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    Clinical Trial Results:
    FEIBA NF: a prospective, open-label, randomized, parallel study to evaluate efficacy and safety of prophylactic versus on-demand treatment in subjects with hemophilia A or B and a high titer inhibitor

    Summary
    EudraCT number
    2008-003855-65
    Trial protocol
    FR   BG   IT   PL  
    Global end of trial date
    17 Oct 2012

    Results information
    Results version number
    v2(current)
    This version publication date
    05 Jun 2016
    First version publication date
    06 Aug 2015
    Other versions
    v1
    Version creation reason
    • New data added to full data set
    Statistics added in description for endpoints on differences in mean transformed annualized bleeding rate as unable to add statistics to these endpoints in EudraCT due to EudraCT limitations of not currently accepting statistics for one analysis group. Pharmacoeconomics endpoints added.

    Trial information

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    Trial identification
    Sponsor protocol code
    090701
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    -
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Baxalta US Inc.
    Sponsor organisation address
    One Baxter Way, Westlake Village CA, United States, 91362-3811
    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
    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
    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?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    17 Oct 2012
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    17 Oct 2012
    Global end of trial reached?
    Yes
    Global end of trial date
    17 Oct 2012
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To demonstrate that the annualized rate of all types of bleeds in subjects on the prophylaxis arm is less than that of the subjects in the on-demand arm
    Protection of trial subjects
    This study was conducted in accordance with the protocol, the International Conference on Harmonisation Guideline for Good Clinical Practice (ICH GCP), Title 21 of the US Code of Federal Regulations (US CFR), the European Clinical Trial Directive (2001/20/EC and 2005/28/EC), and national and local requirements.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    31 Mar 2009
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United States: 2
    Country: Number of subjects enrolled
    Poland: 2
    Country: Number of subjects enrolled
    Brazil: 5
    Country: Number of subjects enrolled
    Ukraine: 8
    Country: Number of subjects enrolled
    Romania: 1
    Country: Number of subjects enrolled
    Croatia: 1
    Country: Number of subjects enrolled
    Russian Federation: 11
    Country: Number of subjects enrolled
    Bulgaria: 2
    Country: Number of subjects enrolled
    Japan: 2
    Country: Number of subjects enrolled
    New Zealand: 2
    Worldwide total number of subjects
    36
    EEA total number of subjects
    6
    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)
    7
    Adults (18-64 years)
    24
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    Enrollment was conducted in Europe, North America, Asia-Pacific, and South America at 17 clinical sites beginning in March 2009.

    Pre-assignment
    Screening details
    52 participants were enrolled. Sixteen participants discontinued, (ten were screen failures and six were withdrawn before randomization (2 sponsor's decision- inhibitors, 3 withdrew consent, and 1 due to investigator decision to have participant on prophylaxis). Therefore 36 participants were randomized.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Not blinded

    Arms
    Are arms mutually exclusive
    No

    Arm title
    On-demand arm
    Arm description
    -
    Arm type
    Experimental

    Investigational medicinal product name
    FEIBA NF
    Investigational medicinal product code
    Other name
    Anti-Inhibitor Coagulant Complex (AICC), Nanofiltered
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous bolus use
    Dosage and administration details
    On demand: Subjects will be treated with the standard FEIBA NF dose and dosing interval prescribed by the treating physician throughout the 12-month study period. The recommended target dose of FEIBA NF for on-demand therapy will be based on the type of bleeding episode and the product will be infused as needed at the discretion of the investigator.

    Arm title
    Prophylaxis arm
    Arm description
    -
    Arm type
    Experimental

    Investigational medicinal product name
    FEIBA NF
    Investigational medicinal product code
    Other name
    Anti-Inhibitor Coagulant Complex (AICC), Nanofiltered
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous bolus use
    Dosage and administration details
    Prophylaxis: 85 ± 15 U/kg (70-100 U/kg) every other day

    Arm title
    On-demand arm versus Prophylaxis arm
    Arm description
    Please note that all uniquely titled arms defined in the results posted in ClinicalTrials.gov are imported into EU results as well. Period arm 'On-demand arm versus Prophylaxis arm' is used for some endpoints and in the statistical analysis section. Baseline characteristics for this period arm contain on-demand and prophylaxis subjects.
    Arm type
    Experimental

    Investigational medicinal product name
    FEIBA NF
    Investigational medicinal product code
    Other name
    Anti-Inhibitor Coagulant Complex (AICC), Nanofiltered
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous bolus use
    Dosage and administration details
    Prophylaxis: 85 ± 15 U/kg (70-100 U/kg) every other day

    Investigational medicinal product name
    FEIBA NF
    Investigational medicinal product code
    Other name
    Anti-Inhibitor Coagulant Complex (AICC), Nanofiltered
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous bolus use
    Dosage and administration details
    On demand: Subjects will be treated with the standard FEIBA NF dose and dosing interval prescribed by the treating physician throughout the 12-month study period. The recommended target dose of FEIBA NF for on-demand therapy will be based on the type of bleeding episode and the product will be infused as needed at the discretion of the investigator.

    Arm title
    On-demand
    Arm description
    Please note that all uniquely titled arms defined in the results posted in ClinicalTrials.gov are imported into EU results as well. 'On-demand' is the same as 'On-demand arm'.
    Arm type
    Experimental

    Investigational medicinal product name
    FEIBA NF
    Investigational medicinal product code
    Other name
    Anti-Inhibitor Coagulant Complex (AICC), Nanofiltered
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous bolus use
    Dosage and administration details
    On demand: Subjects will be treated with the standard FEIBA NF dose and dosing interval prescribed by the treating physician throughout the 12-month study period. The recommended target dose of FEIBA NF for on-demand therapy will be based on the type of bleeding episode and the product will be infused as needed at the discretion of the investigator.

    Arm title
    Prophylaxis
    Arm description
    Please note that all uniquely titled arms defined in the results posted in ClinicalTrials.gov are imported into EU results as well. 'Prophylaxis' is the same as 'Prophylaxis arm'.
    Arm type
    Experimental

    Investigational medicinal product name
    FEIBA NF
    Investigational medicinal product code
    Other name
    Anti-Inhibitor Coagulant Complex (AICC), Nanofiltered
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous bolus use
    Dosage and administration details
    Prophylaxis: 85 ± 15 U/kg (70-100 U/kg) every other day

    Number of subjects in period 1
    On-demand arm Prophylaxis arm On-demand arm versus Prophylaxis arm On-demand Prophylaxis
    Started
    19
    17
    36
    19
    17
    Completed
    17
    16
    33
    17
    16
    Not completed
    2
    1
    3
    2
    1
         Adverse event, serious fatal
    1
    -
    1
    1
    -
         Adverse event, non-fatal
    -
    1
    1
    -
    1
         planned surgery
    1
    -
    1
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    On-demand arm
    Reporting group description
    -

    Reporting group title
    Prophylaxis arm
    Reporting group description
    -

    Reporting group title
    On-demand arm versus Prophylaxis arm
    Reporting group description
    Please note that all uniquely titled arms defined in the results posted in ClinicalTrials.gov are imported into EU results as well. Period arm 'On-demand arm versus Prophylaxis arm' is used for some endpoints and in the statistical analysis section. Baseline characteristics for this period arm contain on-demand and prophylaxis subjects.

    Reporting group title
    On-demand
    Reporting group description
    Please note that all uniquely titled arms defined in the results posted in ClinicalTrials.gov are imported into EU results as well. 'On-demand' is the same as 'On-demand arm'.

    Reporting group title
    Prophylaxis
    Reporting group description
    Please note that all uniquely titled arms defined in the results posted in ClinicalTrials.gov are imported into EU results as well. 'Prophylaxis' is the same as 'Prophylaxis arm'.

    Reporting group values
    On-demand arm Prophylaxis arm On-demand arm versus Prophylaxis arm On-demand Prophylaxis Total
    Number of subjects
    19 17 36 19 17
    Age categorical
    Units: Subjects
    Age continuous
    Age continuous description
    Units: years
        arithmetic mean (standard deviation)
    29.1 ± 15.2 25.6 ± 15.4 27.4 ± 15.2 29.1 ± 15.2 25.6 ± 15.4 -
    Gender categorical
    Gender categorical description
    Units: Subjects
        Female
    0 0 0 0 0 0
        Male
    19 17 36 19 17 108
    Region of Enrollment
    Units: Subjects
        United States
    1 1 2 1 1 6
        Poland
    1 1 2 1 1 6
        Brazil
    3 2 5 3 2 15
        Ukraine
    4 4 8 4 4 24
        Romania
    0 1 1 0 1 3
        Croatia
    0 1 1 0 1 3
        Russian Federation
    8 3 11 8 3 33
        Bulgaria
    0 2 2 0 2 6
        Japan
    1 1 2 1 1 6
        New Zealand
    1 1 2 1 1 6

    End points

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    End points reporting groups
    Reporting group title
    On-demand arm
    Reporting group description
    -

    Reporting group title
    Prophylaxis arm
    Reporting group description
    -

    Reporting group title
    On-demand arm versus Prophylaxis arm
    Reporting group description
    Please note that all uniquely titled arms defined in the results posted in ClinicalTrials.gov are imported into EU results as well. Period arm 'On-demand arm versus Prophylaxis arm' is used for some endpoints and in the statistical analysis section. Baseline characteristics for this period arm contain on-demand and prophylaxis subjects.

    Reporting group title
    On-demand
    Reporting group description
    Please note that all uniquely titled arms defined in the results posted in ClinicalTrials.gov are imported into EU results as well. 'On-demand' is the same as 'On-demand arm'.

    Reporting group title
    Prophylaxis
    Reporting group description
    Please note that all uniquely titled arms defined in the results posted in ClinicalTrials.gov are imported into EU results as well. 'Prophylaxis' is the same as 'Prophylaxis arm'.

    Primary: Reduction in annualized bleeding episode rate (ABR) among participants receiving prophylactic treatment as compared to those treated on-demand

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    End point title
    Reduction in annualized bleeding episode rate (ABR) among participants receiving prophylactic treatment as compared to those treated on-demand [1]
    End point description
    Participants were Randomized to Receive 1 of the 2 Following Treatment Regimens: 1.On-Demand: FEIBA NF dose & dosing interval as prescribed by treating physician 2.Prophylaxis: 85 ± 15 U/kg of FEIBA NF every other day during 12-month prophylactic period Annualized rate of bleeding episodes was calculated as: (Number of bleeding episodes/observed treatment period in days) * 365.25
    End point type
    Primary
    End point timeframe
    12 months ± 14 days
    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: Baseline period arms are not mutually exclusive. Details see under description of period arms.
    End point values
    On-demand arm Prophylaxis arm
    Number of subjects analysed
    19
    17
    Units: bleeds/year
        median (inter-quartile range (Q1-Q3))
    28.7 (17.7 to 50)
    7.9 (2.9 to 11)
    Statistical analysis title
    Statistical analysis 1
    Statistical analysis description
    H0: μ(on-demand) = μ(prophylaxis) Versus H1: μ(on-demand) ≠ μ(prophylaxis) (Where H0 implies no difference in mean bleeding episode rate between prophylaxis and on-demand treatment arms and H1 implies otherwise. This test was performed at a significance level of 5%, two-sided, two sample)
    Comparison groups
    On-demand arm v Prophylaxis arm
    Number of subjects included in analysis
    36
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.0003
    Method
    Two-sample, two-sided t-test
    Confidence interval
         level
    95%

    Secondary: Annualized Bleeding Rate by Treatment Regimen, Bleeding Etiology, and Bleed Type

