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    Clinical Trial Results:
    Prospective, open-label, multicentre phase 3b study to assess the efficacy and safety of personalized prophylaxis with Human-cl rhFVIII in previously treated adult patients with severe haemophilia A

    Summary
    EudraCT number
    		 2014-002986-30
    Trial protocol
    		 FR   NL   FI   SI   HR  
    Global end of trial date
    05 Sep 2018

    Results information
    Results version number
    		 v1(current)
    This version publication date
    08 Nov 2019
    First version publication date
    08 Nov 2019
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    GENA-21b
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02256917
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 IND Number: BB-IND 13722
    Sponsors
    Sponsor organisation name
    Octapharma AG
    Sponsor organisation address
    Seidenstrasse 2, Lachen, Switzerland, CH-8853
    Public contact
    Sigurd Knaub, Octapharma AG, +41 (0)55 451 21 41, sigurd.knaub@octapharma.com
    Scientific contact
    Sigurd Knaub, Octapharma AG, +41 (0)55 451 21 41, sigurd.knaub@octapharma.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
    01 Apr 2019
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    05 Sep 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To compare the annualised total bleeding rate (ABR) of individually tailored prophylaxis with the historical bleeding rate observed in patients having received on-demand treatment with Human-cl rhFVIII from clinical study GENA-01
    Protection of trial subjects
    The study was conducted in accordance with the ethical principles of the Declaration of Helsinki, and ICH-GCP (Note for Guidance CPMP/ICH/135/95), and national regulatory requirements. Inclusion and exclusion criteria were carefully defined in order to protect subjects from contraindications, interactions with other medication and risk factors associated with the investigational medicinal product. Throughout the study safety was assessed, such as occurrence of AEs, documentation of concomitant medication and testing for FVIII inhibitor formation.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    13 May 2015
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Netherlands: 2
    Country: Number of subjects enrolled
    Slovenia: 2
    Country: Number of subjects enrolled
    Croatia: 2
    Country: Number of subjects enrolled
    Finland: 4
    Country: Number of subjects enrolled
    France: 6
    Country: Number of subjects enrolled
    Canada: 4
    Country: Number of subjects enrolled
    Japan: 11
    Country: Number of subjects enrolled
    Macedonia, the former Yugoslav Republic of: 4
    Country: Number of subjects enrolled
    United States: 23
    Worldwide total number of subjects
    58
    EEA total number of subjects
    16
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    57
    From 65 to 84 years
    1
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 Patients with severe haemophilia A (FVII:<1%) having previous treatment with any FVIII product for at least 150 exposure days were screened according to predefined in- and exclusion criteria. Patients in Japan who completed the 6 months of prophylactic treatment in Treatment Phase II were given the option to continue in a Sub-Study Extension Phase

    Period 1
    Period 1 title
    Overall Trial
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 Initial PK Assessment
    Arm description
    		 At the Initial PK Visit, patients were to receive Human-cl rhFVIII at a dose of 60 ± 5 IU/kg (labelled dose).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Human-cl rhFVIII
    Investigational medicinal product code
    Other name
    Nuwiq
    Pharmaceutical forms
    Concentrate and solvent for solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    At the Initial PK Visit, patients were to receive Human-cl rhFVIII at a dose of 60 ± 5 IU/kg (labelled dose)

    Number of subjects in period 1
    		Initial PK Assessment
    Started
    58
    Completed
    58
    Period 2
    Period 2 title
    Prophylactic Treatment—Phase I
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 Prophylactic Treatment—Phase I
    Arm description
    		 The 72-hour sampling time point of the Initial PK Visit marked the beginning of Prophylactic Treatment—Phase I, in which patients were to be treated prophylactically every other day or 3x/week with a dose of 30–40 IU/kg BW for about 1–3 months until PK data had been analysed and discussed with the investigator. Dose escalations were allowed in case of an inadequate frequency and severity of breakthrough bleeding episodes in accordance with the institution’s standard clinical care. The maximum dose for a single infusion was 45 IU/kg BW in Japan.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Human-cl rhFVIII
    Investigational medicinal product code
    Other name
    Nuwiq
    Pharmaceutical forms
    Concentrate and solvent for solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Patients were to be treated prophylactically every other day or 3x/week with a dose of 30–40 IU/kg BW for about 1–3 months until PK data had been analysed and discussed with the investigator. Dose escalations were allowed in case of an inadequate frequency and severity of breakthrough bleeding episodes in accordance with the institution’s standard clinical care. The maximum dose for a single infusion was 45 IU/kg BW in Japan

