Flag of the European Union EU Clinical Trials Register Help

Clinical trials

The European Union Clinical Trials Register allows you to search for protocol and results information on:
  • interventional clinical trials that are conducted in the European Union (EU) and the European Economic Area (EEA);
  • clinical trials conducted outside the EU / EEA that are linked to European paediatric-medicine development.
  • Learn   more about the EU Clinical Trials Register   including the source of the information and the legal basis.


    The EU Clinical Trials Register currently displays   39799   clinical trials with a EudraCT protocol, of which   6533   are clinical trials conducted with subjects less than 18 years old.
    The register also displays information on   18700   older paediatric trials (in scope of Article 45 of the Paediatric Regulation (EC) No 1901/2006).
     
    Examples: Cancer AND drug name. Pneumonia AND sponsor name.
    How to search [pdf]
    Search Tips: Under advanced search you can use filters for Country, Age Group, Gender, Trial Phase, Trial Status, Date Range, Rare Diseases and Orphan Designation. For these items you should use the filters and not add them to your search terms in the text field.
    Advanced Search: Search tools
     

    < Back to search results

    Download PDF

    Clinical Trial Results:
    A phase II/III, randomized, cross-over, open-label trial to demonstrate superiority of prophylaxis over on-demand therapy in previously treated subjects with severe hemophilia A treated with plasma protein-free recombinant FVIII formulated with sucrose (BAY 81-8973)

    Summary
    EudraCT number
    2009-012150-20
    Trial protocol
    CZ  
    Global end of trial date
    05 Dec 2012

    Results information
    Results version number
    v2(current)
    This version publication date
    03 Sep 2016
    First version publication date
    28 Jun 2015
    Other versions
    v1
    Version creation reason
    • New data added to full data set
    • Correction of full data set
    Bayer sponsor contact information to be updated

    Trial information

    Close Top of page
    Trial identification
    Sponsor protocol code
    BAY81-8973/14319
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01233258
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Bayer AG
    Sponsor organisation address
    Kaiser-Wilhelm-Allee, Leverkusen, Germany, D-51368
    Public contact
    Therapeutic Area Head, Bayer AG, clinical-trials-contact@bayer.com
    Scientific contact
    Therapeutic Area Head, Bayer AG, clinical-trials-contact@bayer.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    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
    06 May 2013
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    05 Dec 2012
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To demonstrate that 2-3 times per week prophylaxis therapy with BAY81-8973 is superior to on-demand therapy with BAY81-8973 in subjects with severe Hemophilia A. The hypothesis was that prophylaxis will result in fewer bleeds than on-demand treatment.
    Protection of trial subjects
    The conduct of this clinical study met all local legal and regulatory requirements. The study was conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki and the International Conference on Harmonization guideline E6: Good Clinical Practice. Before entering the study, the informed consent form was read by and explained to all subjects and/or their legally authorized representatives. Participating subjects and/or their legally authorized representatives signed informed consent form and could withdraw from the study at any time without any disadvantage and without having to provide a reason for this decision. Only investigators qualified by training and experience were selected as appropriate experts to investigate the study drug.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    18 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
    Japan: 9
    Country: Number of subjects enrolled
    Mexico: 9
    Country: Number of subjects enrolled
    Romania: 18
    Country: Number of subjects enrolled
    China: 31
    Country: Number of subjects enrolled
    Serbia: 5
    Country: Number of subjects enrolled
    Russian Federation: 7
    Country: Number of subjects enrolled
    Turkey: 5
    Country: Number of subjects enrolled
    Taiwan: 3
    Country: Number of subjects enrolled
    United States: 2
    Country: Number of subjects enrolled
    South Africa: 6
    Country: Number of subjects enrolled
    Czech Republic: 2
    Worldwide total number of subjects
    97
    EEA total number of subjects
    20
    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)
    11
    Adults (18-64 years)
    86
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

    Close Top of page
    Recruitment
    Recruitment details
    Subjects were recruited from specialized hemophilia treatment centers.

    Pre-assignment
    Screening details
    A total of 83 subjects were randomized, but 3 of these terminated the study before their first injection of study drug.

    Period 1
    Period 1 title
    First Intervention (6 Months)
    Is this the baseline period?
    No
    Allocation method
    Randomised - controlled
    Blinding used
    Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    On Demand, BAY81-8973 Potency First EP Then ADJ
    Arm description
    Subjects received on-demand treatment with recombinant factor VIII (rFVIII, BAY81-8973) assayed by Chromogenic Substrate Assay per European Pharmacopoeia (CS/EP) for 6 months, followed by crossover to study drug assayed by Chromogenic Substrate Assay/label adjusted to one-stage assay (CS/ADJ) for 6 months.
    Arm type
    Experimental

    Investigational medicinal product name
    Recombinant factor VIII
    Investigational medicinal product code
    BAY81-8973
    Other name
    rFVIII
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects received BAY81-8973 as an intravenous (IV) injection manually over 1 to 15 minutes. The dosage was adjusted to bleeding location and severity and to current standard of care.

