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    Clinical Trial Results:
    Randomized, active-controlled, double-blind, parallel design study to evaluate the efficacy and safety of a once-a-week prophylaxis treatment with BAY79-4980 compared to three times-per-week prophylaxis with rFVIII-FS in previously treated patients with severe hemophilia A

    Summary
    EudraCT number
    		 2007-003718-32
    Trial protocol
    		 DE   FR   NL   DK   ES   BE   AT   GB   IT   NO  
    Global end of trial date
    05 Oct 2010

    Results information
    Results version number
    		 v1
    This version publication date
    12 Jul 2016
    First version publication date
    03 May 2015
    Other versions
    		 v2

    Trial information

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    Trial identification
    Sponsor protocol code
    BAY79-4980/12781
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT00623727
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Bayer HealthCare AG
    Sponsor organisation address
    Kaiser-Wilhelm-Allee, Leverkusen, D-51368, Germany,
    Public contact
    Therapeutic Area Head, Bayer HealthCare AG, clinical-trials-contact@bayerhealthcare.com
    Scientific contact
    Therapeutic Area Head, Bayer HealthCare AG, clinical-trials-contact@bayerhealthcare.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
    05 Oct 2010
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    05 Oct 2010
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The primary objective was to evaluate the effect of a once-a-week prophylaxis regimen with BAY79-4980 on the protection from total bleeds compared to a three times-per-week prophylaxis regimen with recombinant factor VIII formulated with sucrose (rFVIII-FS).
    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. An independent Data and Safety Monitoring Board (DSMB) supervised the subjects’ safety and performed the pre-specified interim analyses according to the protocol. Before entering the study, the informed consent form was read by and explained to all subjects and/or their legally authorized representative. 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. A Data and Safety Monitoring Board supervised the safety of study subjects.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    30 Jun 2008
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety
    Long term follow-up duration
    		 6 Months
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    France: 3
    Country: Number of subjects enrolled
    Italy: 20
    Country: Number of subjects enrolled
    Netherlands: 4
    Country: Number of subjects enrolled
    Spain: 4
    Country: Number of subjects enrolled
    United Kingdom: 2
    Country: Number of subjects enrolled
    Poland: 28
    Country: Number of subjects enrolled
    Austria: 6
    Country: Number of subjects enrolled
    Denmark: 6
    Country: Number of subjects enrolled
    Canada: 3
    Country: Number of subjects enrolled
    Croatia: 3
    Country: Number of subjects enrolled
    Israel: 18
    Country: Number of subjects enrolled
    Germany: 8
    Country: Number of subjects enrolled
    United States: 36
    Country: Number of subjects enrolled
    Belgium: 2
    Worldwide total number of subjects
    143
    EEA total number of subjects
    86
    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)
    5
    Adults (18-64 years)
    138
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Previously treated subjects with severe hemophilia A [less than (<) 1 percent (%) Factor VIII (FVIII)], who were currently on on-demand or secondary prophylaxis treatment with any FVIII for greater than or equal to (>=)150 exposure days with documented bleeds/injections during the last 6 months prior to study entry could participate in the study.

    Pre-assignment
    Screening details
    		 Of 168 enrolled subjects, 25 failed screening.

    Period 1
    Period 1 title
    Double blind (DB)
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 rFVIII-FS/Pegylated Liposomes (BAY79-4980)
    Arm description
    		 35 international units per kilogram (IU/kg) body weight of BAY79-4980 1x/week plus 2 dummy injections/week [dummy = rFVIII-FS excipient reconstituted in sterile water for injection (WFI)].
    Arm type
    		 Experimental

    Investigational medicinal product name
    rFVIII-FS/Pegylated Liposomes
    Investigational medicinal product code
    BAY79-4980
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    35 IU/kg body weight of BAY79-4980 1x/week.

    Investigational medicinal product name
    Placebo injection: placebo/WFI
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Two placebo injections/week (dummy injections for blinding purposes) containing excipient of rFVIII-FS (packed with WFI solvent for reconstitution).

