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    Clinical Trial Results:
    A Phase 3 clinical study to determine the pharmacokinetics, safety, and efficacy of rVWF:rFVIII and rVWF in the treatment of bleeding episodes in subjects diagnosed with von Willebrand disease

    Summary
    EudraCT number
    2010-024108-84
    Trial protocol
    GB   DE   SE   AT   NL   BE   BG   IT   ES  
    Global end of trial date
    15 Feb 2014

    Results information
    Results version number
    v2(current)
    This version publication date
    12 Mar 2016
    First version publication date
    07 Aug 2015
    Other versions
    v1
    Version creation reason
    • New data added to full data set
    Statistics added in justifications for endpoints 1-3 as unable to add statistics to these endpoints in EudraCT due to EudraCT limitation of not currently accepting statistics for one analysis group. Adverse Events updated. Minor changes to descriptive text.

    Trial information

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    Trial identification
    Sponsor protocol code
    071001
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01410227
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Baxalta Innovations GmbH
    Sponsor organisation address
    Industriestrasse 67, Vienna, Austria, 1221
    Public contact
    Clinical Trial Registries and Results Disclosure, Baxalta Innovations GmbH, ClinicalTrialsDisclosure@baxalta.com
    Scientific contact
    Clinical Trial Registries and Results Disclosure, Baxalta Innovations GmbH, ClinicalTrialsDisclosure@baxalta.com
    Sponsor organisation name
    Baxalta US Inc.
    Sponsor organisation address
    One Baxter Way, Westlake Village, United States, CA 91362
    Public contact
    Clinical Trial Registries and Results Disclosure, Baxalta US Inc., ClinicalTrialsDisclosure@baxalta.com
    Scientific contact
    Clinical Trial Registries and Results Disclosure, Baxalta US Inc., ClinicalTrialsDisclosure@baxalta.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    15 Feb 2014
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    15 Feb 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The objectives of this study were: To compare the pharmacokinetic (PK) parameters of recombinant von Willebrand Factor (rVWF) alone or concomitantly with recombinant Factor VIII (rFVIII) [rVWF:rFVIII] in subjects with type 3 von Willebrand Disease (VWD); To examine the PK parameters of rVWF in subjects with severe VWD; To evaluate the hemostatic efficacy, safety, and tolerability of rVWF:rFVIII and rVWF alone in subjects with VWD receiving the investigational product for the treatment of bleeding episodes (BEs); To evaluate tolerability and safety of rVWF including the development of inhibitory and total binding anti-VWF antibodies and clinically significant changes in laboratory parameters following study product administration; To assess changes in Health-Related Quality of Life (HRQoL)
    Protection of trial subjects
    This study was conducted in accordance with the standards of Good Clinical Practice (GCP) in effect at the time of the study.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    17 Jan 2011
    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
    Austria: 1
    Country: Number of subjects enrolled
    Belgium: 1
    Country: Number of subjects enrolled
    Bulgaria: 2
    Country: Number of subjects enrolled
    Germany: 2
    Country: Number of subjects enrolled
    Spain: 1
    Country: Number of subjects enrolled
    United Kingdom: 3
    Country: Number of subjects enrolled
    India: 1
    Country: Number of subjects enrolled
    Italy: 3
    Country: Number of subjects enrolled
    Japan: 3
    Country: Number of subjects enrolled
    Netherlands: 1
    Country: Number of subjects enrolled
    Poland: 6
    Country: Number of subjects enrolled
    Australia: 2
    Country: Number of subjects enrolled
    Russian Federation: 2
    Country: Number of subjects enrolled
    Sweden: 1
    Country: Number of subjects enrolled
    United States: 8
    Worldwide total number of subjects
    37
    EEA total number of subjects
    21
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    37
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    Subjects were enrolled (signed informed consent) from 30 sites in 15 countries.

    Pre-assignment
    Screening details
    49 subjects provided informed consent and were screened for study, of which 37 were exposed to study product. Reasons for discontinuation are provided in Pre-assignment period.

    Pre-assignment period milestones
    Number of subjects started
    49 [1]
    Number of subjects completed
    37

    Pre-assignment subject non-completion reasons
    Reason: Number of subjects
    Consent withdrawn by subject: 3
    Reason: Number of subjects
    Physician decision: 1
    Reason: Number of subjects
    Screen failure: 6
    Reason: Number of subjects
    High doses of rFVIII for oral procedure: 1
    Reason: Number of subjects
    Arm for which subject eligible was closed: 1
    Notes
    [1] - The number of subjects reported to have started the pre-assignment period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: The worldwide number of subjects enrolled are for subjects treated with study product (N=37) as per definition in EudraCT (Enrolled=Treated) and the number of subjects who started pre-assignment are all subjects enrolled i.e. signed informed consent (N=49).
    Period 1
    Period 1 title
    Overall Trial (Part A and B Combined) (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Investigator, Subject
    Blinding implementation details
    Part Randomized: Subjects in Arms 1 and 2 were randomized at ratio of 1:1 to receive either recombinant von Willebrand Factor:recombinant Factor VIII (rVWF:rFVIII) or rVWF:saline (placebo) for pharmacokinetic (PK) analysis. After a washout period, subjects crossed over to receive the alternative treatment to the initial infusion for a further PK analysis. Subject/investigator were blinded and the study product was reconstituted by an unblinded third party (preferably by the hospital pharmacist)

    Arms
    Are arms mutually exclusive
    No

    Arm title
    PK50+Treatment
    Arm description
    In Part A, (pharmacokinetic [PK] assessment followed by on-demand treatment for bleeding episodes [BEs] for 6 months) subjects were initially infused either with 50 IU/kg recombinant von Willebrand Factor:von Willebrand Ristocetin cofactor (VWF:RCo rVWF) [rVWF] administered together with 38.5 IU/kg recombinant Factor VIII (rFVIII) [rVWF:rFVIII] or 50 IU/kg rVWF administered together with saline. Subjects then crossed over to the alternate infusion after washout (PK). For on-demand treatment, subjects received study product [VWF:rFVIII or rVWF], where BEs were initially treated with rVWF:rFVIII and subsequently with rVWF with or without rFVIII, based on FVIII levels (dose based on previous FVIII levels or if not available from the individual subject's PK data at discretion of investigator). In part, B subjects continued to receive on demand treatment for BEs with study product [VWF:rFVIII or rVWF] for a further 6 months.
    Arm type
    Experimental

    Investigational medicinal product name
    rVWF:rFVIII
    Investigational medicinal product code
    BAX111 with ADVATE
    Other name
    vonicog alfa with ADVATE
    Pharmaceutical forms
    Powder and solvent for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    50 IU/kg von Willebrand Factor:von Willebrand Factor Ristocetin cofactor (VWF:RCo rVWF) [rVWF] co-infused with 38.5 IU/kg recombinant Factor VIII (rFVIII) at a ratio of 1.3:1±0.2 [rVWF:rFVIII] (Arms 1 and 2 -PK50 only). Dose and frequency of study product for on-demand treatment of bleeding episodes for Arms 1, 3 and 4 dependent on severity and location of bleed. The initial bleeding episode was to be treated with rVWF:rFVIII at a ratio of 1.3:1±0.2 with subsequent doses of rVWF alone as long as therapeutic FVIII levels were maintained.

    Investigational medicinal product name
    rVWF
    Investigational medicinal product code
    BAX111
    Other name
    vonicog alfa
    Pharmaceutical forms
    Powder and solvent for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    50 IU/kg von Willebrand Factor:von Willebrand Factor Ristocetin cofactor (VWF:RCo rVWF) [rVWF] (Arms 1 and 2 -PK50 only), 80 IU/kg VWF:RCo rVWF [rVWF] rVWF (Arm 3 - PK80 only). Dose and frequency of study product for on-demand treatment of bleeding episodes for Arms 1, 3 and 4 dependent on severity and location of bleed. The initial bleeding episode was to be treated with rVWF:rFVIII at a ratio of 1.3:1±0.2 with subsequent doses of rVWF alone as long as therapeutic FVIII levels were maintained

    Arm title
    PK50 only
    Arm description
    In Part A, (pharmacokinetic [PK] assessment followed by on-demand treatment for bleeding episodes [BEs] for 6 months) subjects were initially infused either with 50 IU/kg recombinant von Willebrand Factor:von Willebrand Ristocetin cofactor (VWF:RCo rVWF) [rVWF] administered together with 38.5 IU/kg recombinant Factor VIII (rFVIII) [rVWF:rFVIII] or 50 IU/kg rVWF administered together with saline. Subjects then crossed over to the alternate infusion after washout (PK). For on-demand treatment, subjects received study product [VWF:rFVIII or rVWF], where BEs were initially treated with rVWF:rFVIII and subsequently with rVWF with or without rFVIII, based on FVIII levels (dose based on previous FVIII levels or if not available from the individual subject's PK data at discretion of investigator). Subjects then exited the study or could opt to sign informed consent to move to Arm 1 receive treatment for bleeding episodes with study product.
    Arm type
    Experimental

    Investigational medicinal product name
    rVWF
    Investigational medicinal product code
    BAX111
    Other name
    vonicog alfa
    Pharmaceutical forms
    Powder and solvent for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    50 IU/kg von Willebrand Factor:von Willebrand Factor Ristocetin cofactor (VWF:RCo rVWF) [rVWF] (Arms 1 and 2 -PK50 only), 80 IU/kg VWF:RCo rVWF [rVWF] rVWF (Arm 3 - PK80 only). Dose and frequency of study product for on-demand treatment of bleeding episodes for Arms 1, 3 and 4 dependent on severity and location of bleed. The initial bleeding episode was to be treated with rVWF:rFVIII at a ratio of 1.3:1±0.2 with subsequent doses of rVWF alone as long as therapeutic FVIII levels were maintained

    Investigational medicinal product name
    rVWF:rFVIII
    Investigational medicinal product code
    BAX111 with ADVATE
    Other name
    vonicog alfa with ADVATE
    Pharmaceutical forms
    Powder and solvent for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    50 IU/kg von Willebrand Factor:von Willebrand Factor Ristocetin cofactor (VWF:RCo rVWF) [rVWF] co-infused with 38.5 IU/kg recombinant Factor VIII (rFVIII) at a ratio of 1.3:1±0.2 [rVWF:rFVIII] (Arms 1 and 2 -PK50 only). Dose and frequency of study product for on-demand treatment of bleeding episodes for Arms 1, 3 and 4 dependent on severity and location of bleed. The initial bleeding episode was to be treated with rVWF:rFVIII at a ratio of 1.3:1±0.2 with subsequent doses of rVWF alone as long as therapeutic FVIII levels were maintained.

    Arm title
    PK80+Treatment
    Arm description
    In Part A, subjects underwent pharmacokinetic (PK) assessment for 2 infusions of recombinant von Willebrand Factor (rVWF). Subjects initially underwent an initial PK assessment of an infusion of 80 IU/kg recombinant von Willebrand Factor Ristocetin cofactor (VWF:RCo rVWF) [rVWF]. After the first PK assessment subjects received on demand treatment for bleeding episodes (BEs) with study product [VWF:rFVIII or rVWF], where BEs were initially treated with rVWF:rFVIII and subsequently with rWVF with or without rFVIII, based on FVIII levels. If FVIII levels not available, the individual subject's PK data was used to determine rFVIII dose at discretion of investigator. Subjects received on demand treatment for 6 months after the first study product infusion. After 6 months subjects underwent a second PK assessment of an infusion of 80 IU/kg rVWF. In part B, subjects continued to receive on demand treatment for BEs with study product [VWF:rFVIII or rVWF] for a further 6 months.
    Arm type
    Experimental

    Investigational medicinal product name
    rVWF
    Investigational medicinal product code
    BAX111
    Other name
    vonicog alfa
    Pharmaceutical forms
    Powder and solvent for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    50 IU/kg von Willebrand Factor:von Willebrand Factor Ristocetin cofactor (VWF:RCo rVWF) [rVWF] (Arms 1 and 2 -PK50 only), 80 IU/kg VWF:RCo rVWF [rVWF] rVWF (Arm 3 - PK80 only). Dose and frequency of study product for on-demand treatment of bleeding episodes for Arms 1, 3 and 4 dependent on severity and location of bleed. The initial bleeding episode was to be treated with rVWF:rFVIII at a ratio of 1.3:1±0.2 with subsequent doses of rVWF alone as long as therapeutic FVIII levels were maintained

    Investigational medicinal product name
    rVWF:rFVIII
    Investigational medicinal product code
    BAX111 with ADVATE
    Other name
    vonicog alfa with ADVATE
    Pharmaceutical forms
    Powder and solvent for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    50 IU/kg von Willebrand Factor:von Willebrand Factor Ristocetin cofactor (VWF:RCo rVWF) [rVWF] co-infused with 38.5 IU/kg recombinant Factor VIII (rFVIII) at a ratio of 1.3:1±0.2 [rVWF:rFVIII] (Arms 1 and 2 -PK50 only). Dose and frequency of study product for on-demand treatment of bleeding episodes for Arms 1, 3 and 4 dependent on severity and location of bleed. The initial bleeding episode was to be treated with rVWF:rFVIII at a ratio of 1.3:1±0.2 with subsequent doses of rVWF alone as long as therapeutic FVIII levels were maintained.

    Arm title
    Treatment
    Arm description
    In Part A, subjects received on demand treatment for bleeding episodes (BEs) with study product (recombinant von Willebrand Factor [rVWF] administered together with recombinant Factor VIII [rFVIII] (rVWF:rFVIII) or rVWF alone), where BEs were initially treated with rVWF:rFVIII and subsequently with rVWF with or without rFVIII, based on FVIII levels. If not available, the individual subject's PK data was used to determine rFVIII dose at discretion of investigator. Subjects received on demand treatment for 6 months after the first study product infusion. In part, B subjects continued to receive on demand treatment for BEs with study product [VWF:rFVIII or rVWF] for a further 6 months. No pharmacokinetic (PK) assessments were conducted in this arm.
    Arm type
    Experimental

    Investigational medicinal product name
    rVWF:rFVIII
    Investigational medicinal product code
    BAX111 with ADVATE
    Other name
    vonicog alfa with ADVATE
    Pharmaceutical forms
    Powder and solvent for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    50 IU/kg von Willebrand Factor:von Willebrand Factor Ristocetin cofactor (VWF:RCo rVWF) [rVWF] co-infused with 38.5 IU/kg recombinant Factor VIII (rFVIII) at a ratio of 1.3:1±0.2 [rVWF:rFVIII] (Arms 1 and 2 -PK50 only). Dose and frequency of study product for on-demand treatment of bleeding episodes for Arms 1, 3 and 4 dependent on severity and location of bleed. The initial bleeding episode was to be treated with rVWF:rFVIII at a ratio of 1.3:1±0.2 with subsequent doses of rVWF alone as long as therapeutic FVIII levels were maintained.

    Investigational medicinal product name
    rVWF
    Investigational medicinal product code
    BAX111
    Other name
    vonicog alfa
    Pharmaceutical forms
    Powder and solvent for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    50 IU/kg von Willebrand Factor:von Willebrand Factor Ristocetin cofactor (VWF:RCo rVWF) [rVWF] (Arms 1 and 2 -PK50 only), 80 IU/kg VWF:RCo rVWF [rVWF] rVWF (Arm 3 - PK80 only). Dose and frequency of study product for on-demand treatment of bleeding episodes for Arms 1, 3 and 4 dependent on severity and location of bleed. The initial bleeding episode was to be treated with rVWF:rFVIII at a ratio of 1.3:1±0.2 with subsequent doses of rVWF alone as long as therapeutic FVIII levels were maintained

    Arm title
    Safety Analysis Set
    Arm description
    The Safety Analysis Set comprises of subjects who were treated with study product (recombinant von Willebrand Factor [rVWF] with or without recombinant factor VIII [rFVIII]) at least once during the study.
    Arm type
    Experimental

    Investigational medicinal product name
    rVWF
    Investigational medicinal product code
    BAX111
    Other name
    vonicog alfa
    Pharmaceutical forms
    Powder and solvent for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    50 IU/kg von Willebrand Factor:von Willebrand Factor Ristocetin cofactor (VWF:RCo rVWF) [rVWF] (Arms 1 and 2 -PK50 only), 80 IU/kg VWF:RCo rVWF [rVWF] rVWF (Arm 3 - PK80 only). Dose and frequency of study product for on-demand treatment of bleeding episodes for Arms 1, 3 and 4 dependent on severity and location of bleed. The initial bleeding episode was to be treated with rVWF:rFVIII at a ratio of 1.3:1±0.2 with subsequent doses of rVWF alone as long as therapeutic FVIII levels were maintained

    Investigational medicinal product name
    rVWF:rFVIII
    Investigational medicinal product code
    BAX111 with ADVATE
    Other name
    vonicog alfa with ADVATE
    Pharmaceutical forms
    Powder and solvent for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    50 IU/kg von Willebrand Factor:von Willebrand Factor Ristocetin cofactor (VWF:RCo rVWF) [rVWF] co-infused with 38.5 IU/kg recombinant Factor VIII (rFVIII) at a ratio of 1.3:1±0.2 [rVWF:rFVIII] (Arms 1 and 2 -PK50 only). Dose and frequency of study product for on-demand treatment of bleeding episodes for Arms 1, 3 and 4 dependent on severity and location of bleed. The initial bleeding episode was to be treated with rVWF:rFVIII at a ratio of 1.3:1±0.2 with subsequent doses of rVWF alone as long as therapeutic FVIII levels were maintained.

