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    Clinical Trial Results:
    A Phase 3b clinical study to assess whether regular administration of ADVATE in the absence of immunological danger signals reduces the incidence rate of inhibitors in previously untreated patients with hemophilia A

    Due to the EudraCT – Results system being out of service between 31 July 2015 and 12 January 2016, these results have been published in compliance with revised timelines.
    Summary
    EudraCT number
    2011-000410-18
    Trial protocol
    AT   DE   SK   LT   GB   HU   CZ   SE   BE   BG   ES   NL   GR   PL   PT  
    Global end of trial date
    16 Nov 2012

    Results information
    Results version number
    v1(current)
    This version publication date
    13 Feb 2016
    First version publication date
    13 Feb 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    061002
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01376700
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Baxalta US Inc.
    Sponsor organisation address
    One Baxter Way, Westlake Village, United States, CA 91362
    Public contact
    Clinical Trial Registries and Results Disclosure, Baxalta US Inc., ClinicalTrialsDisclosure@baxalta.com
    Scientific contact
    Clinical Trial Registries and Results Disclosure, Baxalta US Inc., ClinicalTrialsDisclosure@baxalta.com
    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
    14 Oct 2013
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    16 Nov 2012
    Global end of trial reached?
    Yes
    Global end of trial date
    16 Nov 2012
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The primary objective of this trial was to determine the incidence rate of inhibitor formation in previously untreated patients (PUPs) with severe and moderately severe hemophilia A during the first 50 exposure days of treatment with ADVATE, starting with a once weekly prophylactic regimen together with the minimization of immunological danger signals
    Protection of trial subjects
    This study was conducted in accordance with the clinical protocol, the International Conference on Harmonisation Guideline for Good Clinical Practice E6 (ICH GCP, April 1996), Title 21 of the US Code of Federal Regulations (US CFR), the European Clinical Trial Directive (2001/20/EC and 2005/28/EC), and applicable national and local regulatory requirements.
    Background therapy
    The inhibitor incidence rate observed during the early prophylaxis regimen in this study was to be compared to the rate previously observed in historical cohorts, including the ADVATE PUP Study (Baxalta study number 060103; historical control).
    Evidence for comparator
    -
    Actual start date of recruitment
    26 Aug 2011
    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
    Germany: 2
    Country: Number of subjects enrolled
    Austria: 1
    Country: Number of subjects enrolled
    Russian Federation: 3
    Country: Number of subjects enrolled
    Bulgaria: 1
    Country: Number of subjects enrolled
    Czech Republic: 2
    Country: Number of subjects enrolled
    Serbia: 1
    Country: Number of subjects enrolled
    Spain: 1
    Country: Number of subjects enrolled
    Poland: 4
    Country: Number of subjects enrolled
    Netherlands: 1
    Country: Number of subjects enrolled
    Canada: 1
    Country: Number of subjects enrolled
    United States: 2
    Worldwide total number of subjects
    19
    EEA total number of subjects
    12
    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)
    19
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    0
    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 and North America at 19 clinical sites.

    Pre-assignment
    Screening details
    22 subjects were enrolled. One was a screen failure; one did not have screening laboratory assessments performed prior to study termination; and one met screening criteria, but was not exposed to investigational product prior to study termination. Therefore, 19 participants were treated.

    Pre-assignment period milestones
    Number of subjects started
    19
    Number of subjects completed
    19

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

    Arms
    Arm title
    ADVATE - Prophylactic Regimen
    Arm description
    The initial dosing regimen of 25 +/-5 IU/kg once weekly was to continue throughout the first 20 exposure days and for as long as possible beyond this early prophylaxis period. If required by the clinical situation, the frequency of infusions could be increased to twice or three times per week by the investigator in accordance with the instructions given in the study protocol. The maximum dose for any once weekly infusion was 50 IU/kg.
    Arm type
    Experimental

    Investigational medicinal product name
    Advate
    Investigational medicinal product code
    Other name
    rAHF-PFM (Antihemophilic Factor (Recombinant) – Plasma/Albumin Free Method)
    Pharmaceutical forms
    Powder and solvent for solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    25 +/-5 IU/kg once weekly

    Number of subjects in period 1
    ADVATE - Prophylactic Regimen
    Started
    19
    Completed
    3
    Not completed
    16
         Low or high titer inhibitor
             8
         Sponsor terminated study early
             8

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    ADVATE - Prophylactic Regimen
    Reporting group description
    The initial dosing regimen of 25 +/-5 IU/kg once weekly was to continue throughout the first 20 exposure days and for as long as possible beyond this early prophylaxis period. If required by the clinical situation, the frequency of infusions could be increased to twice or three times per week by the investigator in accordance with the instructions given in the study protocol. The maximum dose for any once weekly infusion was 50 IU/kg.