    Arm title
    		 rFVIII-FS/WFI (BAY14-2222)
    Arm description
    		 25 IU/kg body weight of rFVIII-FS 3x/week [employing 1% POPC-alone liposome (rFVIII-FS-POPC) as blinding agent used for first weekly injection and rFVIII-FS in WFI for 2nd and 3rd injection].
    Arm type
    		 Active comparator

    Investigational medicinal product name
    rFVIII-FS/WFI
    Investigational medicinal product code
    BAY14-2222
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    25 IU/kg body weight of rFVIII-FS 3x/week [employing 1% POPC-alone liposome (rFVIII-FS-POPC) as blinding agent used for first weekly injection and rFVIII-FS in WFI for 2nd and 3rd injection].

    Number of subjects in period 1
    		rFVIII-FS/Pegylated Liposomes (BAY79-4980) rFVIII-FS/WFI (BAY14-2222)
    Started
    70
    73
    Participants received treatment
    67
    72
    Completed
    34
    41
    Not completed
    36
    32
         Consent withdrawn by subject
    8
    2
         Physician decision
    -
    1
         Protocol violation
    2
    2
         Termination of the double-blind period
    22
    21
         Adverse event
    1
    3
         Lost to follow-up
    1
    1
         Lack of efficacy
    2
    2
    Period 2
    Period 2 title
    Open label
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 rFVIII-FS/WFI (BAY14-2222): Follow up
    Arm description
    		 Few subjects of each group after DB period terminated were entered in to the open label follow up period and received 25 IU/kg body weight of rFVIII-FS 3x/week [employing 1% POPC-alone liposome (rFVIII-FS-POPC) as blinding agent used for first weekly injection and rFVIII-FS in WFI for 2nd and 3rd injection] for a period of 6 months or until completion of 12 months trial participation.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    rFVIII-FS/WFI
    Investigational medicinal product code
    BAY14-2222
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    25 IU/kg body weight of rFVIII-FS 3x/week [employing 1% POPC-alone liposome (rFVIII-FS-POPC) as blinding agent used for first weekly injection and rFVIII-FS in WFI for 2nd and 3rd injection].

    Arm title
    		 rFVIII-FS/Pegylated Liposomes (BAY79-4980): Extension period
    Arm description
    		 Ten subjects of each group entered open-label extension period after completion of DB study and received 35 IU/kg body weight of BAY79-4980 1x/week.
    Arm type
    		 Experimental

    Investigational medicinal product name
    rFVIII-FS/Pegylated Liposomes
    Investigational medicinal product code
    BAY79-4980
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    35 IU/kg body weight of BAY79-4980 1x/week.

    Number of subjects in period 2 [1]
    		rFVIII-FS/WFI (BAY14-2222): Follow up rFVIII-FS/Pegylated Liposomes (BAY79-4980): Extension period
    Started
    26
    20
    Completed
    18
    20
    Not completed
    8
    0
         Consent withdrawn by subject
    1
    -
         Subject convenience
    1
    -
         Study termination
    6
    -
    Notes
    [1] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: Subjects who completed double blind treatment, were offered continuation of open label treatment and due to the early termination of the double-blind study phase, subjects who had not completed double blind treatment were offered continuation in control arm (follow up phase). Hence, the number of subjects starting the period is not consistent with the number completing the preceding period.
    Period 3
    Period 3 title
    Baseline period
    Is this the baseline period?
    		 Yes [2]
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Carer, Assessor

    Arms
    Are arms mutually exclusive
    No

    Arm title
    		 rFVIII-FS/Pegylated Liposomes (BAY79-4980)
    Arm description
    		 35 IU/kg body weight of BAY79-4980 1x/week plus 2 dummy injections/week (dummy = rFVIII-FS excipient reconstituted in WFI). Subjects who received treatment were included in baseline period.
    Arm type
    		 Experimental

    Investigational medicinal product name
    rFVIII-FS/Pegylated Liposomes
    Investigational medicinal product code
    BAY79-4980
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    35 IU/kg body weight of BAY79-4980 1x/week plus 2 dummy injections/week (dummy = rFVIII-FS excipient reconstituted in WFI). Subjects who received treatment were included in baseline period.