    Arm title
    Full Analysis Set
    Arm description
    The Full Analysis Set comprised of subjects treated with study product (recombinant von Willebrand Factor [rVWF] with or without recombinant factor VIII [rFVIII]) for whom at least one efficacy rating scale was available.
    Arm type
    Experimental

    Investigational medicinal product name
    rVWF:rFVIII
    Investigational medicinal product code
    BAX111 with ADVATE
    Other name
    vonicog alfa with ADVATE
    Pharmaceutical forms
    Powder and solvent for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    50 IU/kg von Willebrand Factor:von Willebrand Factor Ristocetin cofactor (VWF:RCo rVWF) [rVWF] co-infused with 38.5 IU/kg recombinant Factor VIII (rFVIII) at a ratio of 1.3:1±0.2 [rVWF:rFVIII] (Arms 1 and 2 -PK50 only). Dose and frequency of study product for on-demand treatment of bleeding episodes for Arms 1, 3 and 4 dependent on severity and location of bleed. The initial bleeding episode was to be treated with rVWF:rFVIII at a ratio of 1.3:1±0.2 with subsequent doses of rVWF alone as long as therapeutic FVIII levels were maintained.

    Investigational medicinal product name
    rVWF
    Investigational medicinal product code
    BAX111
    Other name
    vonicog alfa
    Pharmaceutical forms
    Powder and solvent for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    50 IU/kg von Willebrand Factor:von Willebrand Factor Ristocetin cofactor (VWF:RCo rVWF) [rVWF] (Arms 1 and 2 -PK50 only), 80 IU/kg VWF:RCo rVWF [rVWF] rVWF (Arm 3 - PK80 only). Dose and frequency of study product for on-demand treatment of bleeding episodes for Arms 1, 3 and 4 dependent on severity and location of bleed. The initial bleeding episode was to be treated with rVWF:rFVIII at a ratio of 1.3:1±0.2 with subsequent doses of rVWF alone as long as therapeutic FVIII levels were maintained

    Arm title
    PK50 Arms
    Arm description
    The PK50 arm comprised of subjects who underwent PK analysis of study product (50 IU/kg recombinant von Willebrand Factor (rVWF) administered together with 38.5 IU/kg recombinant Factor VIII (rFVIII) [rVWF:rFVIII] or 50 IU/kg rVWF administered together with saline [rVWF]) i.e. a total subjects from Arm 1 [PK50+Treatment] and Arm 2 [PK50 only]. Subjects in this arm have received at least one PK infusion and have provided data suitable for PK analysis. Only PK data included in this arm.
    Arm type
    Experimental

    Investigational medicinal product name
    rVWF:rFVIII
    Investigational medicinal product code
    BAX111 with ADVATE
    Other name
    vonicog alfa with ADVATE
    Pharmaceutical forms
    Powder and solvent for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    50 IU/kg von Willebrand Factor:von Willebrand Factor Ristocetin cofactor (VWF:RCo rVWF) [rVWF] co-infused with 38.5 IU/kg recombinant Factor VIII (rFVIII) at a ratio of 1.3:1±0.2 [rVWF:rFVIII] (Arms 1 and 2 -PK50 only). Dose and frequency of study product for on-demand treatment of bleeding episodes for Arms 1, 3 and 4 dependent on severity and location of bleed. The initial bleeding episode was to be treated with rVWF:rFVIII at a ratio of 1.3:1±0.2 with subsequent doses of rVWF alone as long as therapeutic FVIII levels were maintained.

    Investigational medicinal product name
    rVWF
    Investigational medicinal product code
    BAX111
    Other name
    vonicog alfa
    Pharmaceutical forms
    Powder and solvent for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    50 IU/kg von Willebrand Factor:von Willebrand Factor Ristocetin cofactor (VWF:RCo rVWF) [rVWF] (Arms 1 and 2 -PK50 only), 80 IU/kg VWF:RCo rVWF [rVWF] rVWF (Arm 3 - PK80 only). Dose and frequency of study product for on-demand treatment of bleeding episodes for Arms 1, 3 and 4 dependent on severity and location of bleed. The initial bleeding episode was to be treated with rVWF:rFVIII at a ratio of 1.3:1±0.2 with subsequent doses of rVWF alone as long as therapeutic FVIII levels were maintained

    Arm title
    PK80 Arm
    Arm description
    The PK80 arm comprised of subjects who underwent PK analysis of study product (80 IU/kg recombinant von Willebrand Factor [rVWF]) i.e. subjects from Arm 3 [PK80+Treatment]. Subjects in this arm have received at least one PK infusion and have provided data suitable for PK analysis. Only PK data included in this arm.
    Arm type
    Experimental

    Investigational medicinal product name
    rVWF
    Investigational medicinal product code
    BAX111
    Other name
    vonicog alfa
    Pharmaceutical forms
    Powder and solvent for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    50 IU/kg von Willebrand Factor:von Willebrand Factor Ristocetin cofactor (VWF:RCo rVWF) [rVWF] (Arms 1 and 2 -PK50 only), 80 IU/kg VWF:RCo rVWF [rVWF] rVWF (Arm 3 - PK80 only). Dose and frequency of study product for on-demand treatment of bleeding episodes for Arms 1, 3 and 4 dependent on severity and location of bleed. The initial bleeding episode was to be treated with rVWF:rFVIII at a ratio of 1.3:1±0.2 with subsequent doses of rVWF alone as long as therapeutic FVIII levels were maintained

    Number of subjects in period 1
    PK50+Treatment PK50 only PK80+Treatment Treatment Safety Analysis Set Full Analysis Set PK50 Arms PK80 Arm
    Started
    8
    8
    15
    6
    37
    22
    16
    15
    Completed
    4
    8
    13
    5
    30
    20
    16
    13
    Not completed
    4
    0
    2
    1
    7
    2
    0
    2
         Pregnancy
    -
    -
    -
    1
    1
    -
    -
    -
         met exclusion criteria after starting study
    -
    -
    1
    -
    1
    -
    -
    1
         Adverse event, non-fatal
    1
    -
    -
    -
    1
    -
    -
    -
         Consent withdrawn by subject
    3
    -
    1
    -
    4
    2
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Overall Trial (Part A and B Combined)
    Reporting group description
    Overall Trial (Part A and B Combined)

    Reporting group values
    Overall Trial (Part A and B Combined) Total
    Number of subjects
    37
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        median (full range (min-max))
    37 (18 to 64) -
    Gender categorical
    Units:
        Female
    20 20
        Male
    17 17

    End points

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    End points reporting groups
    Reporting group title
    PK50+Treatment
    Reporting group description
    In Part A, (pharmacokinetic [PK] assessment followed by on-demand treatment for bleeding episodes [BEs] for 6 months) subjects were initially infused either with 50 IU/kg recombinant von Willebrand Factor:von Willebrand Ristocetin cofactor (VWF:RCo rVWF) [rVWF] administered together with 38.5 IU/kg recombinant Factor VIII (rFVIII) [rVWF:rFVIII] or 50 IU/kg rVWF administered together with saline. Subjects then crossed over to the alternate infusion after washout (PK). For on-demand treatment, subjects received study product [VWF:rFVIII or rVWF], where BEs were initially treated with rVWF:rFVIII and subsequently with rVWF with or without rFVIII, based on FVIII levels (dose based on previous FVIII levels or if not available from the individual subject's PK data at discretion of investigator). In part, B subjects continued to receive on demand treatment for BEs with study product [VWF:rFVIII or rVWF] for a further 6 months.

    Reporting group title
    PK50 only
    Reporting group description
    In Part A, (pharmacokinetic [PK] assessment followed by on-demand treatment for bleeding episodes [BEs] for 6 months) subjects were initially infused either with 50 IU/kg recombinant von Willebrand Factor:von Willebrand Ristocetin cofactor (VWF:RCo rVWF) [rVWF] administered together with 38.5 IU/kg recombinant Factor VIII (rFVIII) [rVWF:rFVIII] or 50 IU/kg rVWF administered together with saline. Subjects then crossed over to the alternate infusion after washout (PK). For on-demand treatment, subjects received study product [VWF:rFVIII or rVWF], where BEs were initially treated with rVWF:rFVIII and subsequently with rVWF with or without rFVIII, based on FVIII levels (dose based on previous FVIII levels or if not available from the individual subject's PK data at discretion of investigator). Subjects then exited the study or could opt to sign informed consent to move to Arm 1 receive treatment for bleeding episodes with study product.

    Reporting group title
    PK80+Treatment
    Reporting group description
    In Part A, subjects underwent pharmacokinetic (PK) assessment for 2 infusions of recombinant von Willebrand Factor (rVWF). Subjects initially underwent an initial PK assessment of an infusion of 80 IU/kg recombinant von Willebrand Factor Ristocetin cofactor (VWF:RCo rVWF) [rVWF]. After the first PK assessment subjects received on demand treatment for bleeding episodes (BEs) with study product [VWF:rFVIII or rVWF], where BEs were initially treated with rVWF:rFVIII and subsequently with rWVF with or without rFVIII, based on FVIII levels. If FVIII levels not available, the individual subject's PK data was used to determine rFVIII dose at discretion of investigator. Subjects received on demand treatment for 6 months after the first study product infusion. After 6 months subjects underwent a second PK assessment of an infusion of 80 IU/kg rVWF. In part B, subjects continued to receive on demand treatment for BEs with study product [VWF:rFVIII or rVWF] for a further 6 months.

    Reporting group title
    Treatment
    Reporting group description
    In Part A, subjects received on demand treatment for bleeding episodes (BEs) with study product (recombinant von Willebrand Factor [rVWF] administered together with recombinant Factor VIII [rFVIII] (rVWF:rFVIII) or rVWF alone), where BEs were initially treated with rVWF:rFVIII and subsequently with rVWF with or without rFVIII, based on FVIII levels. If not available, the individual subject's PK data was used to determine rFVIII dose at discretion of investigator. Subjects received on demand treatment for 6 months after the first study product infusion. In part, B subjects continued to receive on demand treatment for BEs with study product [VWF:rFVIII or rVWF] for a further 6 months. No pharmacokinetic (PK) assessments were conducted in this arm.

    Reporting group title
    Safety Analysis Set
    Reporting group description
    The Safety Analysis Set comprises of subjects who were treated with study product (recombinant von Willebrand Factor [rVWF] with or without recombinant factor VIII [rFVIII]) at least once during the study.

    Reporting group title
    Full Analysis Set
    Reporting group description
    The Full Analysis Set comprised of subjects treated with study product (recombinant von Willebrand Factor [rVWF] with or without recombinant factor VIII [rFVIII]) for whom at least one efficacy rating scale was available.

    Reporting group title
    PK50 Arms
    Reporting group description
    The PK50 arm comprised of subjects who underwent PK analysis of study product (50 IU/kg recombinant von Willebrand Factor (rVWF) administered together with 38.5 IU/kg recombinant Factor VIII (rFVIII) [rVWF:rFVIII] or 50 IU/kg rVWF administered together with saline [rVWF]) i.e. a total subjects from Arm 1 [PK50+Treatment] and Arm 2 [PK50 only]. Subjects in this arm have received at least one PK infusion and have provided data suitable for PK analysis. Only PK data included in this arm.

    Reporting group title
    PK80 Arm
    Reporting group description
    The PK80 arm comprised of subjects who underwent PK analysis of study product (80 IU/kg recombinant von Willebrand Factor [rVWF]) i.e. subjects from Arm 3 [PK80+Treatment]. Subjects in this arm have received at least one PK infusion and have provided data suitable for PK analysis. Only PK data included in this arm.

    Primary: Percentage of subjects with treatment success for treated bleeding episodes

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    End point title
    Percentage of subjects with treatment success for treated bleeding episodes [1] [2]
    End point description
    Treatment success was defined as the extent of control of bleeding episodes (BEs) using a mean efficacy rating score of <2.5 for a subject’s BEs treated with study product (recombinant von Willebrand Factor [rVWF] with or without recombinant factor VIII [rFVIII]) during the study period. Scores used: Excellent = 1 - actual infusions ≤ estimated number of infusions required to treat BE; no additional VWF required (all BEs); Good = 2 - >1-2 infusions (minor/moderate BEs) or <1.5 infusions (major BEs) greater than estimated required to control BE; no additional VWF required (all BEs); Moderate = 3 ≥ 3 infusions (minor/moderate BEs) or ≥ 1.5 infusions (major BEs) greater than estimated required to control BE; no additional VWF required (all BEs); None = 4 - severe uncontrolled bleeding or intensity of bleeding not changed; additional VWF required. Included subjects with available primary efficacy rating (prospective-excluding gastrointestinal bleeds) in the Full Analysis Set
    End point type
    Primary
    End point timeframe
    for 12 months after first infusion of rVWF:rFVIII or rVWF
    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: Currently unable to enter statistics for one analysis group (Full Analysis Set). The null hypothesis H0: p ≤ 0.65 was tested against alternative hypothesis HA: p > 0.65 by two-sided Clopper Pearson 90% CI. Results: Success rate: 100% (90% CI: 84.7-100%).
    [2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Refer to [1]
    End point values
    Full Analysis Set
    Number of subjects analysed
    18
    Units: Percent of subjects
        number (confidence interval 90%)
    100 (84.7 to 100)
    No statistical analyses for this end point

    Secondary: Percentage of treated bleeding episodes treated with an efficacy rating of "excellent" or "good"

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    End point title
    Percentage of treated bleeding episodes treated with an efficacy rating of "excellent" or "good" [3]
    End point description
    Efficacy ratings "excellent" or "good" for the control of bleeding episodes (BEs) with study product (recombinant von Willebrand Factor [rVWF] with or without recombinant factor VIII [rFVIII]) are defined as follows: Excellent - actual infusions ≤ estimated number of infusions required to treat BE; no additional von Willebrand Factor (VWF) required (all BEs); Good - >1-2 infusions (minor/moderate BEs) or <1.5 infusions (major BEs) greater than estimated required to control BE; no additional VWF required (all BEs). The data set included prospectively estimated BEs [N=130] treated with study product with an available efficacy rating from subjects in the Full Analysis Set.
    End point type
    Secondary
    End point timeframe
    for 12 months after first infusion of rVWF:rFVIII or rVWF
    Notes
    [3] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Currently unable to enter statistics for one analysis group (Full Analysis Set). The null hypothesis H0: p ≤ 0.65 was tested against alternative hypothesis HA: p > 0.65 by two-sided Clopper Pearson 90% CI. Results: Success rate: 100% (90% CI: 97.7-100%).
    End point values
    Full Analysis Set
    Number of subjects analysed
    22
    Units: Percent of bleeding episodes
        number (confidence interval 90%)
    100 (97.7 to 100)
    No statistical analyses for this end point

    Secondary: Percentage of treated bleeding episodes with an efficacy rating of "excellent" or "good", excluding gastrointestinal bleeds

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    End point title
    Percentage of treated bleeding episodes with an efficacy rating of "excellent" or "good", excluding gastrointestinal bleeds [4]
    End point description
    Efficacy ratings of "excellent" or "good" for the control of bleeding episodes (BEs) with study product (recombinant von Willebrand Factor [rVWF] with or without recombinant factor VIII [rFVIII]) are defined as follows: Excellent - actual infusions ≤ estimated number of infusions required to treat BE; no additional von Willebrand Factor (VWF) required (all BEs); Good - >1-2 infusions (minor/moderate BEs) or <1.5 infusions (major BEs) greater than estimated required to control BE; no additional VWF required (all BEs). The data set included prospectively estimated BEs [N=126] excluding gastrointestinal (GI) bleeds treated with study product with an available efficacy rating from subjects in the Full Analysis Set.
    End point type
    Secondary
    End point timeframe
    for 12 months after first infusion of rVWF:rFVIII or rVWF
    Notes
    [4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Currently unable to enter statistics for one analysis group (Full Analysis Set). The null hypothesis H0: p ≤ 0.65 was tested against alternative hypothesis HA: p > 0.65 by two-sided Clopper Pearson 90% CI. Results: Success rate: 100% (90% CI: 84.7-100%).
    End point values
    Full Analysis Set
    Number of subjects analysed
    22
    Units: Percent of bleeding episodes
        geometric mean (confidence interval 90%)
    100 (97.7 to 100)
    No statistical analyses for this end point

