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    Clinical Trial Results:
    A Two-Part, Randomized, Cross-Over, Open-Label Trial to Evaluate the Pharmacokinetics, Efficacy, and Safety Profile of Plasma Protein-Free Recombinant FVIII Formulated With Sucrose (BAY81-8973) in Previously Treated Subjects With Severe Hemophilia A Under Prophylaxis Therapy

    Summary
    EudraCT number
    		 2009-012149-43
    Trial protocol
    		 ES   SE   GB   NO   DE   IT   AT   DK  
    Global end of trial date
    14 Mar 2013

    Results information
    Results version number
    		 v3(current)
    This version publication date
    03 Sep 2016
    First version publication date
    09 Jul 2015
    Other versions
    		 v1 , v2
    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
    BAY81-8973/12954
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01029340
    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
    14 Mar 2013
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    14 Mar 2013
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Part A: To demonstrate the pharmacokinetic (PK) non-inferiority of BAY81-8973 as compared to sucrose formulated successor Kogenate (Kogenate FS) using bioequivalence criteria following single dose administration. Part B: To demonstrate the efficacy and safety of BAY81-8973 for the treatment of bleeds and prophylaxis. Part C: To demonstrate efficacy for hemostasis during major surgery.
    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. Participating subjects signed informed consent form and could withdraw from the study at any time without any disadvantage and without having to provide a reason for this decision. Only investigators qualified by training and experience were selected as appropriate experts to investigate the study drug.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    21 Dec 2009
    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
    Hong Kong: 6
    Country: Number of subjects enrolled
    Israel: 19
    Country: Number of subjects enrolled
    Italy: 4
    Country: Number of subjects enrolled
    Germany: 7
    Country: Number of subjects enrolled
    Spain: 6
    Country: Number of subjects enrolled
    Poland: 9
    Country: Number of subjects enrolled
    South Africa: 7
    Country: Number of subjects enrolled
    Turkey: 3
    Country: Number of subjects enrolled
    Denmark: 4
    Country: Number of subjects enrolled
    United Kingdom: 2
    Country: Number of subjects enrolled
    United States: 7
    Worldwide total number of subjects
    74
    EEA total number of subjects
    32
    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)
    15
    Adults (18-64 years)
    59
    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
    		 Fourteen subjects were enrolled in each of Arms 1 and 2 in Part A. Of these, 11 subjects continued into each of Arms 3 and 4 in Part B. Arm 3 enrolled 20 and Arm 4 enrolled 21 additional subjects who had not participated in Part A. Arm 5 enrolled 5 subjects specifically for surgery in Part C who had not participated in Parts A or B.

    Period 1
    Period 1 title
    Part A Treatment Period
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Arm 1: Recombinant Factor VIII (BAY81-8973) Then Kogenate FS
    Arm description
    		 Part A - Arm 1: Subjects first received one single IV injection of BAY81-8973, 50 international unit per kilogram (IU/kg), then 1 single IV injection of Kogenate FS (BAY14-2222) 50 IU/kg with a wash-out period of at least 2-3 days in between.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Recombinant Factor VIII
    Investigational medicinal product code
    BAY81-8973
    Other name
    octocog-alfa, rFVIII
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Exactly 50 IU/kg (without rounding to full vials), single injection (potency determined by Chromogenic substrate assay per European Pharmacopoeia [CS/EP]), manual IV injection over a 10-minute period.

    Investigational medicinal product name
    Kogenate FS
    Investigational medicinal product code
    BAY14-2222
    Other name
    Kogenate Bayer
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Exactly 50 IU/kg (without rounding to full vials), single injection (potency determined by CS/EP), manual IV injection over a 10-minute period.

    Arm title
    		 Arm 2: Kogenate FS Then Recombinant Factor VIII (BAY81-8973)
    Arm description
    		 Part A - Arm 2: Subjects first received one single IV injection of Kogenate FS (BAY14-2222) 50 IU/kg, then 1 single IV injection of BAY81-8973, 50 IU/kg with a wash-out period of at least 2-3 days in between.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Kogenate FS
    Investigational medicinal product code
    BAY14-2222
    Other name
    Kogenate Bayer
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Exactly 50 IU/kg (without rounding to full vials), single injection (potency determined by CS/EP), manual IV injection over a 10-minute period.

    Investigational medicinal product name
    Recombinant Factor VIII
    Investigational medicinal product code
    BAY81-8973
    Other name
    octocog-alfa, rFVIII
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Exactly 50 IU/kg (without rounding to full vials), single injection (potency determined by CS/EP), manual IV injection over a 10-minute period.

    Number of subjects in period 1
    		Arm 1: Recombinant Factor VIII (BAY81-8973) Then Kogenate FS Arm 2: Kogenate FS Then Recombinant Factor VIII (BAY81-8973)
    Started
    14
    14
    Subjects Received Treatment
    14
    14
    Completed
    14
    14
    Period 2
    Period 2 title
    Part A Follow up Period
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    No

    Arm title
    		 Arm 1: Recombinant Factor VIII (BAY81-8973) Then Kogenate FS
    Arm description
    		 Part A - Arm 1: Subjects first received one single IV injection of BAY81-8973, 50 IU/kg, then 1 single IV injection of Kogenate FS (BAY14-2222) 50 IU/kg with a wash-out period of at least 2-3 days in between.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Kogenate FS
    Investigational medicinal product code
    BAY14-2222
    Other name
    Kogenate Bayer
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Exactly 50 IU/kg (without rounding to full vials), single injection (potency determined by CS/EP), manual IV injection over a 10-minute period.

    Investigational medicinal product name
    Recombinant Factor VIII
    Investigational medicinal product code
    BAY81-8973
    Other name
    octocog-alfa, rFVIII
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Exactly 50 IU/kg (without rounding to full vials), single injection (potency determined by CS/EP), manual IV injection over a 10-minute period.

    Arm title
    		 Arm 2: Kogenate FS Then Recombinant Factor VIII (BAY81-8973)
    Arm description
    		 Part A - Arm 2: Subjects first received one single IV injection of Kogenate FS (BAY14-2222) 50 IU/kg, then 1 single IV injection of BAY81-8973, 50 IU/kg with a wash-out period of at least 2-3 days in between.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Recombinant Factor VIII
    Investigational medicinal product code
    BAY81-8973
    Other name
    octocog-alfa, rFVIII
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Exactly 50 IU/kg (without rounding to full vials), single injection (potency determined by CS/EP), manual IV injection over a 10-minute period.

    Investigational medicinal product name
    Kogenate FS
    Investigational medicinal product code
    BAY14-2222
    Other name
    Kogenate Bayer
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Exactly 50 IU/kg (without rounding to full vials), single injection (potency determined by CS/EP), manual IV injection over a 10-minute period.

    Number of subjects in period 2
    		Arm 1: Recombinant Factor VIII (BAY81-8973) Then Kogenate FS Arm 2: Kogenate FS Then Recombinant Factor VIII (BAY81-8973)
    Started
    14
    14
    Completed
    14
    14
    Period 3
    Period 3 title
    Part B Treatment Period
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Arm 3: Recombinant Factor VIII by CS/EP Then by CS/ADJ
    Arm description
    		 Part B - Arm 3: Subjects received IV injection of BAY81-8973 at 20-50 IU/kg 2-3 times per week with BAY81-8973 potency measured by CS/EP for 6 months and then crossed over to study drug measured by Chromogenic substrate assay/adjusted to one-stage assay (CS/ADJ) to Label Potency for 6 months.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Recombinant Factor VIII
    Investigational medicinal product code
    BAY81-8973
    Other name
    octocog-alfa, rFVIII
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    20-50 IU/kg (20, 25, 30, 35, 40, or 50 IU/kg) rounded to full vials, 2-3 times per week (treatment potency assignments determined by CS/EP and CS/ADJ), manual IV injection over 1 to 15 minutes.