    Arm title
    		 rFVIII-FS/WFI (BAY14-2222)
    Arm description
    		 25 IU/kg body weight of rFVIII-FS 3x/week [employing 1% POPC-alone liposome (rFVIII-FS-POPC) as blinding agent used for first weekly injection and rFVIII-FS in WFI for 2nd and 3rd injection]. Subjects who received treatment were included in baseline period.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    rFVIII-FS/WFI
    Investigational medicinal product code
    BAY14-2222
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    25 IU/kg body weight of rFVIII-FS 3x/week [employing 1% POPC-alone liposome (rFVIII-FS-POPC) as blinding agent used for first weekly injection and rFVIII-FS in WFI for 2nd and 3rd injection].

    Notes
    [2] - Period 1 is not the baseline period. It is expected that period 1 will be the baseline period.
    Justification: In overall trial, subjects who were randomized included and the baseline characteristics were provided for only subjects who were treated. Hence, the baseline period of treated subjects was created to publish the baseline characteristics data.
    Number of subjects in period 3
    		rFVIII-FS/Pegylated Liposomes (BAY79-4980) rFVIII-FS/WFI (BAY14-2222)
    Started
    67
    72
    Completed
    67
    72

    Baseline characteristics

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    Baseline characteristics reporting groups [1]
    Reporting group title
    rFVIII-FS/Pegylated Liposomes (BAY79-4980)
    Reporting group description
    		 35 IU/kg body weight of BAY79-4980 1x/week plus 2 dummy injections/week (dummy = rFVIII-FS excipient reconstituted in WFI). Subjects who received treatment were included in baseline period.

    Reporting group title
    rFVIII-FS/WFI (BAY14-2222)
    Reporting group description
    		 25 IU/kg body weight of rFVIII-FS 3x/week [employing 1% POPC-alone liposome (rFVIII-FS-POPC) as blinding agent used for first weekly injection and rFVIII-FS in WFI for 2nd and 3rd injection]. Subjects who received treatment were included in baseline period.

    Notes
    [1] - The number of subjects reported to be in the baseline period is not equal to the worldwide number of subjects enrolled in the trial. It is expected that these numbers will be the same.
    Justification: All enrolled subjects were not randomized and treated with study drugs. Hence, the worldwide number enrolled in the trial differs with the number of subjects reported in the baseline period.
    Reporting group values
    		 rFVIII-FS/Pegylated Liposomes (BAY79-4980) rFVIII-FS/WFI (BAY14-2222) Total
    Number of subjects
    		 67 72
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 33 ± 11.3 34.1 ± 13 -
    Gender categorical
    Units: Subjects
        Male
    		 67 72 139
    Target joint
    The presence or absence of target joints (defined as joints with at least 3 bleeds into the same joint within 6 months) was evaluated.
    Units: Subjects
        Yes
    		 54 56 110
        No
    		 13 16 29
    Previous treatment
    Previous treatment was categorized as prophylaxis versus on demand.
    Units: Subjects
        On demand
    		 35 44 79
        Prophylaxis
    		 32 28 60

    End points

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    End points reporting groups
    Reporting group title
    rFVIII-FS/Pegylated Liposomes (BAY79-4980)
    Reporting group description
    		 35 international units per kilogram (IU/kg) body weight of BAY79-4980 1x/week plus 2 dummy injections/week [dummy = rFVIII-FS excipient reconstituted in sterile water for injection (WFI)].