    Number of subjects in period 2
    		Prophylactic Treatment—Phase I
    Started
    58
    Completed
    56
    Not completed
    2
         Withdrawl by patient
    2
    Period 3
    Period 3 title
    Prophylactic Treatment—Phase II
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 Prophylactic Treatment—Phase II
    Arm description
    		 Patients were to be treated prophylactically for 6 months. Prophylactic doses and dosing intervals were recommended by the Sponsor for each patient based on the analysis of individual PK data obtained at the Initial PK Visit with the one-stage assay.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Human-cl rhFVIII
    Investigational medicinal product code
    Other name
    Nuwiq
    Pharmaceutical forms
    Concentrate and solvent for solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Based on an appropriate PK model, various dosing intervals (usually 12-hr intervals) and corresponding doses (in IU/kg) were calculated, which hypothetically lead to FVIII:C plasma concentrations of at least 0.01 IU/mL at the end of the respective injection interval. The goal was to use the maximum regular prophylactic dosing interval that could be achieved with a maximum dose of not more than 65 IU/kg and that maintained a trough level of ≥0.01 IU/mL. At the 4-Month Visit the dose per injection for the remainder of the study could have been reduced provided that FVIII:C trough levels (one-stage assay) obtained at the 2-Month Visit were ≥0.01 IU/mL and that the patient had not experienced any spontaneous bleed up to the 4-Month Visit.In case of unacceptable frequent and/or severe spontaneous breakthrough bleedings, the dose was to be increased by approximately 5 IU/kg . The maximum dose was preferably not to exceed 65 IU/kg.

    Number of subjects in period 3
    		Prophylactic Treatment—Phase II
    Started
    56
    Completed
    52
    Not completed
    4
         Stopped on his own account
    1
         Lost to follow-up
    3

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Overall Trial
    Reporting group description
    		 -

    Reporting group values
    		 Overall Trial Total
    Number of subjects
    		 58 58
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 57 57
        From 65-84 years
    		 1 1
    Age continuous
    Units: years
        median (full range (min-max))
    		 36.5 (18 to 71) -
    Gender categorical
    Units: Subjects
        Female
    		 0 0
        Male
    		 58 58

    End points

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    End points reporting groups
    Reporting group title
    Initial PK Assessment
    Reporting group description
    		 At the Initial PK Visit, patients were to receive Human-cl rhFVIII at a dose of 60 ± 5 IU/kg (labelled dose).
    Reporting group title
    Prophylactic Treatment—Phase I
    Reporting group description
    		 The 72-hour sampling time point of the Initial PK Visit marked the beginning of Prophylactic Treatment—Phase I, in which patients were to be treated prophylactically every other day or 3x/week with a dose of 30–40 IU/kg BW for about 1–3 months until PK data had been analysed and discussed with the investigator. Dose escalations were allowed in case of an inadequate frequency and severity of breakthrough bleeding episodes in accordance with the institution’s standard clinical care. The maximum dose for a single infusion was 45 IU/kg BW in Japan.
    Reporting group title
    Prophylactic Treatment—Phase II
    Reporting group description
    		 Patients were to be treated prophylactically for 6 months. Prophylactic doses and dosing intervals were recommended by the Sponsor for each patient based on the analysis of individual PK data obtained at the Initial PK Visit with the one-stage assay.

    Subject analysis set title
    GENA-01 (ITT)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    ITT population in the GENA-01 study

    Subject analysis set title
    GENA-21b (PROPH)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    All patients in the ITT population who enter the Prophylactic Treatment—Phase II of the study (i.e., have at least one prophylactic treatment in Phase II)

    Subject analysis set title
    GENA-01 (PP)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    PP- population of GENA-01 study

    Subject analysis set title
    GENA-21b (PROPH-PP)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    All patients in the PP population who enter the Prophylactic Treatment—Phase II of the study – who have evaluable initial PK results for the evaluation of the individual prophylactic treatment schedule – with at least 6 months (–2 weeks) of individual prophylactic treatment (Prophylactic Treatment—Phase II) with Human-cl rhFVIII – who have no significant dosing or treatment errors, e.g., several unexplained interruptions of individual prophylaxis with Human-cl rhFVIII, e.g. >20% of prophylactic injections were not given within the prescribed treatment intervals (± 1 day)