    Arm title
    		 Arm 4: Recombinant Factor VIII by CS/ADJ Then by CS/EP
    Arm description
    		 Part B - Arm 4:. Subjects received IV injection of BAY81-8973 at 20-50 IU/kg 2-3 times per week with BAY81-8973 measured by CS/ADJ to Label Potency for 6 months and then crossed over to study drug measured by CS/EP for 6 months.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Recombinant Factor VIII
    Investigational medicinal product code
    BAY81-8973
    Other name
    octocog-alfa, rFVIII
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Dosage: 20-50 IU/kg (20, 25, 30, 35, 40, or 50 IU/kg) rounded to full vials, 2-3 times per week (treatment potency assignments determined by CS/EP and CS/ADJ), manual IV injection over 1 to 15 minutes.

    Number of subjects in period 3
    		Arm 3: Recombinant Factor VIII by CS/EP Then by CS/ADJ Arm 4: Recombinant Factor VIII by CS/ADJ Then by CS/EP
    Started
    31
    32
    Subjects Received Treatment
    30
    32
    Completed
    29
    32
    Not completed
    2
    0
         Consent withdrawn by subject
    1
    -
         Protocol violation
    1
    -
    Period 4
    Period 4 title
    Part B Follow up Period
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    No

    Arm title
    		 Arm 3: Recombinant Factor VIII by CS/EP Then by CS/ADJ
    Arm description
    		 Part B - Arm 3: Subjects received IV injection of BAY81-8973 at 20-50 IU/kg 2-3 times per week with BAY81-8973 measured by CS/EP for 6 months and then crossed over to study drug measured by CS/ADJ to Label Potency for 6 months. Subjects were followed by a phone call 1-2 weeks after the end of part B treatment period.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Recombinant Factor VIII
    Investigational medicinal product code
    BAY81-8973
    Other name
    octocog-alfa, rFVIII
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    20-50 IU/kg (20, 25, 30, 35, 40, or 50 IU/kg) rounded to full vials, 2-3 times per week (treatment potency assignments determined by CS/EP and CS/ADJ), manual IV injection over 1 to 15 minutes.

    Arm title
    		 Arm 4: Recombinant Factor VIII by CS/ADJ Then by CS/EP
    Arm description
    		 Part B - Arm 4:. Subjects received IV injection of BAY81-8973 at 20-50 IU/kg 2-3 times per week with BAY81-8973 measured by CS/ADJ to Label Potency for 6 months and then crossed over to study drug measured by CS/EP for 6 months. Subjects were followed by a phone call 1-2 weeks after the end of part B treatment period.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Recombinant Factor VIII
    Investigational medicinal product code
    BAY81-8973
    Other name
    octocog-alfa, rFVIII
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Dosage: 20-50 IU/kg (20, 25, 30, 35, 40, or 50 IU/kg) rounded to full vials, 2-3 times per week (treatment potency assignments determined by CS/EP and CS/ADJ), manual IV injection over 1 to 15 minutes.

    Number of subjects in period 4
    		Arm 3: Recombinant Factor VIII by CS/EP Then by CS/ADJ Arm 4: Recombinant Factor VIII by CS/ADJ Then by CS/EP
    Started
    29
    32
    Completed
    29
    32
    Period 5
    Period 5 title
    Extension period
    Is this the baseline period?
    		 No
    Allocation method
    Non-randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 Arm 6: Recombinant Factor VIII (BAY81-8973) Part B + extension
    Arm description
    		 Subjects received IV injections of BAY81-8973 at 20-50 IU/kg 2-3 times per week with BAY81-8973 potency measured by CS/EP for 6 months and CS/ADJ for 6 months sequence according to randomization and up to 12 months (CS/EP) during extension.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Recombinant Factor VIII
    Investigational medicinal product code
    BAY81-8973
    Other name
    octocog-alfa, rFVIII
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects received IV injections of BAY81-8973 at 20-50 IU/kg 2-3 times per week with BAY81-8973 potency measured by Chromogenic Substrate Assay Per European Pharmacopeia (CS/EP) for 6 months and CS/ADJ for 6 months sequence according to randomization and up to 12 months (CS/EP) during extension.

    Number of subjects in period 5
    		Arm 6: Recombinant Factor VIII (BAY81-8973) Part B + extension
    Started
    55
    Completed
    43
    Not completed
    12
         Consent withdrawn by subject
    1
         Physician decision
    1
         Adverse event
    1
         Non-compliance
    1
         Starting another study
    8
    Period 6
    Period 6 title
    Part C Treatment Period
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 Arm 5: Recombinant Factor VIII by CS/EP
    Arm description
    		 Part C - Arm 5: Subjects received a loading dose of approximately 50 IU/kg of BAY81-8973 before the first surgical incision followed by further treatment with BAY81-8973 according to surgical requirements for up to 3 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Recombinant Factor VIII
    Investigational medicinal product code
    BAY81-8973
    Other name
    octocog-alfa, rFVIII
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    All subjects were to receive a pre-op dose of BAY81-8973 at 50 IU/kg for in vivo recovery assessment.

    Number of subjects in period 6
    		Arm 5: Recombinant Factor VIII by CS/EP
    Started
    5
    Subjects Received Treatment
    5
    Completed
    5
    Period 7
    Period 7 title
    Part C Follow up Period
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 Arm 5: Recombinant Factor VIII by CS/EP
    Arm description
    		 Part C - Arm 5: Subjects received a loading dose of approximately 50 IU/kg of BAY81-8973 before the first surgical incision followed by further treatment with BAY81-8973 according to surgical requirements and for up to 3 weeks. Subjects were followed up by telephone after 1 week.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Recombinant Factor VIII
    Investigational medicinal product code
    BAY81-8973
    Other name
    octocog-alfa, rFVIII
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    All subjects were to receive a pre-op dose of BAY81-8973 at 50 IU/kg for in vivo recovery assessment.

    Number of subjects in period 7
    		Arm 5: Recombinant Factor VIII by CS/EP
    Started
    5
    Completed
    5
    Period 8
    Period 8 title
    Baseline period
    Is this the baseline period?
    		 Yes [1]
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    No

    Arm title
    		 Arm 1: Recombinant Factor VIII (BAY81-8973) Then Kogenate FS
    Arm description
    		 Part A - Arm 1: Subjects first received one single IV injection of BAY81-8973, 50 IU/kg, then 1 single IV injection of Kogenate FS (BAY14-2222) 50 IU/kg with a wash-out period of at least 2-3 days in between.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Recombinant Factor VIII
    Investigational medicinal product code
    BAY81-8973
    Other name
    octocog-alfa, rFVIII
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Exactly 50 IU/kg (without rounding to full vials), single injection (potency determined by CS/EP), manual IV injection over a 10-minute period.

    Investigational medicinal product name
    Kogenate FS
    Investigational medicinal product code
    BAY14-2222
    Other name
    Kogenate Bayer
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Exactly 50 IU/kg (without rounding to full vials), single injection (potency determined by CS/EP), manual IV injection over a 10-minute period.