    Secondary: Number of infusions of rVWF:rFVIII and/or rVWF per bleeding episode

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    End point title
    Number of infusions of rVWF:rFVIII and/or rVWF per bleeding episode [5]
    End point description
    The actual number of infusions of recombinant von Willebrand factor:recombinant factor VIII (rVWF:rFVIII) and/or rVWF required to treat a bleeding episode (BE). BEs were to be initially treated with an infusion of rVWF:rFVIII and subsequently with rVWF with or without rFVIII, based on FVIII levels, if available. In cases, where no FVIII levels were available, the individual subject’s PK data was used to determine the rFVIII dose. The data set included prospectively estimated BEs [N=192] treated with study product with an available efficacy rating from subjects in the Full Analysis Set.
    End point type
    Secondary
    End point timeframe
    for 12 months after first infusion of rVWF:rFVIII or rVWF
    Notes
    [5] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Per protocol, only descriptive statistics were collected for this endpoint.
    End point values
    Full Analysis Set
    Number of subjects analysed
    22
    Units: Number of infusions
        median (confidence interval 90%)
    1 (1 to 1)
    No statistical analyses for this end point

    Secondary: Number of units of rVWF:rFVIII and/or rVWF per bleeding episode

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    End point title
    Number of units of rVWF:rFVIII and/or rVWF per bleeding episode [6]
    End point description
    The number of units is provided as the actual dose [IU/kg] of recombinant von Willebrand factor:recombinant factor VIII (rVWF:rFVIII) and/or rVWF required to treat a bleeding episode (BE). BEs were to be initially treated with an infusion of rVWF:rFVIII and subsequently with rVWF with or without rFVIII, based on FVIII levels, if available. In cases, where no FVIII levels were available, the individual subject’s PK data was used to determine the rFVIII dose. The data set included BEs [N=174] treated with study product of known lot number with an available efficacy rating from subjects in the Full Analysis Set.
    End point type
    Secondary
    End point timeframe
    for 12 months after first infusion of rVWF:rFVIII or rVWF
    Notes
    [6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Per protocol, only descriptive statistics were collected for this endpoint.
    End point values
    Full Analysis Set
    Number of subjects analysed
    22
    Units: IU/kg
        median (confidence interval 90%)
    48.2 (43.9 to 50.2)
    No statistical analyses for this end point

    Secondary: Percentage of subjects who develop inhibitory antibodies to FVIII

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    End point title
    Percentage of subjects who develop inhibitory antibodies to FVIII [7]
    End point description
    Development of neutralizing antibodies (inhibitors) to factor VIII (FVIII) was assessed by the Nijmegen modification of the Bethesda assay. Positive FVIII inhibitor tests were defined as ≥ 0.4 Bethesda units/mL (BU/mL) by the Nijmegen-modified Bethesda assay that is confirmed by a second test performed on an independent sample obtained 2-4 weeks following the first test. Category title includes number of subjects [N] who provided data for the category.
    End point type
    Secondary
    End point timeframe
    After signing informed consent until 12 months after first infusion of rVWF:rFVIII or rVWF
    Notes
    [7] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Per protocol, only descriptive statistics were collected for this endpoint.
    End point values
    Safety Analysis Set
    Number of subjects analysed
    37
    Units: Percent of subjects
    number (not applicable)
        Before 1st treatment with study product [N=37]
    0
        During 1st treatment until study end [N=27]
    0
        At final study visit [N=24]
    0
    No statistical analyses for this end point

    Secondary: Percentage of subjects who develop inhibitory antibodies to VWF

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    End point title
    Percentage of subjects who develop inhibitory antibodies to VWF [8]
    End point description
    Neutralizing antibodies (inhibitors) to Von Willebrand Factor Ristocetin cofactor (VWF:RCo), VWF collagen binding (VWF:CB) and VWF Factor VIII binding (VWF:FVIIIB) activities were measured using Nijmegen modification of the Bethesda assay. One Bethesda Unit (BU) is thereby defined as the amount of inhibitor that decreased the measured activity in the assays to 50% of that of the negative control samples. The assays were validated using human plasma samples from two type 3 VWD patients with low (1-2 BU/mL) and high (~10 BU/mL) titer inhibitors and plasma samples from non-human primates immunized with human rVWF (>100 BU/mL). Category title includes number of subjects [N] who provided data for the category.
    End point type
    Secondary
    End point timeframe
    After signing informed consent until 12 months after first infusion of rVWF:rFVIII or rVWF
    Notes
    [8] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Arms in the baseline period are not mutually exclusive - refer to Arm Descriptions in Period 1 (baseline period). Per protocol, only descriptive statistics were collected for this endpoint.
    End point values
    Safety Analysis Set
    Number of subjects analysed
    37
    Units: Percent of subjects
    number (not applicable)
        Before 1st treatment with study product [N=37]
    0
        During 1st treatment until study end [N=27]
    0
        At final study visit [N=24]
    0
    No statistical analyses for this end point

    Secondary: Percentage of subjects who develop binding antibodies to VWF

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    End point title
    Percentage of subjects who develop binding antibodies to VWF [9]
    End point description
    The presence of total binding anti-VWF antibodies was determined by an enzyme-linked immunosorbent assay (ELISA) employing polyclonal anti-human immunoglobulin (Ig) antibodies (IgG, IgM and IgA). Category title includes number of subjects [N] who provided data for the category.
    End point type
    Secondary
    End point timeframe
    After signing informed consent until 12 months after first infusion of rVWF:rFVIII or rVWF
    Notes
    [9] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Per protocol, only descriptive statistics were collected for this endpoint.
    End point values
    Safety Analysis Set
    Number of subjects analysed
    37
    Units: Percent of subjects
    number (not applicable)
        Before 1st treatment with study product [N=37]
    0
        During 1st treatment until study end [N=28]
    0
        At final study visit [N=24]
    0
    No statistical analyses for this end point

    Secondary: Percentage of subjects who develop binding antibodies to CHO

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    End point title
    Percentage of subjects who develop binding antibodies to CHO [10]
    End point description
    The presence of total binding anti-CHO antibodies was determined by measuring total immunoglobulin (Ig) antibodies (IgG, IgA, IgM) against Chinese Hamster Ovary (CHO) protein using an enzyme-linked immunosorbent assay (ELISA). Category title includes number of subjects [N] who provided data for the category.
    End point type
    Secondary
    End point timeframe
    After signing informed consent until 12 months after first infusion of rVWF:rFVIII or rVWF
    Notes
    [10] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Per protocol, only descriptive statistics were collected for this endpoint.
    End point values
    Safety Analysis Set
    Number of subjects analysed
    37
    Units: Percent of subjects
    number (not applicable)
        Before 1st treatment with study product [N=37]
    0
        During 1st treatment until study end [N=28]
    0
        At final study visit [N=24]
    0
    No statistical analyses for this end point

    Secondary: Percentage of subjects who develop binding antibodies to rFurin

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    End point title
    Percentage of subjects who develop binding antibodies to rFurin [11]
    End point description
    The presence of total binding anti-rFurin antibodies was determined by measuring total immunoglobulin (Ig) antibodies (IgG, IgA, IgM) against rFurin protein using an enzyme-linked immunosorbent assay (ELISA). Category title includes number of subjects [N] who provided data for the category.
    End point type
    Secondary
    End point timeframe
    After signing informed consent until 12 months after first infusion of rVWF:rFVIII or rVWF
    Notes
    [11] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Per protocol, only descriptive statistics were collected for this endpoint.
    End point values
    Safety Analysis Set
    Number of subjects analysed
    37
    Units: Percent of subjects
    number (not applicable)
        Before 1st treatment with study product [N=37]
    0
        During 1st treatment until study end [N=28]
    0
        At final study visit [N=24]
    0
    No statistical analyses for this end point

    Secondary: Percentage of subjects who develop binding antibodies to mouse immunoglobulin

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    End point title
    Percentage of subjects who develop binding antibodies to mouse immunoglobulin [12]
    End point description
    The presence of total binding anti-Murine immunoglobulin (IgG) antibodies was determined using an enzyme-linked immunosorbent assay (ELISA). Category title includes number of subjects [N] who provided data for the category.
    End point type
    Secondary
    End point timeframe
    After signing informed consent until 12 months after first infusion of rVWF:rFVIII or rVWF
    Notes
    [12] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Per protocol, only descriptive statistics were collected for this endpoint.
    End point values
    Safety Analysis Set
    Number of subjects analysed
    36
    Units: Percent of subjects
    number (not applicable)
        Before 1st treatment with study product [N=36]
    2.8
        During 1st treatment until study end [N=28]
    0
        At final study visit [N=24]
    0
    No statistical analyses for this end point

    Secondary: Percentage of subjects who had an occurrence of thrombotic events

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    End point title
    Percentage of subjects who had an occurrence of thrombotic events [13]
    End point description
    End point type
    Secondary
    End point timeframe
    After signing informed consent until 12 months after first infusion of rVWF:rFVIII or rVWF
    Notes
    [13] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Per protocol, only descriptive statistics were collected for this endpoint.
    End point values
    Safety Analysis Set
    Number of subjects analysed
    37
    Units: Percent of subjects
        number (not applicable)
    0
    No statistical analyses for this end point

    Secondary: Number of adverse events related to study product including clinically significant changes in laboratory parameters and vital signs

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    End point title
    Number of adverse events related to study product including clinically significant changes in laboratory parameters and vital signs [14]
    End point description
    Adverse Events (AEs) related to study product (recombinant von Willebrand Factor [rVWF] with or without recombinant factor VIII [rFVIII]) are described. Only laboratory parameters (hematology and clinical chemistry) and vital signs (physical examination, ECG) with clinically significant findings that are recorded as AEs are included. Categories presented as Severity-System Organ Class-Preferred Term Seriousness: serious adverse event (SAE); non serious adverse event (nsAE) System Organ Class: Cardiac disorders (CARD); General disorders and administration site conditions (GEN); Investigations (INV); Nervous system disorders (NERV); Skin and subcutaneous tissue disorders (SKN); Vascular disorders (VAS) Category title includes number of AEs [N] for the category.
    End point type
    Secondary
    End point timeframe
    for 12 months after first infusion of rVWF:rFVIII or rVWF
    Notes
    [14] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Per protocol, only descriptive statistics were collected for this endpoint.
    End point values
    Safety Analysis Set
    Number of subjects analysed
    37
    Units: Number of AEs
        SAE-GEN-Chest discomfort [N=1]
    1
        SAE-INV-Heart rate increased [N=1]
    1
        nsAE-CARD-Tachycardia [N=1]
    1
        nsAE-GEN-Infusion site paraesthesia [N=1]
    1
        nsAE-INV-ECG T wave inversion [N=1]
    1
        nsAE-NERV-Dysgeusia [N=1]
    1
        nsAE-SKN-Pruritus generalized [N=1]
    1
        nsAE-VAS-Hot flush [N=1]
    1
    No statistical analyses for this end point

    Secondary: Number of subjects with adverse events related to study product including clinically significant changes in laboratory parameters and vital signs

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    End point title
    Number of subjects with adverse events related to study product including clinically significant changes in laboratory parameters and vital signs [15]
    End point description
    Number of subjects with Adverse Events (AEs) related to study product (recombinant von Willebrand Factor [rVWF] with or without recombinant factor VIII [rFVIII]) are described. Only laboratory parameters (hematology and clinical chemistry) and vital signs (physical examination, ECG) with clinically significant findings that are recorded as AEs are included. Categories presented as Severity-System Organ Class-Preferred Term Seriousness: serious adverse event (SAE); non serious adverse event (nsAE) System Organ Class: Cardiac disorders (CARD); General disorders and administration site conditions (GEN); Investigations (INV); Nervous system disorders (NERV); Skin and subcutaneous tissue disorders (SKN); Vascular disorders (VAS)
    End point type
    Secondary
    End point timeframe
    for 12 months after first infusion of rVWF:rFVIII or rVWF
    Notes
    [15] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Per protocol, only descriptive statistics were collected for this endpoint.
    End point values
    Safety Analysis Set
    Number of subjects analysed
    37
    Units: Number of subjects
        SAE-GEN-Chest discomfort
    1
        SAE-INV-Heart rate increased
    1
        nsAE-CARD-Tachycardia
    1
        nsAE-GEN-Infusion site paraesthesia
    1
        nsAE-INV-ECG T wave inversion
    1
        nsAE-NERV-Dysgeusia
    1
        nsAE-SKN-Pruritus generalized
    1
        nsAE-VAS-Hot flush
    1
    No statistical analyses for this end point

    Secondary: Number of adverse events by infusion related to study product including clinically significant changes in laboratory parameters and vital signs

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    End point title
    Number of adverse events by infusion related to study product including clinically significant changes in laboratory parameters and vital signs [16]
    End point description
    Adverse Events (AEs) by infusion related to study product (recombinant von Willebrand Factor [rVWF] with or without recombinant factor VIII [rFVIII]) are described. Only laboratory parameters (hematology and clinical chemistry) and vital signs (physical examination, ECG) with clinically significant findings that are recorded as AEs are included. Categories presented as Severity-System Organ Class-Preferred Term Seriousness: serious adverse event (SAE); non serious adverse event (nsAE) System Organ Class: Cardiac disorders (CARD); General disorders and administration site conditions (GEN); Investigations (INV); Nervous system disorders (NERV); Skin and subcutaneous tissue disorders (SKN); Vascular disorders (VAS). A total of 318 infusions were given. Category title includes number of AEs by infusion [N] for the category.
    End point type
    Secondary
    End point timeframe
    for 12 months after first infusion of rVWF:rFVIII or rVWF
    Notes
    [16] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Per protocol, only descriptive statistics were collected for this endpoint.
    End point values
    Safety Analysis Set
    Number of subjects analysed
    37
    Units: Number of AEs
        SAE-GEN-Chest discomfort [N=1]
    1
        SAE-INV-Heart rate increased [N=1]
    1
        nsAE-CARD-Tachycardia [N=1]
    1
        nsAE-GEN-Infusion site paraesthesia [N=1]
    1
        nsAE-INV-ECG T wave inversion [N=1]
    1
        nsAE-NERV-Dysgeusia [N=1]
    1
        nsAE-SKN-Pruritus generalized [N=1]
    1
        nSAE-VAS-Hot flush [N=1]
    1
    No statistical analyses for this end point

    Secondary: PK50 - Area under the plasma concentration/time curve from time 0 to infinity (AUC0-∞/Dose) of VWF:RCo

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    End point title
    PK50 - Area under the plasma concentration/time curve from time 0 to infinity (AUC0-∞/Dose) of VWF:RCo [17]
    End point description
    Area under the plasma concentration curve (AUC) from time 0 to infinity of von Willebrand Factor Ristocetin cofactor (VWF:RCo) after infusion of 50 IU/kg recombinant von Willebrand Factor:von Willebrand Factor Ristocetin cofactor (VWF:RCo rVWF) administered together with 38.5 IU/kg recombinant Factor VIII (rFVIII) (ratio of 1.3:1±0.2) [rVWF:rFVIII], or 50 IU/kg VWF:RCo rVWF administered together with saline (placebo) [rVWF] for subjects in the PK50 arms (Arm 1 and Arm 2). Category title includes number of subjects [N] who provided data for the category.
    End point type
    Secondary
    End point timeframe
    PK evaluations at pre-infusion, then at 15, 30 and 60 mins, and 3, 6, 12, 24, 30, 48, 72 and 96 hrs post-infusion. PK evaluation timeframe for 28 ± 3 days after first infusion of study product which includes PK evaluation for both infusions and washout.
    Notes
    [17] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Per protocol, only descriptive statistics were collected for this endpoint.
    End point values
    PK50 Arms
    Number of subjects analysed
    16
    Units: (hours*U/dL)/(U VWF: RCo/kg)
    median (confidence interval 95%)
        rVWF:rFVIII [N=16]
    32.4 (27.5 to 40.1)
        rVWF [N=14]
    32.7 (29 to 47.8)
    No statistical analyses for this end point

