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    Clinical Trial Results:
    A multicenter Phase III uncontrolled open-label trial to evaluate safety and efficacy of BAY 81-8973 in children with severe haemophilia A under prophylaxis therapy

    Summary
    EudraCT number
    		 2010-021781-29
    Trial protocol
    		 HU   LT   SE   DK   IE   LV   BG   IT   PL   AT   ES   GB   NO  
    Global end of trial date

    Results information
    Results version number
    		 v1
    This version publication date
    22 Mar 2020
    First version publication date
    22 Mar 2020
    Other versions
    		 v2 , v3

    Trial information

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    Trial identification
    Sponsor protocol code
    BAY81-8973/13400
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01311648
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Bayer AG
    Sponsor organisation address
    Kaiser-Wilhelm-Allee, Leverkusen, Germany, D-51368
    Public contact
    Therapeutic Area Head, Bayer AG, clinical-trials-contact@bayer.com
    Scientific contact
    Therapeutic Area Head, Bayer AG, clinical-trials-contact@bayer.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    		 EMEA-001064-PIP01-10
    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
    Interim
    Date of interim/final analysis
    10 Oct 2019
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    09 Sep 2019
    Global end of trial reached?
    No
    General information about the trial
    Main objective of the trial
    The primary objective was to evaluate the safety and efficacy of the treatment with BAY81-8973 for prophylaxis and treatment of breakthrough bleeds in children with severe hemophilia A
    Protection of trial subjects
    The conduct of this clinical study met all local legal and regulatory requirements. The study was conducted in accordance with ethical principles that have their origin in the Declaration of Helsinki and the International Council for Harmonization guideline E6: Good Clinical Practice. Before entering the study, the informed consent was read by and explained to all the subjects/legal representatives. Participating subjects/legal representatives signed informed consent form and could withdraw from the study at any time without any disadvantage and without having to provide a reason for this decision. The assent of a minor was also requested where such a person was able to express his own will. His refusal or the withdrawal of his consent was not to be disregarded. Only investigators qualified by training and experience were selected as appropriate experts to investigate the study drug.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    09 Jun 2011
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety, Efficacy
    Long term follow-up duration
    		 18 Months
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Norway: 3
    Country: Number of subjects enrolled
    Poland: 8
    Country: Number of subjects enrolled
    Romania: 9
    Country: Number of subjects enrolled
    Spain: 7
    Country: Number of subjects enrolled
    Austria: 2
    Country: Number of subjects enrolled
    Bulgaria: 10
    Country: Number of subjects enrolled
    Denmark: 2
    Country: Number of subjects enrolled
    Hungary: 5
    Country: Number of subjects enrolled
    Ireland: 1
    Country: Number of subjects enrolled
    Italy: 11
    Country: Number of subjects enrolled
    Latvia: 1
    Country: Number of subjects enrolled
    Lithuania: 7
    Country: Number of subjects enrolled
    Argentina: 1
    Country: Number of subjects enrolled
    Canada: 6
    Country: Number of subjects enrolled
    Israel: 4
    Country: Number of subjects enrolled
    United States: 7
    Country: Number of subjects enrolled
    Mexico: 5
    Country: Number of subjects enrolled
    Russian Federation: 5
    Worldwide total number of subjects
    94
    EEA total number of subjects
    66
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    4
    Infants and toddlers (28 days-23 months)
    37
    Children (2-11 years)
    53
    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
    		 Study Part A was conducted at multiple centers in 12 countries between 09-JUN-2011 (first subject first visit) and 02-JAN-2013 (last subject last visit); Study Part B was conducted at multiple centers in 15 countries between 19-SEP-2012 (first subject first visit) and 09-SEP-2019 (last subject last visit).

    Pre-assignment
    Screening details
    		 Overall, 58 subjects were screened in Part A, of which 7 subjects were screening failures and 51 subjects - received at least one dose of the study drug; 52 subjects were screened in Part B, of which 9 subjects were screening failures and 43 subjects received at least one dose of the study drug.

    Period 1
    Period 1 title
    Overall study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Part A: PTPs 0-<6 years
    Arm description
    		 Previously treated patients (PTPs) aged below 6 years received BAY81-8973 25-50 IU/kg at least 2x/week for 6 months and at least 50 exposure days (ED)
    Arm type
    		 Experimental

    Investigational medicinal product name
    Recombinant Factor VIII
    Investigational medicinal product code
    BAY81-8973
    Other name
    Kovaltry
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    25-50 IU/kg at least 2x/week for 6 months and at least 50 exposure days (ED), intravenous (IV) infusion

    Arm title
    		 Part A: PTPs 6-12 years
    Arm description
    		 Previously treated patients (PTPs) aged 6 to 12 years received BAY81-8973 25-50 IU/kg at least 2x/week for 6 months and at least 50 exposure days (ED)
    Arm type
    		 Experimental

