    4 [2]
    12 [3]
    Units: subjects
        Month 3: Excellent (n=4, 7)
    2
    3
        Month 3: Good (n=4, 7)
    2
    4
        Month 3: Moderate (n=4, 7)
    0
    0
        Month 3: None (n=4, 7)
    0
    0
        Month 6: Excellent (n=4, 10)
    4
    7
        Month 6: Good (n=4, 10)
    0
    3
        Month 6: Moderate (n=4, 10)
    0
    0
        Month 6: None (n=4, 10)
    0
    0
        Month 9: Excellent (n=4, 7)
    4
    4
        Month 9: Good (n=4, 7)
    0
    3
        Month 9: Moderate (n=4, 7)
    0
    0
        Month 9: None (n=4, 7)
    0
    0
        Month 12: Excellent (n=4, 10)
    3
    5
        Month 12: Good (n=4, 10)
    1
    5
        Month 12: Moderate (n=4, 10)
    0
    0
        Month 12: None (n=4, 10)
    0
    0
    Notes
    [2] - Efficacy population; n=subjects with available Investigator's assessment in given month interval.
    [3] - Efficacy population; n=subjects with available Investigator's assessment in given month interval.
    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 [4]
    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
    [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: All efficacy variables were descriptively summarised by treatment arm and overall. No formal statistical tests were performed.
    End point values
    		 Arm 1: Prophylaxis Therapy Arm 2: On-Demand Therapy
    Number of subjects analysed
    4 [5]
    12 [6]
    Units: events
        All NSB Events: Excellent; n=73, 80
    59
    36
        All NSB Events: Good; n=73, 80
    14
    44
        All NSB Events: Moderate; n=73, 80
    0
    0
        All NSB Events: None; n=73, 80
    0
    0
        Spontaneous Events: Excellent; n=59, 62
    49
    26
        Spontaneous Events: Good; n=59, 62
    10
    36
        Spontaneous Events: Moderate; n=59, 62
    0
    0
        Spontaneous Events: None; n=59, 62
    0
    0
        Trauma Events: Excellent; n=14, 18
    10
    10
        Trauma Events: Good; n=14, 18
    4
    8
        Trauma Events: Moderate; n=14, 18
    0
    0
        Trauma Events: None; n=14, 18
    0
    0
        Post-surgery Events: Excellent; n=0, 0
    0
    0
        Post-surgery Events: Good; n=0, 0
    0
    0
        Post-surgery Events: Moderate; n=0, 0
    0
    0
        Post-surgery Events: None; n=0, 0
    0
    0
        Major Events: Excellent; n=3, 26
    1
    13
        Major Events: Good; n=3, 26
    2
    13
        Major Events: Moderate; n=3, 26
    0
    0
        Major Events: None; n=3, 26
    0
    0
        Minor Events: Excellent; n=70, 54
    58
    23
        Minor Events: Good; n=70, 54
    12
    31
        Minor Events: Moderate; n=70, 54
    0
    0
        Minor Events: None; n=70, 54
    0
    0
        Joint Events: Excellent; n=3, 11
    0
    2
        Joint Events: Good; n=3, 11
    3
    9
        Joint Events: Moderate; n=3, 11
    0
    0
        Joint Events: None; n=3, 11
    0
    0
        Mucosal Events: Excellent; n=62, 65
    53
    30
        Mucosal Events: Good; n=62, 65
    9
    35
        Mucosal Events: Moderate; n=62, 65
    0
    0
        Mucosal Events: None; n=62, 65
    0
    0
        Muscle Events: Excellent; n=0, 1
    0
    1
        Muscle Events: Good; n=0, 1
    0
    0
        Muscle Events: Moderate; n=0, 1
    0
    0
        Muscle Events: None; n=0, 1
    0
    0
        Other Events: Excellent; n=8, 3
    6
    3
        Other Events: Good; n=8, 3
    2
    0
        Other Events: Moderate; n=8, 3
    0
    0
        Other Events: None; n=8, 3
    0
    0
    Notes
    [5] - Efficacy population; n=NSB events treated with Biostate and with a haemostatic efficacy assessment.
    [6] - Efficacy population; 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 Non-surgical Bleeding (NSB) Event

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    End point title
    		 Subject's Assessment of Haemostatic Efficacy per Day of Non-surgical Bleeding (NSB) Event [7]
    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
    [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: All efficacy variables were descriptively summarised by treatment arm and overall. No formal statistical tests were performed.
    End point values
    		 Arm 1: Prophylaxis Therapy Arm 2: On-Demand Therapy
    Number of subjects analysed
    4 [8]
    12 [9]
    Units: days
        All Days: Excellent; n=76, 55
    60
    33
        All Days: Good; n=76, 55
    16
    12
        All Days: Moderate; n=76, 55
    0
    10
        All Days: None; n=76, 55
    0
    0
        Day 1: Excellent; n=72, 45
    60
    29
        Day 1: Good; n=72, 45
    12
    7
        Day 1: Moderate; n=72, 45
    0
    9
        Day 1: None; n=72, 45
    0
    0
        Day 2: Excellent; n=1, 8
    0
    3
        Day 2: Good; n=1, 8
    1
    4
        Day 2: Moderate; n=1, 8
    0
    1
        Day 2: None; n=1, 8
    0
    0
        Day 3: Excellent; n=1, 1
    0
    1
        Day 3: Good; n=1, 1
    1
    0
        Day 3: Moderate; n=1, 1
    0
    0
        Day 3: None; n=1, 1
    0
    0
        Day 4: Excellent; n=1, 1
    0
    0
        Day 4: Good; n=1, 1
    1
    1
        Day 4: Moderate; n=1, 1
    0
    0
        Day 4: None; n=1, 1
    0
    0
        Day 5: Excellent; n=1, 0
    0
    0
        Day 5: Good; n=1, 0
    1
    0
        Day 5: Moderate; n=1, 0
    0
    0
        Day 5: None; n=1, 0
    0
    0
    Notes
    [8] - Efficacy population; n=total number of days due to bleeds with available subject's assessment.
    [9] - Efficacy population; 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 at Discharge