    Subject analysis set title
    GENA-01 vs GENA-21b
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Comparison of ABRs between GENA-01 (N=56) and GENA-21b (N=22)

    Subject analysis set title
    PK-PP Population
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    The PK-PP population contained all patients in the PK analysis population who completed the initial PK sampling phase of the trial without significantly violating the inclusion/exclusion criteria or other aspects of the protocol considered to potentially affect the PK results.

    Subject analysis set title
    SAF-Population
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    The SAF population included 58 patients who received at least one infusion of Human-c1 rhFVIII in the GENA-21b trial

    Primary: Annualized Total Bleeding Rate of Individually Tailored Prophylaxis

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    End point title
    		 Annualized Total Bleeding Rate of Individually Tailored Prophylaxis [1]
    End point description
    The analysis population comprised 56 patients who received at least one infusion of Human-cI rhFVIII for individualized prophylaxis in the GENA-21b trial. Their annualized bleeding rate (ABR) was compared with those in patients from the completed GENA-01 trial who received only on-demand treatment. A respective confirmative one-sided one-sample Poisson-test was used to demonstrate if the mean ABR in patients with individually tailored prophylaxis is at least 50% below the mean ABR rate in the GENA-01 trial. (95% CI (2-Sided) 95% 4.06 to 5.79) A confidence interval of 97.5% for confirmative analysis was also used - the respective upper and lower limit CIs were 3.96-5.93
    End point type
    Primary
    End point timeframe
    6 months
    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: Trial has 1 arm only. For entry of statistical analysis at least 2 arms are required, therefore only results for this endpoint are provided. Prim. endpoint was reduction of the ABR in the GENA-01 on-demand study by 50% during individually tailored prophylaxis. The primary endpoint was met, as the confirmative one-sided one-sample Poisson-test demonstrated that the mean ABR in patients with individually tailored prophylaxis (4.87) was at least 50% below the mean ABR rate in GENA-01 trial (49.36).
    End point values
    		 GENA-01 (ITT) GENA-21b (PROPH)
    Number of subjects analysed
    22
    56
    Units: Mean ABR
    number (not applicable)
        Annualized Bleeding Rate (ABR)
    49.36
    4.87
    No statistical analyses for this end point

    Primary: Annualised Total Bleeding Rate of Individually Tailored Prophylaxis

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    End point title
    		 Annualised Total Bleeding Rate of Individually Tailored Prophylaxis [2]
    End point description
    GENA-21b: Number of bleeding episodes / (time in days of the period - days of surgery phases) x 365.25 days. GENA-01: Number of bleeding episodes / (time in days of the period) x 365.25 days Mean ABR per patient was 4.67 in the GENA-21b PROPH population and 58.08 in the GENA-01 ITT population.
    End point type
    Primary
    End point timeframe
    6 months
    Notes
    [2] - 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: Trial has 1 arm only. For entry of statistical analysis at least 2 arms are required, therefore only results for this endpoint are provided. Results for this endpoint are presented as mean only. No statistical analysis performed for this endpoint.
    End point values
    		 GENA-01 (ITT) GENA-21b (PROPH)
    Number of subjects analysed
    22
    56
    Units: ABR
    number (not applicable)
        Mean Annualised Total Bleeding Rate
    58.08
    4.67
        ± SD
    30.78
    6.46
        95% CI for mean lower
    44.43
    2.94
        95% CI for mean upper
    71.73
    6.40
        Median
    54.5
    2.04
        Median range lower
    9.4
    0
        Median range upper
    129.8
    26.8
    No statistical analyses for this end point

    Primary: Comparison of Annualised Total Bleeding Rates (Negative Binomial Regression Model)