    Reporting group values
    ADVATE - Prophylactic Regimen Total
    Number of subjects
    19
    Age categorical
    Units: Subjects
    Age continuous
    Age continuous description
    Units: weeks
        arithmetic mean (standard deviation)
    43.3 ± 10.2 -
    Gender categorical
    Gender categorical description
    Units: Subjects
        Female
    0 0
        Male
    19 19
    Region of Enrollment
    Units: Subjects
        Serbia
    1 1
        United States
    2 2
        Czech Republic
    2 2
        Canada
    1 1
        Spain
    1 1
        Poland
    4 4
        Austria
    1 1
        Russian Federation
    3 3
        Bulgaria
    1 1
        Netherlands
    1 1
        Germany
    2 2
    Subject analysis sets

    Subject analysis set title
    ADVATE - Prophylactic Regimen
    Subject analysis set type
    Full analysis
    Subject analysis set description
    The Full Analysis Set (= Safety Analysis Set) comprises 19 subjects who received at least 1 infusion of Advate.

    Subject analysis set title
    Previously untreated patients (PUPs)
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    PUPs have had no prior exposure to any FVIII containing product before the start of the early low dose prophylactic regimen in this study.

    Subject analysis set title
    Minimally treated patients (MTPs)
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    MTPs have had up to 4 exposures to any FVIII product before the start of the early low dose prophylactic regimen in this study.

    Subject analysis set title
    Subjects with confirmed FVIII inhibitor
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Confirmed inhibitor is defined as any FVIII inhibitor assay result equal or greater than 0.6 BU/mL confirmed by the central laboratory on 2 consecutive samples, i.e. at least 2 positive inhibitor results (including the first positive inhibitor test, in accordance with the study protocol) assessed as either: i. High FVIII inhibitor titer (> 5 BU/mL) or ii. Low FVIII inhibitor titer (≥0.6 - ≤5.0 BU/mL).

    Subject analysis set title
    Subjects with confirmed low-titer FVIII inhibitor
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Low FVIII inhibitor titer (≥0.6 - ≤5.0 BU/mL) confirmed by the central laboratory on 2 consecutive samples, i.e. at least 2 positive inhibitor results (including the first positive inhibitor test, in accordance with the study protocol)

    Subject analysis set title
    Subjects with confirmed high-titer FVIII inhibitor
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    High FVIII inhibitor titer (> 5 BU/mL) confirmed by the central laboratory on 2 consecutive samples, i.e. at least 2 positive inhibitor results (including the first positive inhibitor test, in accordance with the study protocol)

    Subject analysis sets values
    ADVATE - Prophylactic Regimen Previously untreated patients (PUPs) Minimally treated patients (MTPs) Subjects with confirmed FVIII inhibitor Subjects with confirmed low-titer FVIII inhibitor Subjects with confirmed high-titer FVIII inhibitor
    Number of subjects
    19
    11
    8
    8
    5
    3
    Age categorical
    Units: Subjects
    Age continuous
    Age continuous description
    Units: weeks
        arithmetic mean (standard deviation)
    43.3 ± 10.2
    ±
    ±
    ±
    ±
    ±
    Gender categorical
    Gender categorical description
    Units: Subjects
        Female
        Male
    Region of Enrollment
    Units: Subjects
        Serbia
    1
    0
    1
        United States
    2
    0
    2
        Czech Republic
    2
    2
    0
        Canada
    1
    1
    0
        Spain
    1
    1
    0
        Poland
    4
    3
    1
        Austria
    1
    1
    0
        Russian Federation
    3
    3
    0
        Bulgaria
    1
    0
    1
        Netherlands
    1
    0
    1
        Germany
    2
    0
    2

    End points

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    End points reporting groups
    Reporting group title
    ADVATE - Prophylactic Regimen
    Reporting group description
    The initial dosing regimen of 25 +/-5 IU/kg once weekly was to continue throughout the first 20 exposure days and for as long as possible beyond this early prophylaxis period. If required by the clinical situation, the frequency of infusions could be increased to twice or three times per week by the investigator in accordance with the instructions given in the study protocol. The maximum dose for any once weekly infusion was 50 IU/kg.

    Subject analysis set title
    ADVATE - Prophylactic Regimen
    Subject analysis set type
    Full analysis
    Subject analysis set description
    The Full Analysis Set (= Safety Analysis Set) comprises 19 subjects who received at least 1 infusion of Advate.