    Arm title
    On Demand, BAY81-8973 Potency First ADJ Then EP
    Arm description
    Subjects received on-demand treatment with rFVIII (BAY81-8973) assayed by CS/ADJ for 6 months, followed by cross-over to study drug assayed by CS/EP for 6 months.
    Arm type
    Experimental

    Investigational medicinal product name
    Recombinant factor VIII
    Investigational medicinal product code
    BAY81-8973
    Other name
    rFVIII
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects received BAY81-8973 as an IV injection manually over 1 to 15 minutes. The dosage was adjusted to bleeding location and severity and to current standard of care.

    Arm title
    Low Dose Prophylaxis, BAY81-8973 Potency First EP Then ADJ
    Arm description
    Subjects received low dose prophylaxis treatment at 20, 25 or 30 international units per kilogram (IU/kg) twice per week with rFVIII (BAY81-8973) assayed by CS/EP for 6 months then crossed over to study drug assayed by CS/ADJ for 6 months.
    Arm type
    Experimental

    Investigational medicinal product name
    Recombinant factor VIII
    Investigational medicinal product code
    BAY81-8973
    Other name
    rFVIII
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects received low dose prophylaxis treatment at 20, 25 or 30 IU/kg twice per week with rFVIII (BAY81-8973) as an IV injection manually over 1 to 15 minutes, assayed by CS/EP for 6 months then crossed over to study drug assayed by CS/ADJ for 6 months.

    Arm title
    Low Dose Prophylaxis, BAY81-8973 Potency First ADJ Then EP
    Arm description
    Subjects received low dose prophylaxis treatment at 20, 25 or 30 IU/kg twice per week with rFVIII (BAY81-8973) assayed by CS/ADJ for 6 months then crossed over to study drug assayed by CS/EP for 6 months.
    Arm type
    Experimental

    Investigational medicinal product name
    Recombinant factor VIII
    Investigational medicinal product code
    BAY81-8973
    Other name
    rFVIII
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects received low dose prophylaxis treatment at 20, 25 or 30 IU/kg twice per week with rFVIII (BAY81-8973) as an IV injection manually over 1 to 15 minutes, assayed by CS/ADJ for 6 months then crossed over to study drug assayed by CS/EP for 6 months.

    Arm title
    High Dose Prophylaxis, BAY81-8973 Potency First EP Then ADJ
    Arm description
    Subjects received high dose prophylaxis treatment at 30, 35 or 40 IU/kg 3 times per week with rFVIII (BAY81-8973) assayed by CS/EP for 6 months then crossed over to study drug assayed by CS/ADJ for 6 months.
    Arm type
    Experimental

    Investigational medicinal product name
    Recombinant factor VIII
    Investigational medicinal product code
    BAY81-8973
    Other name
    rFVIII
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects received high dose prophylaxis treatment at 30, 35 or 40 IU/kg 3 times per week with rFVIII (BAY81-8973) as an IV injection manually over 1 to 15 minutes, assayed by CS/EP for 6 months then crossed over to study drug assayed by CS/ADJ for 6 months.

    Arm title
    High Dose Prophylaxis, BAY81-8973 Potency First ADJ Then EP
    Arm description
    Subjects received high dose prophylaxis treatment at 30, 35 or 40 IU/kg 3 times per week with rFVIII (BAY81-8973) assayed by CS/ADJ for 6 months then crossed over to study drug assayed by CS/ EP for 6 months.
    Arm type
    Experimental

    Investigational medicinal product name
    Recombinant factor VIII
    Investigational medicinal product code
    BAY81-8973
    Other name
    rFVIII
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects received high dose prophylaxis treatment at 30, 35 or 40 IU/kg 3 times per week with rFVIII (BAY81-8973) as an IV injection manually over 1 to 15 minutes, assayed by CS/ADJ for 6 months then crossed over to study drug assayed by CS/EP for 6 months.

    Number of subjects in period 1
    On Demand, BAY81-8973 Potency First EP Then ADJ On Demand, BAY81-8973 Potency First ADJ Then EP Low Dose Prophylaxis, BAY81-8973 Potency First EP Then ADJ Low Dose Prophylaxis, BAY81-8973 Potency First ADJ Then EP High Dose Prophylaxis, BAY81-8973 Potency First EP Then ADJ High Dose Prophylaxis, BAY81-8973 Potency First ADJ Then EP
    Started
    11
    10
    14
    16
    16
    16
    Treated
    11
    10
    13
    15
    16
    15
    Completed
    10
    10
    13
    15
    16
    15
    Not completed
    1
    0
    1
    1
    0
    1
         Protocol deviation
    -
    -
    1
    -
    -
    -
         Non-compliance with study medication
    1
    -
    -
    -
    -
    -
         Consent withdrawn by subject
    -
    -
    -
    1
    -
    1
    Period 2
    Period 2 title
    Second Intervention (6 months)
    Is this the baseline period?
    No
    Allocation method
    Randomised - controlled
    Blinding used
    Not blinded

    Arms
    Are arms mutually exclusive
    No

    Arm title
    On Demand, BAY81-8973 Potency First EP Then ADJ
    Arm description
    Subjects received on-demand treatment with recombinant factor VIII (rFVIII, BAY81-8973) assayed by CS/EP for 6 months, followed by cross-over to study drug assayed by CS/ADJ for 6 months.
    Arm type
    Experimental

    Investigational medicinal product name
    Recombinant factor VIII
    Investigational medicinal product code
    BAY81-8973
    Other name
    rFVIII
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects received BAY81-8973 as an intravenous (IV) injection manually over 1 to 15 minutes. The dosage was adjusted to bleeding location and severity and to current standard of care.