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    End point title
    		 Comparison of Annualised Total Bleeding Rates (Negative Binomial Regression Model) [3]
    End point description
    Reduction of the annualized total bleeding rate (ABR) observed in the GENA-01 study vs. GENA-21B analyzed with a Negative Binomial regression model including a correction for overdispersion.
    End point type
    Primary
    End point timeframe
    6 months
    Notes
    [3] - 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: Trial has 1 arm only. For entry of statistical analysis at least 2 arms are required, therefore only results for this endpoint are provided. Reduction of the annualized total bleeding rate (ABR) observed in the GENA-01 study vs. GENA-21B analyzed with a Negative Binomial regression model including a correction for overdispersion.
    End point values
    		 GENA-01 vs GENA-21b
    Number of subjects analysed
    56
    Units: Rate ratio
    number (not applicable)
        Rate ratio
    11.89
        95% CI lower limit
    7.50
        95% CI upper limit
    18.86
        p-value (2-sided) <
    0.0001
    No statistical analyses for this end point

    Primary: Comparison of Annualised Total Bleeding Rates (Poisson Regression Model)

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    End point title
    		 Comparison of Annualised Total Bleeding Rates (Poisson Regression Model) [4]
    End point description
    Reduction of the annualized total bleeding rate (ABR) observed in the GENA-01 study vs. GENA-21B analyzed with a Poisson regression model including a correction for overdispersion.
    End point type
    Primary
    End point timeframe
    6 months
    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: Trial has 1 arm only. For entry of statistical analysis at least 2 arms are required, therefore only results for this endpoint are provided. Reduction of the annualized total bleeding rate (ABR) observed in the GENA-01 study vs. GENA-21B analyzed with a Poisson regression model including a correction for overdispersion.
    End point values
    		 GENA-01 vs GENA-21b
    Number of subjects analysed
    56
    Units: Rate Ratio
    number (not applicable)
        Rate ratio
    10.14
        95% CI lower limit
    6.12
        95% CI upper limit
    16.80
        p-value (2-sided) <
    0.0001
    No statistical analyses for this end point

    Secondary: Annualized Spontaneous Bleeding Rate of Individually Tailored Prophylaxis

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    End point title
    		 Annualized Spontaneous Bleeding Rate of Individually Tailored Prophylaxis
    End point description
    The confirmative one-sided one-sample Poisson-test demonstrated that the mean spontaneous ABR in patients with individually tailored prophylaxis (3.12) is at least 50% below the mean spontaneous ABR rate in the GENA-01 trial (32.23). Two-sided 95% confidence interval for parameter of Poisson distribution. ABR = Sum of BEs / Sum of time periods under risk.
    End point type
    Secondary
    End point timeframe
    6 months
    End point values
    		 GENA-21b (PROPH)
    Number of subjects analysed
    56
    Units: ABR
    number (not applicable)
        Annualized Spontaneous Bleeding Rate (ABR)
    3.12
        95% CI for ABR lower limit
    2.48
        95% CI for ABR upper limit
    3.87
    No statistical analyses for this end point

    Secondary: Annualized Spontaneous Bleeding Rate of Individually Tailored Prophylaxis

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    End point title
    		 Annualized Spontaneous Bleeding Rate of Individually Tailored Prophylaxis
    End point description
    Spontaneous annualized bleeding rate (ABR) of individually tailored prophylaxis (GENA-21b) compared to historical bleeding rate in patients having received on-demand treatment (GENA-01) with Human-cl rhFVIII. The analysis population comprised 56 patients who received at least one infusion of Human-cI rhFVIII for individualized prophylaxis in the GENA-21b trial. Their annualized spontaneous bleeding rate was compared with those in patients from the completed GENA-01 trial who received only on-demand treatment.
    End point type
    Secondary
    End point timeframe
    6 months
    End point values
    		 GENA-01 (ITT) GENA-21b (PROPH)
    Number of subjects analysed
    22
    56
    Units: ABR
    number (not applicable)
        Mean Annualised Spontaneous Bleeding Rate
    38.46
    2.98
        ± SD
    28.07
    5.76
        95% CI for mean lower
    26.01
    1.43
        95% CI for mean upper
    50.90
    4.52
        Median
    40.6
    0
        Median range lower
    0
    0
        Median range upper
    99.3
    25.9
    No statistical analyses for this end point

    Secondary: Annualized Total Bleeding Rate in Patients With 2x/Week (or Less) Prophylaxis