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    End point title
    		 Investigator's Assessment of Haemostatic Efficacy During Surgeries at Discharge [10]
    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 Month 12
    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: All efficacy variables were descriptively summarised by treatment arm and overall. No formal statistical tests were performed.
    End point values
    		 Arm 1: Prophylaxis Therapy Arm 2: On-Demand Therapy
    Number of subjects analysed
    4 [11]
    12 [12]
    Units: surgeries
        All surgeries: Excellent; n=0, 8
    0
    7
        All surgeries: Good; n=0, 8
    0
    1
        All surgeries: Moderate; n=0, 8
    0
    0
        All surgeries: None; n=0, 8
    0
    0
        Major surgeries: Excellent; n=0, 0
    0
    0
        Major surgeries: Good; n=0, 0
    0
    0
        Major surgeries: Moderate; n=0, 0
    0
    0
        Major surgeries: None; n=0, 0
    0
    0
        Minor surgeries: Excellent; n=0, 8
    0
    7
        Minor surgeries: Good; n=0, 8
    0
    1
        Minor surgeries: Moderate; n=0, 8
    0
    0
        Minor surgeries: None; n=0, 8
    0
    0
    Notes
    [11] - Efficacy population; n=number of surgeries of given type with available investigator's assessment.
    [12] - Efficacy population; n=number of surgeries of given type with available investigator's assessment.
    No statistical analyses for this end point

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

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    End point title
    		 Investigator's Assessment of Haemostatic Efficacy for Surgeries per In-house Day [13]
    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 Month 12
    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: All efficacy variables were descriptively summarised by treatment arm and overall. No formal statistical tests were performed.
    End point values
    		 Arm 1: Prophylaxis Therapy Arm 2: On-Demand Therapy
    Number of subjects analysed
    4 [14]
    12 [15]
    Units: in-house days due to surgeries
        All Days: Excellent; n=0, 8
    0
    7
        All Days: Good; n=0, 8
    0
    1
        All Days: Moderate; n=0, 8
    0
    0
        All Days: None; n=0, 8
    0
    0
        Day 1: Excellent; n=0, 7
    0
    7
        Day 1: Good; n=0, 7
    0
    0
        Day 1: Moderate; n=0, 7
    0
    0
        Day 1: None; n=0, 7
    0
    0
        Day 7: Excellent; n=0, 1
    0
    0
        Day 7: Good; n=0, 1
    0
    1
        Day 7: Moderate; n=0, 1
    0
    0
        Day 7: None; n=0, 1
    0
    0
    Notes
    [14] - Efficacy population; n=in-house days due to surgeries with available investigator's assessment.
    [15] - Efficacy population; n=in-house days due to surgeries with available investigator's assessment.
    No statistical analyses for this end point

    Primary: Investigator's Post-Surgery Assessment of Haemostatic Efficacy

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    End point title
    		 Investigator's Post-Surgery Assessment of Haemostatic Efficacy [16]
    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 Month 12
    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: All efficacy variables were descriptively summarised by treatment arm and overall. No formal statistical tests were performed.
    End point values
    		 Arm 1: Prophylaxis Therapy Arm 2: On-Demand Therapy
    Number of subjects analysed
    4 [17]
    12 [18]
    Units: surgeries
        All Surgeries: Excellent; n=0, 4
    0
    3
        All Surgeries: Good; n=0, 4
    0
    1
        All Surgeries: Moderate; n=0, 4
    0
    0
        All Surgeries: None; n=0, 4
    0
    0
        Major Surgeries: Excellent; n=0, 0
    0
    0
        Major Surgeries: Good; n=0, 0
    0
    0
        Major Surgeries: Moderate; n=0, 0
    0
    0
        Major Surgeries: None; n=0, 0
    0
    0
        Minor Surgeries: Excellent; n=0, 4
    0
    3
        Minor Surgeries: Good; n=0, 4
    0
    1
        Minor Surgeries: Moderate; n=0, 4
    0
    0
        Minor Surgeries: None; n=0, 4
    0
    0
    Notes
    [17] - Efficacy population; n=surgeries with available investigator's post-surgery assessment.
    [18] - Efficacy population; n=surgeries with available investigator's post-surgery 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 [19]
    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 Month 12
    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: All efficacy variables were descriptively summarised by treatment arm and overall. No formal statistical tests were performed.
    End point values
    		 Arm 1: Prophylaxis Therapy Arm 2: On-Demand Therapy
    Number of subjects analysed
    4 [20]
    12 [21]
    Units: post-surgery days
        All Days: Excellent; n=0, 2
    0
    0
        All Days: Good; n=0, 2
    0
    2
        All Days: Moderate; n=0, 2
    0
    0
        All Days: None; n=0, 2
    0
    0
        Day 6: Excellent; n=0, 1
    0
    0
        Day 6: Good; n=0, 1
    0
    1
        Day 6: Moderate; n=0, 1
    0
    0
        Day 6: None; n=0, 1
    0
    0
        Day 7: Excellent; n=0, 1
    0
    0
        Day 7: Good; n=0, 1
    0
    1
        Day 7: Moderate; n=0, 1
    0
    0
        Day 7: None; n=0, 1
    0
    0
    Notes
    [20] - Efficacy population; n=total post-surgery days at home with available subject's assessment.
    [21] - Efficacy population; n=total post-surgery days at home with available subject's assessment.
    No statistical analyses for this end point