    Investigational medicinal product name
    Recombinant Factor VIII
    Investigational medicinal product code
    BAY81-8973
    Other name
    Kovaltry
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    25-50 IU/kg at least 2x/week for 6 months and at least 50 exposure days (ED), intravenous (IV) infusion

    Arm title
    		 Part B: PUPs/MTPs 0-<6 years
    Arm description
    		 Previously untreated patients (PUPs) or minimally treated patients (MTPs, patients who had no more than 3 exposure days [EDs] with any FVIII product) received BAY81-8973 15-50 IU/kg at least 1x/week for 50 EDs
    Arm type
    		 Experimental

    Investigational medicinal product name
    Recombinant Factor VIII
    Investigational medicinal product code
    BAY81-8973
    Other name
    Kovaltry
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    15-50 IU/kg at least 1x/week, 50 exposure days (ED), intravenous (IV) infusion

    Number of subjects in period 1
    		Part A: PTPs 0-<6 years Part A: PTPs 6-12 years Part B: PUPs/MTPs 0-<6 years
    Started
    25
    26
    43
    Completed
    25
    26
    22
    Not completed
    0
    0
    21
         Consent withdrawn by subject
    -
    -
    2
         Inhibitor management
    -
    -
    17
         Adverse event
    -
    -
    1
         Protocol deviation
    -
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Part A: PTPs 0-<6 years
    Reporting group description
    		 Previously treated patients (PTPs) aged below 6 years received BAY81-8973 25-50 IU/kg at least 2x/week for 6 months and at least 50 exposure days (ED)

    Reporting group title
    Part A: PTPs 6-12 years
    Reporting group description
    		 Previously treated patients (PTPs) aged 6 to 12 years received BAY81-8973 25-50 IU/kg at least 2x/week for 6 months and at least 50 exposure days (ED)

    Reporting group title
    Part B: PUPs/MTPs 0-<6 years
    Reporting group description
    		 Previously untreated patients (PUPs) or minimally treated patients (MTPs, patients who had no more than 3 exposure days [EDs] with any FVIII product) received BAY81-8973 15-50 IU/kg at least 1x/week for 50 EDs

    Reporting group values
    		 Part A: PTPs 0-<6 years Part A: PTPs 6-12 years Part B: PUPs/MTPs 0-<6 years Total
    Number of subjects
    		 25 26 43 94
    Age categorical
    Units: Subjects
        0- <6 years
    		 25 0 43 68
        6- 12 years
    		 0 26 0 26
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 3.8 ( 1.3 ) 8.8 ( 1.8 ) 0.8 ( 0.8 ) -
    Gender categorical
    Units: Subjects
        Female
    		 0 0 0 0
        Male
    		 25 26 43 94
    Race
    Units: Subjects
        White
    		 24 24 37 85
        Black
    		 1 2 1 4
        American Indian or Alaska native
    		 0 0 1 1
        White, American Indian or Alaska native
    		 0 0 1 1
        Not reported
    		 0 0 3 3
    Ethnicity
    Units: Subjects
        Not Hispanic or Latino
    		 23 25 34 82
        Hispanic or Latino
    		 1 0 9 10
        Not reported
    		 1 1 0 2

    End points

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    End points reporting groups
    Reporting group title
    Part A: PTPs 0-<6 years
    Reporting group description
    		 Previously treated patients (PTPs) aged below 6 years received BAY81-8973 25-50 IU/kg at least 2x/week for 6 months and at least 50 exposure days (ED)

    Reporting group title
    Part A: PTPs 6-12 years
    Reporting group description
    		 Previously treated patients (PTPs) aged 6 to 12 years received BAY81-8973 25-50 IU/kg at least 2x/week for 6 months and at least 50 exposure days (ED)

    Reporting group title
    Part B: PUPs/MTPs 0-<6 years
    Reporting group description
    		 Previously untreated patients (PUPs) or minimally treated patients (MTPs, patients who had no more than 3 exposure days [EDs] with any FVIII product) received BAY81-8973 15-50 IU/kg at least 1x/week for 50 EDs

    Subject analysis set title
    Safety analysis set (SAF) - A
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    All subjects who entered Study Part A and received at least one infusion of study medication.

    Subject analysis set title
    Safety analysis set (SAF) - B
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    All subjects who entered Study Part B and received at least one infusion of study medication.

    Subject analysis set title
    Intent-to-treat (ITT) analysis set - A
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All subjects of the SAF-A who had infusion/bleeding data from the electronic patient diary (EPD).

    Subject analysis set title
    Intent-to-treat (ITT) analysis set - B
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All subjects of the SAF-B who had infusion/bleeding data from the electronic patient diary (EPD)

    Subject analysis set title
    PK analysis set (PKS) - A
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    All subjects who entered Study Part A and received at least one infusion of study medication with evaluable pharmacokinetic (PK) data.