    Arm title
    		 Arm 2: Kogenate FS Then Recombinant Factor VIII (BAY81-8973)
    Arm description
    		 Part A - Arm 2: Subjects first received one single IV injection of Kogenate FS (BAY14-2222) 50 IU/kg, then 1 single IV injection of BAY81-8973, 50 IU/kg with a wash-out period of at least 2-3 days in between.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Recombinant Factor VIII
    Investigational medicinal product code
    BAY81-8973
    Other name
    octocog-alfa, rFVIII
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Exactly 50 IU/kg (without rounding to full vials), single injection (potency determined by CS/EP), manual IV injection over a 10-minute period.

    Investigational medicinal product name
    Kogenate FS
    Investigational medicinal product code
    BAY14-2222
    Other name
    Kogenate Bayer
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Exactly 50 IU/kg (without rounding to full vials), single injection (potency determined by CS/EP), manual IV injection over a 10-minute period.

    Arm title
    		 Arm 3: Recombinant Factor VIII by CS/EP Then by CS/ADJ
    Arm description
    		 Part B - Arm 3: Subjects received IV injection of BAY81-8973 at 20-50 IU/kg 2-3 times per week with BAY81-8973 potency measured by CS/EP for 6 months and then crossed over to study drug measured by CS/ADJ to Label Potency for 6 months.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Recombinant Factor VIII
    Investigational medicinal product code
    BAY81-8973
    Other name
    octocog-alfa, rFVIII
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    20-50 IU/kg (20, 25, 30, 35, 40, or 50 IU/kg) rounded to full vials, 2-3 times per week (treatment potency assignments determined by CS/EP and CS/ADJ), manual IV injection over 1 to 15 minutes.

    Arm title
    		 Arm 4: Recombinant Factor VIII by CS/ADJ Then by CS/EP
    Arm description
    		 Part B - Arm 4:. Subjects received IV injection of BAY81-8973 at 20-50 IU/kg 2-3 times per week with BAY81-8973 measured by CS/ADJ to Label Potency for 6 months and then crossed over to study drug measured by CS/EP for 6 months.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Recombinant Factor VIII
    Investigational medicinal product code
    BAY81-8973
    Other name
    octocog-alfa, rFVIII
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Dosage: 20-50 IU/kg (20, 25, 30, 35, 40, or 50 IU/kg) rounded to full vials, 2-3 times per week (treatment potency assignments determined by CS/EP and CS/ADJ), manual IV injection over 1 to 15 minutes.

    Arm title
    		 Arm 5: Recombinant Factor VIII by CS/EP
    Arm description
    		 Part C - Arm 5: Subjects received a loading dose of approximately 50 IU/kg of BAY81-8973 before the first surgical incision followed by further treatment with BAY81-8973 according to surgical requirements and for up to 3 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Recombinant Factor VIII
    Investigational medicinal product code
    BAY81-8973
    Other name
    octocog-alfa, rFVIII
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    All subjects were to receive a pre-op dose of BAY81-8973 at 50 IU/kg for in vivo recovery assessment.

    Notes
    [1] - Period 1 is not the baseline period. It is expected that period 1 will be the baseline period.
    Justification: The study was conducted in three different parts, as Part A, Part B and Part C. Hence, the baseline period of all enrolled subjects in a study was created to publish the baseline characteristics data.
    Number of subjects in period 8
    		Arm 1: Recombinant Factor VIII (BAY81-8973) Then Kogenate FS Arm 2: Kogenate FS Then Recombinant Factor VIII (BAY81-8973) Arm 3: Recombinant Factor VIII by CS/EP Then by CS/ADJ Arm 4: Recombinant Factor VIII by CS/ADJ Then by CS/EP Arm 5: Recombinant Factor VIII by CS/EP
    Started
    14
    14
    30
    32
    5
    Completed
    14
    14
    30
    32
    5

    Baseline characteristics

    		 Close Top of page
    Baseline characteristics reporting groups
    Reporting group title
    Arm 1: Recombinant Factor VIII (BAY81-8973) Then Kogenate FS
    Reporting group description
    		 Part A - Arm 1: Subjects first received one single IV injection of BAY81-8973, 50 IU/kg, then 1 single IV injection of Kogenate FS (BAY14-2222) 50 IU/kg with a wash-out period of at least 2-3 days in between.

    Reporting group title
    Arm 2: Kogenate FS Then Recombinant Factor VIII (BAY81-8973)
    Reporting group description
    		 Part A - Arm 2: Subjects first received one single IV injection of Kogenate FS (BAY14-2222) 50 IU/kg, then 1 single IV injection of BAY81-8973, 50 IU/kg with a wash-out period of at least 2-3 days in between.

    Reporting group title
    Arm 3: Recombinant Factor VIII by CS/EP Then by CS/ADJ
    Reporting group description
    		 Part B - Arm 3: Subjects received IV injection of BAY81-8973 at 20-50 IU/kg 2-3 times per week with BAY81-8973 potency measured by CS/EP for 6 months and then crossed over to study drug measured by CS/ADJ to Label Potency for 6 months.

    Reporting group title
    Arm 4: Recombinant Factor VIII by CS/ADJ Then by CS/EP
    Reporting group description
    		 Part B - Arm 4:. Subjects received IV injection of BAY81-8973 at 20-50 IU/kg 2-3 times per week with BAY81-8973 measured by CS/ADJ to Label Potency for 6 months and then crossed over to study drug measured by CS/EP for 6 months.

    Reporting group title
    Arm 5: Recombinant Factor VIII by CS/EP
    Reporting group description
    		 Part C - Arm 5: Subjects received a loading dose of approximately 50 IU/kg of BAY81-8973 before the first surgical incision followed by further treatment with BAY81-8973 according to surgical requirements and for up to 3 weeks.

    Reporting group values
    		 Arm 1: Recombinant Factor VIII (BAY81-8973) Then Kogenate FS Arm 2: Kogenate FS Then Recombinant Factor VIII (BAY81-8973) Arm 3: Recombinant Factor VIII by CS/EP Then by CS/ADJ Arm 4: Recombinant Factor VIII by CS/ADJ Then by CS/EP Arm 5: Recombinant Factor VIII by CS/EP Total
    Number of subjects
    		 14 14 30 32 5 95
    Age categorical
    Part A based on pharmacokinetic (PK) analysis set; Parts B and C based on safety analysis set. Two subjects in Part A were excluded, as they were not valid for PK analysis set. The data was not available for one subject who was excluded since receiving Kogenate FS twice.
    Units: subjects
        < 18 years
    		 1 4 5 5 0 15
        =/> 18 years
    		 13 10 25 27 5 80
    Gender categorical
    Part A based on PK analysis set; Parts B and C based on safety analysis set.
    Units: subjects
        Male
    		 14 14 30 32 5 95

    End points

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    End points reporting groups
    Reporting group title
    Arm 1: Recombinant Factor VIII (BAY81-8973) Then Kogenate FS
    Reporting group description
    		 Part A - Arm 1: Subjects first received one single IV injection of BAY81-8973, 50 international unit per kilogram (IU/kg), then 1 single IV injection of Kogenate FS (BAY14-2222) 50 IU/kg with a wash-out period of at least 2-3 days in between.

    Reporting group title
    Arm 2: Kogenate FS Then Recombinant Factor VIII (BAY81-8973)
    Reporting group description
    		 Part A - Arm 2: Subjects first received one single IV injection of Kogenate FS (BAY14-2222) 50 IU/kg, then 1 single IV injection of BAY81-8973, 50 IU/kg with a wash-out period of at least 2-3 days in between.
    Reporting group title
    Arm 1: Recombinant Factor VIII (BAY81-8973) Then Kogenate FS
    Reporting group description
    		 Part A - Arm 1: Subjects first received one single IV injection of BAY81-8973, 50 IU/kg, then 1 single IV injection of Kogenate FS (BAY14-2222) 50 IU/kg with a wash-out period of at least 2-3 days in between.

