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    Clinical Trial Results:
    ADVATE Antihemophilic Factor (Recombinant), Plasma/Albumin-Free Method (ADVATE rAHF-PFM): A Phase 4 Study Comparing Two Prophylactic Regimens In Subjects With Severe Or Moderately Severe Hemophilia A

    Due to the EudraCT – Results system being out of service between 31 July 2015 and 12 January 2016, these results have been published in compliance with revised timelines.
    Summary
    EudraCT number
    2005-000347-29
    Trial protocol
    GB   AT   HU   CZ   SI   IT  
    Global end of trial date
    16 Jun 2010

    Results information
    Results version number
    v1(current)
    This version publication date
    05 Mar 2016
    First version publication date
    05 Mar 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    060201
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT00243386
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Baxalta Innovations GmbH
    Sponsor organisation address
    Industriestrasse 67, Vienna, Austria, 1221
    Public contact
    Clinical Trial Registries and Results Disclosure, Baxalta Innovations GmbH, ClinicalTrialsDisclosure@baxalta.com
    Scientific contact
    Clinical Trial Registries and Results Disclosure, Baxalta Innovations GmbH, ClinicalTrialsDisclosure@baxalta.com
    Sponsor organisation name
    Baxalta US Inc.
    Sponsor organisation address
    One Baxter Way, Westlake Village, United States, CA 91362
    Public contact
    Clinical Trial Registries and Results Disclosure, Baxalta US Inc., ClinicalTrialsDisclosure@baxalta.com
    Scientific contact
    Clinical Trial Registries and Results Disclosure, Baxalta US Inc., ClinicalTrialsDisclosure@baxalta.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    Yes
    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
    16 Jun 2010
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    16 Jun 2010
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this study was to compare the rates of bleeding episodes between a standard prophylaxis regimen (20 to 40 IU/kg every 48 ± 6 hours) and a pharmacokinetics (PK)-driven prophylaxis regimen (20 to 80 IU/kg every 72 ± 6 hours).
    Protection of trial subjects
    This study was conducted in accordance with the standards of Good Clinical Practice (GCP) in effect at the time of the study.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    04 Jan 2006
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Austria: 1
    Country: Number of subjects enrolled
    Czech Republic: 6
    Country: Number of subjects enrolled
    Greece: 2
    Country: Number of subjects enrolled
    Hungary: 9
    Country: Number of subjects enrolled
    Italy: 4
    Country: Number of subjects enrolled
    Poland: 26
    Country: Number of subjects enrolled
    Russian Federation: 8
    Country: Number of subjects enrolled
    Slovenia: 1
    Country: Number of subjects enrolled
    United Kingdom: 2
    Country: Number of subjects enrolled
    United States: 23
    Worldwide total number of subjects
    82
    EEA total number of subjects
    51
    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)
    5
    Adolescents (12-17 years)
    8
    Adults (18-64 years)
    69
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    Subjects were enrolled (signed informed consent) at 21 European and 9 United States clinical sites beginning January 2006 and completing in June 2010

    Pre-assignment
    Screening details
    82 subjects were enrolled and screened. 7 were screen failures, 1 was withdrawn for non-compliance, and 1 requested withdrawal. Therefore, 73 of the 82 enrolled were treated with investigational product (rAFH-PFM).

    Pre-assignment period milestones
    Number of subjects started
    82
    Number of subjects completed
    73

    Pre-assignment subject non-completion reasons
    Reason: Number of subjects
    Consent withdrawn by subject: 1
    Reason: Number of subjects
    Screen Failure: 7
    Reason: Number of subjects
    Withdrawn for non compliance: 1
    Period 1
    Period 1 title
    Overall study (Parts 1 and 2) (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Not blinded
    Blinding implementation details
    This open-label study had 2 parts Part 1: Subjects underwent PK evaluation for 48 hours followed by on-demand treatment with rAFH-PFM for 6 months Part 2: Subjects were randomized either to standard prophylaxis or PK-driven prophylaxis (both with rAFH-PFM) for 12 months. Randomization in part 2 stratified based on presence of target joints [joint in which at least 4 bleeds occurred within 6 months or > 20 lifetime bleeds (0 target joints; 1-2 target joints; ≥ target joints) to reduce bias

    Arms
    Are arms mutually exclusive
    No

    Arm title
    All subjects
    Arm description
    All subjects who were exposed to investigational product (rAHF-PFM).
    Arm type
    Experimental

    Investigational medicinal product name
    ADVATE
    Investigational medicinal product code
    rAHF-PFM
    Other name
    Pharmaceutical forms
    Powder and solvent for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Standard Prophylaxis - 20-40 IU/kg every 48±6h; PK-driven Prophylaxis 20-80 IU/kg (determined by PK results) every 72±6h; On-demand - 10-100 IU/kg - dose and frequency dependent on severity and location of bleed

    Arm title
    On-Demand
    Arm description
    On-demand regimen - rAHF-PFM was to be used for the treatment of bleeding episodes according to the severity and type of episode by the protocol-recommended dosing until the episode resolved: superficial (10-20 IU/kg every 12-14 hours), minor joint (20-40 IU/kg every 12-14 hours), deep muscle (30-60 IU/kg every 12-14 hours), major joint or life-threatening (60-100 IU/kg every 8-12 hours), genitourinary, GI, and intracranial (60-100 IU/kg every 8-12 hours).
    Arm type
    Experimental

    Investigational medicinal product name
    ADVATE
    Investigational medicinal product code
    rAHF-PFM
    Other name
    Pharmaceutical forms
    Powder and solvent for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Standard Prophylaxis - 20-40 IU/kg every 48±6h; PK-driven Prophylaxis 20-80 IU/kg (determined by PK results) every 72±6h; On-demand - 10-100 IU/kg - dose and frequency dependent on severity and location of bleed

    Arm title
    Standard Prophylaxis
    Arm description
    Standard prophylaxis regimen - subjects dosed at 20-40 IU/kg of rAHF-PFM every 48 ± 6 hours, exact regimen to be determined by the investigator.
    Arm type
    Experimental

    Investigational medicinal product name
    ADVATE
    Investigational medicinal product code
    rAHF-PFM
    Other name
    Pharmaceutical forms
    Powder and solvent for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Standard Prophylaxis - 20-40 IU/kg every 48±6h; PK-driven Prophylaxis 20-80 IU/kg (determined by PK results) every 72±6h; On-demand - 10-100 IU/kg - dose and frequency dependent on severity and location of bleed

    Arm title
    PK-Driven Prophylaxis
    Arm description
    Pharmacokinetic (PK)-Driven prophylaxis regimen - subjects dosed at 20-80 IU/kg of rAHF-PFM every 72 ± 6 hours, exact regimen to be determined by the sponsor.
    Arm type
    Experimental

    Investigational medicinal product name
    ADVATE
    Investigational medicinal product code
    rAHF-PFM
    Other name
    Pharmaceutical forms
    Powder and solvent for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Standard Prophylaxis - 20-40 IU/kg every 48±6h; PK-driven Prophylaxis 20-80 IU/kg (determined by PK results) every 72±6h; On-demand - 10-100 IU/kg - dose and frequency dependent on severity and location of bleed

    Arm title
    Any Prophylaxis
    Arm description
    Standard Prophylaxis: 20-40 IU/kg of rAHF-PFM every 48 ± 6 hours, exact regimen to be determined by the investigator. PK-Driven Prophylaxis: 20-80 IU/kg of rAHF-PFM every 72 ± 6 hours, exact regimen to be determined by the sponsor
    Arm type
    Experimental