    Primary: Annualized number of total bleeds within 48 h

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    End point title
    		 Annualized number of total bleeds within 48 h [1]
    End point description
    Annualized number of total bleeds (sum of spontaneous bleeds, trauma bleeds, untreated bleeds and 'other' bleeds) that occurred within 48 hours after all prophylaxis infusions was summarized and reported. 'Other' bleeds were infusions with reason given as 'other'.
    End point type
    Primary
    End point timeframe
    Within 48 hours post infusion
    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: Due to the nature of this trial and due to the limited sample size, only descriptive statistics were performed. Neither confirmatory nor exploratory inferential statistical analyses were pre-specified. Thus those analyses were not performed.
    End point values
    		 Part A: PTPs 0-<6 years Part A: PTPs 6-12 years Part B: PUPs/MTPs 0-<6 years
    Number of subjects analysed
    25 [2]
    26 [3]
    43 [4]
    Units: bleed(s)
        arithmetic mean (standard deviation)
    2.23 ( 2.77 )
    1.86 ( 3.08 )
    1.9 ( 3.3 )
    Notes
    [2] - ITT-A
    [3] - ITT-A
    [4] - ITT-B
    No statistical analyses for this end point

    Primary: Annualized number of total bleeds within 48 h

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    End point title
    		 Annualized number of total bleeds within 48 h [5]
    End point description
    Annualized number of total bleeds (sum of spontaneous bleeds, trauma bleeds, untreated bleeds and 'other' bleeds) that occurred within 48 hours after all prophylaxis infusions were summarized and reported. 'Other' bleeds were infusions with reason given as 'other'.
    End point type
    Primary
    End point timeframe
    Within 48 hours post infusion
    Notes
    [5] - 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: Due to the nature of this trial and due to the limited sample size, only descriptive statistics were performed. Neither confirmatory nor exploratory inferential statistical analyses were pre-specified. Thus those analyses were not performed.
    End point values
    		 Part A: PTPs 0-<6 years Part A: PTPs 6-12 years Part B: PUPs/MTPs 0-<6 years
    Number of subjects analysed
    25 [6]
    26 [7]
    43 [8]
    Units: bleed(s)
        median (inter-quartile range (Q1-Q3))
    1.88 (0.00 to 3.97)
    0.00 (0.00 to 1.96)
    0.0 (0.0 to 2.2)
    Notes
    [6] - ITT-A
    [7] - ITT-A
    [8] - ITT-B
    No statistical analyses for this end point

    Secondary: Annualized number of total bleeds during prophylaxis treatment

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    End point title
    		 Annualized number of total bleeds during prophylaxis treatment
    End point description
    Annualized number of total bleeds (sum of spontaneous bleeds, trauma bleeds, untreated bleeds and 'other' bleeds) that occurred during prophylaxis treatment was summarized and reported.. 'Other' bleeds were infusions with reason given as 'other'.
    End point type
    Secondary
    End point timeframe
    Part A: 6 months and at least 50 exposure days; Part B: 50 exposure days
    End point values
    		 Part A: PTPs 0-<6 years Part A: PTPs 6-12 years Part B: PUPs/MTPs 0-<6 years
    Number of subjects analysed
    25 [9]
    26 [10]
    43 [11]
    Units: bleed(s)
        arithmetic mean (standard deviation)
    4.16 ( 5.02 )
    3.37 ( 5.01 )
    7.1 ( 8.6 )
    Notes
    [9] - ITT-A
    [10] - ITT-A
    [11] - ITT-B
    No statistical analyses for this end point

    Secondary: Annualized number of total bleeds during prophylaxis treatment

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    End point title
    		 Annualized number of total bleeds during prophylaxis treatment
    End point description
    Annualized number of total bleeds (sum of spontaneous bleeds, trauma bleeds, untreated bleeds and 'other' bleeds) that occurred during prophylaxis treatment were summarized and reported. 'Other' bleeds were infusions with reason given as 'other'.
    End point type
    Secondary
    End point timeframe
    Part A: 6 months and at least 50 exposure days; Part B: 50 exposure days
    End point values
    		 Part A: PTPs 0-<6 years Part A: PTPs 6-12 years Part B: PUPs/MTPs 0-<6 years
    Number of subjects analysed
    25 [12]
    26 [13]
    43 [14]
    Units: bleed(s)
        median (inter-quartile range (Q1-Q3))
    2.03 (0.00 to 6.02)
    0.93 (0.00 to 5.77)
    4.7 (2.1 to 8.9)
    Notes
    [12] - ITT-A
    [13] - ITT-A
    [14] - ITT-B
    No statistical analyses for this end point