    Reporting group title
    Arm 2: Kogenate FS Then Recombinant Factor VIII (BAY81-8973)
    Reporting group description
    		 Part A - Arm 2: Subjects first received one single IV injection of Kogenate FS (BAY14-2222) 50 IU/kg, then 1 single IV injection of BAY81-8973, 50 IU/kg with a wash-out period of at least 2-3 days in between.
    Reporting group title
    Arm 3: Recombinant Factor VIII by CS/EP Then by CS/ADJ
    Reporting group description
    		 Part B - Arm 3: Subjects received IV injection of BAY81-8973 at 20-50 IU/kg 2-3 times per week with BAY81-8973 potency measured by CS/EP for 6 months and then crossed over to study drug measured by Chromogenic substrate assay/adjusted to one-stage assay (CS/ADJ) to Label Potency for 6 months.

    Reporting group title
    Arm 4: Recombinant Factor VIII by CS/ADJ Then by CS/EP
    Reporting group description
    		 Part B - Arm 4:. Subjects received IV injection of BAY81-8973 at 20-50 IU/kg 2-3 times per week with BAY81-8973 measured by CS/ADJ to Label Potency for 6 months and then crossed over to study drug measured by CS/EP for 6 months.
    Reporting group title
    Arm 3: Recombinant Factor VIII by CS/EP Then by CS/ADJ
    Reporting group description
    		 Part B - Arm 3: Subjects received IV injection of BAY81-8973 at 20-50 IU/kg 2-3 times per week with BAY81-8973 measured by CS/EP for 6 months and then crossed over to study drug measured by CS/ADJ to Label Potency for 6 months. Subjects were followed by a phone call 1-2 weeks after the end of part B treatment period.

    Reporting group title
    Arm 4: Recombinant Factor VIII by CS/ADJ Then by CS/EP
    Reporting group description
    		 Part B - Arm 4:. Subjects received IV injection of BAY81-8973 at 20-50 IU/kg 2-3 times per week with BAY81-8973 measured by CS/ADJ to Label Potency for 6 months and then crossed over to study drug measured by CS/EP for 6 months. Subjects were followed by a phone call 1-2 weeks after the end of part B treatment period.
    Reporting group title
    Arm 6: Recombinant Factor VIII (BAY81-8973) Part B + extension
    Reporting group description
    		 Subjects received IV injections of BAY81-8973 at 20-50 IU/kg 2-3 times per week with BAY81-8973 potency measured by CS/EP for 6 months and CS/ADJ for 6 months sequence according to randomization and up to 12 months (CS/EP) during extension.
    Reporting group title
    Arm 5: Recombinant Factor VIII by CS/EP
    Reporting group description
    		 Part C - Arm 5: Subjects received a loading dose of approximately 50 IU/kg of BAY81-8973 before the first surgical incision followed by further treatment with BAY81-8973 according to surgical requirements for up to 3 weeks.
    Reporting group title
    Arm 5: Recombinant Factor VIII by CS/EP
    Reporting group description
    		 Part C - Arm 5: Subjects received a loading dose of approximately 50 IU/kg of BAY81-8973 before the first surgical incision followed by further treatment with BAY81-8973 according to surgical requirements and for up to 3 weeks. Subjects were followed up by telephone after 1 week.
    Reporting group title
    Arm 1: Recombinant Factor VIII (BAY81-8973) Then Kogenate FS
    Reporting group description
    		 Part A - Arm 1: Subjects first received one single IV injection of BAY81-8973, 50 IU/kg, then 1 single IV injection of Kogenate FS (BAY14-2222) 50 IU/kg with a wash-out period of at least 2-3 days in between.

    Reporting group title
    Arm 2: Kogenate FS Then Recombinant Factor VIII (BAY81-8973)
    Reporting group description
    		 Part A - Arm 2: Subjects first received one single IV injection of Kogenate FS (BAY14-2222) 50 IU/kg, then 1 single IV injection of BAY81-8973, 50 IU/kg with a wash-out period of at least 2-3 days in between.

    Reporting group title
    Arm 3: Recombinant Factor VIII by CS/EP Then by CS/ADJ
    Reporting group description
    		 Part B - Arm 3: Subjects received IV injection of BAY81-8973 at 20-50 IU/kg 2-3 times per week with BAY81-8973 potency measured by CS/EP for 6 months and then crossed over to study drug measured by CS/ADJ to Label Potency for 6 months.

    Reporting group title
    Arm 4: Recombinant Factor VIII by CS/ADJ Then by CS/EP
    Reporting group description
    		 Part B - Arm 4:. Subjects received IV injection of BAY81-8973 at 20-50 IU/kg 2-3 times per week with BAY81-8973 measured by CS/ADJ to Label Potency for 6 months and then crossed over to study drug measured by CS/EP for 6 months.

    Reporting group title
    Arm 5: Recombinant Factor VIII by CS/EP
    Reporting group description
    		 Part C - Arm 5: Subjects received a loading dose of approximately 50 IU/kg of BAY81-8973 before the first surgical incision followed by further treatment with BAY81-8973 according to surgical requirements and for up to 3 weeks.

    Subject analysis set title
    ITT population: Recombinant Factor VIII (BAY81-8973) - Part B
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Subjects received IV injections of BAY81-8973 at 20-50 IU/kg 2-3 times per week with BAY81-8973 measured by CS/EP for 6 months and by CS/ADJ for 6 months, sequence according to randomization. All subjects in the safety population who have injection / bleeding data from the EPD and/or CRF were included in the ITT population in Part B.

    Subject analysis set title
    PK population: Part A-Recombinant Factor VIII (BAY81-8973)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    All subjects who received one single IV injection of recombinant factor VIII (BAY81-8973) 50 IU/kg and with a valid PK profile in part A were included in PK population.

    Subject analysis set title
    PK population: Part A-Kogenate-FS (BAY14-2222)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subjects received one single IV injection of Kogenate FS (BAY14-2222) 50 IU/kg and with a valid PK profile in part A were included in the PK population.

    Subject analysis set title
    Recombinant Factor VIII (BAY81-8973) and Kogenate FS - Part A
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Subjects received one single IV injection of BAY81-8973 50 IU/kg and one single IV injection of Kogenate FS (BAY14-2222) 50 IU/kg were included in the safety population in Part A.

    Subject analysis set title
    Safety population: Recombinant Factor VIII (BAY81-8973)-Part B
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Subjects received IV injections of BAY81-8973 at 20-50 IU/kg 2-3 times per week with BAY81-8973 measured by CS/EP for 6 months and by CS/ADJ for 6 months, sequence according to randomization. All subjects randomized into the study who received study drug or who were surgery-only subjects were included in safety population in Part B.

    Subject analysis set title
    Recombinant Factor VIII (BAY81-8973) by CS/EP - Part B
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Subjects received IV injections of recombinant factor VIII (BAY81-8973) at 20-50 IU/kg 2-3 times per week with BAY81-8973 measured by CS/EP for 6 months and have injection / bleeding data from the electronic patient diary (EPD) and/or case report form (CRF) were included in the intent-to-treat (ITT) population in Part B.

    Subject analysis set title
    Recombinant Factor VIII (BAY81-8973) by CS/ADJ - Part B
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Subjects received IV injection of BAY81-8973 at 20-50 IU/kg 2-3 times per week with BAY81-8973 measured by CS/ADJ to Label Potency for 6 months and have injection / bleeding data from the EPD and/or CRF were included in the ITT population in Part B. One subject in Part B did not receive any Recombinant Factor VIII measured by the CS/ADJ method, leading to 61 subjects (not 62) in that group.