    Investigational medicinal product name
    ADVATE
    Investigational medicinal product code
    rAHF-PFM
    Other name
    Pharmaceutical forms
    Powder and solvent for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Standard Prophylaxis - 20-40 IU/kg every 48±6h; PK-driven Prophylaxis 20-80 IU/kg (determined by PK results) every 72±6h; On-demand - 10-100 IU/kg - dose and frequency dependent on severity and location of bleed

    Number of subjects in period 1
    All subjects On-Demand Standard Prophylaxis PK-Driven Prophylaxis Any Prophylaxis
    Started
    73
    73
    32
    34
    66
    Completed
    63
    66
    32
    31
    63
    Not completed
    10
    7
    0
    3
    3
         Lack of efficacy
             1
             -
             -
             1
             1
         Screen-failure
             2
             2
             -
             -
             -
         Withdrawn for non-compliance
             3
             1
             -
             2
             2
         Consent withdrawn by subject
             2
             2
             -
             -
             -
         Lost to follow-up
             2
             2
             -
             -
             -

    Baseline characteristics

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    Baseline characteristics reporting groups [1]
    Reporting group title
    Overall study (Parts 1 and 2)
    Reporting group description
    Overall study (Parts 1 and 2)

    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: The worldwide number of subjects enrolled only included subjects treated with study product (N=73) as per definition of enrolled in EudraCT (Enrolled=Treated). The number of subjects reported in the baseline period includes all subjects enrolled in the study i.e. signed informed consent (N=82).
    Reporting group values
    Overall study (Parts 1 and 2) Total
    Number of subjects
    73
    Age categorical
    Units: Subjects
    Age continuous
    Age continuous description
    Units: years
        median (full range (min-max))
    26 (7 to 59) -
    Gender categorical
    Gender categorical description
    Units: Subjects
        Female
    0 0
        Male
    73 73

    End points

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    End points reporting groups
    Reporting group title
    All subjects
    Reporting group description
    All subjects who were exposed to investigational product (rAHF-PFM).

    Reporting group title
    On-Demand
    Reporting group description
    On-demand regimen - rAHF-PFM was to be used for the treatment of bleeding episodes according to the severity and type of episode by the protocol-recommended dosing until the episode resolved: superficial (10-20 IU/kg every 12-14 hours), minor joint (20-40 IU/kg every 12-14 hours), deep muscle (30-60 IU/kg every 12-14 hours), major joint or life-threatening (60-100 IU/kg every 8-12 hours), genitourinary, GI, and intracranial (60-100 IU/kg every 8-12 hours).

    Reporting group title
    Standard Prophylaxis
    Reporting group description
    Standard prophylaxis regimen - subjects dosed at 20-40 IU/kg of rAHF-PFM every 48 ± 6 hours, exact regimen to be determined by the investigator.

    Reporting group title
    PK-Driven Prophylaxis
    Reporting group description
    Pharmacokinetic (PK)-Driven prophylaxis regimen - subjects dosed at 20-80 IU/kg of rAHF-PFM every 72 ± 6 hours, exact regimen to be determined by the sponsor.

    Reporting group title
    Any Prophylaxis
    Reporting group description
    Standard Prophylaxis: 20-40 IU/kg of rAHF-PFM every 48 ± 6 hours, exact regimen to be determined by the investigator. PK-Driven Prophylaxis: 20-80 IU/kg of rAHF-PFM every 72 ± 6 hours, exact regimen to be determined by the sponsor

    Subject analysis set title
    Subjects ≥14 Years
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Comprised of subjects ≥14 Years

    Subject analysis set title
    Subjects <14 Years
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Comprised of subjects <14 Years

    Subject analysis set title
    On-Demand Versus Standard Prophylaxis
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    On-demand: rAHF-PFM was to be used for the treatment of bleeding episodes according to the severity and type of episode by the protocol-recommended dosing until the episode resolved: superficial (10-20 IU/kg every 12-14 hours), minor joint (20-40 IU/kg every 12-14 hours), deep muscle (30-60 IU/kg every 12-14 hours), major joint or life-threatening (60-100 IU/kg every 8-12 hours), genitourinary, Gastrointestinal (GI), and intracranial (60-100 IU/kg every 8-12 hours). Standard Prophylaxis: 20-40 IU/kg of rAHF-PFM every 48 ± 6 hours, exact regimen to be determined by the investigator.

    Subject analysis set title
    On-Demand Versus PK-Driven Prophylaxis
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    On-demand: rAHF-PFM was to be used for the treatment of bleeding episodes according to the severity and type of episode by the protocol-recommended dosing until the episode resolved: superficial (10-20 IU/kg every 12-14 hours), minor joint (20-40 IU/kg every 12-14 hours), deep muscle (30-60 IU/kg every 12-14 hours), major joint or life-threatening (60-100 IU/kg every 8-12 hours), genitourinary, GI, and intracranial (60-100 IU/kg every 8-12 hours). PK-driven prophylaxis: 20-80 IU/kg of rAHF-PFM every 72 ± 6 hours, exact regimen to be determined by the sponsor.

    Subject analysis set title
    On-Demand Versus Any Prophylaxis
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    On-demand: rAHF-PFM was to be used for the treatment of bleeding episodes according to the severity and type of episode by the protocol-recommended dosing until the episode resolved: superficial (10-20 IU/kg every 12-14 hours), minor joint (20-40 IU/kg every 12-14 hours), deep muscle (30-60 IU/kg every 12-14 hours), major joint or life-threatening (60-100 IU/kg every 8-12 hours), genitourinary, GI, and intracranial (60-100 IU/kg every 8-12 hours) Prophylaxis: •Standard prophylaxis: 20-40 IU/kg of rAHF-PFM every 48 ± 6 hours, exact regimen to be determined by the investigator •PK-driven prophylaxis: 20-80 IU/kg of rAHF-PFM every 72 ± 6 hours, exact regimen to be determined by the sponsor

    Subject analysis set title
    Subjects with SAEs outside of 3 Treatment Arms
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    Subjects with SAEs that occurred after exposure to investigational product, but outside of the on-demand, standard prophylaxis and PK-driven prophylaxis treatment arms.

    Subject analysis set title
    On-Demand to Standard Prophylaxis
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Comprised of subjects who completed the on-demand and standard prophylaxis regimens.

    Subject analysis set title
    On-Demand to PK-Driven Prophylaxis
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Comprised of subjects who completed the on-demand and PK-driven prophylaxis regimens.

    Subject analysis set title
    On-Demand to Any Prophylaxis
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Comprised of subjects who completed the on-demand and any prophylaxis regimens.

    Subject analysis set title
    Subjects Assessed Before Treatment
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Subjects assessed before treatment with investigational product (rAFH-PFM).