    Reporting group title
    rFVIII-FS/WFI (BAY14-2222)
    Reporting group description
    		 25 IU/kg body weight of rFVIII-FS 3x/week [employing 1% POPC-alone liposome (rFVIII-FS-POPC) as blinding agent used for first weekly injection and rFVIII-FS in WFI for 2nd and 3rd injection].
    Reporting group title
    rFVIII-FS/WFI (BAY14-2222): Follow up
    Reporting group description
    		 Few subjects of each group after DB period terminated were entered in to the open label follow up period and received 25 IU/kg body weight of rFVIII-FS 3x/week [employing 1% POPC-alone liposome (rFVIII-FS-POPC) as blinding agent used for first weekly injection and rFVIII-FS in WFI for 2nd and 3rd injection] for a period of 6 months or until completion of 12 months trial participation.

    Reporting group title
    rFVIII-FS/Pegylated Liposomes (BAY79-4980): Extension period
    Reporting group description
    		 Ten subjects of each group entered open-label extension period after completion of DB study and received 35 IU/kg body weight of BAY79-4980 1x/week.
    Reporting group title
    rFVIII-FS/Pegylated Liposomes (BAY79-4980)
    Reporting group description
    		 35 IU/kg body weight of BAY79-4980 1x/week plus 2 dummy injections/week (dummy = rFVIII-FS excipient reconstituted in WFI). Subjects who received treatment were included in baseline period.

    Reporting group title
    rFVIII-FS/WFI (BAY14-2222)
    Reporting group description
    		 25 IU/kg body weight of rFVIII-FS 3x/week [employing 1% POPC-alone liposome (rFVIII-FS-POPC) as blinding agent used for first weekly injection and rFVIII-FS in WFI for 2nd and 3rd injection]. Subjects who received treatment were included in baseline period.

    Subject analysis set title
    Per protocol (PP) population
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    PP population included those subjects of the ITT population in whom no major protocol violations were identified.

    Subject analysis set title
    Intent-to-treat (ITT) population
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    ITT population included all subjects randomized into the study who received study drug.

    Subject analysis set title
    rFVIII-FS/pegylated liposomes (subgroup)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subjects who completed open label extension period.

    Primary: Percentage of Subjects With Less Than 9 Total Bleeds per Year

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    End point title
    		 Percentage of Subjects With Less Than 9 Total Bleeds per Year [1]
    End point description
    Bleeds occurring on the same day were counted as one bleeding event. Bleeds occurring within 72 hours into the same location were also counted as one bleeding event.
    End point type
    Primary
    End point timeframe
    Up to one year
    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: Statistical analysis was not performed since descriptive statistical analysis was only planned for this endpoint due to the premature termination of the study.
    End point values
    		 rFVIII-FS/Pegylated Liposomes (BAY79-4980) rFVIII-FS/WFI (BAY14-2222)
    Number of subjects analysed
    63 [2]
    68 [3]
    Units: percentage of subjects
        number (not applicable)
    38.1
    72.1
    Notes
    [2] - PP population
    [3] - PP population
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With Less Than 5 Joint Bleeds per Year

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    End point title
    		 Percentage of Subjects With Less Than 5 Joint Bleeds per Year
    End point description
    Bleeds occurring on the same day were counted as one bleeding event. Bleeds occurring within 72 hours into the same location were also counted as one bleeding event.
    End point type
    Secondary
    End point timeframe
    Up to one year
    End point values
    		 rFVIII-FS/Pegylated Liposomes (BAY79-4980) rFVIII-FS/WFI (BAY14-2222)
    Number of subjects analysed
    63 [4]
    68 [5]
    Units: percentage of subjects
        number (not applicable)
    38.1
    63.2
    Notes
    [4] - PP population
    [5] - PP population
    No statistical analyses for this end point