    Subject analysis set title
    Recombinant Factor VIII (BAY81-8973) by CS/EP - Part C
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Subjects received a loading dose of approximately 50 IU/kg of BAY81-8973 before the first surgical incision, followed by further treatment with BAY81-8973 according to surgical requirements for upto 3 weeks. All subjects in the safety population who have injection / bleeding data from the EPD and/or CRF were included in ITT population in Part C.

    Primary: Part A - Area Under the Drug Concentration-time Curve (AUC)

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    End point title
    		 Part A - Area Under the Drug Concentration-time Curve (AUC) [1]
    End point description
    To examine the Pharmacokinetic (PK) characteristics of BAY 81-8973 and ensure that the new drug was similar to Kogenate FS. All results were based on the chromogenic assay and expressed in international units*hours/deciliter (IU*h/dL). Geometric mean and percentage geometric coefficient of variation (%CV) were reported.
    End point type
    Primary
    End point timeframe
    Samples taken at pre-injection, and at 0.25, 0.5, 1, 3, 6, 8, 24, 30 and 48 hours post injection. AUC calculated from time of injection to infinity.
    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: Descriptive statistics were done, no inferential statistical analyses were performed.
    End point values
    		 PK population: Part A-Recombinant Factor VIII (BAY81-8973) PK population: Part A-Kogenate-FS (BAY14-2222)
    Number of subjects analysed
    26 [2]
    26 [3]
    Units: IU*h/dL
        geometric mean (geometric coefficient of variation)
    1889.23 ± 36.11
    1583.91 ± 39.89
    Notes
    [2] - PK Analysis Population
    [3] - PK Analysis Population
    No statistical analyses for this end point

    Primary: Part A - Half-life (t 1/2)

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    End point title
    		 Part A - Half-life (t 1/2) [4]
    End point description
    To examine the PK characteristics of BAY81-8973 and ensure that the new drug is similar to Kogenate FS. All results are based on the chromogenic assay. Geometric mean and percentage geometric coefficient of variation (%CV) were reported.
    End point type
    Primary
    End point timeframe
    Samples taken at pre-injection, and at 0.25, 0.5, 1, 3, 6, 8, 24, 30 and 48 hours post injection.
    Notes
    [4] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Descriptive statistics were done, no inferential statistical analyses were performed.
    End point values
    		 PK population: Part A-Recombinant Factor VIII (BAY81-8973) PK population: Part A-Kogenate-FS (BAY14-2222)
    Number of subjects analysed
    26 [5]
    26 [6]
    Units: Hours
        geometric mean (geometric coefficient of variation)
    13.77 ± 28
    12 ± 28.2
    Notes
    [5] - PK Analysis Population
    [6] - PK Analysis Population
    No statistical analyses for this end point

    Primary: Part B - Annualized Number of Total Bleeds

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    End point title
    		 Part B - Annualized Number of Total Bleeds [7]
    End point description
    The annualized number of bleeds experienced by subjects.
    End point type
    Primary
    End point timeframe
    12 months after randomization
    Notes
    [7] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Descriptive statistics were done, no inferential statistical analyses were performed.
    End point values
    		 ITT population: Recombinant Factor VIII (BAY81-8973) - Part B
    Number of subjects analysed
    62 [8]
    Units: bleeds
        median (inter-quartile range (Q1-Q3))
    1.03 (0 to 5.09)
    Notes
    [8] - ITT Population
    No statistical analyses for this end point

    Secondary: Part B - The in Vivo Recovery Values of Human Factor VIII (FVIII)

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    End point title
    		 Part B - The in Vivo Recovery Values of Human Factor VIII (FVIII)
    End point description
    The amount of Factor VIII found in blood samples taken after the injection of the study drug at the beginning of the CS/EP treatment period. One measurement was taken in all subjects at the start of the CS/EP labelled treatment period (CS/ADJ labelled treatment was experimental and will not be used for the future commercial drug, measurements were taken but are artificial because of the adjusted label).
    End point type
    Secondary
    End point timeframe
    15-30 minutes after the injection
    End point values
    		 ITT population: Recombinant Factor VIII (BAY81-8973) - Part B
    Number of subjects analysed
    59 [9]
    Units: kilogram per deciliter (kg/dL)
        median (inter-quartile range (Q1-Q3))
    2.5 (2.09 to 2.77)
    Notes
    [9] - ITT population, only 59 of the 62 subjects had valid recovery data.
    No statistical analyses for this end point

    Secondary: Part B - Annualized Number of Bleeds in Each 6-month Potency Assignment Period

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    End point title
    		 Part B - Annualized Number of Bleeds in Each 6-month Potency Assignment Period
    End point description
    The annualized number of bleeds experienced by subjects in each of the two treatment periods. Note: One subject in Part B did not receive any Recombinant Factor VIII measured by the CS/ADJ method, leading to 61 subjects (not 62) in that group.
    End point type
    Secondary
    End point timeframe
    6 months on each potency
    End point values
    		 Recombinant Factor VIII (BAY81-8973) by CS/EP - Part B Recombinant Factor VIII (BAY81-8973) by CS/ADJ - Part B
    Number of subjects analysed
    62 [10]
    61 [11]
    Units: bleeds
    median (inter-quartile range (Q1-Q3))
        all subjects
    1.9 (0 to 4.4)
    1.9 (0 to 7.3)
    Notes
    [10] - ITT.
    [11] - ITT.
    No statistical analyses for this end point

    Secondary: Part B - Control of Bleeding as Measured by the Number of Injections Required to Treat a Bleed

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    End point title
    		 Part B - Control of Bleeding as Measured by the Number of Injections Required to Treat a Bleed
    End point description
    The number of injections needed by subject to stop a bleed. Note: One subject in Part B did not receive any Recombinant Factor VIII measured by the CS/ADJ method, leading to 61 subjects (not 62) in that group.
    End point type
    Secondary
    End point timeframe
    6 months on each potency
    End point values
    		 Recombinant Factor VIII (BAY81-8973) by CS/EP - Part B Recombinant Factor VIII (BAY81-8973) by CS/ADJ - Part B
    Number of subjects analysed
    62 [12]
    61 [13]
    Units: injections
    median (full range (min-max))
        Number of Bleeds Analyzed (N = 108, 128)
    1 (0 to 11)
    1 (1 to 48)
    Notes
    [12] - ITT.
    [13] - ITT.
    No statistical analyses for this end point

    Secondary: Part B - Changes From Baseline at 12 Months in Quality of Life (QoL) as Measured by Transformed Total Score of Haemo-QoL Questionnaire

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    End point title
    		 Part B - Changes From Baseline at 12 Months in Quality of Life (QoL) as Measured by Transformed Total Score of Haemo-QoL Questionnaire
    End point description
    A measure of how treatment with BAY81-8973 affected the daily life of subjects. the scoring system has 100 points. 0 is the worst possible score. 100 is the best possible score. Positive changes from baseline indicate an improvement in quality of life and negative changes indicate a deterioration.
    End point type
    Secondary
    End point timeframe
    Baseline and 12 months
    End point values
    		 ITT population: Recombinant Factor VIII (BAY81-8973) - Part B
    Number of subjects analysed
    51 [14]
    Units: scores on a scale
        median (full range (min-max))
    2.02 (-22.9 to 26.5)
    Notes
    [14] - ITT population, only 51 of the 62 subjects had data available for the 12-month QoL analysis.
    No statistical analyses for this end point