    Primary: Initial PK Assessment: Incremental Recovery (IR)

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    End point title
    		 Initial PK Assessment: Incremental Recovery (IR) [22]
    End point description
    Baseline-adjusted IR of von Willebrand factor:ristocetin cofactor (VWF:RCo), von Willebrand factor:antigen (VWF:Ag), von Willebrand factor:collagen binding (VWF:CB) and Factor VIII:coagulant activity (FVIII:C) from the initial PK assessment.
    End point type
    Primary
    End point timeframe
    Day 1: preinfusion; Days 1-3: 0.5 (±15) min, 4 h (±15 min), 8 h (±30 min), 24 (±2) h, 48 (±2) h after the end of infusion.
    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: PK parameters were calculated by non-compartmental analysis based on baseline-adjusted concentrations and actual sampling times and were summarised per infusion (initial or repeat) by descriptive statistics.
    End point values
    		 PK Component
    Number of subjects analysed
    17 [23]
    Units: IU/mL / IU/kg
    geometric mean (geometric coefficient of variation)
        VWF:RCo; n=17
    0.014 ± 19.1
        VWF:Ag; n=17
    0.014 ± 23.7
        VWF:CB; n=17
    0.013 ± 16.9
        FVIII:C; n=16
    0.018 ± 45.8
    Notes
    [23] - PK population; n=number of subjects with an evaluable assessment.
    No statistical analyses for this end point

    Primary: Initial PK Assessment: Half-life (t1/2)

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    End point title
    		 Initial PK Assessment: Half-life (t1/2) [24]
    End point description
    Baseline-adjusted t1/2 of von Willebrand factor:ristocetin cofactor (VWF:RCo), von Willebrand factor:antigen (VWF:Ag), von Willebrand factor:collagen binding (VWF:CB) and Factor VIII:coagulant activity (FVIII:C) from the initial PK assessment.
    End point type
    Primary
    End point timeframe
    Day 1: preinfusion; Days 1-3: 0.5 (±15) min, 4 h (±15 min), 8 h (±30 min), 24 (±2) h, 48 (±2) h after the end of infusion.
    Notes
    [24] - 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 calculated by non-compartmental analysis based on baseline-adjusted concentrations and actual sampling times and were summarised per infusion (initial or repeat) by descriptive statistics.
    End point values
    		 PK Component
    Number of subjects analysed
    17 [25]
    Units: hours
    geometric mean (geometric coefficient of variation)
        VWF:RCo; n=11
    10 ± 49.7
        VWF:Ag; n=16
    11.2 ± 28.3
        VWF:CB; n=16
    10 ± 20.8
        FVIII:C; n=10
    21 ± 52.5
    Notes
    [25] - PK population; n=number of subjects with an evaluable assessment.
    No statistical analyses for this end point

    Primary: Initial PK Assessment: Maximum Concentration (Cmax)

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    End point title
    		 Initial PK Assessment: Maximum Concentration (Cmax) [26]
    End point description
    Baseline-adjusted Cmax of von Willebrand factor:ristocetin cofactor (VWF:RCo), von Willebrand factor:antigen (VWF:Ag), von Willebrand factor:collagen binding (VWF:CB) and Factor VIII:coagulant activity (FVIII:C) from the initial PK assessment.
    End point type
    Primary
    End point timeframe
    Day 1: preinfusion; Days 1-3: 0.5 (±15) min, 4 h (±15 min), 8 h (±30 min), 24 (±2) h, 48 (±2) h after the end of infusion.
    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: PK parameters were calculated by non-compartmental analysis based on baseline-adjusted concentrations and actual sampling times and were summarised per infusion (initial or repeat) by descriptive statistics.
    End point values
    		 PK Component
    Number of subjects analysed
    17 [27]
    Units: IU/mL
    geometric mean (geometric coefficient of variation)
        VWF:RCo; n=17
    1.23 ± 44.9
        VWF:Ag; n=17
    1.91 ± 48.1
        VWF:CB; n=17
    1.67 ± 43.5
        FVIII:C; n=16
    0.75 ± 48.4
    Notes
    [27] - PK population; n=number of subjects with evaluable assessments.
    No statistical analyses for this end point

    Primary: Initial PK Assessment: Area Under the Plasma Concentration-time Curve From Time 0 to the Last Sampling Time (AUC[0-t])

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    End point title
    		 Initial PK Assessment: Area Under the Plasma Concentration-time Curve From Time 0 to the Last Sampling Time (AUC[0-t]) [28]
    End point description
    Baseline-adjusted AUC(0-t) of von Willebrand factor:ristocetin cofactor (VWF:RCo), von Willebrand factor: antigen (VWF:Ag), von Willebrand factor:collagen binding (VWF:CB) and Factor VIII:coagulant activity (FVIII:C) from the initial PK assessment.
    End point type
    Primary
    End point timeframe
    Day 1: preinfusion; Days 1-3: 0.5 (±15) min, 4 h (±15 min), 8 h (±30 min), 24 (±2) h, 48 (±2) h after the end of infusion.
    Notes
    [28] - 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 calculated by non-compartmental analysis based on baseline-adjusted concentrations and actual sampling times and were summarised per infusion (initial or repeat) by descriptive statistics.
    End point values
    		 PK Component
    Number of subjects analysed
    17 [29]
    Units: h*IU/mL
    geometric mean (geometric coefficient of variation)
        VWF:RCo; n=17
    9.85 ± 62.4
        VWF:Ag; n=17
    23 ± 51.8
        VWF:CB; n=17
    18.5 ± 50.3
        FVIII:C; n=16
    16.8 ± 71.3
    Notes
    [29] - PK population; n=number of subjects with evaluable assessment.
    No statistical analyses for this end point