    Secondary: Hemostatic control during major and minor surgeries

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    End point title
    		 Hemostatic control during major and minor surgeries
    End point description
    For patients who underwent major or minor surgeries during the study, hemostasis during the surgeries was assessed as excellent, good, moderate or poor. Number of surgeries per assessment was summarized and reported.
    End point type
    Secondary
    End point timeframe
    Part A: 6 months and at least 50 exposure days; Part B: 50 exposure days
    End point values
    		 Part A: PTPs 0-<6 years Part A: PTPs 6-12 years Part B: PUPs/MTPs 0-<6 years
    Number of subjects analysed
    0 [15]
    1 [16]
    5 [17]
    Units: surgery(s)
        Minor surgery - Excellent
    0
    3
        Minor surgery - Good
    0
    1
        Minor surgery - Moderate
    0
    0
        Minor surgery - Poor
    0
    0
        Minor surgery - Not available
    0
    1
        Major surgery - Excellent
    0
    0
        Major surgery - Good
    1
    1
        Major surgery - Moderate
    0
    0
        Major surgery - Poor
    0
    0
        Major surgery - Not available
    0
    0
    Notes
    [15] - Subjects in SAF-A who underwent major or minor surgeries during the study
    [16] - Subjects in SAF-A who underwent major or minor surgeries during the study
    [17] - Subjects in SAF-B who underwent major or minor surgeries during the study
    No statistical analyses for this end point

    Secondary: Number of subjects with inhibitor development

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    End point title
    		 Number of subjects with inhibitor development
    End point description
    Number of subjects who developed a positive FVIII inhibitor level (≥0.6 Bethesda unit [BU]) during the study was summarized and classified as subjects developing low titer inhibitor (i.e. ≤ 5.0 BU) and subjects developing high titer inhibitor (i.e. > 5.0 BU).
    End point type
    Secondary
    End point timeframe
    Part A: 6 months and at least 50 exposure days; Part B: 50 exposure days
    End point values
    		 Part A: PTPs 0-<6 years Part A: PTPs 6-12 years Part B: PUPs/MTPs 0-<6 years
    Number of subjects analysed
    25 [18]
    26 [19]
    43 [20]
    Units: subject(s)
        Low titer inhibitor
    0
    0
    6
        High titer inhibitor
    0
    0
    17
    Notes
    [18] - SAF-A
    [19] - SAF-A
    [20] - SAF-B
    No statistical analyses for this end point

    Secondary: Factor VIII recovery values

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    End point title
    		 Factor VIII recovery values
    End point description
    Incremental recovery of Factor VIII (FVIII) at 20-30 min after end of infusions was determined and mean recovery values were reported.
    End point type
    Secondary
    End point timeframe
    Part A: 6 months and at least 50 exposure days; Part B: 50 exposure days
    End point values
    		 Part A: PTPs 0-<6 years Part A: PTPs 6-12 years Part B: PUPs/MTPs 0-<6 years
    Number of subjects analysed
    25 [21]
    26 [22]
    32 [23]
    Units: kilogram(s)/deciliter
        arithmetic mean (standard deviation)
    1.63 ( 0.31 )
    1.72 ( 0.46 )
    1.17 ( 0.82 )
    Notes
    [21] - Subjects in ITT-A with valid FVIII recovery values
    [22] - Subjects in ITT-A with valid FVIII recovery values
    [23] - Subjects in ITT-B with valid FVIII recovery values
    No statistical analyses for this end point

    Secondary: Consumption of Factor VIII in all infusions

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    End point title
    		 Consumption of Factor VIII in all infusions
    End point description
    Factor VIII (FVIII) usage/consumption was summarized for all infusions. Consumption per subject's body weight per year was calculated and reported.
    End point type
    Secondary
    End point timeframe
    Part A: 6 months and at least 50 exposure days; Part B: 50 exposure days
    End point values
    		 Part A: PTPs 0-<6 years Part A: PTPs 6-12 years Part B: PUPs/MTPs 0-<6 years
    Number of subjects analysed
    25 [24]
    26 [25]
    43 [26]
    Units: international unit(s)/kilogram/year
        arithmetic mean (standard deviation)
    5499.1 ( 1996.2 )
    4679.1 ( 1688.7 )
    2195.8 ( 1903.6 )
    Notes
    [24] - ITT-A
    [25] - ITT-A
    [26] - ITT-B
    No statistical analyses for this end point