    Primary: Mean Transformed Annualized Bleed Rate Estimates From Each of the 1-year Prophylaxis Regimens

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    End point title
    Mean Transformed Annualized Bleed Rate Estimates From Each of the 1-year Prophylaxis Regimens [1]
    End point description
    Subjects were randomized to receive 1 of the 2 following prophylaxis regimens (Study Part 2): 1. Standard prophylaxis (20-40 IU/kg (every 48 ±6 hours), exact regimen determined by investigator) 2. PK-driven prophylaxis (20-80 IU/kg (every 72 ±6 hours), exact regimen determined by sponsor) Annualized bleed rates were transformed using the square root of the number of bleeding episodes observed (X = bleeds/year), X′ = √(X + 0.5). This transformation was performed to stabilize the variance and align the sample distribution with the assumption of normality inherent in using the t-test. Population: Subjects in the efficacy per-protocol set comprising of all subjects who completed, according to the protocol, both the on-demand treatment regimen and the randomly assigned prophylactic regimen. Subjects did not have major protocol deviations that would impact the assessment of the primary efficacy endpoint.
    End point type
    Primary
    End point timeframe
    12 months ±2 weeks
    Notes
    [1] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Arms in the baseline period are not mutually exclusive. Refer to the description of arms in period 1 (baseline period). Please also note that it is not currently possible to enter statistics for some endpoints in this study due to limitations of EudraCT. All statistics are available for these study results in ClinicalTrials.gov (NCT00243386).
    End point values
    Standard Prophylaxis PK-Driven Prophylaxis
    Number of subjects analysed
    30
    23
    Units: (bleeds/year)^(1/2)
        arithmetic mean (standard deviation)
    1.46 ± 0.98
    1.61 ± 1.1
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    A t-test was used to compare the means of the transformed data. The null-hypothesis tested was H0: X'A(PK-driven prophylaxis) - X'B (standard prophylaxis) = 0 (i.e., no difference for treatment under the 2 prophylactic regimens. X' = (ABR+0.5)^(1/2)
    Comparison groups
    Standard Prophylaxis v PK-Driven Prophylaxis
    Number of subjects included in analysis
    53
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.6016
    Method
    t-test, 2 sided
    Confidence interval

    Primary: Median Annualized Bleed Rate Estimates From Each of the 1 Year Prophylaxis Regimens

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    End point title
    Median Annualized Bleed Rate Estimates From Each of the 1 Year Prophylaxis Regimens [2]
    End point description
    Subjects were randomized to receive 1 of the 2 following prophylaxis regimens (part 2 of the study): 1. Standard prophylaxis- infusions every 48 ±6 hours, dosed at 20 to 40 IU/kg. 2. PK-driven prophylaxis- infusions every 72 ±6 hours dosed at 20 to 80 IU/kg. Population: Subjects in the efficacy intent-to-treat set comprising of all subjects in the prophylaxis treatment regimen who had at least 1 assessment (1 quarterly visit) or who had withdrawn after 3 bleeding episodes prior to reaching the first assessment period.
    End point type
    Primary
    End point timeframe
    12 months ±2 weeks
    Notes
    [2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Arms in the baseline period are not mutually exclusive. Refer to the description of arms in period 1 (baseline period).
    End point values
    Standard Prophylaxis PK-Driven Prophylaxis
    Number of subjects analysed
    32
    34
    Units: Bleeds per year
        median (full range (min-max))
    1 (0 to 25.87)
    2.01 (0 to 17.06)
    Statistical analysis title
    Statistical analysis 1
    Comparison groups
    Standard Prophylaxis v PK-Driven Prophylaxis
    Number of subjects included in analysis
    66
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.1467
    Method
    Wilcoxon-Rank Sum (Mann-Whitney)
    Confidence interval
         level
    95%

    Secondary: Mean Difference of Transformed Annualized Bleeding Rate Between On-Demand and Standard Prophylaxis Treatment Regimens

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    End point title
    Mean Difference of Transformed Annualized Bleeding Rate Between On-Demand and Standard Prophylaxis Treatment Regimens
    End point description
    Annualized bleed rates were transformed using the square root of the number of bleeding episodes observed (X bleeds/year), X′ = √(X + 0.5). This transformation was performed to stabilize the variance and align the sample distribution with the assumption of normality inherent in using the paired t-test. Mean Difference of Transformed Annualized Bleeding Rate (TABR) = (On-Demand Treatment TABR) - (Standard Prophylaxis Treatment TABR). Participants from the On-Demand portion of the study were subsequently randomized to either Standard Prophylaxis or PK-Driven Prophylaxis, (i.e the same participants were analyzed across the two measurement time periods). Population: Subjects in the efficacy intent-to-treat set comprising of all subjects in the prophylaxis treatment regimen who had at least 1 assessment (1 quarterly visit) or who had withdrawn after 3 bleeding episodes prior to reaching the first assessment period.
    End point type
    Secondary
    End point timeframe
    On-demand 6 months (± 2 weeks); followed by Prophylaxis 12 months (± 2 weeks)
    End point values
    On-Demand Versus Standard Prophylaxis
    Number of subjects analysed
    32
    Units: (bleeds/year)^(1/2)
        arithmetic mean (standard deviation)
    5.29 ± 1.46
    No statistical analyses for this end point

    Secondary: Mean Difference of Transformed Annualized Bleeding Rate Between On-Demand and PK-Driven Prophylaxis Treatment Regimens

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    End point title
    Mean Difference of Transformed Annualized Bleeding Rate Between On-Demand and PK-Driven Prophylaxis Treatment Regimens
    End point description
    Annualized bleed rates were transformed using the square root of the number of bleeding episodes observed (X bleeds/year), X′ = √(X + 0.5). This transformation was performed to stabilize the variance and align the sample distribution with the assumption of normality inherent in using the paired t-test. Mean Difference of Transformed Annualized Bleeding Rate (TABR) = (On-Demand Treatment TABR) - (PK-Driven Prophylaxis Treatment TABR) Participants from the On-Demand portion of the study were subsequently randomized to either Standard Prophylaxis or PK-Driven Prophylaxis, (i.e the same participants were analyzed across the two measurement time periods). Population: Subjects in the efficacy intent-to-treat set comprising of all subjects in the prophylaxis treatment regimen who had at least 1 assessment (1 quarterly visit) or who had withdrawn after 3 bleeding episodes prior to reaching the first assessment period.
    End point type
    Secondary
    End point timeframe
    On-demand 6 months (± 2 weeks); followed by Prophylaxis 12 months (± 2 weeks)
    End point values
    On-Demand Versus PK-Driven Prophylaxis
    Number of subjects analysed
    34
    Units: (bleeds/year)^(1/2)
        arithmetic mean (standard deviation)
    5 ± 1.85
    No statistical analyses for this end point

    Secondary: Mean Difference of Transformed Annualized Bleeding Rate Between On-Demand and Any Prophylaxis Treatment Regimens

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    End point title
    Mean Difference of Transformed Annualized Bleeding Rate Between On-Demand and Any Prophylaxis Treatment Regimens
    End point description
    Annualized bleed rates were transformed using the square root of the number of bleeding episodes observed (X bleeds/year), X′ = √(X + 0.5). This transformation was performed to stabilize the variance and align the sample distribution with the assumption of normality inherent in using the paired t-test. Mean Difference of Transformed Annualized Bleeding Rate (TABR) = (On-Demand Treatment TABR) - (Any Prophylaxis Treatment TABR). Any Prophylaxis = Standard or PK-Driven Prophylaxis Participants from the On-Demand portion of the study were subsequently randomized to either Standard Prophylaxis or PK-Driven Prophylaxis, (i.e the same participants were analyzed across the two measurement time periods). Population: Subjects in the efficacy intent-to-treat set comprising of all subjects in the prophylaxis treatment regimen who had at least 1 assessment (1 quarterly visit) or who had withdrawn after 3 bleeding episodes prior to reaching the first assessment period.
    End point type
    Secondary
    End point timeframe
    On-demand 6 months (± 2 weeks); Prophylaxis 12 months (± 2 weeks)
    End point values
    On-Demand Versus Any Prophylaxis
    Number of subjects analysed
    66
    Units: (bleeds/year)^(1/2)
        arithmetic mean (standard deviation)
    5.14 ± 1.66
    No statistical analyses for this end point