    Subject analysis set title
    Previously untreated patients (PUPs)
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    PUPs have had no prior exposure to any FVIII containing product before the start of the early low dose prophylactic regimen in this study.

    Subject analysis set title
    Minimally treated patients (MTPs)
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    MTPs have had up to 4 exposures to any FVIII product before the start of the early low dose prophylactic regimen in this study.

    Subject analysis set title
    Subjects with confirmed FVIII inhibitor
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Confirmed inhibitor is defined as any FVIII inhibitor assay result equal or greater than 0.6 BU/mL confirmed by the central laboratory on 2 consecutive samples, i.e. at least 2 positive inhibitor results (including the first positive inhibitor test, in accordance with the study protocol) assessed as either: i. High FVIII inhibitor titer (> 5 BU/mL) or ii. Low FVIII inhibitor titer (≥0.6 - ≤5.0 BU/mL).

    Subject analysis set title
    Subjects with confirmed low-titer FVIII inhibitor
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Low FVIII inhibitor titer (≥0.6 - ≤5.0 BU/mL) confirmed by the central laboratory on 2 consecutive samples, i.e. at least 2 positive inhibitor results (including the first positive inhibitor test, in accordance with the study protocol)

    Subject analysis set title
    Subjects with confirmed high-titer FVIII inhibitor
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    High FVIII inhibitor titer (> 5 BU/mL) confirmed by the central laboratory on 2 consecutive samples, i.e. at least 2 positive inhibitor results (including the first positive inhibitor test, in accordance with the study protocol)

    Primary: Number of subjects with severe and moderately severe hemophilia A (FVIII ≤ 2%) with Factor VIII (FVIII) inhibitor formation within the first 50 exposure days to ADVATE

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    End point title
    Number of subjects with severe and moderately severe hemophilia A (FVIII ≤ 2%) with Factor VIII (FVIII) inhibitor formation within the first 50 exposure days to ADVATE [1]
    End point description
    Inhibitor testing will be performed in the central laboratory and a non-zero result must be confirmed in the central laboratory as soon as possible, preferably 1 week after inhibitor testing. Confirmed FVIII inhibitor is defined as any FVIII inhibitor assay result equal or greater than 0.6 Bethesda Units (BU)/mL confirmed by the central laboratory on 2 consecutive samples, i.e. at least 2 positive inhibitor results (including the first positive inhibitor test, in accordance with the study protocol) assessed as either: - i. High FVIII inhibitor titer (> 5 BU/mL) or - ii. Low FVIII inhibitor titer (≥0.6 - ≤5.0 BU/mL).
    End point type
    Primary
    End point timeframe
    50 exposure days to ADVATE
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Per protocol, descriptive statistics were collected for this endpoint.
    End point values
    ADVATE - Prophylactic Regimen Previously untreated patients (PUPs) Minimally treated patients (MTPs)
    Number of subjects analysed
    19
    11
    8
    Units: subjects
    8
    4
    4
    No statistical analyses for this end point

    Secondary: Number of subjects with severe hemophilia A (FVIII ≤ 1%) with Factor VIII (FVIII) inhibitor formation within the first 50 exposure days to ADVATE

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    End point title
    Number of subjects with severe hemophilia A (FVIII ≤ 1%) with Factor VIII (FVIII) inhibitor formation within the first 50 exposure days to ADVATE
    End point description
    Inhibitor testing will be performed in the central laboratory and a non-zero result must be confirmed in the central laboratory as soon as possible, preferably 1 week after inhibitor testing. Confirmed FVIII inhibitor is defined as any FVIII inhibitor assay result equal or greater than 0.6 Bethesda Units (BU)/mL confirmed by the central laboratory on 2 consecutive samples, i.e. at least 2 positive inhibitor results (including the first positive inhibitor test, in accordance with the study protocol) assessed as either: - i. High FVIII inhibitor titer (> 5 BU/mL) or - ii. Low FVIII inhibitor titer (≥0.6 - ≤5.0 BU/mL).
    End point type
    Secondary
    End point timeframe
    50 exposure days to ADVATE
    End point values
    ADVATE - Prophylactic Regimen Previously untreated patients (PUPs) Minimally treated patients (MTPs)
    Number of subjects analysed
    19
    11
    8
    Units: subjects
    8
    4
    4
    No statistical analyses for this end point

    Secondary: Number of Exposure Days of Treatment with Advate Prior to First Positive Factor VIII (FVIII) Confirmed Inhibitor Assessment