    Secondary: Consumption of FVIII in infusions for prophylaxis

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    End point title
    		 Consumption of FVIII in infusions for prophylaxis
    End point description
    Factor VIII (FVIII) usage/consumption was summarized for prophylaxis infusions. Consumption per subject's body weight per year was calculated and reported.
    End point type
    Secondary
    End point timeframe
    Part A: 6 months and at least 50 exposure days; Part B: 50 exposure days
    End point values
    		 Part A: PTPs 0-<6 years Part A: PTPs 6-12 years Part B: PUPs/MTPs 0-<6 years
    Number of subjects analysed
    25 [27]
    26 [28]
    42 [29]
    Units: international unit(s)/kilogram/year
        arithmetic mean (standard deviation)
    5224.8 ( 1760.2 )
    4492.7 ( 1667.6 )
    1486.6 ( 963.3 )
    Notes
    [27] - Subjects in ITT-A with at least one dose of prophylaxis treatment with study drug
    [28] - Subjects in ITT-A with at least one dose of prophylaxis treatment with study drug
    [29] - Subjects in ITT-B with at least one dose of prophylaxis treatment with study drug
    No statistical analyses for this end point

    Secondary: Consumption of FVIII in infusions for the treatment of bleeds

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    End point title
    		 Consumption of FVIII in infusions for the treatment of bleeds
    End point description
    Factor VIII (FVIII) usage/consumption was summarized for infusions used to treat breakthrough bleeds. Consumption per subject's body weight per year was calculated and reported.
    End point type
    Secondary
    End point timeframe
    Part A: 6 months and at least 50 exposure days; Part B: 50 exposure days
    End point values
    		 Part A: PTPs 0-<6 years Part A: PTPs 6-12 years Part B: PUPs/MTPs 0-<6 years
    Number of subjects analysed
    15 [30]
    11 [31]
    35 [32]
    Units: international unit(s)/kilogram/year
        arithmetic mean (standard deviation)
    457.07 ( 526.87 )
    391.64 ( 219.61 )
    835.4 ( 1926.4 )
    Notes
    [30] - Subjects in ITT-A with at least one bleed treated with study drug
    [31] - Subjects in ITT-A with at least one bleed treated with study drug
    [32] - Subjects in ITT-B with at least one bleed treated with study drug
    No statistical analyses for this end point

    Secondary: Number of infusions per bleed

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    End point title
    		 Number of infusions per bleed
    End point description
    The number of infusions used to treat a bleed was defined as the first infusion to treat the bleed plus all follow-up infusions to treat the same bleed, if any. The mean value of number of infusions for each bleed was calculated and reported.
    End point type
    Secondary
    End point timeframe
    Part A: 6 months and at least 50 exposure days; Part B: 50 exposure days
    End point values
    		 Part A: PTPs 0-<6 years Part A: PTPs 6-12 years Part B: PUPs/MTPs 0-<6 years
    Number of subjects analysed
    15 [33]
    13 [34]
    37 [35]
    Units: infusions
        arithmetic mean (standard deviation)
    1.3 ( 1.8 )
    1.4 ( 1.7 )
    1.7 ( 8.7 )
    Notes
    [33] - Subjects in ITT-A with at least one bleed
    [34] - Subjects in ITT-A with at least one bleed
    [35] - Subjects in ITT-B with at least one bleed
    No statistical analyses for this end point

    Secondary: Response to treatment of bleeds

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    End point title
    		 Response to treatment of bleeds
    End point description
    Subjects or caregivers were asked to assess the response to treatment of bleeds as excellent, good, moderate or poor. Percentage of bleeds per assessment was summarized and reported.
    End point type
    Secondary
    End point timeframe
    Part A: 6 months and at least 50 exposure days; Part B: 50 exposure days
    End point values
    		 Part A: PTPs 0-<6 years Part A: PTPs 6-12 years Part B: PUPs/MTPs 0-<6 years
    Number of subjects analysed
    15 [36]
    13 [37]
    37 [38]
    Units: percentage of bleeds
    number (not applicable)
        Excellent
    45.5
    32.4
    25.7
        Good
    52.3
    48.6
    53.3
        Moderate
    0.0
    18.9
    15.2
        Poor
    2.3
    0.0
    5.7
    Notes
    [36] - Subjects in ITT-A with at least one bleed; number of bleeds assessed for the response = 44
    [37] - Subjects in ITT-A with at least one bleed; number of bleeds assessed for the response = 37
    [38] - Subjects in ITT-B with at least one bleed; number of bleeds assessed for the response = 105
    No statistical analyses for this end point