    Secondary: Total Weight-Adjusted Dose of rAHF-PFM Used Per Year for Each Prophylaxis Arm

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    End point title
    Total Weight-Adjusted Dose of rAHF-PFM Used Per Year for Each Prophylaxis Arm [3]
    End point description
    Subjects were randomized to receive 1 of the 2 following prophylaxis regimens (part 2 of the study): 1. Standard prophylaxis- infusions every 48 ±6 hours, dosed at 20 to 40 IU/kg. 2. PK-driven prophylaxis- infusions every 72 ±6 hours dosed at 20 to 80 IU/kg. Population: Subjects in the efficacy intent-to-treat set comprising of all subjects in the prophylaxis treatment regimen who had at least 1 assessment (1 quarterly visit) or who had withdrawn after 3 bleeding episodes prior to reaching the first assessment period.
    End point type
    Secondary
    End point timeframe
    12 months ±2 weeks
    Notes
    [3] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Arms in the baseline period are not mutually exclusive. Refer to the description of arms in period 1 (baseline period).
    End point values
    Standard Prophylaxis PK-Driven Prophylaxis
    Number of subjects analysed
    32
    34
    Units: IU/kg
        median (inter-quartile range (Q1-Q3))
    5768.2 (4728 to 6425.4)
    5197.8 (3268.4 to 8273.5)
    Statistical analysis title
    Statistical analysis 1
    Comparison groups
    PK-Driven Prophylaxis v Standard Prophylaxis
    Number of subjects included in analysis
    66
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.4924
    Method
    Wilcoxon-Rank Sum (Mann-Whitney)
    Confidence interval
         level
    95%

    Secondary: Bleeding Episodes Treated With 1 to ≥4 Infusions

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    End point title
    Bleeding Episodes Treated With 1 to ≥4 Infusions [4]
    End point description
    The number of bleeding episodes treated with 1, 2, 3, or ≥4 infusions of rAHF-PFM to achieve adequate hemostasis. Population: Subjects in the efficacy intent-to-treat set comprising of all subjects in the prophylaxis treatment regimen who had at least 1 assessment (1 quarterly visit) or who had withdrawn after 3 bleeding episodes prior to reaching the first assessment period.
    End point type
    Secondary
    End point timeframe
    Throughout the study period (4 years and 5 months)
    Notes
    [4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Arms in the baseline period are not mutually exclusive. Refer to the description of arms in period 1 (baseline period) for this endpoint.
    End point values
    On-Demand Standard Prophylaxis PK-Driven Prophylaxis
    Number of subjects analysed
    62
    13
    22
    Units: Bleeding episodes
        1 infusion (n = 62, 13, 22)
    1168
    68
    90
        2 infusions (n = 51, 6, 9)
    277
    12
    37
        3 infusions (n = 27, 2, 4)
    128
    4
    5
        4 or more infusions (n = 21, 5, 5)
    50
    9
    7
    No statistical analyses for this end point

    Secondary: Assessment of Hemostasis for Treatment of Bleeding Episodes

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    End point title
    Assessment of Hemostasis for Treatment of Bleeding Episodes [5]
    End point description
    Number of rAHF-PFM-treated bleeding episodes with an assessment of hemostasis (4-point ordinal scale): Excellent: Full pain relief & bleeding cessation within ~8 hrs of 1 infusion. Additional infusions may have been given to maintain hemostasis; Good: Definite pain relief and/or improvement in bleeding within ~8 hrs after infusion. Possibly requires >1 infusion for complete resolution; Fair: Probable or slight relief of pain & slight improvement in bleeding within ~8 hrs after infusion. Requires >1 infusion for complete resolution; None: No improvement or condition worsens. Population: Subjects in the hemostatic efficacy rating set comprising of subjects who reported a bleeding episode that was treated with rAFH-PFM.
    End point type
    Secondary
    End point timeframe
    On-demand 6 months (± 2 weeks); Prophylaxis 12 months (± 2 weeks)
    Notes
    [5] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Arms in the baseline period are not mutually exclusive. Refer to the description of arms in period 1 (baseline period).
    End point values
    On-Demand Standard Prophylaxis PK-Driven Prophylaxis
    Number of subjects analysed
    70
    18
    25
    Units: Beeding episodes
        Excellent
    547
    39
    33
        Good
    943
    38
    75
        Fair
    167
    16
    11
        None
    3
    0
    20
        Unknown
    13
    0
    0
    No statistical analyses for this end point

    Secondary: Total Area Under the Curve (AUC)

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    End point title
    Total Area Under the Curve (AUC)
    End point description
    Total AUC estimated by AUC 0-48h plus an area extrapolated from the log-linear regression model. Population: Subjects in the pharmacokinetic (PK) intent-to-treat set comprising of subjects who provided at least 1 evaluable PK assessment.
    End point type
    Secondary
    End point timeframe
    Pharmacokinetic evaluations: 30 minutes pre-infusion up to 48 hours post-infusion
    End point values
    Subjects ≥14 Years Subjects <14 Years
    Number of subjects analysed
    65
    6
    Units: IU*h/dL
        geometric mean (standard deviation)
    1334.45 ± 454.33
    1061.26 ± 452.87
    No statistical analyses for this end point

    Secondary: Area Under the Curve

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    End point title
    Area Under the Curve
    End point description
    Area under the factor VIII (FVIII) plasma concentration versus time curve (AUC) from 0 to 48 hours estimated using the linear trapezoidal method. Population: Subjects in the pharmacokinetic (PK) intent-to-treat set comprising of subjects who provided at least 1 evaluable PK assessment.
    End point type
    Secondary
    End point timeframe
    Pharmacokinetic evaluations: 30 minutes pre-infusion up to 48 hours post-infusion
    End point values
    Subjects ≥14 Years Subjects <14 Years
    Number of subjects analysed
    65
    6
    Units: IU*h/dL
        geometric mean (standard deviation)
    1213.98 ± 323.96
    966.68 ± 330.83
    No statistical analyses for this end point

    Secondary: Maximum Plasma Concentration (C-max)

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    End point title
    Maximum Plasma Concentration (C-max)
    End point description
    Maximal Factor VIII Concentration After Infusion. Population: Subjects in the pharmacokinetic (PK) intent-to-treat set comprising of subjects who provided at least 1 evaluable PK assessment.
    End point type
    Secondary
    End point timeframe
    Within 1 hour post-infusion
    End point values
    Subjects ≥14 Years Subjects <14 Years
    Number of subjects analysed
    65
    6
    Units: IU/dL
        geometric mean (standard deviation)
    91.12 ± 20.15
    74.47 ± 11.3
    No statistical analyses for this end point

    Secondary: Adjusted Incremental Recovery (IR)