    Secondary: PK50 - Area under the plasma concentration/time curve from time 0 to 96 hours (AUC0-96h/Dose) of VWF:RCo

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    End point title
    PK50 - Area under the plasma concentration/time curve from time 0 to 96 hours (AUC0-96h/Dose) of VWF:RCo [18]
    End point description
    Area under the plasma concentration curve (AUC) from time 0 to 96 hours of von Willebrand Factor Ristocetin cofactor (VWF:RCo) after infusion of 50 IU/kg recombinant von Willebrand Factor:von Willebrand Factor Ristocetin cofactor (VWF:RCo rVWF) administered together with 38.5 IU/kg recombinant Factor VIII (rFVIII) (ratio of 1.3:1±0.2) [rVWF:rFVIII], or 50 IU/kg VWF:RCo rVWF administered together with saline (placebo) [rVWF] for subjects in the PK50 arms (Arm 1 and Arm 2). Category title includes number of subjects [N] who provided data for the category.
    End point type
    Secondary
    End point timeframe
    PK evaluations at pre-infusion, then at 15, 30 and 60 mins, and 3, 6, 12, 24, 30, 48, 72 and 96 hrs post-infusion. PK evaluation timeframe for 28 ± 3 days after first infusion of study product which includes PK evaluation for both infusions and washout
    Notes
    [18] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Per protocol, only descriptive statistics were collected for this endpoint.
    End point values
    PK50 Arms
    Number of subjects analysed
    16
    Units: (hours*U/dL)/(U VWF: RCo/kg)
    median (confidence interval 95%)
        rVWF:rFVIII [N=16]
    31.6 (27.3 to 37.3)
        rVWF [N=14]
    31.3 (28.4 to 43.7)
    No statistical analyses for this end point

    Secondary: PK50 - Mean Residence Time of VWF:RCo

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    End point title
    PK50 - Mean Residence Time of VWF:RCo [19]
    End point description
    Mean Residence Time (MRT) of von Willebrand Factor Ristocetin cofactor (VWF:RCo) after infusion of 50 IU/kg recombinant von Willebrand Factor:von Willebrand Factor Ristocetin cofactor (VWF:RCo rVWF) administered together with 38.5 IU/kg recombinant Factor VIII (rFVIII) (ratio of 1.3:1±0.2) [rVWF:rFVIII], or 50 IU/kg VWF:RCo rVWF administered together with saline (placebo) [rVWF] for subjects in the PK50 arms (Arm 1 and Arm 2). Category title includes number of subjects [N] who provided data for the category.
    End point type
    Secondary
    End point timeframe
    PK evaluations at pre-infusion, then at 15, 30 and 60 mins, and 3, 6, 12, 24, 30, 48, 72 and 96 hrs post-infusion. PK evaluation timeframe for 28 ± 3 days after first infusion of study product which includes PK evaluation for both infusions and washout.
    Notes
    [19] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Per protocol, only descriptive statistics were collected for this endpoint.
    End point values
    PK50 Arms
    Number of subjects analysed
    16
    Units: Hours
    median (confidence interval 95%)
        rVWF:rFVIII [N=16]
    25.2 (20 to 30.1)
        rVWF [N=14]
    26.7 (22.7 to 36)
    No statistical analyses for this end point

    Secondary: PK50 - Clearance of VWF:RCo

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    End point title
    PK50 - Clearance of VWF:RCo [20]
    End point description
    Clearance (CL) of von Willebrand Factor Ristocetin cofactor (VWF:RCo) after infusion of 50 IU/kg recombinant von Willebrand Factor:von Willebrand Factor Ristocetin cofactor (VWF:RCo rVWF) administered together with 38.5 IU/kg recombinant Factor VIII (rFVIII) (ratio of 1.3:1±0.2) [rVWF:rFVIII], or 50 IU/kg VWF:RCo rVWF administered together with saline (placebo) [rVWF] for subjects in the PK50 arms (Arm 1 and Arm 2) Category title includes number of subjects [N] who provided data for the category.
    End point type
    Secondary
    End point timeframe
    PK evaluations at pre-infusion, then at 15, 30 and 60 mins, and 3, 6, 12, 24, 30, 48, 72 and 96 hrs post-infusion. PK evaluation timeframe for 28 ± 3 days after first infusion of study product which includes PK evaluation for both infusions and washout.
    Notes
    [20] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Per protocol, only descriptive statistics were collected for this endpoint.
    End point values
    PK50 Arms
    Number of subjects analysed
    16
    Units: dL/kg/hours
    median (confidence interval 95%)
        rVWF:rFVIII [N=16]
    0.031 (0.025 to 0.041)
        rVWF [N=14]
    0.031 (0.021 to 0.035)
    No statistical analyses for this end point

    Secondary: PK50 - Incremental Recovery of VWF:RCo

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    End point title
    PK50 - Incremental Recovery of VWF:RCo [21]
    End point description
    Incremental Recovery (IR) at the maximum plasma concentration of von Willebrand Factor Ristocetin cofactor (VWF:RCo) after infusion of 50 IU/kg recombinant von Willebrand Factor:von Willebrand Factor Ristocetin cofactor (VWF:RCo rVWF) administered together with 38.5 IU/kg recombinant Factor VIII (rFVIII) (ratio of 1.3:1±0.2) [rVWF:rFVIII], or 50 IU/kg VWF:RCo rVWF administered together with saline (placebo) [rVWF] for subjects in the PK50 arms (Arm 1 and Arm 2). Category title includes number of subjects [N] who provided data for the category.
    End point type
    Secondary
    End point timeframe
    PK evaluations at pre-infusion, then at 15, 30 and 60 mins, and 3, 6, 12, 24, 30, 48, 72 and 96 hrs post-infusion. PK evaluation timeframe for 28 ± 3 days after first infusion of study product which includes PK evaluation for both infusions and washout.
    Notes
    [21] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Per protocol, only descriptive statistics were collected for this endpoint.
    End point values
    PK50 Arms
    Number of subjects analysed
    16
    Units: (U/dL)/(U VWF: RCo/kg)
    median (confidence interval 95%)
        rVWF:rFVIII [N=16]
    1.8 (1.6 to 2.4)
        rVWF [N=14]
    1.8 (1.5 to 2.2)
    No statistical analyses for this end point

    Secondary: PK50 - Elimination Phase Half-Life of VWF:Co

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    End point title
    PK50 - Elimination Phase Half-Life of VWF:Co [22]
    End point description
    Elimination Phase Half-Life (T1/2) of von Willebrand Factor Ristocetin cofactor (VWF:RCo) after infusion of 50 IU/kg recombinant von Willebrand Factor:von Willebrand Factor Ristocetin cofactor (VWF:RCo rVWF) administered together with 38.5 IU/kg recombinant FVIII (rFVIII) (ratio of 1.3:1±0.2) [rVWF:rFVIII], or 50 IU/kg VWF:RCo rVWF administered together with saline (placebo) [rVWF] for subjects in the PK50 arms (Arm 1 and Arm 2).. Category title includes number of subjects [N] who provided data for the category.
    End point type
    Secondary
    End point timeframe
    PK evaluations at pre-infusion, then at 15, 30 and 60 mins, and 3, 6, 12, 24, 30, 48, 72 and 96 hrs post-infusion. PK evaluation timeframe for 28 ± 3 days after first infusion of study product which includes PK evaluation for both infusions and washout.
    Notes
    [22] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Per protocol, only descriptive statistics were collected for this endpoint.
    End point values
    PK50 Arms
    Number of subjects analysed
    16
    Units: hours
    median (confidence interval 95%)
        rVWF:rFVIII [N=16]
    16.6 (14.7 to 20.4)
        rVWF [N=14]
    19.4 (15.5 to 31.3)
    No statistical analyses for this end point

    Secondary: PK50 - Volume of Distribution at Steady State of VWF:RCo

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    End point title
    PK50 - Volume of Distribution at Steady State of VWF:RCo [23]
    End point description
    Volume of Distribution at Steady State (Vss) of von Willebrand Factor Ristocetin cofactor (VWF:RCo) after infusion of 50 IU/kg recombinant von Willebrand Factor:von Willebrand Factor Ristocetin cofactor (VWF:RCo rVWF) administered together with 38.5 IU/kg recombinant Factor VIII (rFVIII) (ratio of 1.3:1±0.2) [rVWF:rFVIII], or 50 IU/kg VWF:RCo rVWF administered together with saline (placebo) [rVWF] for subjects in the PK50 arms (Arm 1 and Arm 2). Category title includes number of subjects [N] who provided data for the category.
    End point type
    Secondary
    End point timeframe
    PK evaluations at pre-infusion, then at 15, 30 and 60 mins, and 3, 6, 12, 24, 30, 48, 72 and 96 hrs post-infusion. PK evaluation timeframe for 28 ± 3 days after first infusion of study product which includes PK evaluation for both infusions and washout.
    Notes
    [23] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Per protocol, only descriptive statistics were collected for this endpoint.
    End point values
    PK50 Arms
    Number of subjects analysed
    16
    Units: dL/kg
    median (confidence interval 95%)
        rVWF:rFVIII [N=16]
    0.7 (0.66 to 0.93)
        rVWF [N=14]
    0.83 (0.7 to 0.97)
    No statistical analyses for this end point

    Secondary: PK50 - Area under the plasma concentration/time curve from time 0 to infinity (AUC0-∞/Dose) of VWF:Ag

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    End point title
    PK50 - Area under the plasma concentration/time curve from time 0 to infinity (AUC0-∞/Dose) of VWF:Ag [24]
    End point description
    Area under the plasma concentration curve (AUC) from time 0 to infinity of von Willebrand Factor Antigen (VWF:Ag) after infusion of 50 IU/kg recombinant von Willebrand Factor:von Willebrand Factor Ristocetin cofactor (VWF:RCo rVWF) administered together with 38.5 IU/kg recombinant Factor VIII (rFVIII) (ratio of 1.3:1±0.2) [rVWF:rFVIII], or 50 IU/kg VWF:RCo rVWF administered together with saline (placebo) [rVWF] for subjects in the PK50 arms (Arm 1 and Arm 2). Category title includes number of subjects [N] who provided data for the category.
    End point type
    Secondary
    End point timeframe
    PK evaluations at pre-infusion, then at 15, 30 and 60 mins, and 3, 6, 12, 24, 30, 48, 72 and 96 hrs post-infusion. PK evaluation timeframe for 28 ± 3 days after first infusion of study product which includes PK evaluation for both infusions and washout.
    Notes
    [24] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Per protocol, only descriptive statistics were collected for this endpoint.
    End point values
    PK50 Arms
    Number of subjects analysed
    16
    Units: (hours*U/dL)/(U VWF: RCo/kg)
    median (confidence interval 95%)
        rVWF:rFVIII [N=16]
    67.8 (55.1 to 81.7)
        rVWF [N=14]
    67.1 (55.6 to 80.5)
    No statistical analyses for this end point

    Secondary: PK50 - Area under the plasma concentration/time curve from time 0 to 96 hours (AUC0-96h/Dose) of VWF:Ag

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    End point title
    PK50 - Area under the plasma concentration/time curve from time 0 to 96 hours (AUC0-96h/Dose) of VWF:Ag [25]
    End point description
    Area under the plasma concentration curve (AUC) from time 0 to 96 hours of von Willebrand Factor Antigen (VWF:Ag) after infusion of 50 IU/kg recombinant von Willebrand Factor:von Willebrand Factor Ristocetin cofactor (VWF:RCo rVWF) administered together with 38.5 IU/kg recombinant Factor VIII (rFVIII) (ratio of 1.3:1±0.2) [rVWF:rFVIII], or 50 IU/kg VWF:RCo rVWF administered together with saline (placebo) [rVWF] for subjects in the PK50 arms (Arm 1 and Arm 2). Category title includes number of subjects [N] who provided data for the category.
    End point type
    Secondary
    End point timeframe
    PK evaluations at pre-infusion, then at 15, 30 and 60 mins, and 3, 6, 12, 24, 30, 48, 72 and 96 hrs post-infusion. PK evaluation timeframe for 28 ± 3 days after first infusion of study product which includes PK evaluation for both infusions and washout.
    Notes
    [25] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Per protocol, only descriptive statistics were collected for this endpoint.
    End point values
    PK50 Arms
    Number of subjects analysed
    16
    Units: (hours*U/dL)/(U VWF: RCo/kg)
    median (confidence interval 95%)
        rVWF:rFVIII [N=16]
    62.1 (52.8 to 74.9)
        rVWF [N=14]
    62.2 (54.7 to 74.5)
    No statistical analyses for this end point

    Secondary: PK50 - Mean Residence Time of VWF:Ag

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    End point title
    PK50 - Mean Residence Time of VWF:Ag [26]
    End point description
    Mean Residence Time (MRT) of von Willebrand Factor Antigen (VWF:Ag) after infusion of 50 IU/kg recombinant von Willebrand Factor:von Willebrand Factor Ristocetin cofactor (VWF:RCo rVWF) administered together with 38.5 IU/kg recombinant Factor VIII (rFVIII) (ratio of 1.3:1±0.2) [rVWF:rFVIII], or 50 IU/kg VWF:RCo rVWF administered together with saline (placebo) [rVWF] for subjects in the PK50 arms (Arm 1 and Arm 2). Category title includes number of subjects [N] who provided data for the category.
    End point type
    Secondary
    End point timeframe
    PK evaluations at pre-infusion, then at 15, 30 and 60 mins, and 3, 6, 12, 24, 30, 48, 72 and 96 hrs post-infusion. PK evaluation timeframe for 28 ± 3 days after first infusion of study product which includes PK evaluation for both infusions and washout.
    Notes
    [26] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Per protocol, only descriptive statistics were collected for this endpoint.
    End point values
    PK50 Arms
    Number of subjects analysed
    16
    Units: hours
    median (confidence interval 95%)
        rVWF:rFVIII [N=16]
    32.1 (29.8 to 41.1)
        rVWF [N=14]
    34.3 (30.4 to 41.4)
    No statistical analyses for this end point

    Secondary: PK50 - Clearance of VWF:Ag

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    End point title
    PK50 - Clearance of VWF:Ag [27]
    End point description
    Clearance (CL) of von Willebrand Factor Antigen (VWF:Ag) after infusion of 50 IU/kg recombinant von Willebrand Factor:von Willebrand Factor Ristocetin cofactor (VWF:RCo rVWF) administered together with 38.5 IU/kg recombinant Factor VIII (rFVIII) (ratio of 1.3:1±0.2) [rVWF:rFVIII], or 50 IU/kg VWF:RCo rVWF administered together with saline (placebo) [rVWF] for subjects in the PK50 arms (Arm 1 and Arm 2). Category title includes number of subjects [N] who provided data for the category.
    End point type
    Secondary
    End point timeframe
    PK evaluations at pre-infusion, then at 15, 30 and 60 mins, and 3, 6, 12, 24, 30, 48, 72 and 96 hrs post-infusion. PK evaluation timeframe for 28 ± 3 days after first infusion of study product which includes PK evaluation for both infusions and washout.
    Notes
    [27] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Per protocol, only descriptive statistics were collected for this endpoint.
    End point values
    PK50 Arms
    Number of subjects analysed
    16
    Units: dL/kg/hours
    median (confidence interval 95%)
        rVWF:rFVIII [N=16]
    0.015 (0.013 to 0.018)
        rVWF [N=14]
    0.015 (0.013 to 0.018)
    No statistical analyses for this end point

    Secondary: PK50 - Incremental Recovery of VWF:Ag

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    End point title
    PK50 - Incremental Recovery of VWF:Ag [28]
    End point description
    Incremental Recovery (IR) at the maximum plasma concentration of von Willebrand Factor Antigen (VWF:Ag) after infusion of 50 IU/kg recombinant von Willebrand Factor:von Willebrand Factor Ristocetin cofactor (VWF:RCo rVWF) administered together with 38.5 IU/kg recombinant Factor VIII (rFVIII) (ratio of 1.3:1±0.2) [rVWF:rFVIII], or 50 IU/kg VWF:RCo rVWF administered together with saline (placebo) [rVWF] for subjects in the PK50 arms (Arm 1 and Arm 2). Category title includes number of subjects [N] who provided data for the category.
    End point type
    Secondary
    End point timeframe
    PK evaluations at pre-infusion, then at 15, 30 and 60 mins, and 3, 6, 12, 24, 30, 48, 72 and 96 hrs post-infusion. PK evaluation timeframe for 28 ± 3 days after first infusion of study product which includes PK evaluation for both infusions and washout.
    Notes
    [28] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Per protocol, only descriptive statistics were collected for this endpoint.
    End point values
    PK50 Arms
    Number of subjects analysed
    16
    Units: (U/dL)/(U VWF: RCo/kg)
    median (confidence interval 95%)
        rVWF:rFVIII [N=16]
    2.3 (2 to 2.5)
        rVWF [N=14]
    2.2 (1.9 to 2.5)
    No statistical analyses for this end point