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    End point title
    		 Annualized Total Bleeding Rate in Patients With 2x/Week (or Less) Prophylaxis
    End point description
    A respective confirmative one-sided one-sample Poisson-test was used to demonstrate if the mean ABR in patients with 2x/week prophylaxis or less with individually tailored prophylaxis is at least 50% below the mean ABR rate in the GENA-01 trial
    End point type
    Secondary
    End point timeframe
    6 months
    End point values
    		 GENA-21b (PROPH)
    Number of subjects analysed
    29
    Units: ABR
    number (not applicable)
        Annualised Total Bleeding Rate
    5.03
        95% CI for ABR lower limit
    3.90
        95% CI for ABR upper limit
    6.39
        97.5% CI for ABR lower limit
    3.76
        97.5% CI for ABR upper limit
    6.60
    No statistical analyses for this end point

    Secondary: Annualised Total Bleeding Rates in Patients with 2x/Week Prophylaxis or Less

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    End point title
    		 Annualised Total Bleeding Rates in Patients with 2x/Week Prophylaxis or Less
    End point description
    The analysis population comprised 29 patients who received at least one infusion of Human-cI rhFVIII for individualized prophylaxis in the GENA-21b trial at intervals of 2x/week or less. Their annualized spontaneous bleeding rate was compared with those in patients from the completed GENA-01 trial who received only on-demand treatment.
    End point type
    Secondary
    End point timeframe
    6 months
    End point values
    		 GENA-01 (ITT) GENA-21b (PROPH)
    Number of subjects analysed
    22
    29
    Units: ABR
    number (not applicable)
        Mean Annualised Total Bleeding Rate
    58.08
    4.82
        ± SD
    30.78
    6.98
        95% CI for mean lower
    44.43
    2.16
        95% CI for mean upper
    71.73
    7.47
        Median
    54.5
    2.0
        Median range lower
    9.4
    0
        Median range upper
    129.8
    26.8
    No statistical analyses for this end point

    Secondary: Median Prophylactic Dosing Interval

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    End point title
    		 Median Prophylactic Dosing Interval
    End point description
    Means and medians over median actual dosing intervals between two prophylactic treatments per patient. The analysis population comprised 56 patients who received at least one infusion of Human-cI rhFVIII for individualized prophylaxis in the GENA-21b trial.
    End point type
    Secondary
    End point timeframe
    6 months
    End point values
    		 GENA-21b (PROPH)
    Number of subjects analysed
    56
    Units: Hours
    number (not applicable)
        Median interval between prophylactic doses
    83.9
        Mean interval between prophylactic doses
    82.2
    No statistical analyses for this end point

    Secondary: AUC divided by the dose (AUCnorm) of Human-cl rhFVIII

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    End point title
    		 AUC divided by the dose (AUCnorm) of Human-cl rhFVIII
    End point description
    AUCnorm of Human-cl rhFVIII measured using the one-stage (OS) assay. The PK-PP population contained all patients in the PK analysis population who completed the initial PK sampling phase of the trial without significantly violating the inclusion/exclusion criteria or other aspects of the protocol considered to potentially affect the PK results.
    End point type
    Secondary
    End point timeframe
    Before injection (within 1 h before injection) and up to 72 h (± 2 h) after the end of injection.
    End point values
    		 PK-PP Population
    Number of subjects analysed
    47
    Units: AUCnorm
    arithmetic mean (standard deviation)
        Mean
    0.302 ( 0.116 )
    No statistical analyses for this end point

    Secondary: In-vivo Recovery (IVR) of Human-cl rhFVIII

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    End point title
    		 In-vivo Recovery (IVR) of Human-cl rhFVIII
    End point description
    IVR of Human-cl rhFVIII measured using the one-stage (OS) assay. The PK-PP population contained all patients in the PK analysis population who completed the initial PK sampling phase of the trial without significantly violating the inclusion/exclusion criteria or other aspects of the protocol considered to potentially affect the PK results.
    End point type
    Secondary
    End point timeframe
    Before injection (within 1 h before injection) and up to 72 h (± 2 h) after the end of injection.
    End point values
    		 PK-PP Population
    Number of subjects analysed
    47
    Units: IVR
        arithmetic mean (standard deviation)
    1.775 ( 0.421 )
    No statistical analyses for this end point