    Secondary: Half-life (t1/2) of BAY81-8973 in plasma

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    End point title
    		 Half-life (t1/2) of BAY81-8973 in plasma [39]
    End point description
    Half-life (t1/2) of BAY81-8973 in plasma was measured. Geometric mean and percentage geometric coefficient of variation (%CV) were reported. Occurrence of "±” in relation with coefficient of variation is auto-generated by the database.
    End point type
    Secondary
    End point timeframe
    Pre-infusion and until 24 hours post infusion
    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: PK analysis is only displayed for Part A. The summary of PK values in Part B will be presented in the final report for the extension study due to the limited number of collected samples.
    End point values
    		 Part A: PTPs 0-<6 years Part A: PTPs 6-12 years
    Number of subjects analysed
    2 [40]
    9 [41]
    Units: hour(s)
        geometric mean (geometric coefficient of variation)
    13.2 ( 39.7 )
    12.1 ( 16.3 )
    Notes
    [40] - Subjects in PKS-A with evaluable data for this endpoint
    [41] - Subjects in PKS-A with evaluable data for this endpoint
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Part A: from the first BAY81-8973 infusion and up to 3 days after the last infusion; Part B: from the first BAY81-8973 infusion and up to 7 days after the last infusion
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    22.0
    Reporting groups
    Reporting group title
    Part A: PTPs 0-<6 years
    Reporting group description
    		 Previously treated patients (PTPs) aged below 6 years received BAY81-8973 25-50 IU/kg at least 2x/week for 6 months and at least 50 exposure days (ED).

    Reporting group title
    Part B: PUPs/MTPs 0-<6 years
    Reporting group description
    		 Previously untreated patients (PUPs) or minimally treated patients (MTPs, patients who had no more than 3 exposure days [EDs] with any FVIII product) received BAY81-8973 15-50 IU/kg at least 1x/week for 50 EDs.

    Reporting group title
    Part A: PTPs 6-12 years
    Reporting group description
    		 Previously treated patients (PTPs) aged 6 to 12 years received BAY81-8973 25-50 IU/kg at least 2x/week for 6 months and at least 50 exposure days (ED).