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    End point title
    Annualized Bleeding Rate by Treatment Regimen, Bleeding Etiology, and Bleed Type [2]
    End point description
    Spontaneous includes unknown/undermined etiology
    End point type
    Secondary
    End point timeframe
    12 months ± 14 days
    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: Baseline period arms are not mutually exclusive. Details see under description of period arms.
    End point values
    On-demand arm Prophylaxis arm
    Number of subjects analysed
    19
    17
    Units: Bleeds per year
    median (inter-quartile range (Q1-Q3))
        Spontaneous
    18.9 (10.9 to 43.5)
    5.6 (2.9 to 8)
        Traumatic
    4.7 (1.9 to 10.7)
    2.5 (0 to 3.1)
        Joint
    22.9 (14.1 to 46.9)
    6 (2.9 to 10)
        Non-Joint
    2.9 (1 to 4.9)
    0.5 (0 to 2)
        Spontaneous Joint
    16.6 (9.9 to 40.8)
    4.5 (2.9 to 8)
        Spontaneous Non-Joint
    1 (1 to 2.9)
    0 (0 to 1)
        Traumatic Joint
    4 (1 to 7.1)
    1 (0 to 3.1)
        Traumatic Non-Joint
    0 (0 to 1.9)
    0 (0 to 1)
        All Bleeding Etiologies, and Bleed Types
    28.7 (17.7 to 50)
    7.9 (2.9 to 11)
    No statistical analyses for this end point

    Secondary: Differences in Mean Transformed Annualized Bleeding Rate Between On-Demand and Prophylaxis Treatment Regimens by Bleeding Etiology, and Bleeding Type

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    End point title
    Differences in Mean Transformed Annualized Bleeding Rate Between On-Demand and Prophylaxis Treatment Regimens by Bleeding Etiology, and Bleeding Type [3]
    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 variance and align sample distribution with assumption of normality inherent in using t-test. Difference in mean transformed ABRs was used to perform statistical tests and generate p-values at a significance level of 5% Participants were Randomized to Receive 1 of the 2 Following Treatment Regimens: 1.On-Demand: FEIBA NF dose & dosing interval as prescribed by treating physician 2.Prophylaxis: 85 ± 15 U/kg of FEIBA NF every other day during 12-month prophylactic period. Statistical Analysis (on-demand vs prophylaxis arm, 2-sample, 2-sided t-test): Spontaneous bleeds: p=0.0008; traumatic bleeds: p=0.0199; joint bleeds: p=0.0006; non-joint bleeds: p=0.0227; spontaneous joint bleeds: p=0.0013; spontaneous non-joint bleeds: p=0.003; traumatic joint bleeds: p=0.0254; traumatic non-joint bleeds: p=0.9322.
    End point type
    Secondary
    End point timeframe
    12 months ± 14 days
    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: Baseline period arms are not mutually exclusive. Details see under description of period arms.
    End point values
    On-demand arm versus Prophylaxis arm
    Number of subjects analysed
    36
    Units: (bleeds/year)^(1/2)
    arithmetic mean (standard deviation)
        Spontaneous Bleeds
    2.2 ± 1.8
        Traumatic Bleeds
    1 ± 1.2
        Joint Bleeds
    2.4 ± 1.9
        Non-Joint Bleeds
    0.8 ± 0.9
        Spontaneous Joint Bleeds
    2.1 ± 1.8
        Spontaneous Non-Joint Bleeds
    0.8 ± 0.8
        Traumatic Joint Bleeds
    0.9 ± 1.2
        Traumatic Non-Joint Bleeds
    0 ± 0.9
    No statistical analyses for this end point

    Secondary: Annualized Bleeding Rate for New Target Joints

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    End point title
    Annualized Bleeding Rate for New Target Joints [4]
    End point description
    Target joints are ≥4 bleeds/6 months in any one of the following joints: ankles, knees, elbows, and hips; a target joint bleeding episode refers to an individual anatomical location.
    End point type
    Secondary
    End point timeframe
    12 months ± 14 days
    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: Baseline period arms are not mutually exclusive. Details see under description of period arms.
    End point values
    On-demand arm Prophylaxis arm
    Number of subjects analysed
    19
    17
    Units: Bleeds per year
        median (inter-quartile range (Q1-Q3))
    5.9 (0 to 12.9)
    0 (0 to 4.1)
    No statistical analyses for this end point

    Secondary: Differences in Mean Transformed Annualized Bleeding Rate Between On-Demand and Prophylaxis Treatment Regimens: New Target Joints

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    End point title
    Differences in Mean Transformed Annualized Bleeding Rate Between On-Demand and Prophylaxis Treatment Regimens: New Target Joints [5]
    End point description
    Annualized bleed rates (ABRs) 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 a two-sample, two-sided t-test. The difference in mean transformed ABRs was used to perform statistical tests and generate p-values at a significance level of 5%. Statistical Analysis (on-demand arm versus prophylaxis arm; two-sample, two-sided t-test): p=0.0271.
    End point type
    Secondary
    End point timeframe
    12 months ± 14 days
    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: Baseline period arms are not mutually exclusive. Details see under description of period arms.
    End point values
    On-demand arm versus Prophylaxis arm
    Number of subjects analysed
    36
    Units: (bleeds/year)^(1/2)
        arithmetic mean (standard deviation)
    1.6 ± 2.2
    No statistical analyses for this end point

    Secondary: Number of New Target Joints

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    End point title
    Number of New Target Joints [6]
    End point description
    Target Joints are defined as ≥4 bleeds/6 months in any one of the following joints: ankles, knees, elbows and hips
    End point type
    Secondary
    End point timeframe
    12 months ± 14 days
    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: Baseline period arms are not mutually exclusive. Details see under description of period arms.
    End point values
    On-demand arm Prophylaxis arm
    Number of subjects analysed
    19
    17
    Units: new target joints
    23
    7
    No statistical analyses for this end point

    Secondary: Assessment of Objective Clinical Symptoms- Visual Analog Scale (VAS): Pain in Adolescents and Adults (≥12 years old)

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    End point title
    Assessment of Objective Clinical Symptoms- Visual Analog Scale (VAS): Pain in Adolescents and Adults (≥12 years old) [7]
    End point description
    Pain caused by a bleeding episode in adolescents and adults (≥12 years old) was measured at pre-infusion (pre-inf) and at 6 ± 0.5 hours (h) and 24 ± 1 h post-infusion (post-inf) (after the last infusion given to treat a bleeding episode) on the VAS pain scale in millimeters from 0 (no pain) to 100 (worst possible pain). For analysis purposes, if short acting analgesics (duration of activity approximately 6 ± 0.5 h) were used, pain was assigned the highest possible score (100). Pain assessment occurred after each infusion related to single bleeding episodes. In case participants required an additional infusion within 24h, pain was assessed 6 ± 0.5 h and 24 ±1 h following the subsequent infusion. Change in VAS scores at 6 ± 0.5 h and 24 ±1 h post-infusion were also compared relative to pre-infusion VAS scores (ie, (pre-infusion VAS score) - (post-infusion VAS score)).
    End point type
    Secondary
    End point timeframe
    Throughout the study period, 12 months ± 14 days
    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: Baseline period arms are not mutually exclusive. Details see under description of period arms.
    End point values
    On-demand arm Prophylaxis arm
    Number of subjects analysed
    17
    12
    Units: Scores on a scale
    median (inter-quartile range (Q1-Q3))
        Pre-Infusion (N= 513, 130)
    29 (12 to 55)
    49.5 (34.7 to 81.6)
        6 ± 0.5 hours post-infusion (N= 522, 158)
    10 (4 to 37)
    33.8 (8 to 52.6)
        24 ± 1 hours post-infusion (N= 512,131)
    3 (1 to 14)
    6.2 (1 to 20)
        Change (Pre-Inf to 6h post-inf) (N= 509, 129)
    10 (4 to 21.8)
    19.4 (5 to 41.6)
        Change (Pre-Inf to 24h post-inf) (N= 489, 102)
    18 (8 to 39.6)
    37.8 (17 to 75.5)
    No statistical analyses for this end point

    Secondary: Assessment of Clinical Symptoms - Visual Analog Scale (VAS): Pain in Pediatrics (<12 years old)

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    End point title
    Assessment of Clinical Symptoms - Visual Analog Scale (VAS): Pain in Pediatrics (<12 years old) [8]
    End point description
    Pain caused by a bleeding episode (BE) in pediatric participants (<12 years old) was measured at pre-infusion (pre-inf) and at 6 ± 0.5 h and 24 ± 1 h post-infusion (post-inf) (after the last infusion given to treat a bleeding episode) using the children’s VAS pain scale (a facial expression scale with one end marked as no pain and the opposite end marked as the worst possible pain). For analysis purposes, if short acting analgesics (duration of activity approximately 6 ± 0.5 h) were used, pain was assigned the highest possible score (worst possible pain). Scores on the children's VAS scale are presented as: -No Pain -Mild Pain -Moderate pain -Severe pain -Very severe pain
    End point type
    Secondary
    End point timeframe
    12 months ± 14 days
    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: Baseline period arms are not mutually exclusive. Details see under description of period arms.
    End point values
    On-demand arm Prophylaxis arm
    Number of subjects analysed
    2
    2
    Units: Bleeding episodes
        Pre-Infusion (N= 54, 8) - No Pain
    27
    3
        Pre-Infusion (N= 54, 8) - Mild Pain
    3
    1
        Pre-Infusion (N= 54, 8) - Moderate Pain
    12
    3
        Pre-Infusion (N= 54, 8) - Severe Pain
    10
    1
        Pre-Infusion (N= 54, 8) - Very Severe Pain
    2
    0
        6 ± 0.5 h post-infusion (N= 74, 8) - No Pain
    47
    3
        ± 0.5 h post-infusion (N= 74, 8) - Mild Pain
    9
    3
        ± 0.5 h post-infusion (N= 74, 8) - Moderate Pain
    15
    2
        ± 0.5 h post-infusion (N= 74, 8) - Severe Pain
    3
    0
        ± 0.5 h post-infusion (N= 74, 8)- Very Severe Pain
    0
    0
        24 ± 1 h post-infusion (N= 77, 9) - No Pain
    60
    7
        24 ± 1 h post-infusion (N= 77, 9) - Mild Pain
    11
    1
        24 ± 1 h post-infusion (N= 77, 9) - Moderate Pain
    6
    1
        24 ± 1 h post-infusion (N= 77, 9) - Severe Pain
    0
    0
        24± 1h post-infusion (N = 77, 9) -Very Severe Pain
    0
    0
    No statistical analyses for this end point

    Secondary: Assessment of Clinical Symptoms - Range of Motion (ROM)