    Secondary: Half Life (t1/2) of Human-cl rhFVIII

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    End point title
    		 Half Life (t1/2) of Human-cl rhFVIII
    End point description
    T1/2 of Human-cl rhFVIII measured using the one-stage (OS) assay. The PK-PP population contained all patients in the PK analysis population who completed the initial PK sampling phase of the trial without significantly violating the inclusion/exclusion criteria or other aspects of the protocol considered to potentially affect the PK results.
    End point type
    Secondary
    End point timeframe
    Before injection (within 1 h before injection) and up to 72 h (± 2 h) after the end of injection.
    End point values
    		 PK-PP Population
    Number of subjects analysed
    47
    Units: t1/2
        arithmetic mean (standard deviation)
    15.725 ( 4.029 )
    No statistical analyses for this end point

    Secondary: Mean Residence Time (MRT) of Human-cl rhFVIII

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    End point title
    		 Mean Residence Time (MRT) of Human-cl rhFVIII
    End point description
    MRT of Human-cl rhFVIII measured using the one-stage . The PK-PP population contained all patients in the PK analysis population who completed the initial PK sampling phase of the trial without significantly violating the inclusion/exclusion criteria or other aspects of the protocol considered to potentially affect the PK results.
    End point type
    Secondary
    End point timeframe
    Before injection (within 1 h before injection) and up to 72 h (± 2 h) after the end of injection
    End point values
    		 PK-PP Population
    Number of subjects analysed
    47
    Units: MRT
        arithmetic mean (standard deviation)
    20.762 ( 5.997 )
    No statistical analyses for this end point

    Secondary: Clearance (CL) of Human-cl rhFVIII

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    End point title
    		 Clearance (CL) of Human-cl rhFVIII
    End point description
    CL of Human-cl rhFVIII measured using the one-stage (OS) assay. The PK-PP population contained all patients in the PK analysis population who completed the initial PK sampling phase of the trial without significantly violating the inclusion/exclusion criteria or other aspects of the protocol considered to potentially affect the PK results.
    End point type
    Secondary
    End point timeframe
    Before injection (within 1 h before injection) and up to 72 h (± 2 h) after the end of injection.
    End point values
    		 PK-PP Population
    Number of subjects analysed
    47
    Units: CL
        arithmetic mean (standard deviation)
    3.859 ( 1.670 )
    No statistical analyses for this end point

    Secondary: Volume of Distribution at Steady State (Vss) Human-cl rhFVIII

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    End point title
    		 Volume of Distribution at Steady State (Vss) Human-cl rhFVIII
    End point description
    Vss of Human-cl rhFVIII measured using the one-stage (OS) assay. The PK-PP population contained all patients in the PK analysis population who completed the initial PK sampling phase of the trial without significantly violating the inclusion/exclusion criteria or other aspects of the protocol considered to potentially affect the PK results.
    End point type
    Secondary
    End point timeframe
    Before injection (within 1 h before injection) and up to 72 h (± 2 h) after the end of injection.
    End point values
    		 PK-PP Population
    Number of subjects analysed
    47
    Units: Vss
        arithmetic mean (standard deviation)
    72.901 ( 16.454 )
    No statistical analyses for this end point

    Secondary: Usage of Human-cl rhFVIII (FVIII IU/kg bw Per Week Per Patient)

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    End point title
    		 Usage of Human-cl rhFVIII (FVIII IU/kg bw Per Week Per Patient)
    End point description
    Average weekly consumption of Human-cl rhFVIII reported as IU/kg bw per week per patient was determined during individualized prophylactic treatment. The analysis population comprised 56 patients who received at least one infusion of Human-cI rhFVIII for individualized prophylaxis in the GENA-21b trial.
    End point type
    Secondary
    End point timeframe
    6 months
    End point values
    		 GENA-21b (PROPH)
    Number of subjects analysed
    56
    Units: FVIII IU/kg bw Per Week Per Patient
        arithmetic mean (standard deviation)
    83.7 ( 25.7 )
    No statistical analyses for this end point

    Secondary: Number of Patients With Adverse Events (AEs)

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    End point title
    		 Number of Patients With Adverse Events (AEs)
    End point description
    AEs were documented at each (scheduled or unscheduled) study visit. Severity and seriousness of all AEs were documented by the investigator according to pre-defined criteria. The SAF population included 58 patients who received at least one infusion of Human-c1 rhFVIII in the GENA-21b trial.
    End point type
    Secondary
    End point timeframe
    At each study visit over the study duration (7–9 months)
    End point values
    		 SAF-Population
    Number of subjects analysed
    58
    Units: Patients
        AE
    34
        No AE
    24
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    AEs were reprorted throughout the study from screening visit until study completion visit. Planned surgeries were exempted from the SAE reporting requirement.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    21.0
    Reporting groups
    Reporting group title
    Safety Population (SAF)
    Reporting group description
    		 All patients who received at least one dose of Human-cl rhFVIII.