    Secondary: PK50 - Elimination Phase Half-Life of VWF:Ag

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    End point title
    PK50 - Elimination Phase Half-Life of VWF:Ag [29]
    End point description
    Elimination Phase Half-Life (T1/2) of von Willebrand Factor Antigen (VWF:Ag) after infusion of 50 IU/kg recombinant von Willebrand Factor:von Willebrand Factor Ristocetin cofactor (VWF:RCo rVWF) administered together with 38.5 IU/kg recombinant FVIII (rFVIII) (ratio of 1.3:1±0.2) [rVWF:rFVIII], or 50 IU/kg VWF:RCo rVWF administered together with saline (placebo) [rVWF] for subjects in the PK50 arms (Arm 1 and Arm 2). Category title includes number of subjects [N] who provided data for the category.
    End point type
    Secondary
    End point timeframe
    PK evaluations at pre-infusion, then at 15, 30 and 60 mins, and 3, 6, 12, 24, 30, 48, 72 and 96 hrs post-infusion. PK evaluation timeframe for 28 ± 3 days after first infusion of study product which includes PK evaluation for both infusions and washout.
    Notes
    [29] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Per protocol, only descriptive statistics were collected for this endpoint.
    End point values
    PK50 Arms
    Number of subjects analysed
    16
    Units: hours
    median (confidence interval 95%)
        rVWF:rFVIII [N=16]
    21.8 (19.5 to 27.2)
        rVWF [N=14]
    25.2 (21.9 to 30.3)
    No statistical analyses for this end point

    Secondary: PK50 - Volume of Distribution at Steady State of VWF:Ag

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    End point title
    PK50 - Volume of Distribution at Steady State of VWF:Ag [30]
    End point description
    Volume of Distribution at Steady State (Vss) of von Willebrand Factor Antigen (VWF:Ag) after infusion of 50 IU/kg recombinant von Willebrand Factor:von Willebrand Factor Ristocetin cofactor (VWF:RCo rVWF) administered together with 38.5 IU/kg recombinant Factor VIII (rFVIII) (ratio of 1.3:1±0.2) [rVWF:rFVIII], or 50 IU/kg VWF:RCo rVWF administered together with saline (placebo) [rVWF] for subjects in the PK50 arms (Arm 1 and Arm 2). Category title includes number of subjects [N] who provided data for the category.
    End point type
    Secondary
    End point timeframe
    PK evaluations at pre-infusion, then at 15, 30 and 60 mins, and 3, 6, 12, 24, 30, 48, 72 and 96 hrs post-infusion. PK evaluation timeframe for 28 ± 3 days after first infusion of study product which includes PK evaluation for both infusions and washout.
    Notes
    [30] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Per protocol, only descriptive statistics were collected for this endpoint.
    End point values
    PK50 Arms
    Number of subjects analysed
    16
    Units: dL/kg
    median (confidence interval 95%)
        rVWF:rFVIII [N=16]
    0.5 (0.45 to 0.56)
        rVWF [N=14]
    0.49 (0.45 to 0.58)
    No statistical analyses for this end point

    Secondary: PK50 - Area under the plasma concentration/time curve from time 0 to infinity (AUC0-∞/Dose) of VWF:CB

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    End point title
    PK50 - Area under the plasma concentration/time curve from time 0 to infinity (AUC0-∞/Dose) of VWF:CB [31]
    End point description
    Area under the plasma concentration curve (AUC) from time 0 to infinity of von Willebrand Factor Collagen Binding (VWF:CB) after infusion of 50 IU/kg recombinant von Willebrand Factor:von Willebrand Factor Ristocetin cofactor (VWF:RCo rVWF) administered together with 38.5 IU/kg recombinant Factor VIII (rFVIII) (ratio of 1.3:1±0.2) [rVWF:rFVIII], or 50 IU/kg VWF:RCo rVWF administered together with saline (placebo) [rVWF] for subjects in the PK50 arms (Arm 1 and Arm 2). Category title includes number of subjects [N] who provided data for the category.
    End point type
    Secondary
    End point timeframe
    PK evaluations at pre-infusion, then at 15, 30 and 60 mins, and 3, 6, 12, 24, 30, 48, 72 and 96 hrs post-infusion. PK evaluation timeframe for 28 ± 3 days after first infusion of study product which includes PK evaluation for both infusions and washout.
    Notes
    [31] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Per protocol, only descriptive statistics were collected for this endpoint.
    End point values
    PK50 Arms
    Number of subjects analysed
    16
    Units: (hours*U/dL)/(U VWF: RCo/kg)
    median (confidence interval 95%)
        rVWF:rFVIII [N=16]
    80.1 (68.4 to 95)
        rVWF [N=14]
    81.3 (71.2 to 99.8)
    No statistical analyses for this end point

    Secondary: PK50 - Area under the plasma concentration/time curve from time 0 to 96 hours (AUC0-96h/Dose) of VWF:CB

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    End point title
    PK50 - Area under the plasma concentration/time curve from time 0 to 96 hours (AUC0-96h/Dose) of VWF:CB [32]
    End point description
    Area under the plasma concentration curve (AUC) from time 0 to 96 hours of von Willebrand Factor Collagen Binding (VWF:CB) after infusion of 50 IU/kg recombinant von Willebrand Factor:von Willebrand Factor Ristocetin cofactor (VWF:RCo rVWF) administered together with 38.5 IU/kg recombinant Factor VIII (rFVIII) (ratio of 1.3:1±0.2) [rVWF:rFVIII], or 50 IU/kg VWF:RCo rVWF administered together with saline (placebo) [rVWF] for subjects in the PK50 arms (Arm 1 and Arm 2). Category title includes number of subjects [N] who provided data for the category.
    End point type
    Secondary
    End point timeframe
    PK evaluations at pre-infusion, then at 15, 30 and 60 mins, and 3, 6, 12, 24, 30, 48, 72 and 96 hrs post-infusion. PK evaluation timeframe for 28 ± 3 days after first infusion of study product which includes PK evaluation for both infusions and washout.
    Notes
    [32] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Per protocol, only descriptive statistics were collected for this endpoint.
    End point values
    PK50 Arms
    Number of subjects analysed
    16
    Units: (hours*U/dL)/(U VWF: RCo/kg)
    median (confidence interval 95%)
        rVWF:rFVIII [N=16]
    78.7 (66.5 to 90.5)
        rVWF [N=14]
    75.1 (69.2 to 97)
    No statistical analyses for this end point

    Secondary: PK50 - Mean Residence Time of VWF:CB

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    End point title
    PK50 - Mean Residence Time of VWF:CB [33]
    End point description
    Mean Residence Time (MRT) of von Willebrand Factor Collagen Binding (VWF:CB) after infusion of 50 IU/kg recombinant von Willebrand Factor:von Willebrand Factor Ristocetin cofactor (VWF:RCo rVWF) administered together with 38.5 IU/kg recombinant Factor VIII (rFVIII) (ratio of 1.3:1±0.2) [rVWF:rFVIII], or 50 IU/kg VWF:RCo rVWF administered together with saline (placebo) [rVWF] for subjects in the PK50 arms (Arm 1 and Arm 2). Category title includes number of subjects [N] who provided data for the category.
    End point type
    Secondary
    End point timeframe
    PK evaluations at pre-infusion, then at 15, 30 and 60 mins, and 3, 6, 12, 24, 30, 48, 72 and 96 hrs post-infusion. PK evaluation timeframe for 28 ± 3 days after first infusion of study product which includes PK evaluation for both infusions and washout.
    Notes
    [33] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Per protocol, only descriptive statistics were collected for this endpoint.
    End point values
    PK50 Arms
    Number of subjects analysed
    16
    Units: hours
    median (confidence interval 95%)
        rVWF:rFVIII [N=16]
    27.5 (22.7 to 32.1)
        rVWF [N=14]
    26.1 (25.1 to 33.2)
    No statistical analyses for this end point

    Secondary: PK50 - Clearance of VWF:CB

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    End point title
    PK50 - Clearance of VWF:CB [34]
    End point description
    Clearance (CL) of von Willebrand Factor Collagen Binding (VWF:CB) after infusion of 50 IU/kg recombinant von Willebrand Factor:von Willebrand Factor Ristocetin cofactor (VWF:RCo rVWF) administered together with 38.5 IU/kg recombinant Factor VIII (rFVIII) (ratio of 1.3:1±0.2) [rVWF:rFVIII], or 50 IU/kg VWF:RCo rVWF administered together with saline (placebo) [rVWF] for subjects in the PK50 arms (Arm 1 and Arm 2). Category title includes number of subjects [N] who provided data for the category.
    End point type
    Secondary
    End point timeframe
    PK evaluations at pre-infusion, then at 15, 30 and 60 mins, and 3, 6, 12, 24, 30, 48, 72 and 96 hrs post-infusion. PK evaluation timeframe for 28 ± 3 days after first infusion of study product which includes PK evaluation for both infusions and washout.
    Notes
    [34] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Per protocol, only descriptive statistics were collected for this endpoint.
    End point values
    PK50 Arms
    Number of subjects analysed
    16
    Units: dL/kg/hours
    median (confidence interval 95%)
        rVWF:rFVIII [N=16]
    0.012 (0.011 to 0.015)
        rVWF [N=14]
    0.012 (0.011 to 0.015)
    No statistical analyses for this end point

    Secondary: PK50 - Incremental Recovery of VWF:CB

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    End point title
    PK50 - Incremental Recovery of VWF:CB [35]
    End point description
    Incremental Recovery (IR) at the maximum plasma concentration of von Willebrand Factor Collagen Binding (VWF:CB) after infusion of 50 IU/kg recombinant von Willebrand Factor:von Willebrand Factor Ristocetin cofactor (VWF:RCo rVWF) administered together with 38.5 IU/kg recombinant Factor VIII (rFVIII) (ratio of 1.3:1±0.2) [rVWF:rFVIII], or 50 IU/kg VWF:RCo rVWF administered together with saline (placebo) [rVWF] for subjects in the PK50 arms (Arm 1 and Arm 2). Category title includes number of subjects [N] who provided data for the category.
    End point type
    Secondary
    End point timeframe
    PK evaluations at pre-infusion, then at 15, 30 and 60 mins, and 3, 6, 12, 24, 30, 48, 72 and 96 hrs post-infusion. PK evaluation timeframe for 28 ± 3 days after first infusion of study product which includes PK evaluation for both infusions and washout.
    Notes
    [35] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Per protocol, only descriptive statistics were collected for this endpoint.
    End point values
    PK50 Arms
    Number of subjects analysed
    16
    Units: (U/dL)/(U VWF: RCo/kg)
    median (confidence interval 95%)
        rVWF:rFVIII [N=16]
    3.4 (3 to 3.7)
        rVWF [N=14]
    3.2 (2.8 to 3.7)
    No statistical analyses for this end point

    Secondary: PK50 - Elimination Phase Half-Life of VWF:CB

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    End point title
    PK50 - Elimination Phase Half-Life of VWF:CB [36]
    End point description
    Elimination Phase Half-Life (T1/2) of von Willebrand Factor Collagen Binding (VWF:CB) after infusion of 50 IU/kg recombinant von Willebrand Factor:von Willebrand Factor Ristocetin cofactor (VWF:RCo rVWF) administered together with 38.5 IU/kg recombinant FVIII (rFVIII) (ratio of 1.3:1±0.2) [rVWF:rFVIII], or 50 IU/kg VWF:RCo rVWF administered together with saline (placebo) [rVWF] for subjects in the PK50 arms (Arm 1 and Arm 2). Category title includes number of subjects [N] who provided data for the category.
    End point type
    Secondary
    End point timeframe
    PK evaluations at pre-infusion, then at 15, 30 and 60 mins, and 3, 6, 12, 24, 30, 48, 72 and 96 hrs post-infusion. PK evaluation timeframe for 28 ± 3 days after first infusion of study product which includes PK evaluation for both infusions and washout.
    Notes
    [36] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Per protocol, only descriptive statistics were collected for this endpoint.
    End point values
    PK50 Arms
    Number of subjects analysed
    16
    Units: hours
    median (confidence interval 95%)
        rVWF:rFVIII [N=16]
    19.3 (14.9 to 23.4)
        rVWF [N=14]
    18.3 (17.4 to 24.8)
    No statistical analyses for this end point

    Secondary: PK50 - Volume of Distribution at Steady State of VWF:CB

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    End point title
    PK50 - Volume of Distribution at Steady State of VWF:CB [37]
    End point description
    Volume of Distribution at Steady State (Vss) of von Willebrand Factor Collagen Binding (VWF:CB) after infusion of 50 IU/kg recombinant von Willebrand Factor:von Willebrand Factor Ristocetin cofactor (VWF:RCo rVWF) administered together with 38.5 IU/kg recombinant Factor VIII (rFVIII) (ratio of 1.3:1±0.2) [rVWF:rFVIII], or 50 IU/kg VWF:RCo rVWF administered together with saline (placebo) [rVWF] for subjects in the PK50 arms (Arm 1 and Arm 2). Category title includes number of subjects [N] who provided data for the category.
    End point type
    Secondary
    End point timeframe
    PK evaluations at pre-infusion, then at 15, 30 and 60 mins, and 3, 6, 12, 24, 30, 48, 72 and 96 hrs post-infusion. PK evaluation timeframe for 28 ± 3 days after first infusion of study product which includes PK evaluation for both infusions and washout.
    Notes
    [37] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Per protocol, only descriptive statistics were collected for this endpoint.
    End point values
    PK50 Arms
    Number of subjects analysed
    16
    Units: dL/kg
    median (confidence interval 95%)
        rVWF:rFVIII [N=16]
    0.35 (0.31 to 0.4)
        rVWF [N=14]
    0.36 (0.28 to 0.42)
    No statistical analyses for this end point

    Secondary: PK50 - Area under the plasma concentration/time curve from time 0 to infinity (AUC0-∞/Dose) of FVIII:C

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    End point title
    PK50 - Area under the plasma concentration/time curve from time 0 to infinity (AUC0-∞/Dose) of FVIII:C [38]
    End point description
    Area under the plasma concentration curve (AUC) from time 0 to infinity of Factor VIII activity (FVIII:C) after infusion of 50 IU/kg recombinant von Willebrand Factor:von Willebrand Factor Ristocetin cofactor (VWF:RCo rVWF) administered together with 38.5 IU/kg recombinant Factor VIII (rFVIII) (ratio of 1.3:1±0.2) [rVWF:rFVIII], or 50 IU/kg VWF:RCo rVWF administered together with saline (placebo) [rVWF] for subjects in the PK50 arms (Arm 1 and Arm 2). Category title includes number of subjects [N] who provided data for the category.
    End point type
    Secondary
    End point timeframe
    PK evaluations at pre-infusion, then at 15, 30 and 60 mins, and 3, 6, 12, 24, 30, 48, 72 and 96 hrs post-infusion. PK evaluation timeframe for 28 ± 3 days after first infusion of study product which includes PK evaluation for both infusions and washout.
    Notes
    [38] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Per protocol, only descriptive statistics were collected for this endpoint.
    End point values
    PK50 Arms
    Number of subjects analysed
    16
    Units: hours*U/dL)/(U VWF: RCo/kg)
    median (confidence interval 95%)
        rVWF:rFVIII [N=16]
    145.4 (118.8 to 189.5)
        rVWF [N=14]
    113 (93 to 167.4)
    No statistical analyses for this end point

    Secondary: PK50 - Area under the plasma concentration/time curve from time 0 to 96 hours (AUC0-96h/Dose) of FVIII:C