    Serious adverse events
    		 Part A: PTPs 0-<6 years Part B: PUPs/MTPs 0-<6 years Part A: PTPs 6-12 years
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 25 (0.00%)
    26 / 43 (60.47%)
    5 / 26 (19.23%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Investigations
    Anti factor VIII antibody positive
         subjects affected / exposed
    0 / 25 (0.00%)
    22 / 43 (51.16%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    24 / 24
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Craniocerebral injury
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 43 (2.33%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Mouth injury
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 43 (2.33%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Haematoma
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 43 (2.33%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Surgical and medical procedures
    Central venous catheterisation
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 43 (2.33%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dental cleaning
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 43 (0.00%)
    1 / 26 (3.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebral haemorrhage
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 43 (2.33%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Encephalomalacia
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 43 (0.00%)
    1 / 26 (3.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Blood loss anaemia
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 43 (0.00%)
    1 / 26 (3.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Factor VIII inhibition
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 43 (2.33%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Catheter site haematoma
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 43 (2.33%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Decreased activity
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 43 (2.33%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Extravasation
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 43 (2.33%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Facial pain
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 43 (2.33%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 43 (2.33%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Vomiting
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 43 (2.33%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Haemarthrosis
         subjects affected / exposed
    0 / 25 (0.00%)
    3 / 43 (6.98%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 5
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haematoma muscle
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 43 (2.33%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Soft tissue haemorrhage
         subjects affected / exposed
    0 / 25 (0.00%)
    2 / 43 (4.65%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Bacterial infection
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 43 (0.00%)
    1 / 26 (3.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Escherichia urinary tract infection
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 43 (2.33%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 43 (0.00%)
    1 / 26 (3.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis staphylococcal
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 43 (2.33%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis viral
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 43 (2.33%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tooth abscess
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 43 (0.00%)
    1 / 26 (3.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Viral infection
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 43 (0.00%)
    1 / 26 (3.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 3%
    Non-serious adverse events
    		 Part A: PTPs 0-<6 years Part B: PUPs/MTPs 0-<6 years Part A: PTPs 6-12 years
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    17 / 25 (68.00%)
    27 / 43 (62.79%)
    19 / 26 (73.08%)
    Surgical and medical procedures
    Tooth extraction
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 43 (0.00%)
    2 / 26 (7.69%)
         occurrences all number
    0
    0
    3
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 43 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    0
    1
    Hyperthermia
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 43 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    0
    1
    Infusion site swelling
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 43 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    0
    1
    Injection site bruising
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 43 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    0
    1
    Peripheral swelling
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 43 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    0
    1
    Pyrexia
         subjects affected / exposed
    5 / 25 (20.00%)
    12 / 43 (27.91%)
    2 / 26 (7.69%)
         occurrences all number
    10
    19
    2
    Immune system disorders
    Hypersensitivity
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 43 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    0
    1
    Reproductive system and breast disorders
    Perineal pain
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 43 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    0
    1
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    2 / 25 (8.00%)
    1 / 43 (2.33%)
    4 / 26 (15.38%)
         occurrences all number
    4
    1
    4
    Oropharyngeal pain
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 43 (0.00%)
    2 / 26 (7.69%)
         occurrences all number
    0
    0
    3
    Productive cough
         subjects affected / exposed
    2 / 25 (8.00%)
    0 / 43 (0.00%)
    0 / 26 (0.00%)
         occurrences all number
    3
    0
    0
    Rhinitis allergic
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 43 (0.00%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    0
    Tonsillar hypertrophy
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 43 (0.00%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    0
    Investigations
    Haemoglobin decreased
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 43 (0.00%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    0
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    2 / 25 (8.00%)
    1 / 43 (2.33%)
    0 / 26 (0.00%)
         occurrences all number
    3
    1
    0
    Face injury
         subjects affected / exposed
    0 / 25 (0.00%)
    2 / 43 (4.65%)
    0 / 26 (0.00%)
         occurrences all number
    0
    2
    0
    Fall
         subjects affected / exposed
    0 / 25 (0.00%)
    2 / 43 (4.65%)
    0 / 26 (0.00%)
         occurrences all number
    0
    2
    0
    Genital contusion
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 43 (0.00%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    0
    Head injury
         subjects affected / exposed
    1 / 25 (4.00%)
    1 / 43 (2.33%)
    0 / 26 (0.00%)
         occurrences all number
    1
    1
    0
    Limb injury
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 43 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    0
    1
    Lip injury
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 43 (0.00%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    0
    Road traffic accident
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 43 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    0
    1
    Skin abrasion
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 43 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    0
    1
    Skin injury
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 43 (0.00%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    0
    Skin laceration
         subjects affected / exposed
    1 / 25 (4.00%)
    1 / 43 (2.33%)
    0 / 26 (0.00%)
         occurrences all number
    1
    1
    0
    Subcutaneous haematoma
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 43 (0.00%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    0
    Tongue injury
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 43 (0.00%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    0
    Nervous system disorders
    Headache
         subjects affected / exposed
    2 / 25 (8.00%)
    0 / 43 (0.00%)
    4 / 26 (15.38%)
         occurrences all number
    3
    0
    4
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 25 (0.00%)
    3 / 43 (6.98%)
    1 / 26 (3.85%)
         occurrences all number
    0
    3
    3
    Blood loss anaemia
         subjects affected / exposed
    0 / 25 (0.00%)
    2 / 43 (4.65%)
    0 / 26 (0.00%)
         occurrences all number
    0
    2
    0
    Ear and labyrinth disorders
    Ear pain
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 43 (2.33%)
    1 / 26 (3.85%)
         occurrences all number
    0
    1
    1
    Eye disorders
    Conjunctivitis allergic
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 43 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    0
    1
    Photophobia
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 43 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    0
    1
    Strabismus
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 43 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    0
    3
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 43 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    0
    1
    Abdominal pain upper
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 43 (0.00%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    0
    Constipation
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 43 (2.33%)
    1 / 26 (3.85%)
         occurrences all number
    0
    1
    1
    Dental caries
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 43 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    0
    1
    Diarrhoea
         subjects affected / exposed
    2 / 25 (8.00%)
    6 / 43 (13.95%)
    1 / 26 (3.85%)
         occurrences all number
    3
    8
    2
    Functional gastrointestinal disorder
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 43 (2.33%)
    1 / 26 (3.85%)
         occurrences all number
    0
    1
    2
    Glossodynia
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 43 (0.00%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    0
    Haematochezia
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 43 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    0
    1
    Stomatitis
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 43 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    0
    1
    Teething
         subjects affected / exposed
    0 / 25 (0.00%)
    2 / 43 (4.65%)
    0 / 26 (0.00%)
         occurrences all number
    0
    3
    0
    Toothache
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 43 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    0
    1
    Vomiting
         subjects affected / exposed
    1 / 25 (4.00%)
    4 / 43 (9.30%)
    1 / 26 (3.85%)
         occurrences all number
    1
    8
    1
    Skin and subcutaneous tissue disorders
    Pruritus
         subjects affected / exposed
    3 / 25 (12.00%)
    0 / 43 (0.00%)
    0 / 26 (0.00%)
         occurrences all number
    3
    0
    0
    Rash
         subjects affected / exposed
    0 / 25 (0.00%)
    3 / 43 (6.98%)
    2 / 26 (7.69%)
         occurrences all number
    0
    3
    3
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 43 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    0
    1
    Joint swelling
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 43 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    0
    1
    Muscular weakness
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 43 (0.00%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    0
    Musculoskeletal pain
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 43 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    0
    1
    Pain in extremity
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 43 (2.33%)
    1 / 26 (3.85%)
         occurrences all number
    0
    1
    1
    Synovitis
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 43 (0.00%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    0
    Infections and infestations
    Bronchiolitis
         subjects affected / exposed
    0 / 25 (0.00%)
    2 / 43 (4.65%)
    0 / 26 (0.00%)
         occurrences all number
    0
    4
    0
    Bronchitis
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 43 (0.00%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    0
    Conjunctivitis
         subjects affected / exposed
    2 / 25 (8.00%)
    3 / 43 (6.98%)
    0 / 26 (0.00%)
         occurrences all number
    2
    3
    0
    Cystitis
         subjects affected / exposed
    1 / 25 (4.00%)
    1 / 43 (2.33%)
    0 / 26 (0.00%)
         occurrences all number
    1
    1
    0
    Ear infection
         subjects affected / exposed
    1 / 25 (4.00%)
    2 / 43 (4.65%)
    0 / 26 (0.00%)
         occurrences all number
    1
    2
    0
    Gastroenteritis
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 43 (2.33%)
    1 / 26 (3.85%)
         occurrences all number
    0
    1
    1
    Gastroenteritis viral
         subjects affected / exposed
    0 / 25 (0.00%)
    3 / 43 (6.98%)
    0 / 26 (0.00%)
         occurrences all number
    0
    3
    0
    Gastrointestinal viral infection
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 43 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    0
    1
    Hand-foot-and-mouth disease
         subjects affected / exposed
    1 / 25 (4.00%)
    1 / 43 (2.33%)
    0 / 26 (0.00%)
         occurrences all number
    1
    1
    0
    Hookworm infection
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 43 (0.00%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    0
    Influenza
         subjects affected / exposed
    0 / 25 (0.00%)
    4 / 43 (9.30%)
    1 / 26 (3.85%)
         occurrences all number
    0
    4
    1
    Nasopharyngitis
         subjects affected / exposed
    2 / 25 (8.00%)
    6 / 43 (13.95%)
    2 / 26 (7.69%)
         occurrences all number
    3
    16
    2
    Oral herpes
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 43 (2.33%)
    1 / 26 (3.85%)
         occurrences all number
    0
    1
    1
    Otitis media
         subjects affected / exposed
    1 / 25 (4.00%)
    1 / 43 (2.33%)
    0 / 26 (0.00%)
         occurrences all number
    1
    3
    0
    Otitis media acute
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 43 (2.33%)
    1 / 26 (3.85%)
         occurrences all number
    0
    1
    1
    Pneumonia
         subjects affected / exposed
    1 / 25 (4.00%)
    1 / 43 (2.33%)
    0 / 26 (0.00%)
         occurrences all number
    1
    1
    0
    Rhinitis
         subjects affected / exposed
    1 / 25 (4.00%)
    3 / 43 (6.98%)
    1 / 26 (3.85%)
         occurrences all number
    1
    4
    1
    Tonsillitis
         subjects affected / exposed
    1 / 25 (4.00%)
    1 / 43 (2.33%)
    1 / 26 (3.85%)
         occurrences all number
    2
    1
    1
    Tooth abscess
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 43 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    1
    0
    2
    Tracheitis
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 43 (2.33%)
    1 / 26 (3.85%)
         occurrences all number
    0
    1
    1
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 25 (4.00%)
    3 / 43 (6.98%)
    1 / 26 (3.85%)
         occurrences all number
    1
    3
    2
    Varicella
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 43 (2.33%)
    1 / 26 (3.85%)
         occurrences all number
    0
    1
    1
    Vascular device infection
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 43 (0.00%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    0
    Viral infection
         subjects affected / exposed
    3 / 25 (12.00%)
    1 / 43 (2.33%)
    2 / 26 (7.69%)
         occurrences all number
    3
    1
    2
    Viral upper respiratory tract infection
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 43 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    0
    1
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 43 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    0
    1