    Secondary: Part B - Changes From Baseline at 12 Months in Utility Index as Measured by EQ–5D Questionaire

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    End point title
    		 Part B - Changes From Baseline at 12 Months in Utility Index as Measured by EQ–5D Questionaire
    End point description
    A measure of how treatment with BAY81-8973 affected the daily life of subjects. 1.0 = Best possible score, -0.594 = Worst possible score. Positive changes from baseline indicate an improvement and negative changes indicate a deterioration. Only 61 of the 62 subjects had data available for the Utility Index of the EQ-5D questionnaire at Month 12.
    End point type
    Secondary
    End point timeframe
    Baseline and 12 months
    End point values
    		 ITT population: Recombinant Factor VIII (BAY81-8973) - Part B
    Number of subjects analysed
    61 [15]
    Units: Scores on a scale
        median (full range (min-max))
    0 (-0.6 to 0.5)
    Notes
    [15] - ITT population.
    No statistical analyses for this end point

    Secondary: Part A - Number of Subjects With Inhibitory Antibody Formation

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    End point title
    		 Part A - 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 BAY81-8973.
    End point type
    Secondary
    End point timeframe
    Up to 6 weeks after drug administration
    End point values
    		 Recombinant Factor VIII (BAY81-8973) and Kogenate FS - Part A
    Number of subjects analysed
    28 [16]
    Units: subjects
    0
    Notes
    [16] - Safety population.
    No statistical analyses for this end point

    Secondary: Part A - Number of Subjects With Incidence of Antibody Formation to Heat-shock Protein (HSP-70)

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    End point title
    		 Part A - Number of Subjects With Incidence of Antibody Formation to Heat-shock Protein (HSP-70)
    End point description
    A test to analyze the formation of antibodies to HSP-70.
    End point type
    Secondary
    End point timeframe
    Up to 6 weeks after drug administration
    End point values
    		 Recombinant Factor VIII (BAY81-8973) and Kogenate FS - Part A
    Number of subjects analysed
    28 [17]
    Units: subjects
    0
    Notes
    [17] - Safety population.
    No statistical analyses for this end point

    Secondary: Part C - Number of Subjects With Incidence of Inhibitory Antibody Formation

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    End point title
    		 Part C - Number of Subjects With Incidence of Inhibitory Antibody Formation
    End point description
    A test to ensure that subjects have not developed antibodies that will interfere with the action of BAY81-8973.
    End point type
    Secondary
    End point timeframe
    before and 3 weeks after surgery
    End point values
    		 Recombinant Factor VIII (BAY81-8973) by CS/EP - Part C
    Number of subjects analysed
    5 [18]
    Units: subjects
    0
    Notes
    [18] - ITT.
    No statistical analyses for this end point

    Secondary: Part B - Number of Subjects With Incidence of Inhibitory Antibody Formation

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    End point title
    		 Part B - Number of Subjects With Incidence of Inhibitory Antibody Formation
    End point description
    A test to ensure that subjects have not developed antibodies that will interfere with the action of BAY81-8973.
    End point type
    Secondary
    End point timeframe
    Up to 12 months after drug administration
    End point values
    		 Safety population: Recombinant Factor VIII (BAY81-8973)-Part B
    Number of subjects analysed
    62 [19]
    Units: subjects
    0
    Notes
    [19] - Safety population.
    No statistical analyses for this end point

    Secondary: Part B - Number of Subjects With Incidence of Antibody Formation to Heat-shock Protein (HSP-70)

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    End point title
    		 Part B - Number of Subjects With Incidence of Antibody Formation to Heat-shock Protein (HSP-70)
    End point description
    A test to analyze the formation of antibodies to HSP-70.
    End point type
    Secondary
    End point timeframe
    Up to 12 months after drug administration
    End point values
    		 ITT population: Recombinant Factor VIII (BAY81-8973) - Part B
    Number of subjects analysed
    62 [20]
    Units: subjects
    1
    Notes
    [20] - ITT population
    No statistical analyses for this end point

    Secondary: Part C - Number of Subjects With Incidence of Antibody Formation to Heat-shock Protein (HSP-70)

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    End point title
    		 Part C - Number of Subjects With Incidence of Antibody Formation to Heat-shock Protein (HSP-70)
    End point description
    A test to analyze the formation of antibodies to HSP-70.
    End point type
    Secondary
    End point timeframe
    before and 3 weeks after surgery
    End point values
    		 Recombinant Factor VIII (BAY81-8973) by CS/ADJ - Part B
    Number of subjects analysed
    5 [21]
    Units: subjects
    0
    Notes
    [21] - ITT.
    No statistical analyses for this end point

    Secondary: Part A - Number of Subjects With Incidence of Antibody Formation to Host Cell Proteins (HCP)

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    End point title
    		 Part A - Number of Subjects With Incidence of Antibody Formation to Host Cell Proteins (HCP)
    End point description
    A test to ensure that subjects have not developed antibodies to HCP during the study.
    End point type
    Secondary
    End point timeframe
    Up to 4 weeks after drug administration
    End point values
    		 Recombinant Factor VIII (BAY81-8973) and Kogenate FS - Part A
    Number of subjects analysed
    26 [22]
    Units: subjects
    0
    Notes
    [22] - ITT.
    No statistical analyses for this end point

    Secondary: Part B - Number of Subjects With Incidence of Antibody Formation to Host Cell Proteins (HCP)

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    End point title
    		 Part B - Number of Subjects With Incidence of Antibody Formation to Host Cell Proteins (HCP)
    End point description
    A test to ensure that subjects have not developed antibodies to HCP during the study.
    End point type
    Secondary
    End point timeframe
    Up to 12 months after drug administration
    End point values
    		 ITT population: Recombinant Factor VIII (BAY81-8973) - Part B
    Number of subjects analysed
    62 [23]
    Units: subjects
    0
    Notes
    [23] - ITT population
    No statistical analyses for this end point

    Secondary: Part B - Number of Subjects With Assessment of the Hemostasis During Major Surgery

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    End point title
    		 Part B - Number of Subjects With Assessment of the Hemostasis During Major Surgery
    End point description
    An assessment made by surgeons of how effective BAY81-8973 was in stopping bleeding during major operations.
    End point type
    Secondary
    End point timeframe
    An average of 1 month after start of treatment
    End point values
    		 ITT population: Recombinant Factor VIII (BAY81-8973) - Part B
    Number of subjects analysed
    5 [24]
    Units: subjects
        Excellent
    1
        Good
    4
        Moderate
    0
        Poor
    0
    Notes
    [24] - ITT population
    No statistical analyses for this end point

    Secondary: Part C - Number of Subjects With Incidence of Antibody Formation to Host Cell Proteins (HCP)

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    End point title
    		 Part C - Number of Subjects With Incidence of Antibody Formation to Host Cell Proteins (HCP)
    End point description
    A test to ensure that subjects have not developed antibodies to HCP during the study.
    End point type
    Secondary
    End point timeframe
    before and 3 weeks after surgery
    End point values
    		 Recombinant Factor VIII (BAY81-8973) by CS/EP - Part C
    Number of subjects analysed
    5 [25]
    Units: subjects
    0
    Notes
    [25] - ITT.
    No statistical analyses for this end point

    Secondary: Part C - Number of Subjects With Assessment of the Hemostasis During Major Surgery