    Secondary: Number of Joint Bleeds per Subject per Year in Responders

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    End point title
    		 Number of Joint Bleeds per Subject per Year in Responders
    End point description
    Bleeds occurring on the same day were counted as one bleeding event. Bleeds occurring within 72 hours into the same location were also counted as one bleeding event. Responders were the subjects with less than 9 total bleeds per year.
    End point type
    Secondary
    End point timeframe
    Up to one year
    End point values
    		 rFVIII-FS/Pegylated Liposomes (BAY79-4980) rFVIII-FS/WFI (BAY14-2222)
    Number of subjects analysed
    24 [6]
    49 [7]
    Units: joint bleeds per year
        median (full range (min-max))
    2.341 (0 to 8.91)
    0 (0 to 7.59)
    Notes
    [6] - PP population included subjects with less than 9 total bleeds per year.
    [7] - PP population included subjects with less than 9 total bleeds per year.
    No statistical analyses for this end point

    Other pre-specified: Number of Bleeds per Year

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    End point title
    		 Number of Bleeds per Year
    End point description
    Bleeds occurring on the same day were counted as one bleeding event. Bleeds occurring within 72 hours into the same location were also counted as one bleeding event. Number of bleeds 3 weeks after the first infusion per 12 months.
    End point type
    Other pre-specified
    End point timeframe
    Up to one year
    End point values
    		 rFVIII-FS/Pegylated Liposomes (BAY79-4980) rFVIII-FS/WFI (BAY14-2222)
    Number of subjects analysed
    63 [8]
    68 [9]
    Units: bleeds per year
        median (full range (min-max))
    9.96 (0 to 72.2)
    2.2 (0 to 22.8)
    Notes
    [8] - PP population
    [9] - PP population
    No statistical analyses for this end point

    Other pre-specified: Percentage of Bleeds Treated by Various Numbers of Injections

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    End point title
    		 Percentage of Bleeds Treated by Various Numbers of Injections
    End point description
    Bleeds occurring on the same day were counted as one bleeding event. Bleeds occurring within 72 hours into the same location were also counted as one bleeding event.
    End point type
    Other pre-specified
    End point timeframe
    Up to one year
    End point values
    		 rFVIII-FS/Pegylated Liposomes (BAY79-4980) rFVIII-FS/WFI (BAY14-2222)
    Number of subjects analysed
    63 [10]
    68 [11]
    Units: percentage of bleeds
    number (not applicable)
        1-2 injections
    88.5
    93
        1 injection
    73.2
    81.7
        2 injections
    15.3
    11.3
        3 injections
    6.5
    2.3
        >3 injections
    5
    4.7
    Notes
    [10] - PP population
    [11] - PP population
    No statistical analyses for this end point

    Other pre-specified: Total rFVIII Consumption per Year

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    End point title
    		 Total rFVIII Consumption per Year
    End point description
    Total number of units per kg of study medication (rFVIII) administered to participant for one year. rFVIII is recombinant factor VIII, factor VIII is functional coagulation factor
    End point type
    Other pre-specified
    End point timeframe
    Up to one year
    End point values
    		 rFVIII-FS/Pegylated Liposomes (BAY79-4980) rFVIII-FS/WFI (BAY14-2222)
    Number of subjects analysed
    67 [12]
    72 [13]
    Units: IU per kg
        median (full range (min-max))
    2524 (1580 to 11788)
    4378 (3701 to 12789)
    Notes
    [12] - ITT population
    [13] - ITT population
    No statistical analyses for this end point

    Other pre-specified: Percentage of Subjects With Less Than 9 Total Bleeds per Year in the Open Label Extension Period

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    End point title
    		 Percentage of Subjects With Less Than 9 Total Bleeds per Year in the Open Label Extension Period
    End point description
    Bleeds occurring on the same day were counted as one bleeding event. Bleeds occurring within 72 hours into the same location were also counted as one bleeding event.
    End point type
    Other pre-specified
    End point timeframe
    6 months after start of open label extension period
    End point values
    		 rFVIII-FS/pegylated liposomes (subgroup)
    Number of subjects analysed
    20
    Units: percentage of subjects
        number (not applicable)
    55
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From randomization until end of study
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    13.0
    Reporting groups
    Reporting group title
    rFVIII-FS/pegylated liposomes (BAY79-4980) - Double Blind
    Reporting group description
    		 Reporting Group 1 (RG1): Double Blind Study, 35 IU/kg body weight of BAY79-4980 1x/week plus 2 dummy injections/week (dummy = rFVIII-FS excipient reconstituted in WFI).