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    End point title
    PK50 - Area under the plasma concentration/time curve from time 0 to 96 hours (AUC0-96h/Dose) of FVIII:C [39]
    End point description
    Area under the plasma concentration curve (AUC) from time 0 to 96 hours of Factor VIII activity (FVIII:C) after infusion of 50 IU/kg recombinant von Willebrand Factor:von Willebrand Factor Ristocetin cofactor (VWF:RCo rVWF) administered together with 38.5 IU/kg recombinant Factor VIII (rFVIII) (ratio of 1.3:1±0.2) [rVWF:rFVIII], or 50 IU/kg VWF:RCo rVWF administered together with saline (placebo) [rVWF] for subjects in the PK50 arms (Arm 1 and Arm 2). Category title includes number of subjects [N] who provided data for the category.
    End point type
    Secondary
    End point timeframe
    PK evaluations at pre-infusion, then at 15, 30 and 60 mins, and 3, 6, 12, 24, 30, 48, 72 and 96 hrs post-infusion. PK evaluation timeframe for 28 ± 3 days after first infusion of study product which includes PK evaluation for both infusions and washout.
    Notes
    [39] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Per protocol, only descriptive statistics were collected for this endpoint.
    End point values
    PK50 Arms
    Number of subjects analysed
    16
    Units: hours*U/dL)/(U VWF: RCo/kg)
    median (confidence interval 95%)
        rVWF:rFVIII [N=16]
    127.8 (112.3 to 145.1)
        rVWF [N=14]
    101.8 (74.4 to 124.4)
    No statistical analyses for this end point

    Secondary: PK50 - Mean Residence Time of FVIII:C

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    End point title
    PK50 - Mean Residence Time of FVIII:C [40]
    End point description
    Mean Residence Time (MRT) of Factor VIII activity (FVIII:C) after infusion of 50 IU/kg recombinant von Willebrand Factor:von Willebrand Factor Ristocetin cofactor (VWF:RCo rVWF) administered together with 38.5 IU/kg recombinant Factor VIII (rFVIII) (ratio of 1.3:1±0.2) [rVWF:rFVIII], or 50 IU/kg VWF:RCo rVWF administered together with saline (placebo) [rVWF] for subjects in the PK50 arms (Arm 1 and Arm 2). Category title includes number of subjects [N] who provided data for the category.
    End point type
    Secondary
    End point timeframe
    PK evaluations at pre-infusion, then at 15, 30 and 60 mins, and 3, 6, 12, 24, 30, 48, 72 and 96 hrs post-infusion. PK evaluation timeframe for 28 ± 3 days after first infusion of study product which includes PK evaluation for both infusions and washout.
    Notes
    [40] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Per protocol, only descriptive statistics were collected for this endpoint.
    End point values
    PK50 Arms
    Number of subjects analysed
    16
    Units: hours
    median (confidence interval 95%)
        rVWF:rFVIII [N=16]
    44 (38 to 75)
        rVWF [N=0]
    0 (0 to 0)
    No statistical analyses for this end point

    Secondary: PK50 - Clearance of FVIII:C

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    End point title
    PK50 - Clearance of FVIII:C [41]
    End point description
    Clearance (CL) of Factor VIII activity (FVIII:C) after infusion of 50 IU/kg recombinant von Willebrand Factor:von Willebrand Factor Ristocetin cofactor (VWF:RCo rVWF) administered together with 38.5 IU/kg recombinant Factor VIII (rFVIII) (ratio of 1.3:1±0.2) [rVWF:rFVIII], or 50 IU/kg VWF:RCo rVWF administered together with saline (placebo) [rVWF] for subjects in the PK50 arms (Arm 1 and Arm 2). Category title includes number of subjects [N] who provided data for the category.
    End point type
    Secondary
    End point timeframe
    PK evaluations at pre-infusion, then at 15, 30 and 60 mins, and 3, 6, 12, 24, 30, 48, 72 and 96 hrs post-infusion. PK evaluation timeframe for 28 ± 3 days after first infusion of study product which includes PK evaluation for both infusions and washout.
    Notes
    [41] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Per protocol, only descriptive statistics were collected for this endpoint.
    End point values
    PK50 Arms
    Number of subjects analysed
    16
    Units: dL/kg/hours
    median (confidence interval 95%)
        rVWF:rFVIII [N=16]
    0.007 (0.006 to 0.009)
        rVWF [N=0]
    0 (0 to 0)
    No statistical analyses for this end point

    Secondary: PK50 - Incremental Recovery of FVIII:C

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    End point title
    PK50 - Incremental Recovery of FVIII:C [42]
    End point description
    Incremental Recovery (IR) at the maximum plasma concentration of Factor VIII activity (FVIII:C) after infusion of 50 IU/kg recombinant von Willebrand Factor:von Willebrand Factor Ristocetin cofactor (VWF:RCo rVWF) administered together with 38.5 IU/kg recombinant Factor VIII (rFVIII) (ratio of 1.3:1±0.2) [rVWF:rFVIII], or 50 IU/kg VWF:RCo rVWF administered together with saline (placebo) [rVWF] for subjects in the PK50 arms (Arm 1 and Arm 2). Category title includes number of subjects [N] who provided data for the category.
    End point type
    Secondary
    End point timeframe
    PK evaluations at pre-infusion, then at 15, 30 and 60 mins, and 3, 6, 12, 24, 30, 48, 72 and 96 hrs post-infusion. PK evaluation timeframe for 28 ± 3 days after first infusion of study product which includes PK evaluation for both infusions and washout.
    Notes
    [42] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Per protocol, only descriptive statistics were collected for this endpoint.
    End point values
    PK50 Arms
    Number of subjects analysed
    16
    Units: (U/dL)/(U VWF: RCo/kg)
    median (confidence interval 95%)
        rVWF:rFVIII [N=16]
    2.3 (1.9 to 2.7)
        rVWF [N=0]
    0 (0 to 0)
    No statistical analyses for this end point

    Secondary: PK50 - Elimination Phase Half-Life of FVIII:C

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    End point title
    PK50 - Elimination Phase Half-Life of FVIII:C [43]
    End point description
    Elimination Phase Half-Life (T1/2) of Factor VIII activity (FVIII:C) after infusion of 50 IU/kg recombinant von Willebrand Factor:von Willebrand Factor Ristocetin cofactor (VWF:RCo rVWF) administered together with 38.5 IU/kg recombinant FVIII (rFVIII) (ratio of 1.3:1±0.2) [rVWF:rFVIII], or 50 IU/kg VWF:RCo rVWF administered together with saline (placebo) [rVWF] for subjects in the PK50 arms (Arm 1 and Arm 2). Category title includes number of subjects [N] who provided data for the category.
    End point type
    Secondary
    End point timeframe
    PK evaluations at pre-infusion, then at 15, 30 and 60 mins, and 3, 6, 12, 24, 30, 48, 72 and 96 hrs post-infusion. PK evaluation timeframe for 28 ± 3 days after first infusion of study product which includes PK evaluation for both infusions and washout.
    Notes
    [43] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Per protocol, only descriptive statistics were collected for this endpoint.
    End point values
    PK50 Arms
    Number of subjects analysed
    16
    Units: hours
    median (confidence interval 95%)
        rVWF:rFVIII [N=16]
    24.8 (20.1 to 50.5)
        rVWF [N=0]
    0 (0 to 0)
    No statistical analyses for this end point

    Secondary: PK50 - Volume of Distribution at Steady State of FVIII:C

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    End point title
    PK50 - Volume of Distribution at Steady State of FVIII:C [44]
    End point description
    Volume of Distribution at Steady State (Vss) of Factor VIII activity (FVIII:C) after infusion of 50 IU/kg recombinant von Willebrand Factor:von Willebrand Factor Ristocetin cofactor (VWF:RCo rVWF) administered together with 38.5 IU/kg recombinant Factor VIII (rFVIII) (ratio of 1.3:1±0.2) [rVWF:rFVIII], or 50 IU/kg VWF:RCo rVWF administered together with saline (placebo) [rVWF] for subjects in the PK50 arms (Arm 1 and Arm 2). Category title includes number of subjects [N] who provided data for the category.
    End point type
    Secondary
    End point timeframe
    PK evaluations at pre-infusion, then at 15, 30 and 60 mins, and 3, 6, 12, 24, 30, 48, 72 and 96 hrs post-infusion. PK evaluation timeframe for 28 ± 3 days after first infusion of study product which includes PK evaluation for both infusions and washout.
    Notes
    [44] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Per protocol, only descriptive statistics were collected for this endpoint.
    End point values
    PK50 Arms
    Number of subjects analysed
    16
    Units: dL/kg
    median (confidence interval 95%)
        rVWF:rFVIII [N=16]
    0.32 (0.29 to 0.44)
        rVWF [N=0]
    0 (0 to 0)
    No statistical analyses for this end point

    Secondary: PK80 - Area under the plasma concentration/time curve from time 0 to infinity (AUC0-∞/Dose) of VWF:RCo

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    End point title
    PK80 - Area under the plasma concentration/time curve from time 0 to infinity (AUC0-∞/Dose) of VWF:RCo [45]
    End point description
    Area under the plasma concentration curve (AUC) from time 0 to infinity of von Willebrand Factor Ristocetin cofactor (VWF:RCo) after infusion of 80 IU/kg recombinant von Willebrand Factor:von Willebrand Factor Ristocetin cofactor (VWF:RCo rVWF) [rVWF] for subjects in the PK80 arm (subjects from Arm 3 with PK80 data only). PK assessment conducted at first infusion of 80 IU/kg rWVF [PK1] and the second infusion of 80 IU/kg rVWF after subjects were treated on demand for bleeding episodes for at least 6 months since their first infusion of study product [PK2]. Category title includes number of subjects [N] who provided data for the category.
    End point type
    Secondary
    End point timeframe
    PK evaluations at pre-infusion, then at 15, 30 and 60 mins, and 3, 6, 12, 24, 30, 48, 72 and 96 hrs post-infusion. PK evaluation timeframe for 28 ± 3 days after first infusion of study product which includes PK evaluation for both infusions and washout.
    Notes
    [45] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Per protocol, only descriptive statistics were collected for this endpoint.
    End point values
    PK80 Arm
    Number of subjects analysed
    15
    Units: (hours*U/dL)/(U VWF: RCo/kg)
    median (confidence interval 95%)
        PK1 of rVWF [N=15]
    36.9 (29.2 to 41.7)
        PK2 of rVWF [N=13]
    38.9 (28.1 to 43.3)
    No statistical analyses for this end point

    Secondary: PK80 - Area under the plasma concentration/time curve from time 0 to 96 hours (AUC0-96h/Dose) of VWF:RCo

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    End point title
    PK80 - Area under the plasma concentration/time curve from time 0 to 96 hours (AUC0-96h/Dose) of VWF:RCo [46]
    End point description
    Area under the plasma concentration curve (AUC) from time 0 to 96 hours of von Willebrand Factor Ristocetin cofactor (VWF:RCo) after infusion of 80 IU/kg recombinant von Willebrand Factor:von Willebrand Factor Ristocetin cofactor (VWF:RCo rVWF) [rVWF] for subjects in the PK80 arm (subjects from Arm 3 with PK80 data only). PK assessment conducted at first infusion of 80 IU/kg rWVF [PK1] and the second infusion of 80 IU/kg rVWF after subjects were treated on demand for bleeding episodes for at least 6 months since their first infusion of study product [PK2]. Category title includes number of subjects [N] who provided data for the category.
    End point type
    Secondary
    End point timeframe
    PK evaluations at pre-infusion, then at 15, 30 and 60 mins, and 3, 6, 12, 24, 30, 48, 72 and 96 hrs post-infusion. PK evaluation timeframe for 28 ± 3 days after first infusion of study product which includes PK evaluation for both infusions and washout.
    Notes
    [46] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Per protocol, only descriptive statistics were collected for this endpoint.
    End point values
    PK80 Arm
    Number of subjects analysed
    15
    Units: (hours*U/dL)/(U VWF: RCo/kg)
    median (confidence interval 95%)
        PK1 of rVWF [N=15]
    35.6 (28.9 to 41.2)
        PK2 of rVWF [N=13]
    37.9 (25.9 to 41.8)
    No statistical analyses for this end point

    Secondary: PK80 - Mean Residence Time of VWF:RCo

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    End point title
    PK80 - Mean Residence Time of VWF:RCo [47]
    End point description
    Mean Residence Time (MRT) of von Willebrand Factor Ristocetin cofactor (VWF:RCo) after infusion of 80 IU/kg recombinant von Willebrand Factor:von Willebrand Factor Ristocetin cofactor (VWF:RCo rVWF) [rVWF] for subjects in the PK80 arm (subjects from Arm 3 with PK80 data only). PK assessment conducted at first infusion of 80 IU/kg rWVF [PK1] and the second infusion of 80 IU/kg rVWF after subjects were treated on demand for bleeding episodes for at least 6 months since their first infusion of study product [PK2]. Category title includes number of subjects [N] who provided data for the category.
    End point type
    Secondary
    End point timeframe
    PK evaluations at pre-infusion, then at 15, 30 and 60 mins, and 3, 6, 12, 24, 30, 48, 72 and 96 hrs post-infusion. PK evaluation timeframe for 28 ± 3 days after first infusion of study product which includes PK evaluation for both infusions and washout.
    Notes
    [47] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Per protocol, only descriptive statistics were collected for this endpoint.
    End point values
    PK80 Arm
    Number of subjects analysed
    15
    Units: hours
    median (confidence interval 95%)
        PK1 of rVWF [N=15]
    26.4 (20.9 to 31.1)
        PK2 of rVWF [N=13]
    26.4 (23.7 to 32.8)
    No statistical analyses for this end point

    Secondary: PK80 - Clearance of VWF:RCo

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    End point title
    PK80 - Clearance of VWF:RCo [48]
    End point description
    Clearance (CL) of von Willebrand Factor Ristocetin cofactor (VWF:RCo) after infusion of 80 IU/kg recombinant von Willebrand Factor:von Willebrand Factor Ristocetin cofactor (VWF:RCo rVWF) [rVWF] for subjects in the PK80 arm (subjects from Arm 3 with PK80 data only). PK assessment conducted at first infusion of 80 IU/kg rWVF [PK1] and the second infusion of 80 IU/kg rVWF after subjects were treated on demand for bleeding episodes for at least 6 months since their first infusion of study product [PK2]. Category title includes number of subjects [N] who provided data for the category.
    End point type
    Secondary
    End point timeframe
    PK evaluations at pre-infusion, then at 15, 30 and 60 mins, and 3, 6, 12, 24, 30, 48, 72 and 96 hrs post-infusion. PK evaluation timeframe for 28 ± 3 days after first infusion of study product which includes PK evaluation for both infusions and washout.
    Notes
    [48] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Per protocol, only descriptive statistics were collected for this endpoint.
    End point values
    PK80 Arm
    Number of subjects analysed
    15
    Units: dL/kg/hours
    median (confidence interval 95%)
        PK1 of rVWF [N=15]
    0.027 (0.024 to 0.034)
        PK2 of rVWF [N=13]
    0.026 (0.023 to 0.036)
    No statistical analyses for this end point

    Secondary: PK80 - Incremental Recovery of VWF:RCo

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    End point title
    PK80 - Incremental Recovery of VWF:RCo [49]
    End point description
    Incremental Recovery (IR) at the maximum plasma concentration Area under the plasma concentration curve (AUC) from time 0 to infinity of von Willebrand Factor Ristocetin cofactor (VWF:RCo) after infusion of 80 IU/kg recombinant von Willebrand Factor:von Willebrand Factor Ristocetin cofactor (VWF:RCo rVWF) [rVWF] for subjects in the PK80 arm (subjects from Arm 3 with PK80 data only). PK assessment conducted at first infusion of 80 IU/kg rWVF [PK1] and the second infusion of 80 IU/kg rVWF after subjects were treated on demand for bleeding episodes for at least 6 months since their first infusion of study product [PK2]. Category title includes number of subjects [N] who provided data for the category.
    End point type
    Secondary
    End point timeframe
    PK evaluations at pre-infusion, then at 15, 30 and 60 mins, and 3, 6, 12, 24, 30, 48, 72 and 96 hrs post-infusion. PK evaluation timeframe for 28 ± 3 days after first infusion of study product which includes PK evaluation for both infusions and washout.
    Notes
    [49] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Per protocol, only descriptive statistics were collected for this endpoint.
    End point values
    PK80 Arm
    Number of subjects analysed
    15
    Units: (U/dL)/(U VWF: RCo/kg)
    median (confidence interval 95%)
        PK1 of rVWF [N=15]
    1.8 (1.7 to 2.2)
        PK2 of rVWF [N=13]
    1.8 (1.6 to 2)
    No statistical analyses for this end point