    Serious adverse events
    		 Safety Population (SAF)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    4 / 58 (6.90%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Basosquamous carcinoma
         subjects affected / exposed
    1 / 58 (1.72%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Diffuse large B-cell lymphoma
         subjects affected / exposed
    1 / 58 (1.72%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Injury, poisoning and procedural complications
    Subdural haematoma
         subjects affected / exposed
    1 / 58 (1.72%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    1 / 58 (1.72%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    1 / 58 (1.72%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Metabolism and nutrition disorders
    Hypokalaemia
         subjects affected / exposed
    1 / 58 (1.72%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 3%
    Non-serious adverse events
    		 Safety Population (SAF)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    34 / 58 (58.62%)
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    2 / 58 (3.45%)
         occurrences all number
    3
    Headache
         subjects affected / exposed
    5 / 58 (8.62%)
         occurrences all number
    18
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    2 / 58 (3.45%)
         occurrences all number
    2
    Lymphadenopathy
         subjects affected / exposed
    2 / 58 (3.45%)
         occurrences all number
    2
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    3 / 58 (5.17%)
         occurrences all number
    3
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    3 / 58 (5.17%)
         occurrences all number
    3
    Dyspepsia
         subjects affected / exposed
    2 / 58 (3.45%)
         occurrences all number
    3
    Gastritis
         subjects affected / exposed
    2 / 58 (3.45%)
         occurrences all number
    2
    Respiratory, thoracic and mediastinal disorders
    Nasal congestion
         subjects affected / exposed
    2 / 58 (3.45%)
         occurrences all number
    2
    Oropharyngeal pain
         subjects affected / exposed
    3 / 58 (5.17%)
         occurrences all number
    3
    Psychiatric disorders
    Depression
         subjects affected / exposed
    2 / 58 (3.45%)
         occurrences all number
    2
    Insomnia
         subjects affected / exposed
    2 / 58 (3.45%)
         occurrences all number
    2
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    4 / 58 (6.90%)
         occurrences all number
    9
    Bone pain
         subjects affected / exposed
    2 / 58 (3.45%)
         occurrences all number
    2
    Pain in extremity
         subjects affected / exposed
    2 / 58 (3.45%)
         occurrences all number
    3
    Infections and infestations
    Influenza
         subjects affected / exposed
    3 / 58 (5.17%)
         occurrences all number
    6
    Nasopharyngitis
         subjects affected / exposed
    12 / 58 (20.69%)
         occurrences all number
    17
    Urinary tract infection
         subjects affected / exposed
    3 / 58 (5.17%)
         occurrences all number
    3
    Metabolism and nutrition disorders
    Hypokalaemia
         subjects affected / exposed
    1 / 58 (1.72%)
         occurrences all number
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    23 Jun 2015
    Amendment 02: • ABO Blood Type: Capture of information on ABO blood type was included in order to determine the association between the half-life of Human-cl rhFVIII with ABO blood type. • Hemophilia Joint Health Score (HJHS): assessed within 3 months preceding the screening visit was also acceptable as HJHS will not significantly change in the short term. Clarification regarding the version of HJHS to be used was included and corresponding reference was updated • Information on target joints was to be captured in order to better characterise the patient’s bleeding history • SAE Reporting: Protocol was updated to exempt all planned surgeries from the SAE reporting requirement and not only surgeries planned before study start • for more clarity time windows for PK visit assessments were included.
    26 Oct 2015
    Amendment 03 . The following was included: • inhibitor testing at: Day 14, Day 30, End of Phase I, Phase II 2M and 4M visits; 3-8 weeks after surgery •stopping rules related to the development of a neutralizing antibody (inhibitor) to FVIII • time frame for a second confirmatory test in case an inhibitor result is positive The following was excluded: • participation of patients who are not qualified to give legal consent in Netherlands

    Interruptions (globally)
    Were there any global interruptions to the trial? No

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