    Primary: Initial PK Assessment: Area Under the Plasma Concentration-time Curve From Time 0 to Infinity (AUC[0-inf])

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    End point title
    		 Initial PK Assessment: Area Under the Plasma Concentration-time Curve From Time 0 to Infinity (AUC[0-inf]) [30]
    End point description
    Baseline-adjusted AUC(0-inf) of von Willebrand factor: ristocetin cofactor (VWF:RCo), von Willebrand factor: antigen (VWF:Ag), von Willebrand factor:collagen binding (VWF:CB) and Factor VIII:coagulant activity (FVIII:C) from the initial PK assessment.
    End point type
    Primary
    End point timeframe
    Day 1: preinfusion; Days 1-3: 0.5 (±15) min, 4 h (±15 min), 8 h (±30 min), 24 (±2) h, 48 (±2) h after the end of infusion.
    Notes
    [30] - 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 calculated by non-compartmental analysis based on baseline-adjusted concentrations and actual sampling times and were summarised per infusion (initial or repeat) by descriptive statistics.
    End point values
    		 PK Component
    Number of subjects analysed
    17 [31]
    Units: h*IU/mL
    geometric mean (geometric coefficient of variation)
        VWF:RCo; n=11
    13.3 ± 56.1
        VWF:Ag; n=16
    25.6 ± 51.1
        VWF:CB; n=16
    19.6 ± 50.5
        FVIII:C; n=10
    20.1 ± 96.2
    Notes
    [31] - PK population; n=number of subjects with an evaluable assessment.
    No statistical analyses for this end point

    Primary: Initial PK Assessment: Clearance (CL)

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    End point title
    		 Initial PK Assessment: Clearance (CL) [32]
    End point description
    Baseline-adjusted clearance of von Willebrand factor:ristocetin cofactor (VWF:RCo), von Willebrand factor:antigen (VWF:Ag), von Willebrand factor:collagen binding (VWF:CB) and Factor VIII:coagulant activity (FVIII:C) from the initial PK assessment.
    End point type
    Primary
    End point timeframe
    Day 1: preinfusion; Days 1-3: 0.5 (±15) min, 4 h (±15 min), 8 h (±30 min), 24 (±2) h, 48 (±2) h after the end of infusion.
    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: PK parameters were calculated by non-compartmental analysis based on baseline-adjusted concentrations and actual sampling times and were summarised per infusion (initial or repeat) by descriptive statistics.
    End point values
    		 PK Component
    Number of subjects analysed
    17 [33]
    Units: mL/h/kg
    geometric mean (geometric coefficient of variation)
        VWF:RCo; n=11
    7.23 ± 49.2
        VWF:Ag; n=16
    5.4 ± 45.8
        VWF:CB; n=16
    6.51 ± 27.5
        FVIII:C; n=10
    2.26 ± 171
    Notes
    [33] - PK population;n=number of subjects with evaluable assessments.
    No statistical analyses for this end point

    Primary: Initial PK Assessment: Volume of Distribution at Steady State (Vss)

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    End point title
    		 Initial PK Assessment: Volume of Distribution at Steady State (Vss) [34]
    End point description
    Baseline-adjusted Vss of von Willebrand factor:ristocetin cofactor (VWF:RCo), von Willebrand factor:antigen (VWF:Ag), von Willebrand factor:collagen binding (VWF:CB) and Factor VIII:coagulant activity (FVIII:C) from the initial PK assessment.
    End point type
    Primary
    End point timeframe
    Day 1: preinfusion; Days 1-3: 0.5 (±15) min, 4 h (±15 min), 8 h (±30 min), 24 (±2) h, 48 (±2) h after the end of infusion.
    Notes
    [34] - 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 calculated by non-compartmental analysis based on baseline-adjusted concentrations and actual sampling times and were summarised per infusion (initial or repeat) by descriptive statistics.
    End point values
    		 PK Component
    Number of subjects analysed
    17 [35]
    Units: mL/kg
    geometric mean (geometric coefficient of variation)
        VWF:RCo; n=11
    87 ± 28.2
        VWF:Ag; n=16
    76.1 ± 27
        VWF:CB; n=16
    80.4 ± 18.5
        FVIII:C; n=10
    62.8 ± 57.9
    Notes
    [35] - PK population; n=number of subjects with an evaluable assessment.
    No statistical analyses for this end point

    Primary: Repeat PK Assessment: Incremental Recovery (IR)

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    End point title
    		 Repeat PK Assessment: Incremental Recovery (IR) [36]
    End point description
    Baseline-adjusted IR of von Willebrand factor:ristocetin cofactor (VWF:RCo), von Willebrand factor:antigen (VWF:Ag), von Willebrand factor:collagen binding (VWF:CB) and Factor VIII:coagulant activity (FVIII:C) from the initial PK assessment.
    End point type
    Primary
    End point timeframe
    Day 180: preinfusion, 0.5 (±15) min, 4 h (±15 min), 8 h (±30 min), 24 (±2) h, 48 (±2) h after the end of infusion.
    Notes
    [36] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: PK parameters were calculated by non-compartmental analysis based on baseline-adjusted concentrations and actual sampling times and were summarised per infusion (initial or repeat) by descriptive statistics.
    End point values
    		 PK Component
    Number of subjects analysed
    9 [37]
    Units: (IU/mL)/(IU/kg)
    geometric mean (geometric coefficient of variation)
        VWF:RCo
    0.016 ± 18.9
        VWF:Ag
    0.013 ± 16.1
        VWF:CB
    0.013 ± 14.3
        FVIII:C
    0.02 ± 20.3
    Notes
    [37] - Repeat PK population
    No statistical analyses for this end point