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    End point title
    Assessment of Clinical Symptoms - Range of Motion (ROM) [9]
    End point description
    ROM was measured using a goniometer for 3 key joints (ie, ankles, knees, and elbows) at screening, month 6, and termination (end of study visit)
    End point type
    Secondary
    End point timeframe
    12 months ± 14 days
    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: Baseline period arms are not mutually exclusive. Details see under description of period arms.
    End point values
    On-demand arm Prophylaxis arm
    Number of subjects analysed
    19
    17
    Units: degrees
    median (inter-quartile range (Q1-Q3))
        Left Elbow - Extension: Screening
    15 (0 to 45)
    10 (0 to 25)
        Left Elbow - Extension: Month 6 (n = 18,16)
    10 (0 to 41)
    8 (0 to 42.5)
        Left Elbow - Extension: Termination (n = 17,16)
    20 (0 to 41)
    15.5 (0 to 40)
        Left Elbow - Flexion: Screening (n = 19,17)
    125 (90 to 140)
    115 (80 to 140)
        Left Elbow - Flexion: Month 6 (n = 18,16)
    130 (90 to 140)
    125 (72.5 to 143)
        Left Elbow - Flexion: Termination (n = 17,16)
    110 (90 to 140)
    125 (75 to 145)
        Left Elbow - Pronation: Screening (n = 18,16)
    64 (55 to 90)
    55 (22.5 to 77.5)
        Left Elbow - Pronation: Month 6 (n = 17,14)
    80 (60 to 90)
    67.5 (35 to 80)
        Left Elbow - Pronation: Termination (n = 17,15)
    68 (60 to 90)
    65 (30 to 80)
        Left Elbow - Supination: Screening (n = 18,16)
    75 (50 to 90)
    42.5 (17.5 to 77.5)
        Left Elbow - Supination: Month 6 (n = 17,14)
    80 (50 to 90)
    60 (35 to 80)
        Left Elbow - Supination: Termination (n = 17,15)
    70 (50 to 90)
    70 (35 to 80)
        Right Elbow - Extension: Screening (n = 19,17)
    20 (0 to 50)
    10 (0 to 50)
        Right Elbow - Extension: Month 6 (n = 18,16)
    17.5 (0 to 50)
    10 (0 to 42.5)
        Right Elbow - Extension: Termination (n = 18,16)
    22.5 (0 to 45)
    20 (0 to 62.5)
        Right Elbow - Flexion: Screening (n = 19,17)
    120 (105 to 140)
    100 (80 to 130)
        Right Elbow - Flexion: Month 6 (n = 18,16)
    122.5 (110 to 140)
    100 (85 to 136)
        Right Elbow - Flexion: Termination (n = 18,16)
    121 (110 to 140)
    99 (70 to 127.5)
        Right Elbow - Pronation: Screening (n = 18,16)
    75 (55 to 90)
    57.5 (27.5 to 80)
        Right Elbow - Pronation: Month 6 (n = 17,14)
    80 (55 to 90)
    72.5 (40 to 80)
        Right Elbow - Pronation: Termination (n = 18,15)
    67.5 (55 to 90)
    70 (40 to 80)
        Right Elbow - Supination: Screening (n = 18,16)
    75 (45 to 90)
    52.5 (20 to 80)
        Right Elbow - Supination: Month 6 (n = 17,14)
    70 (45 to 90)
    72.5 (30 to 80)
        Right Elbow - Supination: Termination (n = 18,15)
    75 (45 to 90)
    70 (30 to 80)
        Left Knee - Extension: Screening (n = 18,16)
    15 (5 to 90)
    1.5 (0 to 55.5)
        Left Knee - Extension: Month 6 (n = 17,14)
    15 (5 to 70)
    0 (0 to 20)
        Left Knee - Extension: Termination (n = 18,15)
    15 (5 to 90)
    0 (0 to 70)
        Left Knee - Flexion: Screening (n = 19,17)
    100 (80 to 130)
    90 (65 to 115)
        Left Knee - Flexion: Month 6 (n = 18,16)
    112.5 (80 to 130)
    97.5 (65 to 125)
        Left Knee - Flexion: Termination (n = 18,16)
    105 (60 to 130)
    92.5 (70 to 125)
        Right Knee - Extension: Screening (n = 18,16)
    35 (10 to 90)
    5 (0 to 30)
        Right Knee - Extension: Month 6 (n = 17,14)
    20 (10 to 90)
    10 (2 to 30)
        Right Knee - Extension: Termination (n = 18,15)
    17.5 (10 to 90)
    5 (0 to 30)
        Right Knee - Flexion: Screening (n = 19,17)
    90 (20 to 122)
    80 (60 to 125)
        Right Knee - Flexion: Month 6 (n = 18,16)
    90 (20 to 130)
    82.5 (56 to 127.5)
        Right Knee - Flexion: Termination (n = 18,16)
    85 (20 to 120)
    87.5 (56 to 127.5)
        Left Ankle - Dorsiflexion: Screening (n = 18,16)
    20 (15 to 30)
    17.5 (9 to 37.5)
        Left Ankle - Dorsiflexion: Month 6 (n = 17,14)
    20 (11 to 35)
    17.5 (8 to 50)
        Left Ankle - Dorsiflexion: Termination (n = 17,15)
    15 (11 to 25)
    20 (5 to 50)
        Left Ankle - Plantarflexion: Screening (n = 18,16)
    34.5 (30 to 40)
    30 (10 to 35)
        Left Ankle - Plantarflexion: Month 6 (n = 17,14)
    34 (25 to 35)
    30 (15 to 40)
        Left Ankle - Plantarflexion: Termination (n=17,15)
    35 (30 to 40)
    30 (15 to 35)
        Left Ankle - Pronation: Screening (n = 19,17)
    14 (10 to 20)
    15 (10 to 15)
        Left Ankle - Pronation: Month 6 (n = 18,15)
    15 (10 to 20)
    15 (10 to 16)
        Left Ankle - Pronation: Termination (n = 18,16)
    15 (10 to 20)
    12.5 (10 to 15.5)
        Left Ankle - Supination: Screening (n = 19,17)
    25 (10 to 30)
    15 (10 to 27)
        Left Ankle - Supination: Month 6 (n = 18,15)
    25 (20 to 30)
    25 (10 to 30)
        Left Ankle - Supination: Termination (n = 18,16)
    25 (16 to 30)
    20 (10 to 27.5)
        Right Ankle - Dorsiflexion: Screening (n = 18,16)
    15 (10 to 20)
    20 (7.5 to 35)
        Right Ankle - Dorsiflexion: Month 6 (n = 17,14)
    15 (15 to 20)
    25 (6 to 40)
        Right Ankle - Dorsiflexion: Termination (n= 17,15)
    15 (14 to 20)
    20 (10 to 40)
        Right Ankle - Plantarflexion: Screening (n= 18,16)
    35 (30 to 40)
    20 (9 to 39)
        Right Ankle - Plantarflexion: Month 6 (n= 17,14)
    30 (25 to 40)
    23 (10 to 40)
        Right Ankle - Plantarflexion: Termination(n=17,15)
    30 (25 to 40)
    21 (10 to 40)
        Right Ankle - Pronation: Screening (n = 19,17)
    10 (10 to 15)
    10 (10 to 20)
        Right Ankle - Pronation: Month 6 (n= 18,15)
    10 (10 to 20)
    10 (10 to 20)
        Right Ankle - Pronation: Termination (n= 18,16)
    10 (10 to 17)
    11 (10 to 17.5)
        Right Ankle - Supination: Screening (n = 19,17)
    17 (10 to 30)
    20 (10 to 30)
        Right Ankle - Supination: Month 6 (n= 18,15)
    20 (10 to 30)
    20 (10 to 30)
        Right Ankle - Supination: Termination (n= 18,16)
    20 (10 to 30)
    20 (10 to 30)
    No statistical analyses for this end point

    Secondary: Assessment of Hemostasis for Treatment of Bleeding Episodes- Overall Efficacy Rating at 6 hours

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    End point title
    Assessment of Hemostasis for Treatment of Bleeding Episodes- Overall Efficacy Rating at 6 hours [10]
    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 ~6 hours of 1 infusion. Additional infusions may have been given to maintain hemostasis; Good: Definite pain relief and/or improvement in bleeding within ~6 hours after infusion. Possibly requires >1 infusion for complete resolution; Fair: Probable or slight relief of pain & slight improvement in bleeding within ~6 hours after infusion. Requires >1 infusion for complete resolution; None: No improvement or condition worsens
    End point type
    Secondary
    End point timeframe
    6 h ± 30 min post-infusion
    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: Baseline period arms are not mutually exclusive. Details see under description of period arms.
    End point values
    On-demand arm Prophylaxis arm
    Number of subjects analysed
    19
    14
    Units: bleeding episodes
        Excellent (n = 16, 5)
    109
    16
        Good (n = 19, 14)
    355
    106
        Fair (n = 15, 6)
    142
    42
        None (n = 6, 2)
    14
    5
        Rating Not Done (n = 3, 2)
    3
    2
        Not Available (n = 0, 1)
    0
    2
    No statistical analyses for this end point

    Secondary: Assessment of Hemostasis for Treatment of Bleeding Episodes- Overall Efficacy Rating at 24 hours

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    End point title
    Assessment of Hemostasis for Treatment of Bleeding Episodes- Overall Efficacy Rating at 24 hours [11]
    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 ~24 hours of 1 infusion. Additional infusions may have been given to maintain hemostasis; Good: Definite pain relief and/or improvement in bleeding within ~24 hours after infusion. Possibly requires >1 infusion for complete resolution; Fair: Probable or slight relief of pain & slight improvement in bleeding within ~24 hours after infusion. Requires >1 infusion for complete resolution; None: No improvement or condition worsens
    End point type
    Secondary
    End point timeframe
    24 ± 1 h post-infusion
    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: Baseline period arms are not mutually exclusive. Details see under description of period arms.
    End point values
    On-demand arm Prophylaxis arm
    Number of subjects analysed
    19
    14
    Units: bleeding episodes
        Excellent (n = 16, 6)
    282
    42
        Good (n = 19, 14)
    280
    89
        Fair (n = 9, 3)
    36
    12
        None (n = 1,0)
    1
    0
        Rating Not Done (n = 8, 3)
    24
    28
        Not Available (n = 0, 1)
    0
    2
    No statistical analyses for this end point

    Secondary: Total Weight Adjusted Dose to Control a Bleeding Episode

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    End point title
    Total Weight Adjusted Dose to Control a Bleeding Episode [12]
    End point description
    End point type
    Secondary
    End point timeframe
    12 months ± 14 days
    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: Baseline period arms are not mutually exclusive. Details see under description of period arms.
    End point values
    On-demand arm Prophylaxis arm
    Number of subjects analysed
    19
    14
    Units: Units/kg
        median (inter-quartile range (Q1-Q3))
    4049.7 (2324.5 to 7408.4)
    1524.9 (293.2 to 2883.5)
    Statistical analysis title
    Statistical analysis 1
    Comparison groups
    Prophylaxis arm v On-demand arm
    Number of subjects included in analysis
    33
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.0067
    Method
    Mann-Whitney tests (Wilcoxon-Rank Sum)
    Confidence interval
         level
    95%

    Secondary: The Number of Bleeding Episode (BE) Which Required 1, 2, 3, or ≥4 Infusions to Control Bleeding

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    End point title
    The Number of Bleeding Episode (BE) Which Required 1, 2, 3, or ≥4 Infusions to Control Bleeding [13]
    End point description
    End point type
    Secondary
    End point timeframe
    12 months ± 14 days
    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: Baseline period arms are not mutually exclusive. Details see under description of period arms.
    End point values
    On-demand arm Prophylaxis arm
    Number of subjects analysed
    19
    14
    Units: Bleeding Episodes (BEs)
        1 infusion
    352
    98
        2 infusions
    134
    41
        3 infusions
    62
    13
        ≥4 infusions
    75
    21
    No statistical analyses for this end point

    Secondary: Abnormal Activated Partial Thromboplastin Time (aPTT) Assay Results

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    End point title
    Abnormal Activated Partial Thromboplastin Time (aPTT) Assay Results [14]
    End point description
    The normal reference range of values for aPTT is 22.8 – 31 seconds.
    End point type
    Secondary
    End point timeframe
    Screening visit, Month 3, Month 6, Month 9, and Termination visit
    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: Baseline period arms are not mutually exclusive. Details see under description of period arms.
    End point values
    On-demand arm Prophylaxis arm
    Number of subjects analysed
    19
    16
    Units: seconds
    median (inter-quartile range (Q1-Q3))
        Screening visit (n= 19, 16)
    67.3 (63.1 to 75.1)
    68.5 (61 to 73.1)
        Month 3 (n= 14, 15)
    68 (62.7 to 76.2)
    62.7 (57.5 to 67.2)
        Month 6 (n= 17, 15)
    68.2 (64.6 to 72.1)
    65.6 (62.6 to 69.5)
        Month 9 (n= 17, 15)
    70 (64.6 to 77.9)
    68.1 (58.1 to 73.9)
        Termination visit (n= 18, 16)
    69.8 (63.4 to 75.6)
    69.4 (60.5 to 77.1)
    No statistical analyses for this end point

    Secondary: Abnormal D-Dimer Assay Results

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    End point title
    Abnormal D-Dimer Assay Results [15]
    End point description
    The normal reference range of values for D-dimers is <500 ng/mL.
    End point type
    Secondary
    End point timeframe
    Screening visit, Month 3, Month 6, Month 9, and Termination visit
    Notes
    [15] - 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: Baseline period arms are not mutually exclusive. Details see under description of period arms.
    End point values
    On-demand arm Prophylaxis arm
    Number of subjects analysed
    9
    9
    Units: ng/mL
    median (inter-quartile range (Q1-Q3))
        Screening visit (n= 7, 6)
    862 (647 to 1035)
    833.5 (644 to 1164)
        Month 3 (n= 7, 8)
    690 (561 to 830)
    1021.5 (730 to 1633.5)
        Month 6 (n= 9, 8)
    969 (753 to 1103)
    1032 (652 to 1442.5)
        Month 9 (n= 6, 8)
    731.5 (592 to 1398)
    1121 (942.5 to 1448.5)
        Termination visit (n= 5, 9)
    813 (695 to 1386)
    1031 (872 to 1258)
    No statistical analyses for this end point