    Reporting group title
    rFVIII-FS/WFI (BAY14-2222) - Double Blind
    Reporting group description
    		 Reporting group 2 (RG2): Double Blind Study, 25 IU/kg body weight of rFVIII-FS 3x/week (employing 1 percent POPC-alone liposome (rFVIII-FS-POPC) as blinding agent used for first weekly injection and rFVIII-FS in WFI for 2nd and 3rd injection).

    Reporting group title
    rFVIII-FS/WFI (BAY14-2222) - Follow-up
    Reporting group description
    		 Reporting group 3 (RG3): Open Label Follow-up, 25 IU/kg body weight of rFVIII-FS 3x/week (employing 1 percent POPC-alone liposome (rFVIII-FS-POPC) as blinding agent used for first weekly injection and rFVIII-FS in WFI for 2nd and 3rd injection).

    Reporting group title
    rFVIII-FS/pegylated liposomes (BAY79-4980) - Extension
    Reporting group description
    		 Reporting group 4 (RG4): Open Label Extension, 35 IU/kg body weight of BAY79-4980 1x/week plus 2 dummy injections/week (dummy = rFVIII-FS excipient reconstituted in WFI).

    Serious adverse events
    		 rFVIII-FS/pegylated liposomes (BAY79-4980) - Double Blind rFVIII-FS/WFI (BAY14-2222) - Double Blind rFVIII-FS/WFI (BAY14-2222) - Follow-up rFVIII-FS/pegylated liposomes (BAY79-4980) - Extension
    Total subjects affected by serious adverse events
         subjects affected / exposed
    7 / 67 (10.45%)
    1 / 72 (1.39%)
    0 / 26 (0.00%)
    1 / 20 (5.00%)
         number of deaths (all causes)
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    General disorders and administration site conditions
    Oedema
         subjects affected / exposed
    1 / 67 (1.49%)
    0 / 72 (0.00%)
    0 / 26 (0.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Immune system disorders
    Hypersensitivity
         subjects affected / exposed
    1 / 67 (1.49%)
    0 / 72 (0.00%)
    0 / 26 (0.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Glaucoma
         subjects affected / exposed
    1 / 67 (1.49%)
    0 / 72 (0.00%)
    0 / 26 (0.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Melaena
         subjects affected / exposed
    1 / 67 (1.49%)
    0 / 72 (0.00%)
    0 / 26 (0.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rectal haemorrhage
         subjects affected / exposed
    1 / 67 (1.49%)
    0 / 72 (0.00%)
    0 / 26 (0.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    1 / 67 (1.49%)
    0 / 72 (0.00%)
    0 / 26 (0.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Compartment syndrome
         subjects affected / exposed
    1 / 67 (1.49%)
    0 / 72 (0.00%)
    0 / 26 (0.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Device related infection
         subjects affected / exposed
    0 / 67 (0.00%)
    1 / 72 (1.39%)
    0 / 26 (0.00%)
    0 / 20 (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
    Tinea pedis
         subjects affected / exposed
    1 / 67 (1.49%)
    0 / 72 (0.00%)
    0 / 26 (0.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Varicella
         subjects affected / exposed
    0 / 67 (0.00%)
    0 / 72 (0.00%)
    0 / 26 (0.00%)
    1 / 20 (5.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Abnormal weight gain
         subjects affected / exposed
    1 / 67 (1.49%)
    0 / 72 (0.00%)
    0 / 26 (0.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    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
    		 rFVIII-FS/pegylated liposomes (BAY79-4980) - Double Blind rFVIII-FS/WFI (BAY14-2222) - Double Blind rFVIII-FS/WFI (BAY14-2222) - Follow-up rFVIII-FS/pegylated liposomes (BAY79-4980) - Extension
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    27 / 67 (40.30%)
    27 / 72 (37.50%)
    2 / 26 (7.69%)
    10 / 20 (50.00%)
    Investigations
    Blood amylase increased
         subjects affected / exposed
    1 / 67 (1.49%)
    1 / 72 (1.39%)
    0 / 26 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    1
    4
    0
    2
    Lipase increased
         subjects affected / exposed
    1 / 67 (1.49%)
    1 / 72 (1.39%)