    Primary: Repeat PK Assessment: Half-life (t1/2)

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    End point title
    		 Repeat PK Assessment: Half-life (t1/2) [38]
    End point description
    Baseline-adjusted t1/2 of von Willebrand factor:ristocetin cofactor (VWF:RCo), von Willebrand factor:antigen (VWF:Ag), von Willebrand factor:collagen binding (VWF:CB) and Factor VIII:coagulant activity
    End point type
    Primary
    End point timeframe
    Day 180: preinfusion, 0.5 (±15) min, 4 h (±15 min), 8 h (±30 min), 24 (±2) h, 48 (±2) h after the end of infusion.
    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: PK parameters were calculated by non-compartmental analysis based on baseline-adjusted concentrations and actual sampling times and were summarised per infusion (initial or repeat) by descriptive statistics.
    End point values
    		 PK Component
    Number of subjects analysed
    9 [39]
    Units: hours
    geometric mean (geometric coefficient of variation)
        VWF:RCo; n=9
    12.1 ± 36.3
        VWF:Ag; n=9
    12.4 ± 20.7
        VWF:CB; n=9
    11 ± 19.3
        FVIII:C; n=3
    33.9 ± 25.5
    Notes
    [39] - Repeat PK population; n=number of subjects with an evaluable assessment.
    No statistical analyses for this end point

    Primary: Repeat PK Assessment: Maximum Concentration (Cmax)

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    End point title
    		 Repeat PK Assessment: Maximum Concentration (Cmax) [40]
    End point description
    Baseline-adjusted Cmax of von Willebrand factor:ristocetin cofactor (VWF:RCo), von Willebrand factor:antigen (VWF:Ag), von Willebrand factor:collagen binding (VWF:CB) and Factor VIII:coagulant activity (FVIII:C) from the initial PK assessment.
    End point type
    Primary
    End point timeframe
    Day 180: preinfusion, 0.5 (±15) min, 4 h (±15 min), 8 h (±30 min), 24 (±2) h, 48 (±2) h after the end of infusion.
    Notes
    [40] - 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 calculated by non-compartmental analysis based on baseline-adjusted concentrations and actual sampling times and were summarised per infusion (initial or repeat) by descriptive statistics.
    End point values
    		 PK Component
    Number of subjects analysed
    9 [41]
    Units: IU/mL
    geometric mean (geometric coefficient of variation)
        VWF:RCo
    1.42 ± 18.2
        VWF:Ag
    1.94 ± 27.6
        VWF:CB
    1.75 ± 19.8
        FVIII:C
    0.85 ± 36.5
    Notes
    [41] - Repeat PK population
    No statistical analyses for this end point

    Primary: Repeat PK Assessment: Area Under the Plasma Concentration-time Curve From Time 0 to the Last Sampling Time (AUC[0-t])

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    End point title
    		 Repeat PK Assessment: Area Under the Plasma Concentration-time Curve From Time 0 to the Last Sampling Time (AUC[0-t]) [42]
    End point description
    Baseline-adjusted AUC(0-t) of von Willebrand factor:ristocetin cofactor (VWF:RCo), von Willebrand factor: antigen (VWF:Ag), von Willebrand factor:collagen binding (VWF:CB) and Factor VIII:coagulant activity (FVIII:C) from the initial PK assessment.
    End point type
    Primary
    End point timeframe
    Day 180: preinfusion, 0.5 (±15) min, 4 h (±15 min), 8 h (±30 min), 24 (±2) h, 48 (±2) h after the end of infusion.
    Notes
    [42] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: PK parameters were calculated by non-compartmental analysis based on baseline-adjusted concentrations and actual sampling times and were summarised per infusion (initial or repeat) by descriptive statistics.
    End point values
    		 PK Component
    Number of subjects analysed
    9 [43]
    Units: h*IU/mL
    geometric mean (geometric coefficient of variation)
        VWF:RCo
    13.5 ± 36.8
        VWF:Ag
    27.2 ± 34.3
        VWF:CB
    22.6 ± 33.7
        FVIII:C
    28.1 ± 45.9
    Notes
    [43] - Repeat PK population
    No statistical analyses for this end point

    Primary: Repeat PK Assessment: Area Under the Plasma Concentration-time Curve From Time 0 to Infinity (AUC[0-inf])

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    End point title
    		 Repeat PK Assessment: Area Under the Plasma Concentration-time Curve From Time 0 to Infinity (AUC[0-inf]) [44]
    End point description
    Baseline-adjusted AUC(0-inf) of von Willebrand factor: ristocetin cofactor (VWF:RCo), von Willebrand factor: antigen (VWF:Ag), von Willebrand factor: collagen binding (VWF:CB) and Factor VIII: coagulant activity (FVIII:C) from the initial PK assessment.
    End point type
    Primary
    End point timeframe
    Day 180: preinfusion, 0.5 (±15) min, 4 h (±15 min), 8 h (±30 min), 24 (±2) h, 48 (±2) h after the end of infusion.
    Notes
    [44] - 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 calculated by non-compartmental analysis based on baseline-adjusted concentrations and actual sampling times and were summarised per infusion (initial or repeat) by descriptive statistics.
    End point values
    		 PK Component
    Number of subjects analysed
    9 [45]
    Units: h*IU/mL
    geometric mean (geometric coefficient of variation)
        VWF:RCo; n=9
    15.2 ± 36.4
        VWF:Ag; n=9
    29.2 ± 36.4
        VWF:CB; n=9
    23.8 ± 36.7
        FVIII:C; n=3
    41.3 ± 27.1
    Notes
    [45] - Repeat PK population; n=number of subjects with an evaluable assessment.
    No statistical analyses for this end point