    Secondary: Abnormal Fibrinogen Assay Results

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    End point title
    Abnormal Fibrinogen Assay Results [16]
    End point description
    The normal reference range of values for fibrinogen is 200-400 mg/dL. Note: 99999 entered where there were no abnormal fibrinogen assay results for this arm/group at this time point.
    End point type
    Secondary
    End point timeframe
    Screening visit, Month 3, Month 6, Month 9, and Termination visit
    Notes
    [16] - 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: Baseline period arms are not mutually exclusive. Details see under description of period arms.
    End point values
    On-demand arm Prophylaxis arm
    Number of subjects analysed
    4
    6
    Units: mg/dL
    median (inter-quartile range (Q1-Q3))
        Screening visit (n= 4, 6)
    428 (414 to 478.5)
    422 (411 to 428)
        Month 3 (n= 0, 2)
    99999 (99999 to 99999)
    402 (199 to 605)
        Month 6 (n= 3, 1)
    415 (412 to 418)
    759 (759 to 759)
        Month 9 (n= 1, 4)
    508 (508 to 508)
    326.5 (183.5 to 635.5)
        Termination visit (n= 2, 2)
    456.5 (425 to 488)
    522.5 (414 to 631)
    No statistical analyses for this end point

    Secondary: Abnormal Fibrin Degradation Products (FDP) Assay Results

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    End point title
    Abnormal Fibrin Degradation Products (FDP) Assay Results [17]
    End point description
    The normal reference range of values for FDP is 0-5 ug/mL. Note: 99999 entered where there were no abnormal fibrin degradation products assay results for this arm/group at this time point
    End point type
    Secondary
    End point timeframe
    Screening visit, Month 3, Month 6, Month 9, and Termination visit
    Notes
    [17] - 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: Baseline period arms are not mutually exclusive. Details see under description of period arms.
    End point values
    On-demand arm Prophylaxis arm
    Number of subjects analysed
    3
    2
    Units: ug/mL
    median (inter-quartile range (Q1-Q3))
        Screening visit (n= 1, 2)
    16 (16 to 16)
    12 (8 to 16)
        Month 3 (n= 0, 2)
    99999 (99999 to 99999)
    8 (8 to 8)
        Month 6 (n= 1, 1)
    8 (8 to 8)
    8 (8 to 8)
        Month 9 (n= 1, 2)
    8 (8 to 8)
    8 (8 to 8)
        Termination visit (n= 3, 1)
    8 (8 to 8)
    8 (8 to 8)
    No statistical analyses for this end point

    Secondary: Abnormal Prothrombin Fragment F 1.2 Assay Results

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    End point title
    Abnormal Prothrombin Fragment F 1.2 Assay Results [18]
    End point description
    The normal reference range of values for prothrombin fragment F 1.2 is 69-229 pmol/L.
    End point type
    Secondary
    End point timeframe
    Screening visit, Month 3, Month 6, Month 9, and Termination visit
    Notes
    [18] - 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: Baseline period arms are not mutually exclusive. Details see under description of period arms.
    End point values
    On-demand arm Prophylaxis arm
    Number of subjects analysed
    6
    9
    Units: pmol/L
    median (inter-quartile range (Q1-Q3))
        Screening visit (n= 2, 1)
    284 (278 to 290)
    308 (308 to 308)
        Month 3 (n= 6, 7)
    336.5 (267 to 414)
    579 (354 to 972)
        Month 6 (n= 3, 9)
    448 (272 to 714)
    430 (366 to 504)
        Month 9 (n= 4, 9)
    382 (313 to 405.5)
    415 (272 to 472)
        Termination visit (n= 4, 7)
    252.5 (250 to 265)
    643 (376 to 1679)
    No statistical analyses for this end point

    Secondary: Abnormal Prothrombin Time Assay Results

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    End point title
    Abnormal Prothrombin Time Assay Results [19]
    End point description
    The normal reference range of values for PT is 9.7-12.3 sec. Note: 99999 entered where there were no abnormal prothrombin time assay results for this arm/group at this time point
    End point type
    Secondary
    End point timeframe
    Screening visit, Month 3, Month 6, Month 9, and Termination visit
    Notes
    [19] - 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: Baseline period arms are not mutually exclusive. Details see under description of period arms.
    End point values
    On-demand arm Prophylaxis arm
    Number of subjects analysed
    1
    1
    Units: seconds
    median (inter-quartile range (Q1-Q3))
        Screening visit (n= 1, 1)
    9.4 (9.4 to 9.4)
    9.6 (9.6 to 9.6)
        Month 3 (n= 1, 0)
    9.5 (9.5 to 9.5)
    99999 (99999 to 99999)
        Month 6 (n= 0, 1)
    99999 (99999 to 99999)
    12.5 (12.5 to 12.5)
        Month 9 (n= 1, 1)
    12.7 (12.7 to 12.7)
    13.6 (13.6 to 13.6)
        Termination visit (n= 0, 1)
    99999 (99999 to 99999)
    13.4 (13.4 to 13.4)
    No statistical analyses for this end point

    Secondary: Abnormal Thrombin-Antithrombin III (TAT) Assay Results

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    End point title
    Abnormal Thrombin-Antithrombin III (TAT) Assay Results [20]
    End point description
    The normal reference range of values for TAT is 1-4.1 ug/L. Note: 99999 entered where there were no abnormal Abnormal Thrombin-Antithrombin II assay results for this arm/group at this time point
    End point type
    Secondary
    End point timeframe
    Screening visit, Month 3, Month 6, Month 9, and Termination visit
    Notes
    [20] - 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: Baseline period arms are not mutually exclusive. Details see under description of period arms.
    End point values
    On-demand arm Prophylaxis arm
    Number of subjects analysed
    4
    7
    Units: ug/L
    median (inter-quartile range (Q1-Q3))
        Screening visit (n= 4, 1)
    5.1 (4.4 to 5.9)
    5.6 (5.6 to 5.6)
        Month 3 (n= 3, 7)
    4.7 (4.5 to 5.9)
    12.3 (4.4 to 40.8)
        Month 6 (n= 3, 6)
    7.9 (6.3 to 10.5)
    5.6 (4.4 to 6.1)
        Month 9 (n= 0, 3)
    99999 (99999 to 99999)
    6 (5.6 to 52.9)
        Termination visit (n= 2, 5)
    10.3 (8 to 12.5)
    5.6 (5.1 to 7.3)
    No statistical analyses for this end point

    Secondary: Viral Serology from Screening Visit and Study Termination Visit: Hepatitis A, Hepatitis B, and Hepatitis C

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    End point title
    Viral Serology from Screening Visit and Study Termination Visit: Hepatitis A, Hepatitis B, and Hepatitis C [21]
    End point description
    -Hepatitis A Virus Antibody (HAV Ab) -Hepatitis B Virus Core Antibody (HBcAb) -Hepatitis B Virus Surface Antibody (HBsAb) -Hepatitis B Virus Surface Antigen (HBsAg) -Hepatitis C Virus (HCV)
    End point type
    Secondary
    End point timeframe
    12 months ± 14 days
    Notes
    [21] - 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: Baseline period arms are not mutually exclusive. Details see under description of period arms.
    End point values
    On-demand arm Prophylaxis arm
    Number of subjects analysed
    19
    17
    Units: participants
        HAV Ab: Screening Negative; Termination Positive
    1
    0
        HAV Ab: Screening Negative; Termination Negative
    8
    11
        HAV Ab: Screening Positive; Termination Positive
    8
    4
        HAV Ab: Screening Positive; Termination Negative
    1
    1
        HAV Ab: Serology not available
    1
    1
        HBcAb: Screening Negative; Termination Positive
    0
    1
        HBcAb: Screening Negative; Termination Negative
    8
    11
        HBcAb: Screening Positive; Termination Positive
    9
    4
        HBcAb: Screening Positive; Termination Negative
    1
    0
        HBcAb: Serology not available
    1
    1
        HBsAb: Screening Negative; Termination Positive
    2
    5
        HBsAb: Screening Negative; Termination Negative
    2
    2
        HBsAb: Screening Positive; Termination Positive
    13
    9
        HBsAb: Screening Positive; Termination Negative
    1
    0
        HBsAb: Serology not available
    1
    1
        HBsAg: Screening Negative; Termination Positive
    0
    0
        HBsAg: Screening Negative; Termination Negative
    18
    16
        HBsAg: Serology not available
    1
    1
        HCV: Screening Negative; Termination Positive
    0
    0
        HCV: Screening Negative; Termination Negative
    6
    10
        HCV: Screening Positive; Termination Positive
    12
    6
        HCV: Screening Positive; Termination Negative
    0
    0
        HCV: Serology not available
    1
    1
    No statistical analyses for this end point

    Secondary: Viral Serology From Screening Visit and Study Termination Visit: HIV-1/2 Antibody (Ab)

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    End point title
    Viral Serology From Screening Visit and Study Termination Visit: HIV-1/2 Antibody (Ab) [22]
    End point description
    End point type
    Secondary
    End point timeframe
    12 months ± 14 days
    Notes
    [22] - 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: Baseline period arms are not mutually exclusive. Details see under description of period arms.
    End point values
    On-demand Prophylaxis
    Number of subjects analysed
    19
    17
    Units: participants
        HIV 1/2 Ab: Screen Negative; Termination Positive
    0
    0
        HIV 1/2 Ab: Screen Negative; Termination Negative
    18
    16
        HIV 1/2 Ab: : Serology not available
    1
    1
    No statistical analyses for this end point

    Secondary: Viral Serology From Screening Visit and Study Termination Visit: Parvovirus B19 IgG Antibody [IV]

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    End point title
    Viral Serology From Screening Visit and Study Termination Visit: Parvovirus B19 IgG Antibody [IV] [23]
    End point description
    Normal range (0 - 0.89 IV); High (> 0.89 IV) - Parvovirus B19 IgG Antibody [IV] (Parvo IgG Ab)
    End point type
    Secondary
    End point timeframe
    12 months ± 14 days
    Notes
    [23] - 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: Baseline period arms are not mutually exclusive. Details see under description of period arms.
    End point values
    On-demand Prophylaxis
    Number of subjects analysed
    19
    17
    Units: participants
        Parvo IgG Ab: Screening High ; Termination Normal
    3
    1
        Parvo IgG Ab: Screening High ; Termination High
    14
    13
        Parvo IgG Ab: Screening Normal; Termination Normal
    0
    2
        Parvo IgG Ab: Screening Normal ; Termination High
    1
    0
        Parvo IgG Ab: Serology not available
    1
    1
    No statistical analyses for this end point

    Secondary: Viral Serology From Screening Visit and Study Termination Visit: Parvovirus B19 IgM Antibody [IV]

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    End point title
    Viral Serology From Screening Visit and Study Termination Visit: Parvovirus B19 IgM Antibody [IV] [24]
    End point description
    Normal range (0 - 0.89 IV); High (> 0.89 IV) - Parvovirus B19 IgM Antibody [IV] (Parvo IgM Ab)
    End point type
    Secondary
    End point timeframe
    12 months ± 14 days
    Notes
    [24] - 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: Baseline period arms are not mutually exclusive. Details see under description of period arms.
    End point values
    On-demand Prophylaxis
    Number of subjects analysed
    19
    17
    Units: participants
        Parvo IgM Ab: Screening High ; Termination Normal
    0
    0
        Parvo IgM Ab: Screening High ; Termination High
    1
    0
        Parvo IgM Ab: Screening Normal; Termination Normal
    17
    16
        Parvo IgM Ab: Screening Normal ; Termination High
    0
    0
        Parvo IgM Ab: Serology not available
    1
    1
    No statistical analyses for this end point

    Secondary: Rate of Related Adverse Events (AEs) per Year

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    End point title
    Rate of Related Adverse Events (AEs) per Year [25]
    End point description
    End point type
    Secondary
    End point timeframe
    12 months ± 14 days
    Notes
    [25] - 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: Baseline period arms are not mutually exclusive. Details see under description of period arms.
    End point values
    On-demand arm Prophylaxis arm
    Number of subjects analysed
    19
    17
    Units: Related AEs per year
        median (inter-quartile range (Q1-Q3))
    0 (0 to 0)
    0 (0 to 0.979)
    No statistical analyses for this end point

    Secondary: Rate of Related Adverse Events (AEs) during or within 1 Hour of Infusion per Year