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    End point title
    Number of Exposure Days of Treatment with Advate Prior to First Positive Factor VIII (FVIII) Confirmed Inhibitor Assessment
    End point description
    Confirmed inhibitor is defined as any FVIII inhibitor assay result equal or greater than 0.6 BU/mL confirmed by the central laboratory on 2 consecutive samples, i.e. at least 2 positive inhibitor results (including the first positive inhibitor test, in accordance with the study protocol) assessed as either: - i. High FVIII inhibitor titer (> 5 BU/mL) or - ii. Low FVIII inhibitor titer (≥0.6 - ≤5.0 BU/mL).
    End point type
    Secondary
    End point timeframe
    50 exposure days to ADVATE
    End point values
    Subjects with confirmed FVIII inhibitor Subjects with confirmed low-titer FVIII inhibitor Subjects with confirmed high-titer FVIII inhibitor
    Number of subjects analysed
    8
    5
    3
    Units: days
        median (inter-quartile range (Q1-Q3))
    14.5 (7 to 21)
    15 (14 to 23)
    9 (2 to 19)
    No statistical analyses for this end point

    Secondary: Number of subjects with low-titer, high-titer, transient, and all Factor VIII (FVIII) inhibitors

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    End point title
    Number of subjects with low-titer, high-titer, transient, and all Factor VIII (FVIII) inhibitors
    End point description
    - High FVIII inhibitor titer (> 5 Bethesda Unit (BU)/mL) - Low FVIII inhibitor titer (≥0.6 - ≤5.0 BU/mL)
    End point type
    Secondary
    End point timeframe
    50 exposure days to ADVATE
    End point values
    ADVATE - Prophylactic Regimen
    Number of subjects analysed
    19
    Units: participants
        Low FVIII inhibitor titer
    5
        High FVIII inhibitor titer
    3
        Transient FVIII inhibitors
    0
        All FVIII inhibitors
    8
    No statistical analyses for this end point

    Secondary: Number, type, and severity of all bleeds experienced when different prophylactic dosing frequencies are used (once or twice per week and unknown frequency)