    Primary: Repeat PK Assessment: Clearance (CL)

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    End point title
    		 Repeat PK Assessment: Clearance (CL) [46]
    End point description
    Baseline-adjusted clearance of von Willebrand factor:ristocetin cofactor (VWF:RCo), von Willebrand factor: antigen (VWF:Ag), von Willebrand factor:collagen binding (VWF:CB) and Factor VIII:coagulant activity (FVIII:C) from the initial PK assessment.
    End point type
    Primary
    End point timeframe
    Day 180: preinfusion, 0.5 (±15) min, 4 h (±15 min), 8 h (±30 min), 24 (±2) h, 48 (±2) h after the end of infusion.
    Notes
    [46] - 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 calculated by non-compartmental analysis based on baseline-adjusted concentrations and actual sampling times and were summarised per infusion (initial or repeat) by descriptive statistics.
    End point values
    		 PK Component
    Number of subjects analysed
    17 [47]
    Units: mL/h/kg
    geometric mean (geometric coefficient of variation)
        VWF:RCo; n=9
    5.81 ± 42
        VWF:Ag; n=9
    5.13 ± 19
        VWF:CB; n=9
    5.52 ± 13.9
        FVIII:C; n=3
    0.91 ± 28.1
    Notes
    [47] - Repeat PK population;n=number of subjects with evaluable assessments.
    No statistical analyses for this end point

    Primary: Repeat PK Assessment: Volume of Distribution at Steady State (Vss)

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    End point title
    		 Repeat PK Assessment: Volume of Distribution at Steady State (Vss) [48]
    End point description
    Baseline-adjusted Vss of von Willebrand factor:ristocetin cofactor (VWF:RCo), von Willebrand factor:antigen (VWF:Ag), von Willebrand factor:collagen binding (VWF:CB) and Factor VIII:coagulant activity (FVIII:C) from the initial PK assessment.
    End point type
    Primary
    End point timeframe
    Day 180: preinfusion, 0.5 (±15) min, 4 h (±15 min), 8 h (±30 min), 24 (±2) h, 48 (±2) h after the end of infusion.
    Notes
    [48] - 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 calculated by non-compartmental analysis based on baseline-adjusted concentrations and actual sampling times and were summarised per infusion (initial or repeat) by descriptive statistics.
    End point values
    		 PK Component
    Number of subjects analysed
    9 [49]
    Units: mL/kg
    geometric mean (geometric coefficient of variation)
        VWF:RCo; n=9
    87.9 ± 21.6
        VWF:Ag; n=9
    81.8 ± 25.1
        VWF:CB; n=9
    77.3 ± 18
        FVIII:C; n=3
    41.9 ± 7.1
    Notes
    [49] - Repeat PK population; n=number of subjects with an evaluable 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 [50]
    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
    [50] - 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
    		 Arm 1: Prophylaxis Therapy Arm 2: On-Demand Therapy
    Number of subjects analysed
    4 [51]
    12 [52]
    Units: surgeries
        All Surgeries: Less Than Expected; n=0, 8
    0
    0
        All Surgeries: Equivalent To Expected; n=0, 8
    0
    8
        All Surgeries: More Than Expected; n=0, 8
    0
    0
        Major Surgeries: Less Than Expected; n=0, 0
    0
    0
        Major Surgeries: Equivalent To Expected; n=0, 0
    0
    0
        Major Surgeries: More Than Expected; n=0, 0
    0
    0
        Minor Surgeries: Less Than Expected; n=0, 8
    0
    0
        Minor Surgeries: Equivalent To Expected; n=0, 8
    0
    8
        Minor Surgeries: More Than Expected; n=0, 8
    0
    0
    Notes
    [51] - Efficacy population; n=number of surgeries of given type.
    [52] - Efficacy population; n=number of surgeries of given type.
    No statistical analyses for this end point

    Primary: Number of Subjects Requiring Blood Product Transfusions

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    End point title
    		 Number of Subjects Requiring Blood Product Transfusions [53]
    End point description
    Blood products include any infusions of whole blood, packed red blood cells, and platelets.
    End point type
    Primary
    End point timeframe
    Up to Month 12
    Notes
    [53] - 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
    		 Arm 1: Prophylaxis Therapy Arm 2: On-Demand Therapy
    Number of subjects analysed
    4 [54]
    12 [55]
    Units: subjects
    0
    0
    Notes
    [54] - Efficacy population
    [55] - Efficacy population
    No statistical analyses for this end point

    Primary: Initial PK Assessment: Mean Residence Time (MRT)

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    End point title
    		 Initial PK Assessment: Mean Residence Time (MRT) [56]
    End point description
    Baseline-adjusted MRT of von Willebrand factor:ristocetin cofactor (VWF:RCo), von Willebrand factor:antigen (VWF:Ag), von Willebrand factor:collagen binding (VWF:CB) and Factor VIII:coagulant activity (FVIII:C) from the initial PK assessment.
    End point type
    Primary
    End point timeframe
    Day 1: preinfusion; Days 1-3: 0.5 (±15) min, 4 h (±15 min), 8 h (±30 min), 24 (±2) h, 48 (±2) h after the end of infusion.
    Notes
    [56] - 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 calculated by non-compartmental analysis based on baseline-adjusted concentrations and actual sampling times and were summarised per infusion (initial or repeat) by descriptive statistics.
    End point values
    		 PK Component
    Number of subjects analysed
    17 [57]
    Units: hours
    geometric mean (geometric coefficient of variation)
        VWF:RCo; n=11
    12.0269 ± 61.2
        VWF:Ag; n=16
    14.081 ± 33.9
        VWF:CB; n=16
    12.3401 ± 24.2
        FVIII:C; n=10
    27.7228 ± 56.4
    Notes
    [57] - PK population; n=number of subjects with evaluable assessments.
    No statistical analyses for this end point