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    End point title
    		 Part C - Number of Subjects With Assessment of the Hemostasis During Major Surgery
    End point description
    An assessment made by surgeons of how effective BAY81-8973 was in stopping bleeding during major operations.
    End point type
    Secondary
    End point timeframe
    at the time of surgery
    End point values
    		 Recombinant Factor VIII (BAY81-8973) by CS/EP - Part C
    Number of subjects analysed
    5 [26]
    Units: subjects
        Excellent
    1
        Good
    4
        Moderate
    0
        Poor
    0
    Notes
    [26] - ITT.
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From the date of signing informed consent through study completion ie 21 Dec 2009 to 14 Mar 2013
    Adverse event reporting additional description
    The objective of Part C was efficacy assessment of surgery hemostasis, not safety assessment. It was allowed to include the same subject for several surgeries and for each surgery the subject was assigned a new subject number. Due to this approach, one subject with 3 surgeries was analyzed as 3 different subjects, therefore the number at risk is 7.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    15.1
    Reporting groups
    Reporting group title
    Recombinant Factor VIII (BAY81-8973) - Part A
    Reporting group description
    		 Participants received one single intravenous (IV) injection of BAY81-8973 50 IU/kg

    Reporting group title
    Recombinant Factor VIII (BAY81-8973) Part B and extension
    Reporting group description
    		 Participants received IV injections of BAY81-8973 at 20-50 IU/kg 2-3 times per week with BAY81-8973 measured by Chromogenic Substrate Assay Potency Per European Pharmacopeia (CS/EP) for 6 months and CS/ADJ for 6 mon seq according to random

    Reporting group title
    Recombinant Factor VIII (BAY81-8973) by CS/EP - Part C
    Reporting group description
    		 Partic received a loading dose of approx 50 IU/kg of BAY81-8973 (nearest whole vial amount) for less than 15min before the first surgical incision Then they will rec further treatment with BAY81-8973 accord to surgical requir for up to 3 weeks

    Reporting group title
    Kogenate FS (BAY14-2222) - Part A
    Reporting group description
    		 Participants received one single intravenous (IV) injection of Kogenate FS (BAY14-2222) 50 IU/kg

    Serious adverse events
    		 Recombinant Factor VIII (BAY81-8973) - Part A Recombinant Factor VIII (BAY81-8973) Part B and extension Recombinant Factor VIII (BAY81-8973) by CS/EP - Part C Kogenate FS (BAY14-2222) - Part A
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 27 (0.00%)
    12 / 62 (19.35%)
    1 / 7 (14.29%)
    0 / 28 (0.00%)
         number of deaths (all causes)
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    Injury, poisoning and procedural complications
    Injury
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 62 (1.61%)
    0 / 7 (0.00%)
    0 / 28 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 62 (1.61%)
    0 / 7 (0.00%)
    0 / 28 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Epilepsy
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 62 (1.61%)
    0 / 7 (0.00%)
    0 / 28 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Loss of consciousness
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 62 (1.61%)
    0 / 7 (0.00%)
    0 / 28 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Peripheral sensory neuropathy
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 62 (1.61%)
    0 / 7 (0.00%)
    0 / 28 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pregnancy, puerperium and perinatal conditions
    Cephalhaematoma
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 62 (1.61%)
    0 / 7 (0.00%)
    0 / 28 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    0 / 27 (0.00%)
    2 / 62 (3.23%)
    0 / 7 (0.00%)
    0 / 28 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Spinal pain
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 62 (1.61%)
    0 / 7 (0.00%)
    0 / 28 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Social circumstances
    Miscarriage of partner
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 62 (1.61%)
    0 / 7 (0.00%)
    0 / 28 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Ascites
         subjects affected / exposed
    0 / 27 (0.00%)
    0 / 62 (0.00%)
    1 / 7 (14.29%)
    0 / 28 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Suicidal ideation
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 62 (1.61%)
    0 / 7 (0.00%)
    0 / 28 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Somatoform disorder
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 62 (1.61%)
    0 / 7 (0.00%)
    0 / 28 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 62 (1.61%)
    0 / 7 (0.00%)
    0 / 28 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Compartment syndrome
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 62 (1.61%)
    0 / 7 (0.00%)
    0 / 28 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Joint range of motion decreased
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 62 (1.61%)
    0 / 7 (0.00%)
    0 / 28 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Erysipelas
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 62 (1.61%)
    0 / 7 (0.00%)
    0 / 28 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Recombinant Factor VIII (BAY81-8973) - Part A Recombinant Factor VIII (BAY81-8973) Part B and extension Recombinant Factor VIII (BAY81-8973) by CS/EP - Part C Kogenate FS (BAY14-2222) - Part A
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    0 / 27 (0.00%)
    43 / 62 (69.35%)
    5 / 7 (71.43%)
    1 / 28 (3.57%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    0 / 27 (0.00%)
    5 / 62 (8.06%)
    0 / 7 (0.00%)
    0 / 28 (0.00%)
         occurrences all number
    0
    5
    0
    0
    Blood and lymphatic system disorders
    Thymus disorder
         subjects affected / exposed
    0 / 27 (0.00%)
    0 / 62 (0.00%)
    1 / 7 (14.29%)
    0 / 28 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Anaemia
         subjects affected / exposed
    0 / 27 (0.00%)
    0 / 62 (0.00%)
    1 / 7 (14.29%)
    0 / 28 (0.00%)
         occurrences all number
    0
    0
    1
    0
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    0 / 27 (0.00%)
    4 / 62 (6.45%)
    0 / 7 (0.00%)
    0 / 28 (0.00%)
         occurrences all number
    0
    4
    0
    0
    Pyrexia
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 62 (1.61%)
    2 / 7 (28.57%)
    0 / 28 (0.00%)
         occurrences all number
    0
    1
    2
    0
    Gastrointestinal disorders
    Dental caries
         subjects affected / exposed
    0 / 27 (0.00%)
    4 / 62 (6.45%)
    0 / 7 (0.00%)
    0 / 28 (0.00%)
         occurrences all number
    0
    4
    0
    0
    Diarrhoea
         subjects affected / exposed
    0 / 27 (0.00%)
    4 / 62 (6.45%)
    2 / 7 (28.57%)
    0 / 28 (0.00%)
         occurrences all number
    0
    7
    2
    0
    Dyspepsia
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 62 (1.61%)
    1 / 7 (14.29%)
    0 / 28 (0.00%)
         occurrences all number
    0
    1
    1
    0
    Nausea
         subjects affected / exposed
    0 / 27 (0.00%)
    4 / 62 (6.45%)
    1 / 7 (14.29%)
    0 / 28 (0.00%)
         occurrences all number
    0
    4
    2
    0
    Vomiting
         subjects affected / exposed
    0 / 27 (0.00%)
    4 / 62 (6.45%)
    0 / 7 (0.00%)
    0 / 28 (0.00%)
         occurrences all number
    0
    4
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    0 / 27 (0.00%)
    5 / 62 (8.06%)
    0 / 7 (0.00%)
    0 / 28 (0.00%)
         occurrences all number
    0
    5
    0
    0
    Pleural effusion
         subjects affected / exposed
    0 / 27 (0.00%)
    0 / 62 (0.00%)
    1 / 7 (14.29%)
    0 / 28 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Pulmonary artery dilatation
         subjects affected / exposed
    0 / 27 (0.00%)
    0 / 62 (0.00%)
    1 / 7 (14.29%)
    0 / 28 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Skin and subcutaneous tissue disorders
    Dermatitis contact
         subjects affected / exposed
    0 / 27 (0.00%)
    0 / 62 (0.00%)
    1 / 7 (14.29%)
    0 / 28 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Renal and urinary disorders
    Anuria
         subjects affected / exposed
    0 / 27 (0.00%)
    0 / 62 (0.00%)
    1 / 7 (14.29%)
    0 / 28 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 27 (0.00%)
    6 / 62 (9.68%)
    0 / 7 (0.00%)
    0 / 28 (0.00%)
         occurrences all number
    0
    10
    0
    0
    Back pain
         subjects affected / exposed
    0 / 27 (0.00%)
    4 / 62 (6.45%)
    0 / 7 (0.00%)
    0 / 28 (0.00%)
         occurrences all number
    0
    4
    0
    0
    Infections and infestations
    Influenza
         subjects affected / exposed
    0 / 27 (0.00%)
    6 / 62 (9.68%)
    0 / 7 (0.00%)
    0 / 28 (0.00%)
         occurrences all number
    0
    6
    0
    0
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 27 (0.00%)
    8 / 62 (12.90%)
    0 / 7 (0.00%)
    1 / 28 (3.57%)
         occurrences all number
    0
    14
    0
    2
    Nasopharyngitis
         subjects affected / exposed
    0 / 27 (0.00%)
    14 / 62 (22.58%)
    0 / 7 (0.00%)
    0 / 28 (0.00%)
         occurrences all number
    0
    22
    0
    0
    Pharyngitis
         subjects affected / exposed
    0 / 27 (0.00%)
    5 / 62 (8.06%)
    0 / 7 (0.00%)
    0 / 28 (0.00%)
         occurrences all number
    0
    7
    0
    0
    Device related infection
         subjects affected / exposed
    0 / 27 (0.00%)
    0 / 62 (0.00%)
    1 / 7 (14.29%)
    0 / 28 (0.00%)
         occurrences all number
    0
    0
    1
    0