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    End point title
    Number, type, and severity of all bleeds experienced when different prophylactic dosing frequencies are used (once or twice per week and unknown frequency)
    End point description
    Nominal Dosing Frequency: 1 time per week, 2 times per week, Unknown dosing frequency (UK). Bleeding Type (BT): Skin, Muscle and Soft Tissue, Mucosal, Joint, Other, Multiple, Total. Bleeding severity: Minor, Moderate, Severe, Total.
    End point type
    Secondary
    End point timeframe
    50 exposure days to ADVATE
    End point values
    ADVATE - Prophylactic Regimen
    Number of subjects analysed
    19
    Units: Bleeds
    number (not applicable)
        Dose: 1/week; skin; minor bleed
    130
        Dose: 1/week; skin; moderate bleed
    2
        Dose: 1/week; skin; severe bleed
    0
        Dose: 1/week; skin; total bleeds
    132
        Dose: 1/week; muscle & soft tissue; minor bleed
    8
        Dose: 1/week; muscle & soft tissue; moderate bleed
    10
        Dose: 1/week; muscle & soft tissue; severe bleed
    0
        Dose: 1/week; muscle & soft tissue; total bleeds
    18
        Dose: 1/week; mucosal; minor bleed
    9
        Dose: 1/week; mucosal; moderate bleed
    3
        Dose: 1/week; mucosal; severe bleed
    0
        Dose: 1/week; mucosal; total bleeds
    12
        Dose: 1/week; joint; minor bleed
    0
        Dose: 1/week; joint; moderate bleed
    0
        Dose: 1/week; joint; severe bleed
    0
        Dose: 1/week; joint; total bleeds
    0
        Dose: 1/week; other BT; minor bleed
    3
        Dose: 1/week; other BT; moderate bleed
    3
        Dose: 1/week; other BT; severe bleed
    1
        Dose: 1/week; other BT; total bleeds
    7
        Dose: 1/week; multiple BT; minor bleed
    2
        Dose: 1/week; multiple BT; moderate bleed
    1
        Dose: 1/week; multiple BT; severe bleed
    0
        Dose: 1/week; multiple BT; total bleeds
    3
        Dose: 1/week; total BT; minor bleed
    152
        Dose: 1/week; total BT; moderate bleed
    19
        Dose: 1/week; total BT; severe bleed
    1
        Dose: 1/week; total BT; total bleeds
    172
        Dose: 2/week; skin; minor bleed
    9
        Dose: 2/week; skin; moderate bleed
    0
        Dose: 2/week; skin; severe bleed
    0
        Dose: 2/week; skin; total bleeds
    9
        Dose: 2/week; muscle & soft tissue; minor bleed
    0
        Dose: 2/week; muscle & soft tissue; moderate bleed
    1
        Dose: 2/week; muscle & soft tissue; severe bleed
    0
        Dose: 2/week; muscle & soft tissue; total bleeds
    1
        Dose: 2/week; mucosal; minor bleed
    3
        Dose: 2/week; mucosal; moderate bleed
    1
        Dose: 2/week; mucosal; severe bleed
    0
        Dose: 2/week; mucosal; total bleeds
    4
        Dose: 2/week; joint; minor bleed
    0
        Dose: 2/week; joint; moderate bleed
    0
        Dose: 2/week; joint; severe bleed
    0
        Dose: 2/week; joint; total bleeds
    0
        Dose: 2/week; other BT; minor bleed
    0
        Dose: 2/week; other BT; moderate bleed
    0
        Dose: 2/week; other BT; severe bleed
    0
        Dose: 2/week; other BT; total bleeds
    0
        Dose: 2/week; multiple BT; minor bleed
    0
        Dose: 2/week; multiple BT; moderate bleed
    0
        Dose: 2/week; multiple BT; severe bleed
    0
        Dose: 2/week; multiple BT; total bleeds
    0
        Dose: 2/week; total BT; minor bleed
    12
        Dose: 2/week; total BT; moderate bleed
    2
        Dose: 2/week; total BT; severe bleed
    0
        Dose: 2/week; total BT; total bleeds
    14
        Dose: UK/week; skin; minor bleed
    4
        Dose: UK/week; skin; moderate bleed
    1
        Dose: UK/week; skin; severe bleed
    0
        Dose: UK/week; skin; total bleeds
    5
        Dose: UK/week; muscle & soft tissue; minor bleed
    0
        Dose: UK/week; muscle & soft tissue;moderate bleed
    1
        Dose: UK/week; muscle & soft tissue; severe bleed
    0
        Dose: UK/week; muscle & soft tissue; total bleeds
    1
        Dose: UK/week; mucosal; minor bleed
    0
        Dose: UK/week; mucosal; moderate bleed
    0
        Dose: UK/week; mucosal; severe bleed
    0
        Dose: UK/week; mucosal; total bleeds
    0
        Dose: UK/week; joint; minor bleed
    0
        Dose: UK/week; joint; moderate bleed
    1
        Dose: UK/week; joint; severe bleed
    0
        Dose: UK/week; joint; total bleeds
    1
        Dose: UK/week; other BT; minor bleed
    0
        Dose: UK/week; other BT; moderate bleed
    0
        Dose: UK/week; other BT; severe bleed
    0
        Dose: UK/week; other BT; total bleeds
    0
        Dose: UK/week; multiple BT; minor bleed
    0
        Dose: UK/week; multiple BT; moderate bleed
    0
        Dose: UK/week; multiple BT; severe bleed
    0
        Dose: UK/week; multiple BT; total bleeds
    0
        Dose: UK/week; total BT; minor bleed
    4
        Dose: UK/week; total BT; moderate bleed
    3
        Dose: UK/week; total BT; severe bleed
    0
        Dose: UK/week; total BT; total bleeds
    7
    No statistical analyses for this end point

    Secondary: Number and type of surgeries

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    End point title
    Number and type of surgeries
    End point description
    - Elective surgery is not allowed during period of first 20 exposure days (EDs). - Abbreviation PICC = Peripherally inserted central catheter
    End point type
    Secondary
    End point timeframe
    50 exposure days to ADVATE
    End point values
    ADVATE - Prophylactic Regimen
    Number of subjects analysed
    19
    Units: surgeries
        Surgery: Cimino Shunt
    1
        Surgery: PICC Line Insertion in right arm
    1
    No statistical analyses for this end point

    Secondary: Total Factor VIII (FVIII) consumption by subject

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    End point title
    Total Factor VIII (FVIII) consumption by subject
    End point description
    Due to the low number of subjects available for evaluation, no statistical tests were performed to assess the total FVIII consumption by subject.
    End point type
    Secondary
    End point timeframe
    50 exposure days to ADVATE
    End point values
    ADVATE - Prophylactic Regimen
    Number of subjects analysed
    0 [2]
    Units: International Units (IU)
    Notes
    [2] - No statistical tests performed due to low number of subjects (see endpoint description)
    No statistical analyses for this end point

    Secondary: Correlation of known risk factors to Factor VIII (FVIII) inhibitor formation