    Arm title
    On Demand, BAY81-8973 Potency First ADJ Then EP
    Arm description
    Subjects received on-demand treatment with rFVIII (BAY81-8973) assayed by CS/ADJ for 6 months, followed by cross-over to study drug assayed by CS/EP for 6 months.
    Arm type
    Experimental

    Investigational medicinal product name
    Recombinant factor VIII
    Investigational medicinal product code
    BAY81-8973
    Other name
    rFVIII
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects received BAY81-8973 as an IV injection manually over 1 to 15 minutes. The dosage was adjusted to bleeding location and severity and to current standard of care.

    Arm title
    Low Dose Prophylaxis, BAY81-8973 Potency First EP Then ADJ
    Arm description
    Subjects received low dose prophylaxis treatment at 20, 25 or 30 IU/kg twice per week with rFVIII (BAY81-8973) assayed by CS/ EP for 6 months then crossed over to study drug assayed by CS/ADJ for 6 months.
    Arm type
    Experimental

    Investigational medicinal product name
    Recombinant factor VIII
    Investigational medicinal product code
    BAY81-8973
    Other name
    rFVIII
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects received low dose prophylaxis treatment at 20, 25 or 30 IU/kg twice per week with rFVIII (BAY81-8973) as an IV injection manually over 1 to 15 minutes, assayed by CS/EP for 6 months then crossed over to study drug assayed by CS/ADJ for 6 months.

    Arm title
    Low Dose Prophylaxis, BAY81-8973 Potency First ADJ Then EP
    Arm description
    Subjects received low dose prophylaxis treatment at 20, 25 or 30 IU/kg twice per week with rFVIII (BAY81-8973) assayed by CS/ADJ for 6 months then crossed over to study drug assayed by CS/EP for 6 months.
    Arm type
    Experimental

    Investigational medicinal product name
    Recombinant factor VIII
    Investigational medicinal product code
    BAY81-8973
    Other name
    rFVIII
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects received low dose prophylaxis treatment at 20, 25 or 30 IU/kg twice per week with rFVIII (BAY81-8973) as an IV injection manually over 1 to 15 minutes, assayed by CS/ADJ for 6 months then crossed over to study drug assayed by CS/EP for 6 months.

    Arm title
    High Dose Prophylaxis, BAY81-8973 Potency First EP Then ADJ
    Arm description
    Subjects received high dose prophylaxis treatment at 30, 35 or 40 IU/kg 3 times per week with rFVIII (BAY81-8973) assayed by CS/EP for 6 months then crossed over to study drug assayed by CS/ADJ for 6 months.
    Arm type
    Experimental

    Investigational medicinal product name
    Recombinant factor VIII
    Investigational medicinal product code
    BAY81-8973
    Other name
    rFVIII
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects received high dose prophylaxis treatment at 30, 35 or 40 IU/kg 3 times per week with rFVIII (BAY81-8973) as an IV injection manually over 1 to 15 minutes, assayed by CS/EP for 6 months then crossed over to study drug assayed by CS/ADJ for 6 months.

    Arm title
    High Dose Prophylaxis, BAY81-8973 Potency First ADJ Then EP
    Arm description
    Subjects received high dose prophylaxis treatment at 30, 35 or 40 IU/kg 3 times per week with rFVIII (BAY81-8973) assayed by CS/ADJ for 6 months then crossed over to study drug assayed by CS/ EP for 6 months.
    Arm type
    Experimental

    Investigational medicinal product name
    Recombinant factor VIII
    Investigational medicinal product code
    BAY81-8973
    Other name
    rFVIII
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects received high dose prophylaxis treatment at 30, 35 or 40 IU/kg 3 times per week with rFVIII (BAY81-8973) as an IV injection manually over 1 to 15 minutes, assayed by CS/ADJ for 6 months then crossed over to study drug assayed by CS/EP for 6 months.