    Secondary: PK80 - Elimination Phase Half-Life of VWF:Co

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    End point title
    PK80 - Elimination Phase Half-Life of VWF:Co [50]
    End point description
    Elimination Phase Half-Life (T1/2) of von Willebrand Factor Ristocetin cofactor (VWF:RCo) after infusion of 80 IU/kg recombinant von Willebrand Factor:von Willebrand Factor Ristocetin cofactor (VWF:RCo rVWF) [rVWF] for subjects in the PK80 arm (subjects from Arm 3 with PK80 data only). PK assessment conducted at first infusion of 80 IU/kg rWVF [PK1] and the second infusion of 80 IU/kg rVWF after subjects were treated on demand for bleeding episodes for at least 6 months since their first infusion of study product [PK2]. Category title includes number of subjects [N] who provided data for the category.
    End point type
    Secondary
    End point timeframe
    PK evaluations at pre-infusion, then at 15, 30 and 60 mins, and 3, 6, 12, 24, 30, 48, 72 and 96 hrs post-infusion. PK evaluation timeframe for 28 ± 3 days after first infusion of study product which includes PK evaluation for both infusions and washout.
    Notes
    [50] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Per protocol, only descriptive statistics were collected for this endpoint.
    End point values
    PK80 Arm
    Number of subjects analysed
    15
    Units: hours
    median (confidence interval 95%)
        PK1 of rVWF [N=15]
    18.4 (16.4 to 22.1)
        PK2 of rVWF [N=13]
    19.8 (15.2 to 23.6)
    No statistical analyses for this end point

    Secondary: PK80 - Volume of Distribution at Steady State of VWF:RCo

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    End point title
    PK80 - Volume of Distribution at Steady State of VWF:RCo [51]
    End point description
    Volume of Distribution at Steady State (Vss) of von Willebrand Factor Ristocetin cofactor (VWF:RCo) after infusion of 80 IU/kg recombinant von Willebrand Factor:von Willebrand Factor Ristocetin cofactor (VWF:RCo rVWF) [rVWF] for subjects in the PK80 arm (subjects from Arm 3 with PK80 data only). PK assessment conducted at first infusion of 80 IU/kg rWVF [PK1] and the second infusion of 80 IU/kg rVWF after subjects were treated on demand for bleeding episodes for at least 6 months since their first infusion of study PK evaluations at pre-infusion, then at 15, 30 and 60 minutes, and 3, 6, 12, 24, 48, 72 and 96 hours post-infusion. PK assessment conducted at first infusion of 80 IU/kg rWVF [PK1] and the second infusion of 80 IU/kg rVWF after subjects were treated on demand for bleeding episodes for at least 6 months since their first infusion of study product [PK2]. Category title includes number of subjects [N] who provided data for the category.
    End point type
    Secondary
    End point timeframe
    PK evaluations at pre-infusion, then at 15, 30 and 60 mins, and 3, 6, 12, 24, 30, 48, 72 and 96 hrs post-infusion. PK evaluation timeframe for 28 ± 3 days after first infusion of study product which includes PK evaluation for both infusions and washout.
    Notes
    [51] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Per protocol, only descriptive statistics were collected for this endpoint.
    End point values
    PK80 Arm
    Number of subjects analysed
    15
    Units: dL/kg
    median (confidence interval 95%)
        PK1 of rVWF [N=15]
    0.78 (0.58 to 0.86)
        PK2 of rVWF [N=13]
    0.75 (0.58 to 1.01)
    No statistical analyses for this end point

    Secondary: PK80 - Area under the plasma concentration/time curve from time 0 to infinity (AUC0-∞/Dose) of VWF:Ag

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    End point title
    PK80 - Area under the plasma concentration/time curve from time 0 to infinity (AUC0-∞/Dose) of VWF:Ag [52]
    End point description
    Area under the plasma concentration curve (AUC) from time 0 to infinity of von Willebrand Factor Antigen (VWF:Ag) after infusion of 80 IU/kg recombinant von Willebrand Factor:von Willebrand Factor Ristocetin cofactor (VWF:RCo rVWF) [rVWF] for subjects in the PK80 arm (subjects from Arm 3 with PK80 data only). PK assessment conducted at first infusion of 80 IU/kg rWVF [PK1] and the second infusion of 80 IU/kg rVWF after subjects were treated on demand for bleeding episodes for at least 6 months since their first infusion of study product [PK2]. Category title includes number of subjects [N] who provided data for the category.
    End point type
    Secondary
    End point timeframe
    PK evaluations at pre-infusion, then at 15, 30 and 60 mins, and 3, 6, 12, 24, 30, 48, 72 and 96 hrs post-infusion. PK evaluation timeframe for 28 ± 3 days after first infusion of study product which includes PK evaluation for both infusions and washout.
    Notes
    [52] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Per protocol, only descriptive statistics were collected for this endpoint.
    End point values
    PK80 Arm
    Number of subjects analysed
    15
    Units: (hours*U/dL)/(U VWF: RCo/kg)
    median (confidence interval 95%)
        PK1 of rVWF [N=15]
    66.6 (50.4 to 89.4)
        PK2 of rVWF [N=13]
    86.9 (54.9 to 100.5)
    No statistical analyses for this end point

    Secondary: PK80 - Area under the plasma concentration/time curve from time 0 to 96 hours (AUC0-96h/Dose) of VWF:Ag

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    End point title
    PK80 - Area under the plasma concentration/time curve from time 0 to 96 hours (AUC0-96h/Dose) of VWF:Ag [53]
    End point description
    Area under the plasma concentration curve (AUC) from time 0 to 96 hours of von Willebrand Factor Antigen (VWF:Ag) after infusion of 80 IU/kg recombinant von Willebrand Factor:von Willebrand Factor Ristocetin cofactor (VWF:RCo rVWF) [rVWF] for subjects in the PK80 arm (subjects from Arm 3 with PK80 data only). PK assessment conducted at first infusion of 80 IU/kg rWVF [PK1] and the second infusion of 80 IU/kg rVWF after subjects were treated on demand for bleeding episodes for at least 6 months since their first infusion of study product [PK2]. Category title includes number of subjects [N] who provided data for the category.
    End point type
    Secondary
    End point timeframe
    PK evaluations at pre-infusion, then at 15, 30 and 60 mins, and 3, 6, 12, 24, 30, 48, 72 and 96 hrs post-infusion. PK evaluation timeframe for 28 ± 3 days after first infusion of study product which includes PK evaluation for both infusions and washout.
    Notes
    [53] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Per protocol, only descriptive statistics were collected for this endpoint.
    End point values
    PK80 Arm
    Number of subjects analysed
    15
    Units: (hours*U/dL)/(U VWF: RCo/kg)
    median (confidence interval 95%)
        PK1 of rVWF [N=15]
    61.3 (48.8 to 73.7)
        PK2 of rVWF [N=13]
    77.4 (53 to 87.6)
    No statistical analyses for this end point

    Secondary: PK80 - Mean Residence Time of VWF:Ag

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    End point title
    PK80 - Mean Residence Time of VWF:Ag [54]
    End point description
    Mean Residence Time (MRT) of von Willebrand Factor Antigen (VWF:Ag) after infusion of 80 IU/kg recombinant von Willebrand Factor:von Willebrand Factor Ristocetin cofactor (VWF:RCo rVWF) [rVWF] for subjects in the PK80 arm (subjects from Arm 3 with PK80 data only). PK assessment conducted at first infusion of 80 IU/kg rWVF [PK1] and the second infusion of 80 IU/kg rVWF after subjects were treated on demand for bleeding episodes for at least 6 months since their first infusion of study product [PK2]. Category title includes number of subjects [N] who provided data for the category.
    End point type
    Secondary
    End point timeframe
    PK evaluations at pre-infusion, then at 15, 30 and 60 mins, and 3, 6, 12, 24, 30, 48, 72 and 96 hrs post-infusion. PK evaluation timeframe for 28 ± 3 days after first infusion of study product which includes PK evaluation for both infusions and washout.
    Notes
    [54] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Per protocol, only descriptive statistics were collected for this endpoint.
    End point values
    PK80 Arm
    Number of subjects analysed
    15
    Units: hours
    median (confidence interval 95%)
        PK1 of rVWF [N=15]
    38.4 (31.9 to 48.1)
        PK2 of rVWF [N=13]
    36.9 (30 to 50.8)
    No statistical analyses for this end point

    Secondary: PK80 - Clearance of VWF:Ag

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    End point title
    PK80 - Clearance of VWF:Ag [55]
    End point description
    Clearance (CL) of von Willebrand Factor Antigen (VWF:Ag) after infusion of 80 IU/kg recombinant von Willebrand Factor:von Willebrand Factor Ristocetin cofactor (VWF:RCo rVWF) [rVWF] for subjects in the PK80 arm (subjects from Arm 3 with PK80 data only). PK assessment conducted at first infusion of 80 IU/kg rWVF [PK1] and the second infusion of 80 IU/kg rVWF after subjects were treated on demand for bleeding episodes for at least 6 months since their first infusion of study product [PK2]. Category title includes number of subjects [N] who provided data for the category.
    End point type
    Secondary
    End point timeframe
    PK evaluations at pre-infusion, then at 15, 30 and 60 mins, and 3, 6, 12, 24, 30, 48, 72 and 96 hrs post-infusion. PK evaluation timeframe for 28 ± 3 days after first infusion of study product which includes PK evaluation for both infusions and washout.
    Notes
    [55] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Per protocol, only descriptive statistics were collected for this endpoint.
    End point values
    PK80 Arm
    Number of subjects analysed
    15
    Units: dL/kg/hours
    median (confidence interval 95%)
        PK1 of rVWF [N=15]
    0.015 (0.011 to 0.02)
        PK2 of rVWF [N=13]
    0.012 (0.01 to 0.018)
    No statistical analyses for this end point

    Secondary: PK80 - Incremental Recovery of VWF:Ag

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    End point title
    PK80 - Incremental Recovery of VWF:Ag [56]
    End point description
    Incremental Recovery (IR) at the maximum plasma concentration Area under the plasma concentration curve (AUC) from time 0 to infinity of von Willebrand Factor Antigen (VWF:Ag) after infusion of 80 IU/kg recombinant von Willebrand Factor:von Willebrand Factor Ristocetin cofactor (VWF:RCo rVWF) [rVWF] for subjects in the PK80 arm (subjects from Arm 3 with PK80 data only). PK assessment conducted at first infusion of 80 IU/kg rWVF [PK1] and the second infusion of 80 IU/kg rVWF after subjects were treated on demand for bleeding episodes for at least 6 months since their first infusion of study product [PK2]. Category title includes number of subjects [N] who provided data for the category.
    End point type
    Secondary
    End point timeframe
    PK evaluations at pre-infusion, then at 15, 30 and 60 mins, and 3, 6, 12, 24, 30, 48, 72 and 96 hrs post-infusion. PK evaluation timeframe for 28 ± 3 days after first infusion of study product which includes PK evaluation for both infusions and washout.
    Notes
    [56] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Per protocol, only descriptive statistics were collected for this endpoint.
    End point values
    PK80 Arm
    Number of subjects analysed
    15
    Units: (U/dL)/(U VWF: RCo/kg)
    median (confidence interval 0%)
        PK1 of rVWF [N=15]
    2.2 (1.9 to 2.6)
        PK2 of rVWF [N=13]
    2.4 (2 to 2.9)
    No statistical analyses for this end point

    Secondary: PK80 - Elimination Phase Half-Life of VWF:Ag

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    End point title
    PK80 - Elimination Phase Half-Life of VWF:Ag [57]
    End point description
    Elimination Phase Half-Life (T1/2) of von Willebrand Factor Antigen (VWF:Ag) after infusion of 80 IU/kg recombinant von Willebrand Factor:von Willebrand Factor Ristocetin cofactor (VWF:RCo rVWF) [rVWF] for subjects in the PK80 arm (subjects from Arm 3 with PK80 data only). PK assessment conducted at first infusion of 80 IU/kg rWVF [PK1] and the second infusion of 80 IU/kg rVWF after subjects were treated on demand for bleeding episodes for at least 6 months since their first infusion of study product [PK2]. Category title includes number of subjects [N] who provided data for the category.
    End point type
    Secondary
    End point timeframe
    PK evaluations at pre-infusion, then at 15, 30 and 60 mins, and 3, 6, 12, 24, 30, 48, 72 and 96 hrs post-infusion. PK evaluation timeframe for 28 ± 3 days after first infusion of study product which includes PK evaluation for both infusions and washout.
    Notes
    [57] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Per protocol, only descriptive statistics were collected for this endpoint.
    End point values
    PK80 Arm
    Number of subjects analysed
    15
    Units: hours
    median (confidence interval 95%)
        PK1 of rVWF [N=15]
    27.5 (22.5 to 34)
        PK2 of rVWF [N=13]
    24.8 (21.1 to 37.7)
    No statistical analyses for this end point

    Secondary: PK80 - Volume of Distribution at Steady State of VWF:Ag

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    End point title
    PK80 - Volume of Distribution at Steady State of VWF:Ag [58]
    End point description
    Volume of Distribution at Steady State (Vss) of von Willebrand Factor Antigen (VWF:Ag) after infusion of 80 IU/kg recombinant von Willebrand Factor:von Willebrand Factor Ristocetin cofactor (VWF:RCo rVWF) [rVWF] for subjects in the PK80 arm (subjects from Arm 3 with PK80 data only). PK assessment conducted at first infusion of 80 IU/kg rWVF [PK1] and the second infusion of 80 IU/kg rVWF after subjects were treated on demand for bleeding episodes for at least 6 months since their first infusion of study product [PK2]. Category title includes number of subjects [N] who provided data for the category.
    End point type
    Secondary
    End point timeframe
    PK evaluations at pre-infusion, then at 15, 30 and 60 mins, and 3, 6, 12, 24, 30, 48, 72 and 96 hrs post-infusion. PK evaluation timeframe for 28 ± 3 days after first infusion of study product which includes PK evaluation for both infusions and washout.
    Notes
    [58] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Per protocol, only descriptive statistics were collected for this endpoint.
    End point values
    PK80 Arm
    Number of subjects analysed
    15
    Units: dL/kg
    median (confidence interval 95%)
        PK1 of rVWF [N=15]
    0.55 (0.46 to 0.61)
        PK2 of rVWF [N=13]
    0.5 (0.41 to 0.57)
    No statistical analyses for this end point

    Secondary: PK80 - Area under the plasma concentration/time curve from time 0 to infinity (AUC0-∞/Dose) of VWF:CB

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    End point title
    PK80 - Area under the plasma concentration/time curve from time 0 to infinity (AUC0-∞/Dose) of VWF:CB [59]
    End point description
    Area under the plasma concentration curve (AUC) from time 0 to infinity of von Willebrand Factor Collagen Binding (VWF:CB) after infusion of 80 IU/kg recombinant von Willebrand Factor:von Willebrand Factor Ristocetin cofactor (VWF:RCo rVWF) [rVWF] for subjects in the PK80 arm (subjects from Arm 3 with PK80 data only). PK assessment conducted at first infusion of 80 IU/kg rWVF [PK1] and the second infusion of 80 IU/kg rVWF after subjects were treated on demand for bleeding episodes for at least 6 months since their first infusion of study product [PK2]. Category title includes number of subjects [N] who provided data for the category.
    End point type
    Secondary
    End point timeframe
    PK evaluations at pre-infusion, then at 15, 30 and 60 mins, and 3, 6, 12, 24, 30, 48, 72 and 96 hrs post-infusion. PK evaluation timeframe for 28 ± 3 days after first infusion of study product which includes PK evaluation for both infusions and washout.
    Notes
    [59] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Per protocol, only descriptive statistics were collected for this endpoint.
    End point values
    PK80 Arm
    Number of subjects analysed
    15
    Units: (hours*U/dL)/(U VWF: RCo/kg)
    median (confidence interval 95%)
        PK1 of rVWF [N=15]
    73.9 (57.3 to 96.2)
        PK2 of rVWF [N=13]
    90.8 (66 to 105.2)
    No statistical analyses for this end point

    Secondary: PK80 - Area under the plasma concentration/time curve from time 0 to 96 hours (AUC0-96h/Dose) of VWF:CB

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    End point title
    PK80 - Area under the plasma concentration/time curve from time 0 to 96 hours (AUC0-96h/Dose) of VWF:CB [60]
    End point description
    Area under the plasma concentration curve (AUC) from time 0 to 96 hours of von Willebrand Factor Collagen Binding (VWF:CB) after infusion of 80 IU/kg recombinant von Willebrand Factor:von Willebrand Factor Ristocetin cofactor (VWF:RCo rVWF) [rVWF] for subjects in the PK80 arm (subjects from Arm 3 with PK80 data only). PK assessment conducted at first infusion of 80 IU/kg rWVF [PK1] and the second infusion of 80 IU/kg rVWF after subjects were treated on demand for bleeding episodes for at least 6 months since their first infusion of study product [PK2]. Category title includes number of subjects [N] who provided data for the category.
    End point type
    Secondary
    End point timeframe
    PK evaluations at pre-infusion, then at 15, 30 and 60 mins, and 3, 6, 12, 24, 30, 48, 72 and 96 hrs post-infusion. PK evaluation timeframe for 28 ± 3 days after first infusion of study product which includes PK evaluation for both infusions and washout.
    Notes
    [60] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Per protocol, only descriptive statistics were collected for this endpoint.
    End point values
    PK80 Arm
    Number of subjects analysed
    15
    Units: (hours*U/dL)/(U VWF: RCo/kg)
    median (confidence interval 95%)
        PK1 of rVWF [N=15]
    71.9 (57 to 89.8)
        PK2 of rVWF [N=13]
    88.1 (63.8 to 96.3)
    No statistical analyses for this end point