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    End point title
    Correlation of known risk factors to Factor VIII (FVIII) inhibitor formation
    End point description
    Known genetic risk factors to inhibitor formation include FVIII gene mutation type, FVIII haplotype, human leukocyte antigen (HLA) haplotypes, severity of hemophilia, family history of inhibitors and immunomodulatory gene polymorphisms. Due to the low number of subjects available for evaluation, no statistical tests were performed to assess associations between known risk factors to inhibitor formation.
    End point type
    Secondary
    End point timeframe
    50 exposure days to ADVATE
    End point values
    ADVATE - Prophylactic Regimen
    Number of subjects analysed
    0 [3]
    Units: subjects
    Notes
    [3] - No statistical tests performed due to low number of subjects (see endpoint description)
    No statistical analyses for this end point

    Secondary: FVIII-Specific Antibody Isotype for All Subjects at Study Entry and Every 10 Exposure Days (EDs)

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    End point title
    FVIII-Specific Antibody Isotype for All Subjects at Study Entry and Every 10 Exposure Days (EDs)
    End point description
    Summary statistics of FVIII-specific antibody isotypes were not performed due to the early termination of the study.
    End point type
    Secondary
    End point timeframe
    50 exposure days to ADVATE
    End point values
    ADVATE - Prophylactic Regimen
    Number of subjects analysed
    0 [4]
    Units: subjects
    Notes
    [4] - Summary statistics of FVIII-specific antibody isotypes not performed due to early study termination
    No statistical analyses for this end point

    Secondary: Number of serious adverse events (SAEs) and non-serious adverse events (non-SAEs) at least possibly related to ADVATE

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    End point title
    Number of serious adverse events (SAEs) and non-serious adverse events (non-SAEs) at least possibly related to ADVATE
    End point description
    Possibly or probably related adverse events
    End point type
    Secondary
    End point timeframe
    50 exposure days to ADVATE
    End point values
    ADVATE - Prophylactic Regimen
    Number of subjects analysed
    19
    Units: adverse events
        SAEs
    9
        non-SAEs
    1
    No statistical analyses for this end point

    Post-hoc: Number of subjects with Factor VIII (FVIII) Inhibitors by Inhibitor Type (Only ‘true’ inhibitors)

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    End point title
    Number of subjects with Factor VIII (FVIII) Inhibitors by Inhibitor Type (Only ‘true’ inhibitors)
    End point description
    ’True’ positive inhibitor (PI) defined as any FVIII inhibitor assay result ≥0.6 Bethesda Units (BU)/mL confirmed by central lab on 2 consecutive samples, ie ≥2 PI results (including first PI test, in accordance with study protocol) assessed as either: i. High FVIII inhibitor titer (> 5 BU/mL) ii. Low FVIII inhibitor titer (≥0.6 - ≤5.0 BU/mL). In addition, to be classified as ‘true’ positive low FVIII inhibitors titer (≥0.6 - ≤5.0 BU/mL), one of following criteria must be met: - a) Lower or absent therapeutic response at infusion of standard replacement doses (“clinically relevant”) as deemed by the clinician in charge. - b) Any lab result of binding FVIII antibodies (IgM, IgA, IgG, IgG1, IgG2, IgG3, or IgG4) must be positive. Classification based on first positive FVIII inhibitor assessment. Inhibitor test result is: - > 5 BU/mL, then categorized as a high-titer inhibitor - ≥0.6 BU/mL but ≤5 BU/mL, then categorized as a low-titer.
    End point type
    Post-hoc
    End point timeframe
    50 exposure days to ADVATE
    End point values
    ADVATE - Prophylactic Regimen
    Number of subjects analysed
    19
    Units: subjects
        Inhibitor Type: Low-Titer
    3
        Inhibitor Type: High-Titer
    3
        Inhibitor Type: All Inhibitors
    6
    No statistical analyses for this end point

    Post-hoc: Number of Inhibitors in Previously Untreated Patients (PUPs) and Minimally Treated Patients (MTPs) - (Only ‘true’ inhibitors)