    Number of subjects in period 2
    On Demand, BAY81-8973 Potency First EP Then ADJ On Demand, BAY81-8973 Potency First ADJ Then EP Low Dose Prophylaxis, BAY81-8973 Potency First EP Then ADJ Low Dose Prophylaxis, BAY81-8973 Potency First ADJ Then EP High Dose Prophylaxis, BAY81-8973 Potency First EP Then ADJ High Dose Prophylaxis, BAY81-8973 Potency First ADJ Then EP
    Started
    10
    10
    13
    15
    16
    15
    Completed
    10
    10
    13
    15
    16
    15
    Period 3
    Period 3 title
    Baseline period
    Is this the baseline period?
    Yes [1]
    Allocation method
    Randomised - controlled
    Blinding used
    Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    rFVIII (BAY81-8973) on Demand
    Arm description
    Subjects received on-demand treatment with rFVIII (BAY81-8973) assayed by CS/EP for 6 months and by CS/ADJ for 6 months, sequence according to randomization. Subjects who received treatment were included in baseline period.
    Arm type
    Experimental

    Investigational medicinal product name
    Recombinant factor VIII
    Investigational medicinal product code
    BAY81-8973
    Other name
    rFVIII
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects received BAY81-8973 as an IV injection manually over 1 to 15 minutes. The dosage was adjusted to bleeding location and severity and to current standard of care.

    Arm title
    rFVIII (BAY81-8973) Prophylaxis Low-dose
    Arm description
    Subjects received low dose prophylaxis treatment at 20, 25 or 30 IU/kg twice per week with rFVIII (BAY81-8973) assayed by CS/EP for 6 months and by CS/ADJ for 6 months, sequence according to randomization. Subjects who received treatment were included in baseline period.
    Arm type
    Experimental

    Investigational medicinal product name
    Recombinant factor VIII
    Investigational medicinal product code
    BAY81-8973
    Other name
    rFVIII
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects received low dose prophylaxis treatment at 20, 25 or 30 IU/kg twice per week with rFVIII (BAY81-8973) as an IV injection manually over 1 to 15 minutes, assayed by CS/EP for 6 months then crossed over to study drug assayed by CS/ADJ for 6 months.

    Arm title
    rFVIII (BAY81-8973) Prophylaxis High-dose
    Arm description
    Subjects received high dose prophylaxis treatment at 30, 35 or 40 IU/kg 3 times per week with rFVIII (BAY81-8973) assayed by CS/EP for 6 months and by CS/ADJ for 6 months, sequence according to randomization. Subjects who received treatment were included in baseline period.
    Arm type
    Experimental

    Investigational medicinal product name
    Recombinant factor VIII
    Investigational medicinal product code
    BAY81-8973
    Other name
    rFVIII
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects received high dose prophylaxis treatment at 30, 35 or 40 IU/kg 3 times per week with rFVIII (BAY81-8973) assayed by CS/EP for 6 months and by CS/ADJ for 6 months, sequence according to randomization.

    Notes
    [1] - Period 1 is not the baseline period. It is expected that period 1 will be the baseline period.
    Justification: All randomized subjects were included in the intervention periods but the baseline characteristics were recorded only for treated subjects as planned. Hence, a baseline period consisting of only treated subjects was created after the intervention periods.
    Number of subjects in period 3 [2]
    rFVIII (BAY81-8973) on Demand rFVIII (BAY81-8973) Prophylaxis Low-dose rFVIII (BAY81-8973) Prophylaxis High-dose
    Started
    21
    28
    31
    Completed
    21
    28
    31
    Notes
    [2] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: Not all enrolled subjects were treated with study drugs. As baseline included only treated subjects, the worldwide number enrolled in the trial differs with the number of subjects reported in the baseline period.

    Baseline characteristics

    Close Top of page
    Baseline characteristics reporting groups
    Reporting group title
    rFVIII (BAY81-8973) on Demand
    Reporting group description
    Subjects received on-demand treatment with rFVIII (BAY81-8973) assayed by CS/EP for 6 months and by CS/ADJ for 6 months, sequence according to randomization. Subjects who received treatment were included in baseline period.

    Reporting group title
    rFVIII (BAY81-8973) Prophylaxis Low-dose
    Reporting group description
    Subjects received low dose prophylaxis treatment at 20, 25 or 30 IU/kg twice per week with rFVIII (BAY81-8973) assayed by CS/EP for 6 months and by CS/ADJ for 6 months, sequence according to randomization. Subjects who received treatment were included in baseline period.

    Reporting group title
    rFVIII (BAY81-8973) Prophylaxis High-dose
    Reporting group description
    Subjects received high dose prophylaxis treatment at 30, 35 or 40 IU/kg 3 times per week with rFVIII (BAY81-8973) assayed by CS/EP for 6 months and by CS/ADJ for 6 months, sequence according to randomization. Subjects who received treatment were included in baseline period.

    Reporting group values
    rFVIII (BAY81-8973) on Demand rFVIII (BAY81-8973) Prophylaxis Low-dose rFVIII (BAY81-8973) Prophylaxis High-dose Total
    Number of subjects
    21 28 31 80
    Age categorical
    Units: Subjects
        Adolescents (12-17 years)
    2 4 4 10
        Adults (18-64 years)
    19 24 27 70
    Total
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    31.4 ± 10.9 28.8 ± 10.9 29.1 ± 11.5 -
    Total
    Gender categorical
    Units: participants
        Male
    21 28 31 80

    End points

    Close Top of page
    End points reporting groups
    Reporting group title
    On Demand, BAY81-8973 Potency First EP Then ADJ
    Reporting group description
    Subjects received on-demand treatment with recombinant factor VIII (rFVIII, BAY81-8973) assayed by Chromogenic Substrate Assay per European Pharmacopoeia (CS/EP) for 6 months, followed by crossover to study drug assayed by Chromogenic Substrate Assay/label adjusted to one-stage assay (CS/ADJ) for 6 months.