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    End point title
    Rate of Related Adverse Events (AEs) during or within 1 Hour of Infusion per Year [26]
    End point description
    End point type
    Secondary
    End point timeframe
    12 months ± 14 days
    Notes
    [26] - 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: Baseline period arms are not mutually exclusive. Details see under description of period arms.
    End point values
    On-demand arm Prophylaxis arm
    Number of subjects analysed
    19
    17
    Units: Related AEs within/during 1hr per year
        median (inter-quartile range (Q1-Q3))
    0 (0 to 0)
    0 (0 to 0)
    No statistical analyses for this end point

    Secondary: Number of Related Thromboembolic Adverse Events (AEs)

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    End point title
    Number of Related Thromboembolic Adverse Events (AEs) [27]
    End point description
    End point type
    Secondary
    End point timeframe
    12 months ± 14 days
    Notes
    [27] - 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: Baseline period arms are not mutually exclusive. Details see under description of period arms.
    End point values
    On-demand arm Prophylaxis arm
    Number of subjects analysed
    19
    17
    Units: Related thromboembolic AEs
    0
    0
    No statistical analyses for this end point

    Secondary: Absolute Changes in Inhibitor Titer of Hemophilia A Participants with Shifts in Factor VIII (FVIII) Inhibitor Titer Levels

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    End point title
    Absolute Changes in Inhibitor Titer of Hemophilia A Participants with Shifts in Factor VIII (FVIII) Inhibitor Titer Levels [28]
    End point description
    Absolute Changes in Inhibitor Titer (or no change in low or high titer status): -Inhibitor Titer went from Low (≤5 BU) to Low (≤5 BU) -Inhibitor Titer went from Low (≤5 BU) to High (>5 BU) -Inhibitor Titer went from High (>5 BU) to Low (≤5 BU) -Inhibitor Titer went from High (>5 BU) to High (>5 BU) Note: 99999 entered where there were no inhibitor titer shifts for this arm/group at this time point
    End point type
    Secondary
    End point timeframe
    12 months ± 14 days
    Notes
    [28] - 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: Baseline period arms are not mutually exclusive. Details see under description of period arms.
    End point values
    On-demand arm Prophylaxis arm
    Number of subjects analysed
    17
    16
    Units: Bethesda Units (BU)
    median (inter-quartile range (Q1-Q3))
        Screening to 3 Month- Low to High (N=2, 3)
    12.1 (12.1 to 12.1)
    4 (0.7 to 16.8)
        Screening to 3 Month- High to Low (N=1, 0)
    2 (2 to 2)
    99999 (99999 to 99999)
        Screening to 6 Month- Low to High (N=2, 1)
    12.9 (4.9 to 20.8)
    5.3 (5.3 to 5.3)
        Screening to 6 Month- High to Low (N=1, 0)
    3.4 (3.4 to 3.4)
    99999 (99999 to 99999)
        Screening to 9 Month- Low to High (N=2, 1)
    5 (4.3 to 5.6)
    3.7 (3.7 to 3.7)
        Screening to 9 Month- High to Low (N=0, 2)
    99999 (99999 to 99999)
    2.1 (0.9 to 3.2)
        Screening to Termination- Low to High (N=2, 1)
    39.2 (3.8 to 74.7)
    5.8 (5.8 to 5.8)
        Screening to Termination- High to Low (N=1, 2)
    14.6 (14.6 to 14.6)
    3.3 (3.3 to 3.3)
    No statistical analyses for this end point

    Secondary: Absolute Changes in Inhibitor Titer of Hemophilia B Participants with Shifts in Factor IX (FIX) Inhibitor Titer Levels

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    End point title
    Absolute Changes in Inhibitor Titer of Hemophilia B Participants with Shifts in Factor IX (FIX) Inhibitor Titer Levels [29]
    End point description
    Absolute Changes in Inhibitor Titer (or no change in low or high titer status): -Inhibitor Titer went from Low (≤5 BU) to Low (≤5 BU) -Inhibitor Titer went from Low (≤5 BU) to High (>5 BU) -Inhibitor Titer went from High (>5 BU) to Low (≤5 BU) -Inhibitor Titer went from High (>5 BU) to High (>5 BU) Note: 99999 entered where there were no inhibitor titer shifts for this arm/group at this time point
    End point type
    Secondary
    End point timeframe
    12 months ± 14 days
    Notes
    [29] - 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: Baseline period arms are not mutually exclusive. Details see under description of period arms.
    End point values
    On-demand arm Prophylaxis arm
    Number of subjects analysed
    1
    1
    Units: Bethesda Units (BU)
    median (inter-quartile range (Q1-Q3))
        Screening to 3 Month- Low to Low (N=1, 0)
    3.2 (3.2 to 3.2)
    99999 (99999 to 99999)
        Screening to 3 Month- Low to High (N=0, 0)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
        Screening to 3 Month- High to Low (N=0, 0)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
        Screening to 3 Month- High to High (N=1, 1)
    0.3 (0.3 to 0.3)
    10.7 (10.7 to 10.7)
        Screening to 6 Month- Low to Low (N=1, 0)
    1.5 (1.5 to 1.5)
    99999 (99999 to 99999)
        Screening to 6 Month- Low to High (N=0, 0)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
        Screening to 6 Month- High to Low (N=0, 0)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
        Screening to 6 Month- High to High (N=1, 1)
    1.7 (1.7 to 1.7)
    23.2 (23.2 to 23.2)
        Screening to 9 Month- Low to Low (N=1, 0)
    3.2 (3.2 to 3.2)
    99999 (99999 to 99999)
        Screening to 9 Month- Low to High (N=0, 0)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
        Screening to 9 Month- High to Low (N=0, 0)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
        Screening to 9 Month- High to High (N=0, 1)
    99999 (99999 to 99999)
    37 (37 to 37)
        Screening to Termination - Low to Low (N=0, 0)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
        Screening to Termination- Low to High (N=0, 0)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
        Screening to Termination- High to Low (N=0, 0)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
        Screening to Termination - High to High (N=1, 1)
    11.3 (11.3 to 11.3)
    21.4 (21.4 to 21.4)
    No statistical analyses for this end point

    Secondary: Pharmacoeconomics: Annual days lost due to bleeding (work or school)

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    End point title
    Pharmacoeconomics: Annual days lost due to bleeding (work or school) [30]
    End point description
    End point type
    Secondary
    End point timeframe
    12 months ± 14 days
    Notes
    [30] - 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: Baseline period arms are not mutually exclusive. Details see under description of period arms.
    End point values
    On-demand arm Prophylaxis arm
    Number of subjects analysed
    17
    16
    Units: days
        arithmetic mean (standard deviation)
    16.4 ± 25.76
    8.8 ± 14.42
    No statistical analyses for this end point

    Secondary: Pharmacoeconomics: Annual number of hospitalizations for bleeding

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    End point title
    Pharmacoeconomics: Annual number of hospitalizations for bleeding [31]
    End point description
    End point type
    Secondary
    End point timeframe
    12 months ± 14 days
    Notes
    [31] - 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: Baseline period arms are not mutually exclusive. Details see under description of period arms.
    End point values
    On-demand arm Prophylaxis arm
    Number of subjects analysed
    18
    16
    Units: hospitalizations
        arithmetic mean (standard deviation)
    0.6 ± 1.15
    0.6 ± 2.03
    No statistical analyses for this end point

    Secondary: Pharmacoeconomics: Annual number of hospitalizations for indwelling line

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    End point title
    Pharmacoeconomics: Annual number of hospitalizations for indwelling line [32]
    End point description
    End point type
    Secondary
    End point timeframe
    12 months ± 14 days
    Notes
    [32] - 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: Baseline period arms are not mutually exclusive. Details see under description of period arms.
    End point values
    On-demand arm Prophylaxis arm
    Number of subjects analysed
    18
    16
    Units: hospitalizations
        arithmetic mean (standard deviation)
    0.1 ± 0.32
    0.1 ± 0.25
    No statistical analyses for this end point

    Secondary: Pharmacoeconomics: Annual number of emergency room visits

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    End point title
    Pharmacoeconomics: Annual number of emergency room visits [33]
    End point description
    End point type
    Secondary
    End point timeframe
    12 months ± 14 days
    Notes
    [33] - 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: Baseline period arms are not mutually exclusive. Details see under description of period arms.
    End point values
    On-demand arm Prophylaxis arm
    Number of subjects analysed
    18
    16
    Units: Emergency room visits
        arithmetic mean (standard deviation)
    0.4 ± 0.98
    0.4 ± 1.09
    No statistical analyses for this end point

    Secondary: Pharmacoeconomics: Annual number of physician’s office visits

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    End point title
    Pharmacoeconomics: Annual number of physician’s office visits [34]
    End point description
    End point type
    Secondary
    End point timeframe
    12 months ± 14 days
    Notes
    [34] - 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: Baseline period arms are not mutually exclusive. Details see under description of period arms.
    End point values
    On-demand arm Prophylaxis arm
    Number of subjects analysed
    18
    16
    Units: Physician's office visits
        arithmetic mean (standard deviation)
    2.2 ± 4.15
    2.6 ± 4.6
    No statistical analyses for this end point

    Secondary: Pharmacoeconomics: Annual total length of hospitalization for bleeding

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    End point title
    Pharmacoeconomics: Annual total length of hospitalization for bleeding [35]
    End point description
    End point type
    Secondary
    End point timeframe
    12 months ± 14 days
    Notes
    [35] - 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: Baseline period arms are not mutually exclusive. Details see under description of period arms.
    End point values
    On-demand arm Prophylaxis arm
    Number of subjects analysed
    18
    16
    Units: Days
        arithmetic mean (standard deviation)
    5 ± 9.48
    5.3 ± 17
    No statistical analyses for this end point

    Secondary: Pharmacoeconomics: Annual total length of hospitalization for indwelling line

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    End point title
    Pharmacoeconomics: Annual total length of hospitalization for indwelling line [36]
    End point description
    End point type
    Secondary
    End point timeframe
    12 months ± 14 days
    Notes
    [36] - 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: Baseline period arms are not mutually exclusive. Details see under description of period arms.
    End point values
    On-demand arm Prophylaxis arm
    Number of subjects analysed
    18
    16
    Units: Days
        arithmetic mean (standard deviation)
    0.7 ± 2.61
    0.7 ± 2.75
    No statistical analyses for this end point

    Secondary: Pharmacoeconomics: Annual total number of days lost (work or school)

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    End point title
    Pharmacoeconomics: Annual total number of days lost (work or school) [37]
    End point description
    End point type
    Secondary
    End point timeframe
    12 months ± 14 days
    Notes
    [37] - 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: Baseline period arms are not mutually exclusive. Details see under description of period arms.
    End point values
    On-demand arm Prophylaxis arm
    Number of subjects analysed
    17
    16
    Units: Days
        arithmetic mean (standard deviation)
    17.4 ± 25.42
    15.4 ± 24.28
    No statistical analyses for this end point

    Secondary: Health-Related Quality of Life (HRQoL): EuroQoL (Quality of Life)-5 Dimensions (EQ-5D) Index Scores

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    End point title
    Health-Related Quality of Life (HRQoL): EuroQoL (Quality of Life)-5 Dimensions (EQ-5D) Index Scores [38]
    End point description
    EQ-5D is a participant answered questionnaire scoring 5 dimensions - mobility, self-care, usual activities, pain/discomfort and anxiety/depression. The EQ-5D total score ranges from 0 (worst health state) to 1 (perfect health state) and 1 reflects the best outcome. EQ-5D Index scores based on EQ-5D questionnaire were calculated for participants ≥14 years of age, at screening, 6 months, and at termination visit. Changes in scores at 6 months and termination were also calculated. A relatively higher score represents better quality of life.
    End point type
    Secondary
    End point timeframe
    12 months ± 14 days
    Notes
    [38] - 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: Baseline period arms are not mutually exclusive. Details see under description of period arms.
    End point values
    On-demand arm Prophylaxis arm
    Number of subjects analysed
    16
    12
    Units: Scores on a scale
    arithmetic mean (standard deviation)
        Screening (N= 16, 12)
    0.627 ± 0.2067
    0.62 ± 0.1841
        6 Months (N= 15, 11)
    0.621 ± 0.188
    0.729 ± 0.1392
        Termination (N= 15, 10)
    0.605 ± 0.2146
    0.7 ± 0.1233
        Change (Screening - Month 6) (N= 15, 11)
    -0.006 ± 0.2088
    -0.096 ± 0.2403
        Change (Screening - Termination) (N= 15, 10)
    0.01 ± 0.247
    -0.075 ± 0.2594
        Change (Month 6 - Termination) (N= 15, 10)
    0.016 ± 0.1765
    0.001 ± 0.1493
    No statistical analyses for this end point