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    End point title
    Number of Inhibitors in Previously Untreated Patients (PUPs) and Minimally Treated Patients (MTPs) - (Only ‘true’ inhibitors)
    End point description
    PUPs = no previous FVIII exposure; MTPs ≤4 previous FVIII exposures ’True’ positive inhibitor (PI) = any FVIII inhibitor assay result ≥0.6 Bethesda Units (BU)/mL confirmed by central lab on 2 consecutive samples, ie ≥2 PI results (including first PI test, per study protocol) assessed as either: i. High FVIII inhibitor titer (>5 BU/mL) ii. Low FVIII inhibitor titer (≥0.6 - ≤5.0 BU/mL). In addition, to be classified as ‘true’ positive low FVIII inhibitors titer (≥0.6 - ≤5.0 BU/mL), one of following criteria must be met: - a) Lower or absent therapeutic response at infusion of standard replacement doses (“clinically relevant”) as deemed by clinician in charge. - b) Any lab result of binding FVIII antibodies (IgM, IgA, IgG, IgG1, IgG2, IgG3, or IgG4) must be positive. Classification based on first positive FVIII inhibitor assessment. Inhibitor test result is: - > 5 BU/mL, categorized as high-titer inhibitor - ≥0.6 BU/mL but ≤5 BU/mL, categorized as low-titer
    End point type
    Post-hoc
    End point timeframe
    50 exposure days to ADVATE
    End point values
    Previously untreated patients (PUPs) Minimally treated patients (MTPs)
    Number of subjects analysed
    11
    8
    Units: inhibitors
    3
    3
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    1 year and 3 months
    Assessment type
    Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    N/A
    Reporting groups
    Reporting group title
    ADVATE - Prophylactic Regimen
    Reporting group description
    Weekly infusions of ADVATE. Study visits (physical examination, lab tests including FVIII inhibitor tests) every week during the first 10 exposure days (EDs), every 5 weeks during the next 10 EDs and every 10 weeks thereafter. Recombinant antihemophilic factor, plasma/albumin-free method (rAHF-PFM): Intravenous infusion at a dose of 25 ± 5 IU/kg once per week. After 20 exposure days, the weekly infusions should be continued for as long as possible following the early prophylaxis period. If required by the clinical situation, dosing may be increased to twice weekly or even three times weekly after 20 exposure days, while keeping the low dose.