    Reporting group title
    On Demand, BAY81-8973 Potency First ADJ Then EP
    Reporting group description
    Subjects received on-demand treatment with rFVIII (BAY81-8973) assayed by CS/ADJ for 6 months, followed by cross-over to study drug assayed by CS/EP for 6 months.

    Reporting group title
    Low Dose Prophylaxis, BAY81-8973 Potency First EP Then ADJ
    Reporting group description
    Subjects received low dose prophylaxis treatment at 20, 25 or 30 international units per kilogram (IU/kg) twice per week with rFVIII (BAY81-8973) assayed by CS/EP for 6 months then crossed over to study drug assayed by CS/ADJ for 6 months.

    Reporting group title
    Low Dose Prophylaxis, BAY81-8973 Potency First ADJ Then EP
    Reporting group description
    Subjects received low dose prophylaxis treatment at 20, 25 or 30 IU/kg twice per week with rFVIII (BAY81-8973) assayed by CS/ADJ for 6 months then crossed over to study drug assayed by CS/EP for 6 months.

    Reporting group title
    High Dose Prophylaxis, BAY81-8973 Potency First EP Then ADJ
    Reporting group description
    Subjects received high dose prophylaxis treatment at 30, 35 or 40 IU/kg 3 times per week with rFVIII (BAY81-8973) assayed by CS/EP for 6 months then crossed over to study drug assayed by CS/ADJ for 6 months.

    Reporting group title
    High Dose Prophylaxis, BAY81-8973 Potency First ADJ Then EP
    Reporting group description
    Subjects received high dose prophylaxis treatment at 30, 35 or 40 IU/kg 3 times per week with rFVIII (BAY81-8973) assayed by CS/ADJ for 6 months then crossed over to study drug assayed by CS/ EP for 6 months.
    Reporting group title
    On Demand, BAY81-8973 Potency First EP Then ADJ
    Reporting group description
    Subjects received on-demand treatment with recombinant factor VIII (rFVIII, BAY81-8973) assayed by CS/EP for 6 months, followed by cross-over to study drug assayed by CS/ADJ for 6 months.

    Reporting group title
    On Demand, BAY81-8973 Potency First ADJ Then EP
    Reporting group description
    Subjects received on-demand treatment with rFVIII (BAY81-8973) assayed by CS/ADJ for 6 months, followed by cross-over to study drug assayed by CS/EP for 6 months.

    Reporting group title
    Low Dose Prophylaxis, BAY81-8973 Potency First EP Then ADJ
    Reporting group description
    Subjects received low dose prophylaxis treatment at 20, 25 or 30 IU/kg twice per week with rFVIII (BAY81-8973) assayed by CS/ EP for 6 months then crossed over to study drug assayed by CS/ADJ for 6 months.

    Reporting group title
    Low Dose Prophylaxis, BAY81-8973 Potency First ADJ Then EP
    Reporting group description
    Subjects received low dose prophylaxis treatment at 20, 25 or 30 IU/kg twice per week with rFVIII (BAY81-8973) assayed by CS/ADJ for 6 months then crossed over to study drug assayed by CS/EP for 6 months.

    Reporting group title
    High Dose Prophylaxis, BAY81-8973 Potency First EP Then ADJ
    Reporting group description
    Subjects received high dose prophylaxis treatment at 30, 35 or 40 IU/kg 3 times per week with rFVIII (BAY81-8973) assayed by CS/EP for 6 months then crossed over to study drug assayed by CS/ADJ for 6 months.

    Reporting group title
    High Dose Prophylaxis, BAY81-8973 Potency First ADJ Then EP
    Reporting group description
    Subjects received high dose prophylaxis treatment at 30, 35 or 40 IU/kg 3 times per week with rFVIII (BAY81-8973) assayed by CS/ADJ for 6 months then crossed over to study drug assayed by CS/ EP for 6 months.
    Reporting group title
    rFVIII (BAY81-8973) on Demand
    Reporting group description
    Subjects received on-demand treatment with rFVIII (BAY81-8973) assayed by CS/EP for 6 months and by CS/ADJ for 6 months, sequence according to randomization. Subjects who received treatment were included in baseline period.

    Reporting group title
    rFVIII (BAY81-8973) Prophylaxis Low-dose
    Reporting group description
    Subjects received low dose prophylaxis treatment at 20, 25 or 30 IU/kg twice per week with rFVIII (BAY81-8973) assayed by CS/EP for 6 months and by CS/ADJ for 6 months, sequence according to randomization. Subjects who received treatment were included in baseline period.