    Secondary: PK80 - Mean Residence Time of VWF:CB

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    End point title
    PK80 - Mean Residence Time of VWF:CB [61]
    End point description
    Mean Residence Time (MRT) of von Willebrand Factor Collagen Binding (VWF:CB) after infusion of 80 IU/kg recombinant von Willebrand Factor:von Willebrand Factor Ristocetin cofactor (VWF:RCo rVWF) [rVWF] for subjects in the PK80 arm (subjects from Arm 3 with PK80 data only). PK assessment conducted at first infusion of 80 IU/kg rWVF [PK1] and the second infusion of 80 IU/kg rVWF after subjects were treated on demand for bleeding episodes for at least 6 months since their first infusion of study product [PK2]. Category title includes number of subjects [N] who provided data for the category.
    End point type
    Secondary
    End point timeframe
    PK evaluations at pre-infusion, then at 15, 30 and 60 mins, and 3, 6, 12, 24, 30, 48, 72 and 96 hrs post-infusion. PK evaluation timeframe for 28 ± 3 days after first infusion of study product which includes PK evaluation for both infusions and washout.
    Notes
    [61] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Per protocol, only descriptive statistics were collected for this endpoint.
    End point values
    PK80 Arm
    Number of subjects analysed
    15
    Units: hours
    median (confidence interval 95%)
        PK1 of rVWF [N=15]
    30.9 (24.3 to 35)
        PK2 of rVWF [N=13]
    28.7 (25.6 to 37.2)
    No statistical analyses for this end point

    Secondary: PK80 - Clearance of VWF:CB

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    End point title
    PK80 - Clearance of VWF:CB [62]
    End point description
    Clearance (CL) of von Willebrand Factor Collagen Binding (VWF:CB) after infusion of 80 IU/kg recombinant von Willebrand Factor:von Willebrand Factor Ristocetin cofactor (VWF:RCo rVWF) [rVWF] for subjects in the PK80 arm (subjects from Arm 3 with PK80 data only). PK assessment conducted at first infusion of 80 IU/kg rWVF [PK1] and the second infusion of 80 IU/kg rVWF after subjects were treated on demand for bleeding episodes for at least 6 months since their first infusion of study product [PK2]. Category title includes number of subjects [N] who provided data for the category.
    End point type
    Secondary
    End point timeframe
    PK evaluations at pre-infusion, then at 15, 30 and 60 mins, and 3, 6, 12, 24, 30, 48, 72 and 96 hrs post-infusion. PK evaluation timeframe for 28 ± 3 days after first infusion of study product which includes PK evaluation for both infusions and washout.
    Notes
    [62] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Per protocol, only descriptive statistics were collected for this endpoint.
    End point values
    PK80 Arm
    Number of subjects analysed
    15
    Units: dL/kg/hours
    median (confidence interval 95%)
        PK1 of rVWF [N=15]
    0.014 (0.01 to 0.017)
        PK2 of rVWF [N=13]
    0.011 (0.01 to 0.015)
    No statistical analyses for this end point

    Secondary: PK80 - Incremental Recovery of VWF:CB

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    End point title
    PK80 - Incremental Recovery of VWF:CB [63]
    End point description
    Incremental Recovery (IR) at the maximum plasma concentration Area under the plasma concentration curve (AUC) from time 0 to infinity of von Willebrand Factor Collagen Binding (VWF:CB) after infusion of 80 IU/kg recombinant von Willebrand Factor:von Willebrand Factor Ristocetin cofactor (VWF:RCo rVWF) [rVWF] for subjects in the PK80 arm (subjects from Arm 3 with PK80 data only). PK assessment conducted at first infusion of 80 IU/kg rWVF [PK1] and the second infusion of 80 IU/kg rVWF after subjects were treated on demand for bleeding episodes for at least 6 months since their first infusion of study product [PK2]. Category title includes number of subjects [N] who provided data for the category.
    End point type
    Secondary
    End point timeframe
    PK evaluations at pre-infusion, then at 15, 30 and 60 mins, and 3, 6, 12, 24, 30, 48, 72 and 96 hrs post-infusion. PK evaluation timeframe for 28 ± 3 days after first infusion of study product which includes PK evaluation for both infusions and washout.
    Notes
    [63] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Per protocol, only descriptive statistics were collected for this endpoint.
    End point values
    PK80 Arm
    Number of subjects analysed
    15
    Units: (U/dL)/(U VWF: RCo/kg)
    median (confidence interval 95%)
        PK1 of rVWF [N=15]
    3.1 (2.8 to 3.6)
        PK2 of rVWF [N=13]
    3.7 (2.7 to 4)
    No statistical analyses for this end point

    Secondary: PK80 - Elimination Phase Half-Life of VWF:CB

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    End point title
    PK80 - Elimination Phase Half-Life of VWF:CB [64]
    End point description
    Elimination Phase Half-Life (T1/2) of von Willebrand Factor Collagen Binding (VWF:CB) after infusion of 80 IU/kg recombinant von Willebrand Factor:von Willebrand Factor Ristocetin cofactor (VWF:RCo rVWF) [rVWF] for subjects in the PK80 arm (subjects from Arm 3 with PK80 data only). PK assessment conducted at first infusion of 80 IU/kg rWVF [PK1] and the second infusion of 80 IU/kg rVWF after subjects were treated on demand for bleeding episodes for at least 6 months since their first infusion of study product [PK2]. Category title includes number of subjects [N] who provided data for the category.
    End point type
    Secondary
    End point timeframe
    PK evaluations at pre-infusion, then at 15, 30 and 60 mins, and 3, 6, 12, 24, 30, 48, 72 and 96 hrs post-infusion. PK evaluation timeframe for 28 ± 3 days after first infusion of study product which includes PK evaluation for both infusions and washout.
    Notes
    [64] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Per protocol, only descriptive statistics were collected for this endpoint.
    End point values
    PK80 Arm
    Number of subjects analysed
    15
    Units: hours
    median (confidence interval 95%)
        PK1 of rVWF [N=15]
    18.8 (16.6 to 24.9)
        PK2 of rVWF [N=13]
    20.9 (17.8 to 23.5)
    No statistical analyses for this end point

    Secondary: PK80 - Volume of Distribution at Steady State of VWF:CB

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    End point title
    PK80 - Volume of Distribution at Steady State of VWF:CB [65]
    End point description
    Volume of Distribution at Steady State (Vss) of von Willebrand Factor Collagen Binding (VWF:CB) after infusion of 80 IU/kg recombinant von Willebrand Factor:von Willebrand Factor Ristocetin cofactor (VWF:RCo rVWF) [rVWF] for subjects in the PK80 arm (subjects from Arm 3 with PK80 data only). PK assessment conducted at first infusion of 80 IU/kg rWVF [PK1] and the second infusion of 80 IU/kg rVWF after subjects were treated on demand for bleeding episodes for at least 6 months since their first infusion of study product [PK2]. Category title includes number of subjects [N] who provided data for the category.
    End point type
    Secondary
    End point timeframe
    PK evaluations at pre-infusion, then at 15, 30 and 60 mins, and 3, 6, 12, 24, 30, 48, 72 and 96 hrs post-infusion. PK evaluation timeframe for 28 ± 3 days after first infusion of study product which includes PK evaluation for both infusions and washout.
    Notes
    [65] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Per protocol, only descriptive statistics were collected for this endpoint.
    End point values
    PK80 Arm
    Number of subjects analysed
    15
    Units: dL/kg
    median (confidence interval 95%)
        PK1 of rVWF [N=15]
    0.39 (0.34 to 0.46)
        PK2 of rVWF [N=13]
    0.36 (0.33 to 0.4)
    No statistical analyses for this end point

    Secondary: PK80 - Area under the plasma concentration/time curve from time 0 to infinity (AUC0-∞/Dose) of FVIII:C

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    End point title
    PK80 - Area under the plasma concentration/time curve from time 0 to infinity (AUC0-∞/Dose) of FVIII:C [66]
    End point description
    Area under the plasma concentration curve (AUC) from time 0 to infinity of Factor VIII activity (FVIII:C) after infusion of 80 IU/kg recombinant von Willebrand Factor:von Willebrand Factor Ristocetin cofactor (VWF:RCo rVWF) [rVWF] for subjects in the PK80 arm (subjects from Arm 3 with PK80 data only). PK assessment conducted at first infusion of 80 IU/kg rWVF [PK1] and the second infusion of 80 IU/kg rVWF after subjects were treated on demand for bleeding episodes for at least 6 months since their first infusion of study product [PK2]. Category title includes number of subjects [N] who provided data for the category.
    End point type
    Secondary
    End point timeframe
    PK evaluations at pre-infusion, then at 15, 30 and 60 mins, and 3, 6, 12, 24, 30, 48, 72 and 96 hrs post-infusion. PK evaluation timeframe for 28 ± 3 days after first infusion of study product which includes PK evaluation for both infusions and washout.
    Notes
    [66] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Per protocol, only descriptive statistics were collected for this endpoint.
    End point values
    PK80 Arm
    Number of subjects analysed
    15
    Units: (hours*U/dL)/(U VWF: RCo/kg)
    median (confidence interval 95%)
        PK1 of rVWF [N=15]
    96.8 (64 to 126.5)
        PK2 of rVWF [N=13]
    94.8 (60.4 to 106.5)
    No statistical analyses for this end point

    Secondary: PK80 - Area under the plasma concentration/time curve from time 0 to 96 hours (AUC0-96h/Dose) of FVIII:C

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    End point title
    PK80 - Area under the plasma concentration/time curve from time 0 to 96 hours (AUC0-96h/Dose) of FVIII:C [67]
    End point description
    Area under the plasma concentration curve (AUC) from time 0 to 96 hours of Factor VIII activity (FVIII:C) after infusion of 80 IU/kg recombinant von Willebrand Factor:von Willebrand Factor Ristocetin cofactor (VWF:RCo rVWF) [rVWF] for subjects in the PK80 arm (subjects from Arm 3 with PK80 data only). PK assessment conducted at first infusion of 80 IU/kg rWVF [PK1] and the second infusion of 80 IU/kg rVWF after subjects were treated on demand for bleeding episodes for at least 6 months since their first infusion of study product [PK2]. Category title includes number of subjects [N] who provided data for the category.
    End point type
    Secondary
    End point timeframe
    PK evaluations at pre-infusion, then at 15, 30 and 60 mins, and 3, 6, 12, 24, 30, 48, 72 and 96 hrs post-infusion. PK evaluation timeframe for 28 ± 3 days after first infusion of study product which includes PK evaluation for both infusions and washout.
    Notes
    [67] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Per protocol, only descriptive statistics were collected for this endpoint.
    End point values
    PK80 Arm
    Number of subjects analysed
    15
    Units: (hours*U/dL)/(U VWF: RCo/kg)
    median (confidence interval 95%)
        PK1 of rVWF [N=15]
    81.7 (54.7 to 104.3)
        PK2 of rVWF [N=13]
    71.8 (49.6 to 89.2)
    No statistical analyses for this end point

    Secondary: PK80- Ratio of intra-subject PK of VWF:RCo, VWF:Ag and VWF:CB at baseline and after 6 months

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    End point title
    PK80- Ratio of intra-subject PK of VWF:RCo, VWF:Ag and VWF:CB at baseline and after 6 months [68]
    End point description
    Area under the plasma concentration curve (AUC) from time 0 to infinity per dose (AUC0-∞/dose) for von Willebrand Factor Ristocetin cofactor (VWF:RCo), von Willebrand Factor Antigen (VWF:Ag) and von Willebrand Factor Collagen Binding (VWF:CB). Each parameter was compared between the two PK assessments after infusion of 80 IU/kg recombinant von Willebrand Factor:von Willebrand Factor Ristocetin cofactor (VWF:RCo rVWF) [rVWF] for subjects in the PK80 arm (subjects from Arm 3 with PK80 data only). PK assessment conducted at first infusion of 80 IU/kg rWVF [PK1] and the second infusion of 80 IU/kg rVWF after subjects were treated on demand for bleeding episodes for at least 6 months since their first infusion of study product [PK2]. 13 subjects had data available for this endpoint i.e. data for PK1 and PK2.
    End point type
    Secondary
    End point timeframe
    PK evaluations at pre-infusion, then at 15, 30 and 60 mins, and 3, 6, 12, 24, 30, 48, 72 and 96 hrs post-infusion. PK evaluation timeframe for 28 ± 3 days after first infusion of study product which includes PK evaluation for both infusions and washout.
    Notes
    [68] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Per protocol, only descriptive statistics were collected for this endpoint.
    End point values
    PK80 Arm
    Number of subjects analysed
    13
    Units: ratio of AUC0-∞/dose
    geometric mean (confidence interval 90%)
        AUC0-∞/dose - VWF:RCo
    0.9587 (0.8466 to 1.0857)
        AUC0-∞/dose - VWF:Ag
    1.0914 (1.0132 to 1.1757)
        AUC0-∞/dose - VWF:CB
    1.0666 (1.0004 to 1.1372)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    for 12 months after first infusion of recombinant von Willebrand Factor (rVWF) with or without recombinant Factor VIII (rVWF:rFVIII)
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    17.1
    Reporting groups
    Reporting group title
    Safety Analysis Set
    Reporting group description
    The Safety Analysis Set comprises of subjects who were treated with study product at least once during the study.

    Serious adverse events
    Safety Analysis Set
    Total subjects affected by serious adverse events
         subjects affected / exposed
    7 / 37 (18.92%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Pregnancy, puerperium and perinatal conditions
    Abortion spontaneous
         subjects affected / exposed
    1 / 37 (2.70%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    General disorders and administration site conditions
    Chest discomfort
         subjects affected / exposed
    1 / 37 (2.70%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    1 / 37 (2.70%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Mesenteric haematoma
         subjects affected / exposed
    1 / 37 (2.70%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 37 (2.70%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Haemorrhoids
         subjects affected / exposed
    1 / 37 (2.70%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Reproductive system and breast disorders
    Uterine polyp
         subjects affected / exposed
    1 / 37 (2.70%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Heart rate increased
         subjects affected / exposed
    1 / 37 (2.70%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Osteomyelitis
         subjects affected / exposed
    1 / 37 (2.70%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Safety Analysis Set
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    10 / 37 (27.03%)
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    2 / 37 (5.41%)
         occurrences all number
    2
    Laceration
         subjects affected / exposed
    2 / 37 (5.41%)
         occurrences all number
    4
    Blood and lymphatic system disorders
    Iron deficiency anaemia
         subjects affected / exposed
    3 / 37 (8.11%)
         occurrences all number
    4
    Anaemia
         subjects affected / exposed
    2 / 37 (5.41%)
         occurrences all number
    2
    Nervous system disorders
    Headache
         subjects affected / exposed
    4 / 37 (10.81%)
         occurrences all number
    12
    General disorders and administration site conditions
    Infusion site paraesthesia
         subjects affected / exposed
    2 / 37 (5.41%)
         occurrences all number
    2
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    2 / 37 (5.41%)
         occurrences all number
    3
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    2 / 37 (5.41%)
         occurrences all number
    2
    Vomiting
         subjects affected / exposed
    3 / 37 (8.11%)
         occurrences all number
    4
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    3 / 37 (8.11%)
         occurrences all number
    16
    Back pain
         subjects affected / exposed
    2 / 37 (5.41%)
         occurrences all number
    3
    Infections and infestations
    Upper respiratory tract infection
         subjects affected / exposed
    3 / 37 (8.11%)
         occurrences all number
    5

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    15 Nov 2011
    Exclusion criteria updated to ensure specific cohort of patients plus hypersensitivity of study product components. New study arm added (PK80 analysis). Update for safety stopping rules.
    10 Aug 2012
    Clarification on procedure for enabling home treatment of bleeding episodes. Inclusion criteria updated to better reflect real life clinical practice for this cohort of patients. Option to use premixed or sequential infusion of study product (when administered together with recombinant Factor VIII).
    26 Jul 2013
    Final report to be done after completion of study Parts A and B.

    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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