    Secondary: Hemophilia-specific Quality of Life questionnaire for adults (Haem-A-QoL) ≥ 16 Years Old

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    End point title
    Hemophilia-specific Quality of Life questionnaire for adults (Haem-A-QoL) ≥ 16 Years Old [39]
    End point description
    The Haem-A-QoL instrument has been developed and used in Hemophilia A patients. As a hemophilia-specific instrument, this measure assesses very specific aspects of dealing with hemophilia. The areas covered by this instrument are: Physical Health (PH), Sports & Leisure (S&L), School & Work (W&S), Dealing with Hemophilia (Dealing), Family Planning (FP), Feeling, Relationships (R'ships), Treatment, View, and Outlook for the Future (Future). A Haem-A-QoL Total Score (Total) was also calculated. For the Haem-A-QoL, higher scores indicate a worse quality of life. Scores on a scale range between 0 and 100. Haem-A-QoL scores at screening, 6 months, and at termination visit were collected. Changes in scores at 6 months and termination were also calculated.
    End point type
    Secondary
    End point timeframe
    12 months ± 14 days
    Notes
    [39] - 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: Baseline period arms are not mutually exclusive. Details see under description of period arms.
    End point values
    On-demand arm Prophylaxis arm
    Number of subjects analysed
    15
    12
    Units: Scores on a scale
    arithmetic mean (standard deviation)
        Dealing- Screening (N=15, 12)
    35 ± 19.72
    26 ± 15.84
        Dealing- Month 6 (N=14, 11)
    25 ± 16.67
    18.9 ± 21.11
        Dealing- Termination (N=14, 11)
    25.6 ± 25.21
    23.7 ± 22.15
        Dealing- Change (Screening - Month 6) (N=14, 11)
    10.7 ± 18.61
    3.4 ± 22.62
        Dealing- Change(Screening - Termination)(N=14, 11)
    10.1 ± 27.19
    -1.4 ± 21.37
        Dealing- Change (Month 6 - Termination)(N=14, 11)
    -0.6 ± 16.81
    -4.8 ± 21.26
        FP- Screening (N=9, 8)
    16.7 ± 20.49
    34.9 ± 31.31
        FP- Month 6 (N=12, 7)
    20.5 ± 26.71
    14.3 ± 11.25
        FP- Termination (N=13, 8)
    19.1 ± 16.25
    21.1 ± 22.14
        FP- Change (Screening - Month 6) (N=9, 7)
    -3.7 ± 26.94
    14.9 ± 28.73
        FP- Change(Screening - Termination)(N=9, 7)
    -2.5 ± 25.57
    13.1 ± 20.26
        FP- Change (Month 6 - Termination)(N=11, 6)
    -0.8 ± 32.68
    -8.3 ± 28.41
        Feeling- Screening (N=15, 12)
    39.6 ± 28.22
    48.2 ± 29.02
        Feeling- Month 6 (N=14, 11)
    33.9 ± 28.77
    29 ± 17.29
        Feeling- Termination (N=14, 11)
    30.8 ± 28.53
    26.1 ± 20.69
        Feeling- Change (Screening - Month 6) (N=14, 11)
    4.9 ± 27.75
    17.3 ± 34.72
        Feeling- Change(Screening - Termination)(N=14, 11)
    8 ± 31.91
    20.2 ± 24.58
        Feeling- Change (Month 6 - Termination)(N=14, 11)
    3.1 ± 16.4
    2.8 ± 23.94
        Future- Screening (N=14, 12)
    46.8 ± 28.46
    48.6 ± 23.32
        Future- Month 6 (N=14, 11)
    40.2 ± 26.14
    46 ± 18.03
        Future- Termination (N=14, 11)
    47.9 ± 25.47
    46.8 ± 18.74
        Future- Change (Screening - Month 6) (N=13, 11)
    4 ± 26.84
    1.1 ± 24.34
        Future- Change(Screening - Termination)(N=13, 11)
    -3.8 ± 20.53
    0.3 ± 16.58
        Future- Change (Month 6 - Termination)(N=14, 11)
    -7.7 ± 20.25
    -0.8 ± 16.3
        PH- Screening (N=15, 12)
    64 ± 22.46
    66.4 ± 24.21
        PH- Month 6 (N=14, 11)
    50.8 ± 27.55
    43.1 ± 25.24
        PH- Termination (N=14, 11)
    56.1 ± 24.98
    42.3 ± 18.86
        PH- Change (Screening - Month 6) (N=14, 11)
    14.6 ± 21.7
    21.1 ± 28.77
        PH- Change(Screening - Termination)(N=14, 11)
    9.3 ± 23.93
    21.9 ± 24.79
        PH- Change (Month 6 - Termination)(N=14, 11)
    -5.3 ± 10.65
    0.8 ± 20.2
        R'ships- Screening (N=15, 11)
    28.3 ± 36.57
    26.9 ± 28.83
        R'ships- Month 6 (N=14, 11)
    19 ± 28.2
    15.2 ± 13.85
        R'ships- Termination (N=14, 10)
    17.9 ± 22.13
    15 ± 17.48
        R'ships- Change (Screening - Month 6) (N=14, 10)
    7.7 ± 34.04
    10.4 ± 27.45
        R'ships- Change(Screening - Termination)(N=14, 10)
    8.9 ± 30.57
    12.1 ± 25.49
        R'ships- Change (Month 6 - Termination)(N=14, 10)
    1.2 ± 21.4
    1.7 ± 16.57
        S&L- Screening (N=12, 8)
    69.3 ± 17.11
    83.1 ± 14.13
        S&L- Month 6 (N=12, 8)
    63.1 ± 23.09
    69.7 ± 19.75
        S&L- Termination (N=12, 8)
    72.3 ± 17.3
    78.1 ± 12.52
        S&L- Change (Screening - Month 6) (N=9, 5)
    9.9 ± 19.75
    20.5 ± 27.97
        S&L- Change(Screening - Termination)(N=9, 5)
    1.2 ± 15.91
    7 ± 21.68
        S&L- Change (Month 6 - Termination)(N=11, 7)
    -10.2 ± 13.44
    -2.5 ± 15.61
        Treatment- Screening (N=15, 12)
    36.9 ± 13.32
    39.6 ± 20.7
        Treatment- Month 6 (N=14, 11)
    30.4 ± 19.82
    40.9 ± 16.96
        Treatment- Termination (N=14, 11)
    34.8 ± 14.87
    42.6 ± 17.8
        Treatment- Change (Screening - Month 6) (N=14, 11)
    6.5 ± 23.72
    0 ± 16.74
        Treatment-Change(Screening -Termination)(N=14, 11)
    2.1 ± 17.81
    -1.7 ± 23.86
        Treatment- Change (Month 6- Termination)(N=14, 11)
    -4.4 ± 15.07
    -1.7 ± 18.7
        View- Screening (N=15, 12)
    52.3 ± 24.49
    55.6 ± 11.97
        View- Month 6 (N=14, 11)
    44.3 ± 27.66
    40 ± 13.23
        View- Termination (N=14, 11)
    47.9 ± 22.59
    37.7 ± 21.26
        View- Change (Screening - Month 6) (N=14, 11)
    7.5 ± 23.68
    14.3 ± 17.25
        View- Change (Screening -Termination)(N=14, 11)
    3.9 ± 23.79
    16.6 ± 15.01
        View- Change (Month 6- Termination)(N=14, 11)
    -3.6 ± 17.03
    2.3 ± 20.78
        W&S-Screening (N=13, 10)
    43.8 ± 25.9
    57.7 ± 17.87
        W&S- Month 6 (N=13, 9)
    31.7 ± 26.82
    37.5 ± 20.73
        W&S- Termination (N=12, 9)
    28.6 ± 22.53
    36.8 ± 19.63
        W&S- Change (Screening - Month 6) (N=12, 8)
    10.9 ± 30.98
    25.3 ± 25.6
        W&S- Change (Screening -Termination)(N=12, 8)
    16.1 ± 33.86
    25.3 ± 19.01
        W&S- Change (Month 6- Termination)(N=12, 9)
    5.2 ± 15.95
    0.7 ± 21.75
        Total- Screening (N=14, 12)
    44 ± 15.5
    49.2 ± 15.43
        Total- Month 6 (N=14, 11)
    37.4 ± 19.37
    38.1 ± 11.34
        Total- Termination (N=14, 11)
    40.2 ± 17.55
    38.7 ± 14.21
        Total- Change (Screening - Month 6) (N=13, 11)
    9.2 ± 18.44
    10.2 ± 17.84
        Total- Change (Screening -Termination)(N=13, 11)
    6.1 ± 15.41
    9.5 ± 12.77
        Total- Change (Month 6- Termination)(N=14, 11)
    -2.7 ± 9.21
    -0.7 ± 14.4
    No statistical analyses for this end point

    Secondary: Hemophilia-specific Quality of Life questionnaire for Children and Adolescents < 16 Years Old (Haemo-QoL) - Parent's Evaluation