    Primary: Repeat PK Assessment: Mean Residence Time (MRT)

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    End point title
    		 Repeat PK Assessment: Mean Residence Time (MRT) [58]
    End point description
    Baseline-adjusted MRT of von Willebrand factor:ristocetin cofactor (VWF:RCo), von Willebrand factor:antigen (VWF:Ag), von Willebrand factor:collagen binding (VWF:CB) and Factor VIII:coagulant activity.
    End point type
    Primary
    End point timeframe
    Day 180: preinfusion, 0.5 (±15) min, 4 h (±15 min), 8 h (±30 min), 24 (±2) h, 48 (±2) h after the end of infusion.
    Notes
    [58] - 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 calculated by non-compartmental analysis based on baseline-adjusted concentrations and actual sampling times and were summarised per infusion (initial or repeat) by descriptive statistics.
    End point values
    		 PK Component
    Number of subjects analysed
    9 [59]
    Units: hours
    geometric mean (geometric coefficient of variation)
        VWF:RCo; n=9
    15.1403 ± 38.4
        VWF:Ag; n=9
    15.958 ± 21.2
        VWF:CB; n=9
    14.007 ± 21.4
        FVIII:C; n=3
    45.907 ± 25.5
    Notes
    [59] - Repeat PK population; n=number of subjects with an evaluable assessment.
    No statistical analyses for this end point

    Primary: Repeat PK Assessment: Minimum Concentration (Cmin)

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    End point title
    		 Repeat PK Assessment: Minimum Concentration (Cmin) [60]
    End point description
    Baseline-adjusted Cmin of von Willebrand factor:ristocetin cofactor (VWF:RCo), von Willebrand factor:antigen (VWF:Ag), von Willebrand factor:collagen binding (VWF:CB) and Factor VIII:coagulant activity (FVIII:C) from the repeat PK assessment. For the calculation of Cmin, values below the lower limit of quantification (LLOQ), preceding the first quantifiable measurement in a profile, was set to zero. (The geometric mean was calculated for values >0). LLOQ for this parameter was <0.1 IU/mL.
    End point type
    Primary
    End point timeframe
    Day 180: preinfusion, 0.5 (±15) min, 4 h (±15 min), 8 h (±30 min), 24 (±2) h, 48 (±2) h after the end of infusion.
    Notes
    [60] - 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 calculated by non-compartmental analysis based on baseline-adjusted concentrations and actual sampling times and were summarised per infusion (initial or repeat) by descriptive statistics.
    End point values
    		 PK Component
    Number of subjects analysed
    9 [61]
    Units: IU/mL
    arithmetic mean (standard deviation)
        VWF:RCo
    0 ± 0
        VWF:Ag
    0 ± 0
        VWF:CB
    0 ± 0
        FVIII:C
    0 ± 0
    Notes
    [61] - Repeat PK population
    No statistical analyses for this end point

    Secondary: Percentage of Subjects with Treatment Emergent Adverse Events

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    End point title
    		 Percentage of Subjects with Treatment Emergent Adverse Events
    End point description
    An adverse event (AE) is any untoward medical occurrence in a subject administered the IMP. An AE does not necessarily have a causal relationship with the IMP. A serious AE (SAE) is defined as any untoward medical occurrence that at any dose: results in death; is life-threatening; requires in-patient hospitalisation or prolongation of existing hospitalization; results in persistent or significant disability or incapacity; is a congenital anomaly or birth defect; or is medically significant. Treatment emergent AEs (TEAEs) occured after exposure to study drug. Adverse drug reacions (ADRs) are TEAEs that were considered at least possibly related to Biostate.
    End point type
    Secondary
    End point timeframe
    From first administration of the IMP until Final Visit or until 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
    		 Arm 1: Prophylaxis Therapy Arm 2: On-Demand Therapy
    Number of subjects analysed
    4 [62]
    13 [63]
    Units: Percentage of subjects
    number (not applicable)
        At Least 1 TEAE
    75
    69.2
        At Least 1 Severe TEAE
    50
    7.7
        At Least 1 ADR
    25
    7.7
        At Least 1 Serious TEAE
    0
    0
    Notes
    [62] - Safety population
    [63] - Safety population
    No statistical analyses for this end point

    Secondary: VWF and Factor VIII Inhibitors

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    End point title
    		 VWF and Factor VIII Inhibitors
    End point description
    Number of subjects with VWF and Factor VIII inhibitors at given time points.
    End point type
    Secondary
    End point timeframe
    Screening, Months 3, 6, 9, 12
    End point values
    		 Arm 1: Prophylaxis Therapy Arm 2: On-Demand Therapy
    Number of subjects analysed
    4 [64]
    12 [65]
    Units: subjects
    number (not applicable)
        VWF Inhibitor: Screening; n=4, 13
    0
    0
        VWF Inhibitor: Month 3; n=4, 12
    0
    0
        VWF Inhibitor: Month 6; n=4, 13
    0
    0
        VWF Inhibitor: Month 9; n=4, 13
    0
    0
        VWF Inhibitor: Month 12; n=4, 13
    0
    0
        FVIII Inhibitor: Screening; n=4, 13
    0
    0
        FVIII Inhibitor: Month 3; n=4, 13
    0
    0
        FVIII Inhibitor: Month 6; n=4, 13
    0
    0
        FVIII Inhibitor: Month 9; n=4, 13
    0
    0
        FVIII Inhibitor: Month 12; n=4, 13
    0
    0
    Notes
    [64] - Safety population; n=subjects with an available test result for given visit.
    [65] - Safety population; n=subjects with an available test result for given visit.
    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 until 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
    Prophylaxis Arm
    Reporting group description
    		 Subjects who were treated on a set prophylaxis regimen with a VWF product at the time of study entry were enrolled into the prophylaxis arm to receive Biostate as a pre-defined prophylaxis regimen determined by the severity of their disease for a period of 12 months.