    Reporting group title
    rFVIII (BAY81-8973) Prophylaxis High-dose
    Reporting group description
    Subjects received high dose prophylaxis treatment at 30, 35 or 40 IU/kg 3 times per week with rFVIII (BAY81-8973) assayed by CS/EP for 6 months and by CS/ADJ for 6 months, sequence according to randomization. Subjects who received treatment were included in baseline period.

    Subject analysis set title
    rFVIII (BAY81-8973) Prophylaxis Treatment
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Subjects received prophylaxis treatment with rFVIII (BAY81-8973) at low-dose (20, 25 or 30 IU/kg twice per week ) and high-dose (30, 35 or 40 IU/kg 3 times per week ) assayed by CS/EP for 6 months and by CS/ADJ for 6 months, sequence according to randomization.

    Subject analysis set title
    Safety population
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    All subjects randomized into the study who received at least 1 injection of study medication.

    Subject analysis set title
    rFVIII (BAY81-8973) on Demand Assayed by CS/EP
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Subjects received on-demand treatment with rFVIII (BAY81-8973) assayed by CS/EP for 6 months.

    Subject analysis set title
    rFVIII (BAY81-8973) on Demand Assayed by CS/ADJ
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Subjects received on-demand treatment with rFVIII (BAY81-8973) assayed by CS/ADJ for 6 months.

    Subject analysis set title
    rFVIII (BAY81-8973) Prophylaxis Treatment Assayed by CS/EP
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Subjects received prophylaxis treatment with rFVIII (BAY81-8973) at low-dose (20, 25 or 30 IU/kg twice per week) and high-dose (30, 35 or 40 IU/kg 3 times per week) assayed by CS/EP for 6 months.

    Subject analysis set title
    ITT population
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    All subjects in the safety population who have injection / bleeding data from the electronic patient diary (EPD) and/or case report form (CRF).

    Subject analysis set title
    rFVIII (BAY81-8973) Prophylaxis Treatment Assayed by CS/ADJ
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Subjects received prophylaxis treatment with rFVIII (BAY81-8973) at low-dose (20, 25 or 30 IU/kg twice per week) and high-dose (30, 35 or 40 IU/kg 3 times per week) assayed by CS/ADJ for 6 months.

    Primary: Annualized Number of All Bleeds

    Close Top of page
    End point title
    Annualized Number of All Bleeds [1]
    End point description
    The annualized number of bleeds experienced by subjects.
    End point type
    Primary
    End point timeframe
    Up to 12 months (6 months per mode of potency assignment according to the randomized cross-over design)
    Notes
    [1] - 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: Low and high dose prophylaxis arms of the baseline period and both potencies combined as planned for the statistical analysis to achieve intended sample size. Hence, the end point is reporting statistics for a combined arm (created as a subject analysis set) instead of the individual arms in the baseline period.
    End point values
    rFVIII (BAY81-8973) on Demand rFVIII (BAY81-8973) Prophylaxis Treatment
    Number of subjects analysed
    21 [2]
    59 [3]
    Units: Bleeds per year per subject
        arithmetic mean (standard deviation)
    57.7 ± 24.6
    4.9 ± 6.8
    Notes
    [2] - ITT population
    [3] - ITT population
    Statistical analysis title
    On Demand versus Prophylaxis Treatment
    Statistical analysis description
    Null hypothesis: bleeding rates are equal, alternative hypothesis rates are unequal. Power calculation: Assumption 5 bleeds per year on prophylactic treatment, 15 on on-demand treatment; combined standard deviation of 11; 3:1 randomization; 2-sided alpha 5% and 90% power.
    Comparison groups
    rFVIII (BAY81-8973) on Demand v rFVIII (BAY81-8973) Prophylaxis Treatment
    Number of subjects included in analysis
    80
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0001
    Method
    ANOVA
    Confidence interval

    Secondary: Annualized Number of All Bleeds During CS/EP Period

    Close Top of page
    End point title
    Annualized Number of All Bleeds During CS/EP Period
    End point description
    The annualized number of bleeds experienced by subjects while they were taking rFVIII (BAY81-8973) assayed by CS/EP
    End point type
    Secondary
    End point timeframe
    Up to 6 months (6 months on CS/EP potency assignment)
    End point values
    rFVIII (BAY81-8973) on Demand Assayed by CS/EP rFVIII (BAY81-8973) Prophylaxis Treatment Assayed by CS/EP
    Number of subjects analysed
    21 [4]
    59 [5]
    Units: Bleeds per year per subject
        arithmetic mean (standard deviation)
    57.6 ± 24.3
    5.1 ± 8
    Notes
    [4] - ITT population
    [5] - ITT population
    Statistical analysis title
    On Demand versus Prophylaxis Treatment
    Statistical analysis description
    Null hypothesis: bleeding rates are equal, alternative hypothesis rates are unequal. Power calculation not done for this comparison as not primary comparison.
    Comparison groups
    rFVIII (BAY81-8973) Prophylaxis Treatment Assayed by CS/EP v rFVIII (BAY81-8973) on Demand Assayed by CS/EP
    Number of subjects included in analysis
    80
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0001
    Method
    ANOVA
    Confidence interval