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    End point title
    Hemophilia-specific Quality of Life questionnaire for Children and Adolescents < 16 Years Old (Haemo-QoL) - Parent's Evaluation [40]
    End point description
    The Haemo-QoL is a quality of life (QoL) assessment instrument for children and adolescents with haemophilia. As a hemophilia-specific instrument, this measure assesses very specific aspects of dealing with hemophilia. The areas covered by this instrument are: Physical Health (PH), Sports & School (S&S), Dealing with Hemophilia (Dealing), Family, Feeling, Relationships (R'ships), Treatment, View, Outlook for the Future (Future), Friends, Others, and Support. A Haemo-QoL Total Score (Total) was also calculated. For the Haemo-QoL, higher scores indicate a worse quality of life. Scores on a scale range between 0 and 100. Haemo-QoL scores at screening, 6 months, and at termination visit were collected. Changes in scores at 6 months and termination were also calculated.
    End point type
    Secondary
    End point timeframe
    12 months ± 14 days
    Notes
    [40] - 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: Baseline period arms are not mutually exclusive. Details see under description of period arms.
    End point values
    On-demand arm Prophylaxis arm
    Number of subjects analysed
    4
    5
    Units: Scores on a scale
    arithmetic mean (standard deviation)
        Dealing- Screening (N=4, 4)
    25.9 ± 11.8
    39.3 ± 17
        Dealing- Month 6 (N=4, 4)
    25.6 ± 19.31
    36.6 ± 16.07
        Dealing- Termination (N=4, 5)
    21.4 ± 16.24
    28.6 ± 13.36
        Dealing- Change (Screening - Month 6) (N=4, 4)
    0.3 ± 8.61
    2.7 ± 7.92
        Dealing- Change(Screening - Termination)(N=4, 4)
    4.5 ± 7.92
    13.4 ± 5.36
        Dealing- Change (Month 6 - Termination)(N=4, 4)
    4.2 ± 11.85
    10.7 ± 7.72
        Family- Screening (N=4, 5)
    55.3 ± 19.05
    50.9 ± 8.72
        Family- Month 6 (N=4, 5)
    50.3 ± 27.65
    49.1 ± 10.27
        Family- Termination (N=4, 5)
    45.8 ± 31.03
    39.8 ± 13.77
        Family- Change (Screening - Month 6) (N=4, 5)
    5 ± 9.26
    1.7 ± 15.65
        Family- Change(Screening - Termination)(N=4, 5)
    9.5 ± 15.52
    11.1 ± 19.22
        Family- Change (Month 6 - Termination)(N=4, 5)
    4.5 ± 12.16
    9.3 ± 5.24
        Feeling- Screening (N=4, 5)
    44.1 ± 14.25
    38.2 ± 2.77
        Feeling- Month 6 (N=4, 5)
    50.3 ± 27.02
    37.5 ± 22.21
        Feeling- Termination (N=4, 5)
    33.6 ± 36.07
    27.8 ± 16.97
        Feeling- Change (Screening - Month 6) (N=4, 5)
    -6.3 ± 24.27
    0.7 ± 24.02
        Feeling- Change(Screening - Termination)(N=4, 5)
    10.5 ± 27.92
    10.5 ± 19.45
        Feeling- Change (Month 6 - Termination)(N=4, 5)
    16.7 ± 13.85
    9.7 ± 20.64
        Friends- Screening (N=4, 5)
    35.9 ± 20.65
    52.1 ± 17.18
        Friends- Month 6 (N=4, 5)
    26.6 ± 17.95
    36.3 ± 29.78
        Friends- Termination (N=4, 5)
    34.4 ± 14.88
    66.3 ± 20.06
        Friends- Change (Screening - Month 6) (N=4, 5)
    9.4 ± 27.72
    15.8 ± 21.88
        Friends- Change(Screening - Termination)(N=4, 5)
    1.6 ± 17.95
    -14.2 ± 28.31
        Friends- Change (Month 6 - Termination)(N=4, 5)
    -7.8 ± 22.46
    -30 ± 31.68
        Future- Screening (N=2, 2)
    53.1 ± 13.26
    43.8 ± 17.68
        Future- Month 6 (N=2, 2)
    40.6 ± 13.26
    37.5 ± 8.84
        Future- Termination (N=2, 2)
    31.3 ± 0
    43.8 ± 8.84
        Future- Change (Screening - Month 6) (N=2, 2)
    12.5 ± 0
    6.3 ± 8.84
        Future- Change(Screening - Termination)(N=2, 2)
    21.9 ± 13.26
    0 ± 8.84
        Future- Change (Month 6 - Termination)(N=2, 2)
    9.4 ± 13.26
    -6.3 ± 0
        Others- Screening (N=4, 5)
    27.1 ± 34.44
    29.2 ± 16.67
        Others- Month 6 (N=4, 5)
    42.7 ± 39.14
    24.2 ± 15.7
        Others- Termination (N=4, 5)
    28.1 ± 32.87
    25.8 ± 13.63
        Others- Change (Screening - Month 6) (N=4, 5)
    -15.6 ± 16.8
    5 ± 20.28
        Others- Change(Screening - Termination)(N=4, 5)
    -1 ± 15.36
    3.3 ± 15.98
        Others- Change (Month 6 - Termination)(N=4, 5)
    14.6 ± 19.98
    -1.7 ± 10.87
        PH- Screening (N=4, 5)
    58 ± 11.06
    52.1 ± 23.23
        PH- Month 6 (N=4, 5)
    53.6 ± 13.98
    48 ± 17.23
        PH- Termination (N=4, 5)
    41.1 ± 11.85
    40.4 ± 17.02
        PH- Change (Screening - Month 6) (N=4, 5)
    4.5 ± 12.16
    4.1 ± 32.71
        PH- Change(Screening - Termination)(N=4, 5)
    17 ± 17.1
    11.8 ± 29.6
        PH- Change (Month 6 - Termination)(N=4, 5)
    12.5 ± 22.87
    7.7 ± 22.25
        R'ships- Screening (N=2, 2)
    12.5 ± 17.68
    43.8 ± 8.84
        R'ships- Month 6 (N=2, 2)
    25 ± 35.36
    43.8 ± 8.84
        R'ships- Termination (N=2, 2)
    0 ± 0
    37.5 ± 17.68
        R'ships- Change (Screening - Month 6) (N=2, 2)
    -12.5 ± 17.68
    0 ± 0
        R'ships-Change(Screening -Termination)(N=2, 2)
    12.5 ± 17.68
    6.3 ± 8.84
        R'ships- Change (Month 6- Termination)(N=2, 2)
    25 ± 35.36
    6.3 ± 8.84
        S&S- Screening (N=4, 5)
    67.1 ± 10.68
    59.1 ± 23.73
        S&S- Month 6 (N=4, 5)
    62.5 ± 7.74
    56.5 ± 9.07
        S&S- Termination (N=4, 5)
    55.6 ± 17.16
    57.2 ± 17.29
        S&S- Change (Screening - Month 6) (N=4, 5)
    4.6 ± 6.89
    2.6 ± 16.32
        S&S- Change (Screening -Termination)(N=4, 5)
    11.5 ± 12.02
    1.9 ± 10.22
        S&S- Change (Month 6- Termination)(N=4, 5)
    6.9 ± 18.07
    -0.8 ± 8.94
        Support-Screening (N=4, 4)
    28.1 ± 25.77
    51.6 ± 9.38
        Support-Month 6 (N=4, 4)
    18.8 ± 29.32
    42.2 ± 17.95
        Support- Termination (N=4, 5)
    32.8 ± 32.02
    48.8 ± 20.44
        Support- Change (Screening - Month 6) (N=4, 4)
    9.4 ± 24.21
    9.4 ± 10.83
        Support- Change (Screening -Termination)(N=4, 4
    -4.7 ± 13.86
    3.1 ± 15.73
        Support- Change (Month 6- Termination)(N=4, 4)
    -14.1 ± 21.27
    -6.3 ± 8.84
        Treatment- Screening (N=4, 5)
    29 ± 13.23
    64.2 ± 22.6
        Treatment- Month 6 (N=4, 5)
    21.9 ± 6.9
    54.8 ± 14.53
        Treatment- Termination (N=4, 5)
    17.1 ± 22.12
    41 ± 13.34
        Treatment- Change (Screening - Month 6) (N=4, 5)
    7.1 ± 10.1
    9.4 ± 13.06
        Treatment- Change(Screening -Termination)(N=4, 5)
    11.9 ± 17.16
    23.2 ± 16.94
        Treatment- Change (Month 6- Termination)(N=4, 5)
    4.8 ± 22.47
    13.8 ± 11.14
        View-Screening (N=4, 5)
    47.4 ± 18.25
    36.7 ± 16.94
        View-Month 6 (N=4, 5)
    46.3 ± 24.45
    36.4 ± 22.04
        View- Termination (N=4, 5)
    32.8 ± 35.68
    30.8 ± 12.85
        View- Change (Screening - Month 6) (N=4, 5)
    1.1 ± 6.38
    0.3 ± 7.63
        View- Change (Screening -Termination)(N=4, 5)
    14.7 ± 18.62
    5.9 ± 10.08
        View- Change (Month 6- Termination)(N=4, 5)
    13.5 ± 13.02
    5.6 ± 16.7
        Total-Screening (N=4, 5)
    43.7 ± 13.67
    48.1 ± 8.84
        Total-Month 6 (N=4, 5)
    42 ± 13.84
    42.3 ± 11.08
        Total- Termination (N=4, 5)
    34.5 ± 21.83
    39.5 ± 8.52
        Total- Change (Screening - Month 6) (N=4, 5)
    1.7 ± 1.19
    5.7 ± 14.97
        Total- Change (Screening -Termination)(N=4, 5)
    9.1 ± 8.57
    8.6 ± 8.72
        Total- Change (Month 6- Termination)(N=4, 5)
    7.4 ± 8.91
    2.8 ± 7.06
    No statistical analyses for this end point

    Secondary: Hemophilia-specific Quality of Life questionnaire for Children and Adolescents < 16 Years Old (Haemo-QoL) - Child's Evaluation