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    End point title
    Adjusted Incremental Recovery (IR)
    End point description
    Change in factor VIII concentration from pre- to post-infusion at initial and termination study visits. Adjusted IR defined as: [Cmax (IU/dL) – pre-infusion FVIII (IU/dL)]/dose (IU/kg). Population: Subjects in the pharmacokinetic (PK) intent-to-treat set comprising of subjects who provided at least 1 evaluable PK assessment.
    End point type
    Secondary
    End point timeframe
    30 minutes pre-infusion to 48 hours post-infusion
    End point values
    Subjects ≥14 Years Subjects <14 Years
    Number of subjects analysed
    65
    6
    Units: IU/dL per IU/kg
        geometric mean (standard deviation)
    1.81 ± 0.41
    1.47 ± 0.27
    No statistical analyses for this end point

    Secondary: Terminal Half-life

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    End point title
    Terminal Half-life
    End point description
    Computed from the regression slope in the terminal phase of the model. Terminal half life is the time it takes for the plasma concentration or the amount of drug in the body to be reduced by 50%. Population: Subjects in the pharmacokinetic (PK) intent-to-treat set comprising of subjects who provided at least 1 evaluable PK assessment.
    End point type
    Secondary
    End point timeframe
    Pharmacokinetic evaluations: 30 minutes pre-infusion up to 48 hours post-infusion
    End point values
    Subjects ≥14 Years Subjects <14 Years
    Number of subjects analysed
    65
    6
    Units: Hours
        arithmetic mean (standard deviation)
    13.91 ± 5.07
    14.66 ± 5.21
    No statistical analyses for this end point

    Secondary: Weight-Adjusted Clearance

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    End point title
    Weight-Adjusted Clearance
    End point description
    Computed as the weight-adjusted dose divided by total area under the curve (AUC). Population: Subjects in the pharmacokinetic (PK) intent-to-treat set comprising of subjects who provided at least 1 evaluable PK assessment.
    End point type
    Secondary
    End point timeframe
    Pharmacokinetic evaluations: 30 minutes pre-infusion up to 48 hours post-infusion
    End point values
    Subjects ≥14 Years Subjects <14 Years
    Number of subjects analysed
    65
    6
    Units: mL/(kg*h)
        arithmetic mean (standard deviation)
    3.89 ± 1.21
    5.17 ± 1.94
    No statistical analyses for this end point

    Secondary: Mean Residence Time

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    End point title
    Mean Residence Time
    End point description
    Computed as total Area Under the Moment Curve (AUMC) divided by the total area under the curve (AUC). Population: Subjects in the pharmacokinetic (PK) intent-to-treat set comprising of subjects who provided at least 1 evaluable PK assessment.Population: Comprised of subjects who provided at least 1 evaluable pharmacokinetic (PK) assessment.
    End point type
    Secondary
    End point timeframe
    Pharmacokinetic evaluations: 30 minutes pre-infusion up to 48 hours post-infusion
    End point values
    Subjects ≥14 Years Subjects <14 Years
    Number of subjects analysed
    65
    6
    Units: Hours
        arithmetic mean (standard deviation)
    17.71 ± 7.16
    17.88 ± 5.67
    No statistical analyses for this end point

    Secondary: Volume of Distribution at Steady State

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    End point title
    Volume of Distribution at Steady State
    End point description
    Computed as weight-adjusted clearance * mean residence time. Population: Subjects in the pharmacokinetic (PK) intent-to-treat set comprising of subjects who provided at least 1 evaluable PK assessment.
    End point type
    Secondary
    End point timeframe
    Pharmacokinetic evaluations: 30 minutes pre-infusion up to 48 hours post-infusion
    End point values
    Subjects ≥14 Years Subjects <14 Years
    Number of subjects analysed
    65
    6
    Units: dL/kg
        arithmetic mean (standard deviation)
    0.65 ± 0.19
    0.84 ± 0.19
    No statistical analyses for this end point

    Secondary: Factor VIII Inhibitor Development

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    End point title
    Factor VIII Inhibitor Development [6]
    End point description
    Number of treated subjects who developed factor VIII inhibitors. Population: All subjects in the safety analysis set comprising of all subjects who were exposed to rAHF-PFM.
    End point type
    Secondary
    End point timeframe
    Throughout study period (4 years and 5 months)
    Notes
    [6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Arms in the baseline period are not mutually exclusive. Refer to the description of arms in period 1 (baseline period).
    End point values
    All subjects
    Number of subjects analysed
    73
    Units: Subjects
    0
    No statistical analyses for this end point

    Secondary: Number of Subjects with AEs Related to Investigational Product (IP)

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    End point title
    Number of Subjects with AEs Related to Investigational Product (IP) [7]
    End point description
    Number of treated subjects with AEs judged to be possibly or probably related to treatment with IP. Population: All subjects in the safety analysis set comprising of all subjects who were exposed to rAHF-PFM.
    End point type
    Secondary
    End point timeframe
    Throughout study period (4 years and 5 months)
    Notes
    [7] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Arms in the baseline period are not mutually exclusive. Refer to the description of arms in period 1 (baseline period).
    End point values
    All subjects
    Number of subjects analysed
    73
    Units: Subjects
    4
    No statistical analyses for this end point

    Secondary: Number of Subjects who reported ≥1 AE Regardless of Relatedness to Investigational Product (IP)

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    End point title
    Number of Subjects who reported ≥1 AE Regardless of Relatedness to Investigational Product (IP) [8]
    End point description
    Number of treated subjects with 1 or more AE regardless of relatedness to IP. Population: All subjects in the safety analysis set comprising of all subjects who were exposed to rAHF-PFM.
    End point type
    Secondary
    End point timeframe
    Throughout study period (4 years and 5 months)
    Notes
    [8] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Arms in the baseline period are not mutually exclusive. Refer to the description of arms in period 1 (baseline period) .
    End point values
    All subjects
    Number of subjects analysed
    73
    Units: Subjects
    44
    No statistical analyses for this end point

    Secondary: Number of Subjects who reported ≥1 AE Regardless of Relatedness to Investigational Product (IP) by treatment regimen

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    End point title
    Number of Subjects who reported ≥1 AE Regardless of Relatedness to Investigational Product (IP) by treatment regimen [9]
    End point description
    Population: All subjects in the safety analysis set comprising of all subjects who were exposed to rAHF-PFM.
    End point type
    Secondary
    End point timeframe
    Throughout the study period (4 years and 5 months)
    Notes
    [9] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Arms in the baseline period are not mutually exclusive. Refer to the description of arms in period 1 (baseline period).
    End point values
    On-Demand Standard Prophylaxis PK-Driven Prophylaxis
    Number of subjects analysed
    72
    32
    34
    Units: Subjects
    33
    15
    19
    No statistical analyses for this end point

    Secondary: Number of Subjects with SAEs by Preferred MedDRA Term and Treatment Regimen