    Secondary: Annualized Number of All Bleeds During CS/ADJ Period

    Close Top of page
    End point title
    Annualized Number of All Bleeds During CS/ADJ Period
    End point description
    The annualized number of bleeds experienced by subjects while they were taking rFVIII (BAY81-8973) assayed by CS/ADJ.
    End point type
    Secondary
    End point timeframe
    Up to 6 months (6 months on CS/ADJ potency assignment)
    End point values
    rFVIII (BAY81-8973) on Demand Assayed by CS/ADJ rFVIII (BAY81-8973) Prophylaxis Treatment Assayed by CS/ADJ
    Number of subjects analysed
    20 [6]
    59 [7]
    Units: Bleeds per year per subject
        arithmetic mean (standard deviation)
    59.7 ± 25.1
    4.8 ± 6.8
    Notes
    [6] - ITT population
    [7] - ITT population
    Statistical analysis title
    On Demand versus Prophylaxis Treatment
    Statistical analysis description
    Null hypothesis: bleeding rates are equal, alternative hypothesis rates are unequal. Power calculation not done for this comparison as not primary comparison.
    Comparison groups
    rFVIII (BAY81-8973) Prophylaxis Treatment Assayed by CS/ADJ v rFVIII (BAY81-8973) on Demand Assayed by CS/ADJ
    Number of subjects included in analysis
    79
    Analysis specification
    Pre-specified
    Analysis type
    superiority [8]
    P-value
    = 0.0001
    Method
    ANOVA
    Confidence interval
    Notes
    [8] - comment

    Secondary: Percentage of Bleeds Per Subject Controlled With ≤ 2 Injections in Subjects Treated on Demand With rFVIII (BAY81-8973)

    Close Top of page
    End point title
    Percentage of Bleeds Per Subject Controlled With ≤ 2 Injections in Subjects Treated on Demand With rFVIII (BAY81-8973)
    End point description
    The percentage of bleeds per subject on on-demand treatment that stopped after two or fewer injections
    End point type
    Secondary
    End point timeframe
    Up to 12 months (6 months per mode of potency assignment according to the randomized cross-over design)
    End point values
    rFVIII (BAY81-8973) on Demand Assayed by CS/EP rFVIII (BAY81-8973) on Demand Assayed by CS/ADJ
    Number of subjects analysed
    21 [9]
    20 [10]
    Units: Percentage of bleeds
        median (full range (min-max))
    96.8 (77.8 to 100)
    100 (65.7 to 100)
    Notes
    [9] - ITT population
    [10] - ITT population
    Statistical analysis title
    CS/EP versus CS/ADJ
    Statistical analysis description
    Null hypothesis: the proportion of bleeds controlled by no more than 2 infusions in the CS/EP group +10% is less than the proportion of bleeds controlled by no more than 2 infusions in the CS/ADJ group. Alternative hypothesis: the proportion of bleeds controlled by no more than 2 infusions in the CS/EP group + 10% is greater than or equal to the proportion of bleeds controlled by no more than 2 infusions in the CS/ADJ group. Confidence interval calculated with exact Hodges-Lehmann estimates.
    Comparison groups
    rFVIII (BAY81-8973) on Demand Assayed by CS/ADJ v rFVIII (BAY81-8973) on Demand Assayed by CS/EP
    Number of subjects included in analysis
    41
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority [11]
    P-value
    = 0.0001 [12]
    Method
    Exact Permutation Test for paired sample
    Parameter type
    Median difference (net)
    Point estimate
    0
    Confidence interval
         level
    95%
         sides
    1-sided
         lower limit
    -0.049
         upper limit
    -
    Notes
    [11] - Non-inferiority margin 10%
    [12] - No multiplicity adjustment as this was not primary endpoint

    Other pre-specified: Number of Bleeds During Treatment

    Close Top of page
    End point title
    Number of Bleeds During Treatment
    End point description
    The number of bleeds experienced by each subject
    End point type
    Other pre-specified
    End point timeframe
    12 months
    End point values
    rFVIII (BAY81-8973) on Demand rFVIII (BAY81-8973) Prophylaxis Low-dose rFVIII (BAY81-8973) Prophylaxis High-dose
    Number of subjects analysed
    21 [13]
    28 [14]
    31 [15]
    Units: Bleeds
        median (inter-quartile range (Q1-Q3))
    60 (42 to 77)
    4 (0 to 8)
    2 (0 to 5)
    Notes
    [13] - ITT population
    [14] - ITT population
    [15] - ITT population
    No statistical analyses for this end point

    Other pre-specified: Number of Subjects With Inhibitory Antibody Formation

    Close Top of page
    End point title
    Number of Subjects With Inhibitory Antibody Formation
    End point description
    A test to ensure that subjects have not developed antibodies that will interfere with the action of rFVIII (BAY81-8973)
    End point type
    Other pre-specified
    End point timeframe
    3, 6, 9 and 12 months after baseline
    End point values
    rFVIII (BAY81-8973) on Demand rFVIII (BAY81-8973) Prophylaxis Low-dose rFVIII (BAY81-8973) Prophylaxis High-dose
    Number of subjects analysed
    21 [16]
    28 [17]
    31 [18]
    Units: subjects
    number (not applicable)
        3 months after baseline
    0
    0
    0
        6 months after baseline
    0
    0
    0
        9 months after baseline
    0
    0
    0
        12 months after baseline
    0
    0
    0
    Notes
    [16] - Safety population.
    [17] - Safety population.
    [18] - Safety population.
    No statistical analyses for this end point