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    End point title
    Hemophilia-specific Quality of Life questionnaire for Children and Adolescents < 16 Years Old (Haemo-QoL) - Child's Evaluation [41]
    End point description
    The Haemo-QoL is a quality of life (QoL) assessment instrument for children and adolescents with haemophilia. As a hemophilia-specific instrument, this measure assesses very specific aspects of dealing with hemophilia. The areas covered by this instrument are: Physical Health (PH), Sports & School (S&S), Dealing with Hemophilia (Dealing), Family, Feeling, Relationships (R'ships), Treatment, View, Outlook for the Future (Future), Friends, Others, and Support. A Haemo-QoL Total Score (Total) was also calculated. For the Haemo-QoL, higher scores indicate a worse quality of life. Scores on a scale range between 0 and 100. Haemo-QoL scores at screening, 6 months, and at termination visit were collected. Changes in scores at 6 months and termination were also calculated.
    End point type
    Secondary
    End point timeframe
    12 months ± 14 days
    Notes
    [41] - 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: Baseline period arms are not mutually exclusive. Details see under description of period arms.
    End point values
    On-demand arm Prophylaxis arm
    Number of subjects analysed
    4
    5
    Units: Scores on a scale
    arithmetic mean (standard deviation)
        Dealing- Screening (N=4, 4)
    33 ± 17.1
    44.6 ± 20.72
        Dealing- Month 6 (N=4, 4)
    21.4 ± 2.92
    37.5 ± 13.2
        Dealing- Termination (N=4, 5)
    25 ± 9.22
    32.9 ± 12.73
        Dealing- Change (Screening - Month 6) (N=4, 4)
    11.6 ± 15.26
    7.1 ± 8.75
        Dealing- Change(Screening - Termination)(N=4, 4)
    8 ± 15.26
    14.3 ± 12.37
        Dealing- Change (Month 6 - Termination)(N=4, 4)
    -3.6 ± 6.52
    7.1 ± 6.52
        Family- Screening (N=4, 5)
    50.5 ± 23.94
    35.6 ± 22.05
        Family- Month 6 (N=4, 5)
    43.4 ± 28.78
    36.4 ± 23.06
        Family- Termination (N=4, 5)
    38.3 ± 21.25
    32.5 ± 21.09
        Family- Change (Screening - Month 6) (N=4, 5)
    7 ± 20.31
    -0.7 ± 16.38
        Family- Change(Screening - Termination)(N=4, 5)
    12.2 ± 25.72
    3.1 ± 15.51
        Family- Change (Month 6 - Termination)(N=4, 5)
    5.2 ± 13.66
    3.9 ± 12.2
        Feeling- Screening (N=4, 5)
    54.8 ± 31.91
    34.9 ± 12.89
        Feeling- Month 6 (N=4, 5)
    41.4 ± 43.03
    22 ± 18.68
        Feeling- Termination (N=4, 5)
    34.4 ± 39.48
    19.2 ± 15.39
        Feeling- Change (Screening - Month 6) (N=4, 5)
    13.4 ± 16.91
    12.9 ± 27.77
        Feeling- Change(Screening - Termination)(N=4, 5)
    20.4 ± 11.77
    15.7 ± 23.2
        Feeling- Change (Month 6 - Termination)(N=4, 5)
    7 ± 7.79
    2.8 ± 15.26
        Friends- Screening (N=4, 5)
    34.4 ± 25.26
    58.8 ± 20.54
        Friends- Month 6 (N=4, 5)
    28.1 ± 15.73
    42.5 ± 29.78
        Friends- Termination (N=4, 5)
    32.8 ± 12.88
    56.3 ± 27.24
        Friends- Change (Screening - Month 6) (N=4, 5)
    6.3 ± 25.52
    16.3 ± 24.84
        Friends- Change(Screening - Termination)(N=4, 5)
    1.6 ± 28.58
    2.5 ± 22.79
        Friends- Change (Month 6 - Termination)(N=4, 5)
    -4.7 ± 17.95
    -13.8 ± 20.44
        Future- Screening (N=2, 2)
    40.6 ± 13.26
    43.8 ± 17.68
        Future- Month 6 (N=2, 2)
    43.8 ± 17.68
    43.8 ± 17.68
        Future- Termination (N=2, 2)
    46.9 ± 22.1
    28.1 ± 22.1
        Future- Change (Screening - Month 6) (N=2, 2)
    -3.1 ± 4.42
    0 ± 0
        Future- Change(Screening - Termination)(N=2, 2)
    -6.3 ± 8.84
    15.6 ± 4.42
        Future- Change (Month 6 - Termination)(N=2, 2)
    -3.1 ± 4.42
    15.6 ± 4.42
        Others- Screening (N=4, 5)
    42.7 ± 33.74
    26.7 ± 20.11
        Others- Month 6 (N=4, 5)
    33.3 ± 40.11
    16.7 ± 15.02
        Others- Termination (N=4, 5)
    18.8 ± 21.11
    13.3 ± 12.64
        Others- Change (Screening - Month 6) (N=4, 5)
    9.4 ± 8.59
    10 ± 25.79
        Others- Change(Screening - Termination)(N=4, 5)
    24 ± 14.18
    13.3 ± 23.09
        Others- Change (Month 6 - Termination)(N=4, 5)
    14.6 ± 19.39
    3.3 ± 16.24
        PH- Screening (N=4, 5)
    67 ± 24.98
    42.1 ± 32.28
        PH- Month 6 (N=4, 5)
    49.1 ± 14.69
    33.9 ± 16.66
        PH- Termination (N=4, 5)
    41.1 ± 23.05
    25.7 ± 10.83
        PH- Change (Screening - Month 6) (N=4, 5)
    17.9 ± 19.56
    8.2 ± 34.43
        PH- Change(Screening - Termination)(N=4, 5)
    25.9 ± 14.4
    16.4 ± 29.73
        PH- Change (Month 6 - Termination)(N=4, 5)
    8 ± 12.16
    8.2 ± 20.66
        R'ships- Screening (N=2, 2)
    6.3 ± 8.84
    43.8 ± 8.84
        R'ships- Month 6 (N=2, 2)
    18.8 ± 26.52
    43.8 ± 8.84
        R'ships- Termination (N=2, 2)
    6.3 ± 8.84
    18.8 ± 26.52
        R'ships- Change (Screening - Month 6) (N=2, 2)
    -12.5 ± 17.68
    0 ± 0
        R'ships-Change(Screening -Termination)(N=2, 2)
    0 ± 0
    25 ± 17.68
        R'ships- Change (Month 6- Termination)(N=2, 2)
    12.5 ± 17.68
    25 ± 17.68
        S&S- Screening (N=4, 5)
    53.3 ± 14.74
    51.3 ± 19.82
        S&S- Month 6 (N=4, 5)
    46.8 ± 13.42
    54.2 ± 5.53
        S&S- Termination (N=4, 5)
    33.2 ± 5.64
    49.8 ± 18.49
        S&S- Change (Screening - Month 6) (N=4, 5)
    6.5 ± 11.42
    -2.8 ± 18.53
        S&S- Change (Screening -Termination)(N=4, 5)
    20.1 ± 14.74
    1.5 ± 18.74
        S&S- Change (Month 6- Termination)(N=4, 5)
    13.5 ± 9.1
    4.4 ± 15.19
        Support-Screening (N=4, 4)
    32.8 ± 3.13
    62.5 ± 31.04
        Support-Month 6 (N=4, 4)
    28.1 ± 10.83
    56.3 ± 31.87
        Support- Termination (N=4, 5)
    17.2 ± 17.21
    65 ± 15.69
        Support- Change (Screening - Month 6) (N=4, 4)
    4.7 ± 12.88
    6.3 ± 31.46
        Support- Change (Screening -Termination)(N=4, 4
    15.6 ± 18.75
    -3.1 ± 18.75
        Support- Change (Month 6- Termination)(N=4, 4)
    10.9 ± 10.67
    -9.4 ± 25.77
        Treatment- Screening (N=4, 5)
    27.3 ± 15.38
    69.6 ± 25.63
        Treatment- Month 6 (N=4, 5)
    30.6 ± 16.5
    56.8 ± 15.89
        Treatment- Termination (N=4, 5)
    35.9 ± 26.1
    44.2 ± 27.1
        Treatment- Change (Screening - Month 6) (N=4, 5)
    -3.2 ± 4.43
    12.9 ± 21.22
        Treatment- Change(Screening -Termination)(N=4, 5)
    -8.6 ± 13.86
    25.4 ± 28
        Treatment- Change (Month 6- Termination)(N=4, 5)
    -5.3 ± 11.25
    12.6 ± 15.53
        View-Screening (N=4, 5)
    46 ± 19.33
    31.9 ± 14.36
        View-Month 6 (N=4, 5)
    39.3 ± 33.02
    32.4 ± 19.41
        View- Termination (N=4, 5)
    32.5 ± 32.75
    32.2 ± 8.6
        View- Change (Screening - Month 6) (N=4, 5)
    6.7 ± 14.96
    -0.5 ± 18.94
        View- Change (Screening -Termination)(N=4, 5)
    13.5 ± 16.56
    -0.3 ± 10.77
        View- Change (Month 6- Termination)(N=4, 5)
    6.8 ± 8.67
    0.2 ± 13.48
        Total-Screening (N=4, 5)
    44.9 ± 12.28
    45.1 ± 9.16
        Total-Month 6 (N=4, 5)
    37.4 ± 17.91
    37.7 ± 9.87
        Total- Termination (N=4, 5)
    32.2 ± 17.96
    35.3 ± 9.06
        Total- Change (Screening - Month 6) (N=4, 5)
    7.5 ± 7.21
    7.4 ± 16.57
        Total- Change (Screening -Termination)(N=4, 5)
    12.7 ± 8.69
    9.8 ± 12.35
        Total- Change (Month 6- Termination)(N=4, 5)
    5.2 ± 3.55
    2.5 ± 9.46
    No statistical analyses for this end point

    Secondary: Health-Related Quality of Life (HRQoL) - General Pain Assessment Using a Visual Analogue Scale (VAS) in Adults and Adolescents ≥12 Years Old

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    End point title
    Health-Related Quality of Life (HRQoL) - General Pain Assessment Using a Visual Analogue Scale (VAS) in Adults and Adolescents ≥12 Years Old [42]
    End point description
    General pain was assessed using a VAS pain scale at screening, 6 months, and at termination. Unlike the VAS pain assessment for pain of bleeding episodes (Outcome above), this general pain assessment did not take use of analgesics into account. For the pain scale, a higher number indicates worse pain. The visual analog scale ranges from 0 to 100 where the endpoints are labeled 'Worst imaginable health state' (=0) and 'Best imaginable health state' (=100). A positive change from baseline indicates improvement. Change in VAS scores at 6 months and study termination were also compared relative to Baseline/Screening scores (ie, (Baseline/Screening VAS score) - (VAS score at 6 months and study termination).
    End point type
    Secondary
    End point timeframe
    Baseline, 6 months and 12 months ± 14 days
    Notes
    [42] - 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: Baseline period arms are not mutually exclusive. Details see under description of period arms.
    End point values
    On-demand arm Prophylaxis arm
    Number of subjects analysed
    17
    15
    Units: Scores on a scale
    arithmetic mean (standard deviation)
        Screening (N= 17, 15)
    35.2 ± 30.15
    55.5 ± 23.68
        Month 6 (N= 16, 14)
    36.6 ± 25.81
    32.7 ± 26.24
        Termination (N= 16, 14)
    32.4 ± 21.97
    29.8 ± 30.48
        Change (Screening - Month 6) (N= 16, 14)
    0.8 ± 31.77
    20.3 ± 38.91
        Change (Screening - Termination) (N= 16, 14)
    5 ± 28.7
    23.2 ± 46.61
        Change (Month 6 - Termination) (N= 16, 14)
    4.2 ± 21.82
    2.9 ± 19.62
    No statistical analyses for this end point

    Secondary: Health-Related Quality of Life (HRQoL) - General Pain Assessment Using a Visual Analogue Scale (VAS) in Pediatrics <12 Years Old

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    End point title
    Health-Related Quality of Life (HRQoL) - General Pain Assessment Using a Visual Analogue Scale (VAS) in Pediatrics <12 Years Old [43]
    End point description
    General pain was assessed using the children’s VAS pain scale (a facial expression scale with one end marked as no pain and the opposite end marked as the worst possible pain). Assessments were done at the screening, 6 months, and termination visits. Scores on the children's VAS scale are presented as: -No Pain -Mild Pain -Moderate pain -Severe pain -Very severe pain Unlike the VAS pain assessment for pain of bleeding episodes (Outcome above), this general pain assessment did not take use of analgesics into account. Change in VAS scores at 6 months and study termination were also compared relative to Baseline/Screening scores (ie, (Baseline/Screening VAS score) - (VAS score at 6 months and study termination).
    End point type
    Secondary
    End point timeframe
    Baseline, 6 months and 12 months ± 14 days
    Notes
    [43] - 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: Baseline period arms are not mutually exclusive. Details see under description of period arms.
    End point values
    On-demand arm Prophylaxis arm
    Number of subjects analysed
    2
    2
    Units: participants
        Screening - No Pain
    1
    0
        Screening - Mild Pain
    0
    1
        Screening - Moderate Pain
    1
    0
        Screening - Severe Pain
    0
    1
        Screening - Very Severe Pain
    0
    0
        Month 6 - No Pain
    0
    0
        Month 6 - Mild Pain
    1
    2
        Month 6 - Moderate Pain
    1
    0
        Month 6 - Severe Pain
    0
    0
        Month 6 - Very Severe Pain
    0
    0
        Termination visit - No Pain
    0
    1
        Termination visit - Mild Pain
    0
    0
        Termination visit - Moderate Pain
    1
    1
        Termination visit - Severe Pain
    0
    0
        Termination visit - Very Severe Pain
    1
    0
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Throughout the study period of 3 years and 7 months
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    15.0
    Reporting groups
    Reporting group title
    On-demand arm
    Reporting group description
    Factor VIII Inhibitor Bypassing Activity (nanofiltered, vapor heat-treated) : Standard FEIBA NF dose and dosing interval as prescribed by the treating physician

    Reporting group title
    Prophylaxis arm
    Reporting group description
    Factor VIII Inhibitor Bypassing Activity (nanofiltered, vapor heat-treated) : 85 ± 15 U/kg of FEIBA NF every other day during the 12-month ± 14 days prophylactic period

    Serious adverse events
    On-demand arm Prophylaxis arm
    Total subjects affected by serious adverse events
         subjects affected / exposed
    7 / 19 (36.84%)
    6 / 17 (35.29%)
         number of deaths (all causes)
    1
    0
         number of deaths resulting from adverse events
    Vascular disorders
    Arteriosclerosis
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 17 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Haematoma
         subjects affected / exposed
    0 / 19 (0.00%)
    1 / 17 (5.88%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhage
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 17 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertensive Crisis
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 17 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Femoral Neck Fracture
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 17 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Surgical and medical procedures
    Catheter Removal
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 17 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Hepatitis B Surface Antibody Positive
         subjects affected / exposed
    1 / 19 (5.26%)
    2 / 17 (11.76%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Epistaxis
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 17 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal Wall Haematoma
         subjects affected / exposed
    0 / 19 (0.00%)
    1 / 17 (5.88%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Haematuria
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 17 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis Acute
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 17 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Haemarthrosis
         subjects affected / exposed
    1 / 19 (5.26%)
    2 / 17 (11.76%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arthropathy
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 17 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Muscle Haemorrhage
         subjects affected / exposed
    0 / 19 (0.00%)
    1 / 17 (5.88%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Haematoma Infection
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 17 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    On-demand arm Prophylaxis arm
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    4 / 19 (21.05%)
    3 / 17 (17.65%)
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    1 / 19 (5.26%)
    1 / 17 (5.88%)
         occurrences all number
    1
    1
    Oropharyngeal Pain
         subjects affected / exposed
    1 / 19 (5.26%)
    1 / 17 (5.88%)
         occurrences all number
    1
    1
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    2 / 19 (10.53%)
    0 / 17 (0.00%)
         occurrences all number
    2
    0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    2 / 19 (10.53%)
    0 / 17 (0.00%)
         occurrences all number
    4
    0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    1 / 19 (5.26%)
    1 / 17 (5.88%)
         occurrences all number
    2
    1
    Nausea
         subjects affected / exposed
    2 / 19 (10.53%)
    0 / 17 (0.00%)
         occurrences all number
    2
    0
    Vomiting
         subjects affected / exposed
    2 / 19 (10.53%)
    0 / 17 (0.00%)
         occurrences all number
    2
    0
    Skin and subcutaneous tissue disorders
    Acne
         subjects affected / exposed
    1 / 19 (5.26%)
    1 / 17 (5.88%)
         occurrences all number
    1
    1
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    2 / 19 (10.53%)
    1 / 17 (5.88%)
         occurrences all number
    3
    1
    Arthropathy
         subjects affected / exposed
    1 / 19 (5.26%)
    0 / 17 (0.00%)
         occurrences all number
    1
    0

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? No

    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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