    0 / 26 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    1
    3
    0
    2
    Injury, poisoning and procedural complications
    Limb injury
         subjects affected / exposed
    0 / 67 (0.00%)
    0 / 72 (0.00%)
    0 / 26 (0.00%)
    2 / 20 (10.00%)
         occurrences all number
    0
    0
    0
    2
    Cardiac disorders
    Tachycardia
         subjects affected / exposed
    0 / 67 (0.00%)
    0 / 72 (0.00%)
    0 / 26 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    0
    1
    Nervous system disorders
    Headache
         subjects affected / exposed
    6 / 67 (8.96%)
    8 / 72 (11.11%)
    0 / 26 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    8
    11
    0
    1
    Blood and lymphatic system disorders
    Lymphadenopathy
         subjects affected / exposed
    0 / 67 (0.00%)
    2 / 72 (2.78%)
    0 / 26 (0.00%)
    2 / 20 (10.00%)
         occurrences all number
    0
    2
    0
    2
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    3 / 67 (4.48%)
    3 / 72 (4.17%)
    1 / 26 (3.85%)
    1 / 20 (5.00%)
         occurrences all number
    3
    3
    1
    1
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    4 / 67 (5.97%)
    2 / 72 (2.78%)
    0 / 26 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    5
    3
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Oropharyngeal pain
         subjects affected / exposed
    4 / 67 (5.97%)
    4 / 72 (5.56%)
    0 / 26 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    4
    8
    0
    0
    Skin and subcutaneous tissue disorders
    Dermatitis contact
         subjects affected / exposed
    0 / 67 (0.00%)
    0 / 72 (0.00%)
    0 / 26 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    0
    1
    Rash
         subjects affected / exposed
    3 / 67 (4.48%)
    4 / 72 (5.56%)
    0 / 26 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    6
    4
    0
    0
    Renal and urinary disorders
    Dysuria
         subjects affected / exposed
    0 / 67 (0.00%)
    0 / 72 (0.00%)
    0 / 26 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    0
    1
    Haematuria
         subjects affected / exposed
    0 / 67 (0.00%)
    0 / 72 (0.00%)
    0 / 26 (0.00%)
    2 / 20 (10.00%)
         occurrences all number
    0
    0
    0
    2
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    4 / 67 (5.97%)
    2 / 72 (2.78%)
    0 / 26 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    4
    2
    0
    2
    Arthralgia
         subjects affected / exposed
    7 / 67 (10.45%)
    5 / 72 (6.94%)
    1 / 26 (3.85%)
    0 / 20 (0.00%)
         occurrences all number
    9
    12
    1
    0
    Neck pain
         subjects affected / exposed
    0 / 67 (0.00%)
    0 / 72 (0.00%)
    0 / 26 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    0
    1
    Haemophilic arthropathy
         subjects affected / exposed
    0 / 67 (0.00%)
    0 / 72 (0.00%)
    0 / 26 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    0
    1
    Infections and infestations
    Influenza
         subjects affected / exposed
    5 / 67 (7.46%)
    2 / 72 (2.78%)
    0 / 26 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    6
    2
    0
    0
    Nasopharyngitis
         subjects affected / exposed
    10 / 67 (14.93%)
    12 / 72 (16.67%)
    0 / 26 (0.00%)
    6 / 20 (30.00%)
         occurrences all number
    15
    18
    0
    8
    Localised infection
         subjects affected / exposed
    0 / 67 (0.00%)
    0 / 72 (0.00%)
    0 / 26 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    0
    1
    Varicella
         subjects affected / exposed
    0 / 67 (0.00%)
    0 / 72 (0.00%)
    0 / 26 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    0
    0
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    26 Feb 2008