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    End point title
    Number of Subjects with SAEs by Preferred MedDRA Term and Treatment Regimen [10]
    End point description
    Number of Subjects with serious adverse events (SAEs) by Preferred MedDRA Term and Treatment Regimen (On-demand; Standard Prophylaxis and pharmacokinetic (PK)-driven Prophylaxis) Population: All subjects in the safety analysis set comprising of all subjects who were exposed to rAHF-PFM.
    End point type
    Secondary
    End point timeframe
    Throughout the study period (4 years and 5 months)
    Notes
    [10] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Arms in the baseline period are not mutually exclusive. Refer to the description of arms in period 1 (baseline period).
    End point values
    On-Demand Standard Prophylaxis PK-Driven Prophylaxis Subjects with SAEs outside of 3 Treatment Arms
    Number of subjects analysed
    72
    32
    34
    1
    Units: Subjects
        ABDOMINAL PAIN
    1
    0
    0
    0
        NAUSEA
    1
    0
    0
    0
        TOOTH ABSCESS
    1
    0
    0
    0
        JOINT DISLOCATION
    1
    0
    0
    0
        HAEMOPHILIC ARTHROPATHY
    1
    0
    1
    0
        SYNOVITIS
    1
    0
    0
    0
        CALCULUS URINARY
    1
    0
    0
    0
        HOSPITALIZATION
    1
    0
    0
    0
        PULPITIS DENTAL
    0
    1
    0
    0
        SOMNAMBULISM
    0
    1
    0
    0
        FACTOR VIII INHIBITION (UNCONFIRMED)
    0
    0
    1
    0
        APPENDICITIS
    0
    0
    1
    0
        PAIN IN EXTREMITY
    0
    0
    0
    1
    No statistical analyses for this end point

    Secondary: AEs with onset ≤1 hour following the end of an infusion, regardless of relatedness

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    End point title
    AEs with onset ≤1 hour following the end of an infusion, regardless of relatedness [11]
    End point description
    Population: All subjects in the safety analysis set comprising of all subjects who were exposed to rAHF-PFM.
    End point type
    Secondary
    End point timeframe
    Throughout study period (4 years and 5 months)
    Notes
    [11] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Arms in the baseline period are not mutually exclusive. Refer to the description of arms in period 1 (baseline period).
    End point values
    All subjects
    Number of subjects analysed
    73
    Units: Adverse events
    39
    No statistical analyses for this end point

    Secondary: Number of Subjects with Severe SAEs and Severe non-SAEs by Preferred MedDRA Term and Treatment Regimen

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    End point title
    Number of Subjects with Severe SAEs and Severe non-SAEs by Preferred MedDRA Term and Treatment Regimen [12]
    End point description
    This outcome is focused only on SEVERE serious adverse events (SAEs) and SEVERE non-SAEs. Population: All subjects in the safety analysis set comprising of all subjects who were exposed to rAHF-PFM.
    End point type
    Secondary
    End point timeframe
    Throughout the study period (4 years and 5 months)
    Notes
    [12] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Arms in the baseline period are not mutually exclusive. Refer to the description of arms in period 1 (baseline period).
    End point values
    On-Demand Standard Prophylaxis PK-Driven Prophylaxis
    Number of subjects analysed
    72
    32
    34
    Units: Subjects
        TOOTH ABSCESS (SAE)
    1
    0
    0
        HAEMOPHILIC ARTHROPATHY (SAE)
    0
    0
    1
        HAEMOPHILIC ARTHROPATHY (non-SAE)
    1
    0
    1
        ABDOMINAL PAIN (non-SAE)
    1
    0
    0
        ARTHRALGIA (non-SAE)
    1
    0
    0
    No statistical analyses for this end point

    Secondary: Baseline Health-related Quality of Life (HRQoL) Scores: PF, RP, BP, GH, VT, SF, RE, MH, PCS, and MCS

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    End point title
    Baseline Health-related Quality of Life (HRQoL) Scores: PF, RP, BP, GH, VT, SF, RE, MH, PCS, and MCS
    End point description
    Physical Functioning (PF); Role Limitation Due to Physical Health (RP); Bodily Pain (BP); General Health (GH); Vitality (VT); Social Functioning (SF); Role Limitation Due to Emotional Problems (RE); Mental Health (MH), Physical Component Score (PCS); Mental Component Score (MCS). Baseline SF-36v1 Scores, where data available. Scores range 0-100, higher scores represent better health. There is no total overall score; scoring is done for subscores and summary scores. The raw data from the SF-36 items were transformed to norm based scores for each of the 8 HRQoL/SF-36 health domain scores. Population: All subjects in pharmacoeconomic (PE) set comprising of subjects who completed a HRQoL assessment.
    End point type
    Secondary
    End point timeframe
    Baseline
    End point values
    Subjects Assessed Before Treatment
    Number of subjects analysed
    71
    Units: Scores on a scale
    median (full range (min-max))
        Physical Functioning (PF)
    44.56 (17.29 to 57.14)
        Role-Physical (RP)
    42.1 (27.95 to 56.24)
        Bodily Pain (BP)
    46.48 (25.07 to 62.75)
        General Health (GH)
    43.87 (19.52 to 64)
        Vitality (VT)
    51.42 (25.39 to 67.2)
        Social Functioning (SF)
    46.28 (19.14 to 57.14)
        Role-Emotional (RE)
    55.34 (23.74 to 55.34)
        Mental Health (MH)
    50.44 (20.91 to 64.07)
        Physical Component Score (PCS)
    42.32 (20.1 to 67.67)
        Mental Component Score (MCS)
    52.65 (22.56 to 68.1)
    No statistical analyses for this end point

    Secondary: Health-related Quality of Life (HRQoL) Scores: PF, RP, BP, GH, VT, SF, RE, MH, PCS, and MCS at the End of Treatment Regimens

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    End point title
    Health-related Quality of Life (HRQoL) Scores: PF, RP, BP, GH, VT, SF, RE, MH, PCS, and MCS at the End of Treatment Regimens [13]
    End point description
    Physical Functioning (PF); Role Limitation Due to Physical Health (RP); Bodily Pain (BP); General Health (GH); Vitality (VT); Social Functioning (SF); Role Limitation Due to Emotional Problems (RE); Mental Health (MH), Physical Component Score (PCS); Mental Component Score (MCS). Baseline SF-36v1 Scores, where data available. Scores range 0-100, higher scores represent better health. There is no total overall score; scoring is done for subscores and summary scores. The raw data from the SF-36 items were transformed to norm based scores for each of the 8 HRQoL/SF-36 health domain scores. Population: All subjects in pharmacoeconomic (PE) set comprising of subjects who completed a HRQoL assessment.
    End point type
    Secondary
    End point timeframe
    End of on-demand treatment period (6 months) and at study termination (approximately 18 months)
    Notes
    [13] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Arms in the baseline period are not mutually exclusive. Refer to the description of arms in period 1 (baseline period).
    End point values
    On-Demand Standard Prophylaxis PK-Driven Prophylaxis Any Prophylaxis
    Number of subjects analysed
    63
    31
    34
    65
    Units: Scores on a scale
    median (full range (min-max))
        Bodily Pain (BP)
    46.5 (29.4 to 62.8)
    51.6 (19.9 to 62.8)
    51.6 (29.4 to 62.8)
    51.6 (19.9 to 62.8)
        General Health (GH)
    43.9 (19.5 to 64)
    48.6 (19.5 to 64)
    46.2 (29.8 to 60.3)
    48.6 (19.5 to 64)
        Mental Component Score (MCS), On-Demand n=62
    54.9 (22.8 to 69.9)
    56.1 (13.3 to 69.6)
    54.5 (11.4 to 62.5)
    55 (11.4 to 69.6)
        Mental Health (MH), On-Demand n=62
    51.6 (14.1 to 64.1)
    50.4 (20.9 to 64.1)
    52.7 (7.3 to 64.1)
    50.4 (7.3 to 64.1)
        Physical Component Score (PCS), On-Demand n=62
    44 (16.1 to 61.2)
    50.2 (17.6 to 68.8)
    47.3 (25.3 to 62.3)
    47.8 (17.6 to 68.8)
        Physical Functioning (PF), On-Demand n=62
    48.8 (17.3 to 57.1)
    46.7 (21.5 to 57.1)
    46.7 (17.3 to 57.1)
    46.7 (17.3 to 57.1)
        Role Emotional (RE)
    55.3 (23.7 to 55.3)
    55.3 (23.7 to 55.3)
    55.3 (23.7 to 55.3)
    55.3 (23.7 to 55.3)
        Role Physical (RP)
    49.2 (28 to 56.2)
    56.2 (28 to 56.2)
    56.2 (28 to 56.2)
    56.2 (28 to 56.2)
        Social Functioning (SF)
    46.3 (30 to 57.1)
    51.7 (24.6 to 57.1)
    51.7 (13.7 to 57.1)
    51.7 (13.7 to 57.1)
        Vitality (VT)
    53.8 (32.5 to 70.4)
    56.2 (27.8 to 70.4)
    56.2 (23 to 68)
    56.2 (23 to 70.4)
    No statistical analyses for this end point