    Adverse events

    Close Top of page
    Adverse events information
    Timeframe for reporting adverse events
    Treatment-emergent adverse event data reported here were collected from start of first treatment up to 12.5 months (end of observation period) but no later than 3 days after last study medication intake
    Assessment type
    Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    15.1
    Reporting groups
    Reporting group title
    rFVIII (BAY81-8973) treatment
    Reporting group description
    Subjects received on-demand or prophylaxis treatment with recombinant factor VIII(rFVIII, BAY81-8973) assayed by CS/EP for 6 months and by CS/ADJ for 6 months, sequence according to Randomization.

    Serious adverse events
    rFVIII (BAY81-8973) treatment
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 80 (2.50%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Injury, poisoning and procedural complications
    Head injury
         subjects affected / exposed
    1 / 80 (1.25%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    1 / 80 (1.25%)
         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
    rFVIII (BAY81-8973) treatment
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    23 / 80 (28.75%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    5 / 80 (6.25%)
         occurrences all number
    18
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    4 / 80 (5.00%)
         occurrences all number
    7
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    13 / 80 (16.25%)
         occurrences all number
    23
    Influenza
         subjects affected / exposed
    4 / 80 (5.00%)
         occurrences all number
    4
    Upper respiratory tract infection
         subjects affected / exposed
    6 / 80 (7.50%)
         occurrences all number
    6

    More information

    Close Top of page

    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    23 Mar 2010
    1. Clarifications regarding the surgery indication, such as definitions of the surgery types, safety data required prior to surgery, and evaluation times of the surgery outcome data during the study, were given as requested by the regulatory agencies 2. The regulatory agencies recommended studying two different dosing regimens to arrive at the optimal dose of BAY81-8973. Consistent with this recommendation, the study design was revised from prophylaxis (20-40 IU/kg BAY81-8973 administered 2-3 times/week) versus on-demand treatment to prophylaxis using 2 different dosing regimens (BAY81-8973 high-dose [30-40 IU 3 times/week] or low-dose [20-30 IU 2 times/week]) versus on-demand treatment 3. Addition of a secondary objective of demonstration of non-inferiority of BAY81-8973 dose determined by CS/EP versus BAY81-8973 dose determined by CS/ADJ as measured by the proportion of bleeds controlled by 1 or 2 infusions (among all bleeds) in subjects treated on-demand
    10 Jun 2010
    1. The definition of severe hemophilia A in the inclusion criteria was clarified and expanded to allow subjects with previous medical history documentation of < 1% FVIII:C, determined by one-stage clotting assay, included in the trial without further testing/confirmation of severe hemophilia A, if the screening result turned out to be equal to or higher than 1%. The rationale for the change was to allow subjects with previously documented severe hemophilia A enrolled into the trial without the delay of having another one-stage clotting assay performed, since severity is not known to change during the course of the disease. The documented historical evidence of severe hemophilia A could be either from a previous Bayer hemophilia clinical trial, or from a previously performed one-stage clotting assay from a certified laboratory 2. The number of surgeries was increased from ≥10 to ≥15, and the classification of surgery types was clarified to enable a more thorough evaluation of the safety and efficacy of BAY 81-8973 in the surgical setting. The amendment further specified that ≥8 surgeries were major surgical procedures 3. To further ensure subject safety, the requirement was added that BAY 81-8973 was not to be supplied for use in the surgical setting until its hemostatic activity had been assessed in at least 20 bleeding events 4. To be consistent with the sister protocol (Study 12954; EudraCT Number: 2009-012149-43), the following exclusion criterion was added: “Any subject who cannot forego at least 3 days without receiving FVIII for washout purposes.” 5. The dosage range for prophylaxis treatment was clarified as occurring in 5 IU/kg increments over the range of 20-40 IU/kg 2-3 times per week (ie, low dose: 20, 25, or 30 IU/kg, administered 2 times per week; high dose 30, 35, or 40 IU/kg administered 3 times per week)
    15 Mar 2011
    1. For safety reasons, subjects with known hypersensitivity to mouse protein were excluded from participation in the study 2. Primary and secondary study objectives were revised and rearranged to include objectives for results of this study alone, and addendum objectives were added for the pooled results of this study and Study 12954

    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
    The status of studies in GB is no longer updated from 1.1.2021
    For the UK, as from 1.1.2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI
    EU Clinical Trials Register Service Desk: https://servicedesk.ema.europa.eu
    European Medicines Agency © 1995-2021 | Domenico Scarlattilaan 6, 1083 HS Amsterdam, The Netherlands
    Legal notice
    EMA HMA