    Reporting group title
    On-Demand Therapy Arm
    Reporting group description
    		 Subjects who were not treated on a set prophylaxis regimen with a VWF product at the time of study entry and who required a VWF product for the treatment of non-surgical bleeding (NSB) events (control during surgery, or spontaneous, or trauma induced) were enrolled to start Biostate treatment of NSB events (on-demand therapy). If Biostate was used for irregular prevention of bleedings, this was considered as “on demand” therapy. Subjects who had been previously on an on-demand therapy were allowed to switch to prophylaxis therapy at the beginning of the efficacy component.

    Serious adverse events
    		 Prophylaxis Arm On-Demand Therapy Arm
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 13 (0.00%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Prophylaxis Arm On-Demand Therapy Arm
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    3 / 4 (75.00%)
    9 / 13 (69.23%)
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    2 / 4 (50.00%)
    0 / 13 (0.00%)
         occurrences all number
    3
    0
    Joint Injury
         subjects affected / exposed
    2 / 4 (50.00%)
    0 / 13 (0.00%)
         occurrences all number
    2
    0
    Skin Laceration
         subjects affected / exposed
    2 / 4 (50.00%)
    0 / 13 (0.00%)
         occurrences all number
    2
    0
    Clavicle Fracture
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    1
    Eye Injury
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 13 (0.00%)
         occurrences all number
    1
    0
    Injury
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 13 (0.00%)
         occurrences all number
    1
    0
    Injury Corneal
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 13 (0.00%)
         occurrences all number
    1
    0
    Mouth Injury
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 13 (0.00%)
         occurrences all number
    1
    0
    Road Traffic Accident
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 13 (0.00%)
         occurrences all number
    1
    0
    Congenital, familial and genetic disorders
    Heart Disease Congenital
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    1
    Cardiac disorders
    Cardiomyopathy
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    1
    Sinus Arrhythmia
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    1
    Supraventricular Extrasystoles
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    1
    Nervous system disorders
    Tongue Biting
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 13 (0.00%)
         occurrences all number
    3
    0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    1 / 4 (25.00%)
    5 / 13 (38.46%)
         occurrences all number
    1
    10
    Infusion Site Erythema
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 13 (0.00%)
         occurrences all number
    1
    0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    1
    Ear and labyrinth disorders
    Ear Pain
         subjects affected / exposed
    1 / 4 (25.00%)
    1 / 13 (7.69%)
         occurrences all number
    1
    1
    Eye disorders
    Conjunctivitis
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 13 (0.00%)
         occurrences all number
    1
    0
    Gastrointestinal disorders
    Abdominal Pain Upper
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 13 (0.00%)
         occurrences all number
    3
    0
    Cheilitis
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 13 (0.00%)
         occurrences all number
    1
    0
    Diarrhoea
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    1
    Stomatitis
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 13 (0.00%)
         occurrences all number
    1
    0
    Tooth Loss
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 13 (0.00%)
         occurrences all number
    1
    0
    Toothache
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    1
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    2 / 4 (50.00%)
    2 / 13 (15.38%)
         occurrences all number
    2
    2
    Adenoidal Hypertrophy
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    1
    Tonsillar Hypertrophy
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    1
    Upper Airway Obstruction
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    1
    Musculoskeletal and connective tissue disorders
    Muscle Spasms
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 13 (0.00%)
         occurrences all number
    1
    0
    Musculoskeletal Pain
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 13 (0.00%)
         occurrences all number
    1
    0
    Infections and infestations
    Rhinitis
         subjects affected / exposed
    1 / 4 (25.00%)
    3 / 13 (23.08%)
         occurrences all number
    3
    6
    Nasopharyngitis
         subjects affected / exposed
    1 / 4 (25.00%)
    2 / 13 (15.38%)
         occurrences all number
    2
    2
    Acute Tonsilitis
         subjects affected / exposed
    1 / 4 (25.00%)
    1 / 13 (7.69%)
         occurrences all number
    1
    1
    Bronchitis
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    1
    Chlamydial Infection
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 13 (0.00%)
         occurrences all number
    1
    0
    Ear Infection
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    1
    Gastroenteritis
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 13 (0.00%)
         occurrences all number
    2
    0
    Pulpitis Dental
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    1
    Tonsilitis Streptococcal
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 13 (0.00%)
         occurrences all number
    1
    0
    Tracheitis
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    1
    Upper Respiratory Tract Infection
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 13 (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
    08 Nov 2010
    - Data recording by eCRF: Correction of number of enrolled subjects from 20 to 12. - An additional primary endpoint was added: Assessment of response was to also include haemostasis during surgical procedure, blood loss, and transfusion requirements. - Correction of blood volumes for PK and efficacy component. - Modification of inclusion criterion 5, because no HAV vaccine is available for children aged younger than 1 year. - Modification of inclusion criterion 4 to comply with upper limit of VWF:RCo activity range as outlined in Guideline CPMP/BPWG/220/02. - Inclusion of monitoring of thrombogenicity markers for subjects undergoing surgery (Paul Ehrlich Institute). - Contact details for SAE reporting were changed.
    19 Apr 2011
    - Updates to the nominal VWF concentration. - List of personnel was removed, contact details for SAE reporting was changed.

    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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    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
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