    Serious adverse events
    ADVATE - Prophylactic Regimen
    Total subjects affected by serious adverse events
         subjects affected / exposed
    11 / 19 (57.89%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Vascular disorders
    HAEMORRHAGE
         subjects affected / exposed
    2 / 19 (10.53%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    Injury, poisoning and procedural complications
    TRAUMATIC HAEMATOMA
         subjects affected / exposed
    1 / 19 (5.26%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    HEAD INJURY
         subjects affected / exposed
    1 / 19 (5.26%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Surgical and medical procedures
    ARTERIOVENOUS FISTULA OPERATION
         subjects affected / exposed
    1 / 19 (5.26%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Blood and lymphatic system disorders
    FACTOR VIII INHIBITION
         subjects affected / exposed
    8 / 19 (42.11%)
         occurrences causally related to treatment / all
    8 / 8
         deaths causally related to treatment / all
    0 / 0
    Musculoskeletal and connective tissue disorders
    SOFT TISSUE HAEMORRHAGE
         subjects affected / exposed
    1 / 19 (5.26%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    ADVATE - Prophylactic Regimen
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    19 / 19 (100.00%)
    Vascular disorders
    HAEMATOMA
         subjects affected / exposed
    1 / 19 (5.26%)
         occurrences all number
    1
    VASCULAR RUPTURE
         subjects affected / exposed
    1 / 19 (5.26%)
         occurrences all number
    1
    Immune system disorders
    FOOD ALLERGY
         subjects affected / exposed
    1 / 19 (5.26%)
         occurrences all number
    1
    General disorders and administration site conditions
    PYREXIA
         subjects affected / exposed
    10 / 19 (52.63%)
         occurrences all number
    13
    Injury, poisoning and procedural complications
    FACE INJURY
         subjects affected / exposed
    1 / 19 (5.26%)
         occurrences all number
    1
    FALL
         subjects affected / exposed
    1 / 19 (5.26%)
         occurrences all number
    1
    LIP INJURY
         subjects affected / exposed
    1 / 19 (5.26%)
         occurrences all number
    2
    TONGUE INJURY
         subjects affected / exposed
    1 / 19 (5.26%)
         occurrences all number
    1
    VACCINATION COMPLICATION
         subjects affected / exposed
    1 / 19 (5.26%)
         occurrences all number
    1
    WRONG DRUG ADMINISTERED
         subjects affected / exposed
    1 / 19 (5.26%)
         occurrences all number
    3
    Blood and lymphatic system disorders
    FACTOR VIII INHIBITION (UNCONFIRMED)
         subjects affected / exposed
    1 / 19 (5.26%)
         occurrences all number
    1
    LYMPHADENOPATHY
         subjects affected / exposed
    1 / 19 (5.26%)
         occurrences all number
    1
    Respiratory, thoracic and mediastinal disorders
    NASAL CONGESTION
         subjects affected / exposed
    1 / 19 (5.26%)
         occurrences all number
    1
    COUGH
         subjects affected / exposed
    6 / 19 (31.58%)
         occurrences all number
    6
    NASAL DRYNESS
         subjects affected / exposed
    1 / 19 (5.26%)
         occurrences all number
    2
    RHINORRHOEA
         subjects affected / exposed
    2 / 19 (10.53%)
         occurrences all number
    3
    OROPHARYNGEAL PAIN
         subjects affected / exposed
    1 / 19 (5.26%)
         occurrences all number
    1
    Eye disorders
    EYE DISCHARGE
         subjects affected / exposed
    1 / 19 (5.26%)
         occurrences all number
    1
    LACRIMATION INCREASED
         subjects affected / exposed
    1 / 19 (5.26%)
         occurrences all number
    1
    Ear and labyrinth disorders
    MIDDLE EAR EFFUSION
         subjects affected / exposed
    1 / 19 (5.26%)
         occurrences all number
    1
    Gastrointestinal disorders
    CONSTIPATION
         subjects affected / exposed
    1 / 19 (5.26%)
         occurrences all number
    1
    DIARRHOEA
         subjects affected / exposed
    3 / 19 (15.79%)
         occurrences all number
    3
    TEETHING
         subjects affected / exposed
    4 / 19 (21.05%)
         occurrences all number
    10
    VOMITING
         subjects affected / exposed
    5 / 19 (26.32%)
         occurrences all number
    6
    Skin and subcutaneous tissue disorders
    DERMATITIS
         subjects affected / exposed
    1 / 19 (5.26%)
         occurrences all number
    1
    DERMATITIS ALLERGIC
         subjects affected / exposed
    1 / 19 (5.26%)
         occurrences all number
    1
    ECZEMA
         subjects affected / exposed
    1 / 19 (5.26%)
         occurrences all number
    1
    DERMATITIS DIAPER
         subjects affected / exposed
    1 / 19 (5.26%)
         occurrences all number
    5
    RASH
         subjects affected / exposed
    3 / 19 (15.79%)
         occurrences all number
    3
    ERYTHEMA
         subjects affected / exposed
    1 / 19 (5.26%)
         occurrences all number
    1
    Musculoskeletal and connective tissue disorders
    JOINT RANGE OF MOTION DECREASED
         subjects affected / exposed
    1 / 19 (5.26%)
         occurrences all number
    1
    Metabolism and nutrition disorders
    VITAMIN D DEFICIENCY
         subjects affected / exposed
    1 / 19 (5.26%)
         occurrences all number
    1
    Infections and infestations
    BRONCHITIS
         subjects affected / exposed
    1 / 19 (5.26%)
         occurrences all number
    2
    ACUTE TONSILLITIS
         subjects affected / exposed
    1 / 19 (5.26%)
         occurrences all number
    2
    EAR INFECTION
         subjects affected / exposed
    2 / 19 (10.53%)
         occurrences all number
    2
    CANDIDIASIS
         subjects affected / exposed
    1 / 19 (5.26%)
         occurrences all number
    1
    COXSACKIE VIRAL INFECTION
         subjects affected / exposed
    1 / 19 (5.26%)
         occurrences all number
    1
    GASTROENTERITIS
         subjects affected / exposed
    1 / 19 (5.26%)
         occurrences all number
    2
    GASTROENTERITIS VIRAL
         subjects affected / exposed
    1 / 19 (5.26%)
         occurrences all number
    1
    NASOPHARYNGITIS
         subjects affected / exposed
    6 / 19 (31.58%)
         occurrences all number
    7
    RESPIRATORY TRACT INFECTION
         subjects affected / exposed
    1 / 19 (5.26%)
         occurrences all number
    1
    HORDEOLUM
         subjects affected / exposed
    1 / 19 (5.26%)
         occurrences all number
    1
    RHINITIS
         subjects affected / exposed
    8 / 19 (42.11%)
         occurrences all number
    13
    TONSILLITIS
         subjects affected / exposed
    1 / 19 (5.26%)
         occurrences all number
    1
    UPPER RESPIRATORY TRACT INFECTION
         subjects affected / exposed
    3 / 19 (15.79%)
         occurrences all number
    7
    VIRAL INFECTION
         subjects affected / exposed
    1 / 19 (5.26%)
         occurrences all number
    1

    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.
    Early termination led to: -) No statistical tests done on risk factors & inhibitor formation -) FVIII consumption by subject not calculated due to large variation in # of exposure days -) FVIII-specific antibody isotypes summary statistics not done
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