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    20 Nov 2009
    Amendment 1, specified the following modifications: 1. The regulatory agencies requested clarification regarding the surgery indication, such as a definition of the surgery types, safety data required prior to surgery, and evaluation times of the surgery outcome data during the study. 2. The study criteria were clarified as >= 10 surgeries in >= 10 subjects. 3. The PK blood sampling scheme was revised to include an additional timepoint, 30 h post-injection, to comply with the regulatory agencies’ request for additional timepoints. 4. Amendment 1 specified that following randomization, subjects were to be supplied with and were to use only antihemophilic factor (recombinant), Kogenate FS where there was a need for FVIII treatment, and the investigational product, BAY81-8973, was not provided. 5.The one-time titration and change in dose per injection was removed, thus, a fixed, consistent dose was to be administered for each injection. 6. The injection time for PK (Part A) and for in vivo recovery (Part A and Part B) was changed to 10 min instead of 5-10 min. Treatment interruption of prophylaxis treatment was revised as not permitted. The dosage range for prophylaxis treatment was clarified as occurring in 5 IU/kg increments over the range of 20-40 IU/kg (ie, 20, 25, 30, 35, or 40 IU/kg), administered 2-3 times per week, at the investigator’s discretion. 7. Editorial changes in primary objective and changes in most efficacy objectives to reflect that efficacy data will be combined with Protocol 2009-012150-20 (14319) for statistical analysis. Change in secondary objective of the study from “demonstrate the non-inferiority of BAY 81-8973 based on potency determinations (CS/EP vs CS/ADJ)” to “compare BAY 81-8973 based on potency determinations (CS/EP vs CS/ADJ) as measured by in vivo recovery”.
    08 Apr 2010
    Amendment 5, specified the following modifications: - The inclusion criterion for current inhibitor antibody was clarified and the washout time was revised to be consistent with a washout period of 3 days specified throughout the protocol. In addition, the inhibitor history inclusion criterion was corrected from >1.0 to 1 BU. In the original protocol, the inhibitor inclusion criterion was 1 Bethesda unit (BU). It was changed in error to >1 BU in Amendment 1. In Amendment 5 it was corrected back to 1 BU. - The exclusion criterion for CD4 lymphocyte cell count (< 400 cells/microliter) was revised to be consistent with previous studies (< 250 cells/microliter). In addition, the exclusion criterion of portal vein hypertension was clarified as “significant portal vein hypertension in the judgement of the investigator”. - The number of subjects to be enrolled into Part A of the protocol was revised from 16 to up to 30. - Since it was not required that Kogenate was to be administered within 15 minutes (min) of surgery, this condition was deleted. Also, since a urine dipstick test was not performed (only urinalysis), the dipstick test was deleted. - The treatment administration time was changed from 5 – 10 min to 1 – 15 min. This change was made to be consistent with the product labeling for Kogenate FS. - Concomitant therapy was revised to allow subjects with arthritis to receive treatment with NSAIDS.
    11 May 2010
    Amendment 6, specified the following modifications: - The definition for 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 the one-stage clotting assay, to be included in the trial without further testing/confirmation of severe hemophilia A if the screening result turned out to be >=1%. - The number of surgeries (across both studies 12954 and 14319) was increased from “>=10 surgeries in >= 10 subjects” to “ >=15 surgeries in >=15 subjects”, and the classification of surgery types was clarified (“at least 8 must be classified as major surgical procedures”) to enable a more thorough evaluation of the safety and efficacy of BAY 81-8973 in the surgical setting. - To further ensure subject safety, the requirement was added that BAY81-8973 should not be supplied for use in the surgical setting until at least 20 bleeding events (across both studies) had been assessed to ensure the hemostatic activity of BAY81-8973. It was further specified that all sites were to be informed by the Sponsor when surgical treatment using BAY81-8973 was allowed to commence. - Editorial revision of the change regarding dipstick urine test. - Since the 3-day washout of FVIII applied to both Part A and B and not just Part A, the appropriate exclusion criterion was revised. "Any subject in Part A who cannot forego at least 3 days without receiving FVIII before the PK sessions for washout purposes." was changed to "Any subject who cannot forego at least 3 days without receiving FVIII for washout purposes.
    21 Sep 2010
    Amendment 7, became effective after 28 subjects had started treatment. It specified the following modification: Addition of “known hypersensitivity against mouse protein” as an exclusion criterion.
    13 Jan 2011
    Amendment 8, specified the following modifications: - The study objectives of Part B of the study were reorganized to ensure that the primary and secondary study objectives included objectives for results of this study alone, and a separate category, “addendum objectives”, was added to include objectives for the pooled results of this study and Study 2009-012150-20 (14319). Importantly, no Part B objectives were deleted or significantly revised. - The highest dosage was increased from 40 IU/kg to 50 IU/kg in Part B of the study, in order to account for standard of care of some centers who use this dose as a standard prophylaxis dosing. - A pharmacogenetic sample for FVIII genetic analysis was added which allows the genetic analysis of FVIII polymorphism in different ethnic groups participating in this trial. - If another product had to be used during the study to control the bleed (according to the local standard of care), the product was no longer required to be a marketed recombinant FVIII product, and could be another marketed FVIII product as not all participating sites were using recombinant products as standard of care. - Visit 4 and Visit 5 were combined into one visit, Visit 4/5, because 2 visits within 3 days were thought to be very difficult to arrange for young subjects who are in an active life, and could be a barrier for recruitment. The recovery required at Visit 4, the end of the first period, was changed to Visit 3.
    01 Apr 2011
    Amendment 9, specified the following modifications: - Additions to study objectives (“additional objectives”), description of Part C (“Major Surgery Arm”), inclusion criteria, and other protocol sections to account for major surgeries. - Introduction of the extension period (treatment beyond the 1-year treatment period for 1 further year) and a detailed description of this in the appropriate protocol sections.

    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.
    The study specific characteristics 'Most recent treatment before enrolment in the study' could not be reported due to database constrains. Occurrence of "±” in relation with geometric CV(%) is auto-generated and cannot be deleted.
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    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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