    Secondary: HRQoL Scores Change From On-Demand Treatment Regimen Period Through Prophylaxis Period

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    End point title
    HRQoL Scores Change From On-Demand Treatment Regimen Period Through Prophylaxis Period
    End point description
    Differences in health domain scores = (End of on-demand treatment) – (End of prophylaxis regimen). A negative value for the median difference equates to a larger domain score for the prophylaxis regimen. Physical Functioning (PF); Role Limitation Due to Physical Health (RP); Bodily Pain (BP); General Health (GH); Vitality (VT); Social Functioning (SF); Role Limitation Due to Emotional Problems (RE); Mental Health (MH), Physical Component Score (PCS); Mental Component Score (MCS). Scores range 0-100, higher scores represent better health. There is no total overall score; scoring is done for subscores and summary scores. The raw data from the SF-36 items were transformed to norm based scores for each of the 8 HRQoL/SF-36 health domain scores. Population: Subjects ≥14 years in pharmacoeconomic (PE) set comprising of subjects ≥14 years who completed a Health Related Quality of Life (HRQoL) assessment.
    End point type
    Secondary
    End point timeframe
    End of on-demand treatment period (6 months) and at study termination (approximately 18 months)
    End point values
    On-Demand to Standard Prophylaxis On-Demand to PK-Driven Prophylaxis On-Demand to Any Prophylaxis
    Number of subjects analysed
    27
    30
    57
    Units: Scores on a scale
    median (full range (min-max))
        Physical Functioning (PF)
    0 (-10.48 to 14.68)
    -2.1 (-18.88 to 20.97)
    -2.1 (-18.88 to 20.97)
        Role Physical (RP)
    0 (-28.29 to 21.21)
    0 (-28.29 to 28.29)
    0 (-28.29 to 28.29)
        Bodily Pain (BP)
    0 (-29.55 to 17.55)
    -4.29 (-25.27 to 13.28)
    0 (-29.55 to 17.55)
        General Health (GH)
    -3.74 (-21.07 to 18.73)
    -2.34 (-20.13 to 17.79)
    -2.34 (-21.07 to 18.73)
        Vitality (VT)
    0 (-9.47 to 23.67)
    0 (-16.57 to 30.77)
    0 (-16.57 to 30.77)
        Social Functioning (SF)
    0 (-21.72 to 16.29)
    0 (-16.29 to 16.29)
    0 (-21.72 to 16.29)
        Role Emotional (RE)
    0 (-10.53 to 31.6)
    0 (-31.6 to 21.07)
    0 (-31.6 to 31.6)
        Mental Health (MH)
    0 (-13.63 to 15.9)
    -1.13 (-40.9 to 34.08)
    0 (-40.9 to 34.08)
        Physical Component Score (PCS)
    -2.55 (-20.22 to 8.69)
    -3.14 (-16.78 to 19.7)
    -2.76 (-20.22 to 19.7)
        Mental Component Score (MCS)
    1.52 (-8.31 to 21.64)
    0.79 (-35.25 to 24.56)
    1.3 (-35.25 to 24.56)
    No statistical analyses for this end point

    Secondary: Bodily Pain HRQoL Scores Change From On-Demand Period Through Prophylaxis Period

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    End point title
    Bodily Pain HRQoL Scores Change From On-Demand Period Through Prophylaxis Period
    End point description
    After an on-demand treatment period, subjects were randomized to 1 of 2 prophylactic regimens for 12 months. The standard prophylactic regimen was dosed at 20 to 40 IU/kg every 48 ±6 hours, and the PK-driven prophylaxis regimen was dosed at 20 to 80 IU/kg every 72 ±6 hours. Bodily Pain Health Related Quality of Life (HRQoL) Scores Change = (End of on-demand treatment) – (End of prophylaxis regimen). A negative value for the median difference equates to a larger domain score for the prophylaxis regimen. Scores range 0-100, higher scores represent better health. There is no total overall score; scoring is done for subscores and summary scores. The raw data from the SF-36 items were transformed to norm based scores. Population: Subjects ≥14 years in pharmacoeconomic (PE) set comprising of subjects ≥14 years who completed a HRQoL assessment.
    End point type
    Secondary
    End point timeframe
    End of on-demand treatment period (6 months) and at study termination (approximately 18 months)
    End point values
    On-Demand to Any Prophylaxis
    Number of subjects analysed
    57
    Units: Scores on a scale
        median (full range (min-max))
    0 (-29.55 to 17.55)
    No statistical analyses for this end point

    Secondary: Physical Component Scores (PCS) HRQoL Scores Change From On-Demand Period Through Prophylaxis Period

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    End point title
    Physical Component Scores (PCS) HRQoL Scores Change From On-Demand Period Through Prophylaxis Period
    End point description
    After an on-demand treatment period, subjects were randomized to 1 of 2 prophylactic regimens for 12 months. The standard prophylactic regimen was dosed at 20 to 40 IU/kg every 48 ±6 hours, and the PK-driven prophylaxis regimen was dosed at 20 to 80 IU/kg every 72 ±6 hours. PCS Health Related Quality of Life (HRQoL) Scores Change = (End of on-demand treatment) – (End of prophylaxis regimen) A negative value for the median difference equates to a larger domain score for the prophylaxis regimen. Scores range 0-100, higher scores represent better health. There is no total overall score; scoring is done for subscores and summary scores. The raw data from the SF-36 items were transformed to norm based scores. Population: Subjects ≥14 years in pharmacoeconomic (PE) set comprising of subjects ≥14 years who completed a HRQoL assessment.
    End point type
    Secondary
    End point timeframe
    End of on-demand treatment period (6 months) and at study termination (approximately 18 months)
    End point values
    On-Demand to Any Prophylaxis
    Number of subjects analysed
    57
    Units: Scores on a scale
        median (full range (min-max))
    -2.76 (-20.22 to 19.7)
    No statistical analyses for this end point