    - The dosage for the treatment of bleeds and minor surgical interventions was limited to 1 single infusion with 35 IU/kg of BAY 79-4980 or rFVIII-POPC. The proposed treatment of bleeds and minor surgical interventions with extended dosages of BAY 79-4980 with up to 70 IU/kg/day was not accepted by a national authority. - The definition of a target joint was added. - The physical assessment of joints for the determination of the Gilbert Score was deleted at Month 6 and end of trial, as no change was expected during a 1-year observation period in subjects treated with prophylaxis. - The screening period was prolonged to from 1-3 weeks to 3-5 weeks due to logistical requirements. - Inhibitor development as reason for withdrawal was clarified. - The exclusion criterion regarding active hepatic disease was clarified.
    21 Jul 2009
    - The interim safety analysis on lipid kinetics was to be performed in a subset of 20 subjects and the interim efficacy analysis was to be performed after 100 subjects had completed 6 months of treatment. This change was due to the slow recruitment into the study. In addition, the study was extended to new countries where prophylaxis is not the treatment standard in adult hemophilia subjects. Inclusion criterion number 4 was adapted accordingly to increase the percentage of subjects on on-demand treatment. - The screening period was prolonged to 3-8 weeks due to logistic reasons. - The upper dose limit was set to 4500 IU/infusion corresponding to a body weight of 131 kg, because extreme overweight is not related to a proportional increase in distribution volume. - The endpoint related to change in joint status was deleted because no Gilbert score was determined at the end of the study. - Specification that fasting after infusion of study medication was no longer required for the lipid PK, because this has no impact on the first sample after 6 hour. Lipid values for inclusion into the lipid pharmacokinetics (PK) were defined based on American Heart Association’s Adult Treatment Panel (AHA-ATP) III recommendations. - For the repeat FVIII PK at Week 26, specification that the study medication had to be administered with the same infusion rate as used during the first infusion (20-30 minutes). - The original protocol specified that the efficacy analyses would be performed on the ITT population. A modification was made to specify that the primary efficacy analysis would be performed on the PP population and the secondary analysis on the ITT population since this is a more conservative approach for non-inferiority trials.
    15 Jan 2010
    - Based on the DSMB’s interim efficacy check of the data of 108 subjects with a treatment period of 6 months, this amendment specified that recruitment had been halted on 22 December 2009 and would not be re-started. The double-blind treatment period was prematurely terminated and study participants were offered a participation in an open treatment arm (follow-up period). All subjects were offered a treatment with the comparator drug (rFVIII-FS-POPC/rFVIII-FS-WFI) and/or open-label rFVIII-FS-WFI for 6 months or until completion of the 12-month total study duration. Participation was according to the subjects’ preference. This applied also to subjects who had not yet started the treatment phase. Blinding was to be preserved until clean data base of the blinded study. - The DSMB concluded that the study would not be able to establish non-inferiority of BAY79-4980 compared to the control treatment with a non-inferiority margin of 15% and recommended to halt recruitment. The sponsor decided to discontinue the investigational treatment and to guarantee the treatment of subjects until study completion or at least 6 months in the comparator arm.

    Interruptions (globally)
    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    22 Dec 2009
    The recruitment and double-blind study phase were prematurely terminated after a scheduled interim analysis confirmed overt failure regarding the primary endpoint as judged by the independent DSMB.
    -

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/20059562
    http://www.ncbi.nlm.nih.gov/pubmed/23014711
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