    Post-hoc: Median (IQR) Annualized Bleed Rates

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    End point title
    Median (IQR) Annualized Bleed Rates [14]
    End point description
    Bleed rates (number of bleeding episodes per subject) were annualized to account for the varying number of days a subject may have actually been on each regimen. Population: Subjects in the efficacy intent-to-treat set comprising of all subjects in the prophylaxis treatment segment who had at least 1 assessment (1 quarterly visit) or who had withdrawn after 3 bleeding episodes prior to reaching the first assessment period.
    End point type
    Post-hoc
    End point timeframe
    On-demand 6 months (± 2 weeks); Prophylaxis 12 months (± 2 weeks)
    Notes
    [14] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Arms in the baseline period are not mutually exclusive. Refer to the description of arms in period 1 (baseline period).
    End point values
    On-Demand Standard Prophylaxis PK-Driven Prophylaxis Any Prophylaxis
    Number of subjects analysed
    53
    30
    23
    53
    Units: Bleeding episodes
        median (inter-quartile range (Q1-Q3))
    43.98 (35.73 to 56.53)
    0.99 (0 to 2.14)
    1 (0 to 4.08)
    1 (0 to 4.07)
    Statistical analysis title
    Statistical analysis 1
    Comparison groups
    On-Demand v Any Prophylaxis
    Number of subjects included in analysis
    106
    Analysis specification
    Post-hoc
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    Wilcoxon Signed-Rank Test
    Confidence interval
         level
    95%

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Throughout the study period (4 years and 5 months)
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    N/A
    Reporting groups
    Reporting group title
    On-Demand
    Reporting group description
    On-demand: rAHF-PFM was to be used for the treatment of bleeding episodes according to the severity and type of episode by the protocol-recommended dosing until the episode resolved: superficial (10-20 IU/kg every 12-14 hours), minor joint (20-40 IU/kg every 12-14 hours), deep muscle (30-60 IU/kg every 12-14 hours), major joint or life-threatening (60-100 IU/kg every 8-12 hours), genitourinary, GI, and intracranial (60-100 IU/kg every 8-12 hours)

    Reporting group title
    PK-Driven Prophylaxis
    Reporting group description
    PK-driven prophylaxis regimen dosed at 20 to 80 IU/kg (every 72 ±6 hours) exact regimen to be determined by the sponsor

    Reporting group title
    SAEs Outside of the 3 Treatment Arms
    Reporting group description
    Participants with SAEs that occurred after exposure to investigational product, but outside of the three treatment arms

    Reporting group title
    Standard Prophylaxis
    Reporting group description
    Standard prophylaxis regimen dosed at 20 to 40 IU/kg (every 48 ±6 hours), exact regimen to be determined by the investigator

    Serious adverse events
    On-Demand PK-Driven Prophylaxis SAEs Outside of the 3 Treatment Arms Standard Prophylaxis
    Total subjects affected by serious adverse events
         subjects affected / exposed
    7 / 73 (9.59%)
    3 / 34 (8.82%)
    1 / 1 (100.00%)
    2 / 32 (6.25%)
         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
    JOINT DISLOCATION
         subjects affected / exposed
    1 / 73 (1.37%)
    0 / 34 (0.00%)
    0 / 1 (0.00%)
    0 / 32 (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
    Surgical and medical procedures
    HOSPITALIZATION
         subjects affected / exposed
    1 / 73 (1.37%)
    0 / 34 (0.00%)
    0 / 1 (0.00%)
    0 / 32 (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
    Blood and lymphatic system disorders
    FACTOR VIII INHIBITION
    Additional description: This event was unconfirmed and therefore did not meet protocol definition for a Factor VIII inhibitor.
         subjects affected / exposed
    0 / 73 (0.00%)
    1 / 34 (2.94%)
    0 / 1 (0.00%)
    0 / 32 (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
    Psychiatric disorders
    SOMNAMBULISM
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 34 (0.00%)
    0 / 1 (0.00%)
    1 / 32 (3.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    ABDOMINAL PAIN
         subjects affected / exposed
    1 / 73 (1.37%)
    0 / 34 (0.00%)
    0 / 1 (0.00%)
    0 / 32 (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
    NAUSEA
         subjects affected / exposed
    1 / 73 (1.37%)
    0 / 34 (0.00%)
    0 / 1 (0.00%)
    0 / 32 (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
    Renal and urinary disorders
    CALCULUS URINARY
         subjects affected / exposed
    1 / 73 (1.37%)
    0 / 34 (0.00%)
    0 / 1 (0.00%)
    0 / 32 (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
    HAEMOPHILIC ARTHROPATHY
         subjects affected / exposed
    1 / 73 (1.37%)
    1 / 34 (2.94%)
    0 / 1 (0.00%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    SYNOVITIS
         subjects affected / exposed
    1 / 73 (1.37%)
    0 / 34 (0.00%)
    0 / 1 (0.00%)
    0 / 32 (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
    PAIN IN EXTREMITY
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 34 (0.00%)
    1 / 1 (100.00%)
    0 / 32 (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
    Infections and infestations
    TOOTH ABSCESS
         subjects affected / exposed
    1 / 73 (1.37%)
    0 / 34 (0.00%)
    0 / 1 (0.00%)
    0 / 32 (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
    PULPITIS DENTAL
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 34 (0.00%)
    0 / 1 (0.00%)
    1 / 32 (3.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    APPENDICITIS
         subjects affected / exposed
    0 / 73 (0.00%)
    1 / 34 (2.94%)
    0 / 1 (0.00%)
    0 / 32 (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
    On-Demand PK-Driven Prophylaxis SAEs Outside of the 3 Treatment Arms Standard Prophylaxis
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    18 / 73 (24.66%)
    7 / 34 (20.59%)
    0 / 1 (0.00%)
    4 / 32 (12.50%)
    Respiratory, thoracic and mediastinal disorders
    COUGH
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 34 (0.00%)
    0 / 1 (0.00%)
    2 / 32 (6.25%)
         occurrences all number
    0
    0
    0
    2
    Nervous system disorders
    HEADACHE
         subjects affected / exposed
    4 / 73 (5.48%)
    3 / 34 (8.82%)
    0 / 1 (0.00%)
    0 / 32 (0.00%)
         occurrences all number
    6
    5
    0
    0
    Gastrointestinal disorders
    DIARRHOEA
         subjects affected / exposed
    4 / 73 (5.48%)
    0 / 34 (0.00%)
    0 / 1 (0.00%)
    0 / 32 (0.00%)
         occurrences all number
    4
    0
    0
    0
    IRRITABLE BOWEL SYNDROME
         subjects affected / exposed
    0 / 73 (0.00%)
    2 / 34 (5.88%)
    0 / 1 (0.00%)
    0 / 32 (0.00%)
         occurrences all number
    0
    4
    0
    0
    Musculoskeletal and connective tissue disorders
    ARTHRALGIA
         subjects affected / exposed
    0 / 73 (0.00%)
    0 / 34 (0.00%)
    0 / 1 (0.00%)
    2 / 32 (6.25%)
         occurrences all number
    0
    0
    0
    3
    Infections and infestations
    NASOPHARYNGITIS
         subjects affected / exposed
    6 / 73 (8.22%)
    0 / 34 (0.00%)
    0 / 1 (0.00%)
    0 / 32 (0.00%)
         occurrences all number
    7
    0
    0
    0
    UPPER RESPIRATORY TRACT INFECTION
         subjects affected / exposed
    4 / 73 (5.48%)
    2 / 34 (5.88%)
    0 / 1 (0.00%)
    0 / 32 (0.00%)
         occurrences all number
    4
    2
    0
    0

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    30 May 2006
    Provision of criteria for assessing the severity and cause of bleeding episodes and recording the anatomical site(s) affected.
    20 Sep 2007
    Change in inclusion criteria.

    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

    Online references

    http://www.ncbi.nlm.nih.gov/pubmed/22212248
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