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    31 Mar 2011
    Amendment 1 implemented mainly an improved explanation of the staggered enrollment and the number of subjects to be enrolled, clarification of start of prophylaxis in PUPs, revision of pharmacokinetic (PK) sampling scheme in Part A, updated information on BAY81-8973, clarification of in- and exclusion criteria and measurements of vital signs.
    03 Sep 2012
    Amendment 3 implemented mainly that PK sampling was no longer limited to subjects in Part A, the number of subjects for Part B (PUPs) was increased to ≥25 and ≤50, revisions and clarifications, and further clarification of in- and exclusion criteria.
    08 Apr 2014
    Amendment 4 introduced an optional pharmacogenetic analysis and epitope mapping of samples from subjects confirmed positive for inhibitor antibodies.
    19 Feb 2016
    Amendment 6 implemented clarifications on inhibitor testing during the extension phase and on FVIII:C determinations at screening. Visits in Part B were no longer described in months but in EDs. Furthermore, the possibility to enroll MTPs in Part B was added to the protocol. Consequently, inhibitor evaluation was added at screening in Part B for MTPs only.
    30 May 2017
    Amendment 7 increased the number of subjects in Part B to an additional 25. A staggered approach for subject enrollment was introduced in Part B as a safety measure. 10 subjects were recruited first, and enrollment to the next cohort could only start after the previous 10 subjects had 20 EDs without safety concerns. Inclusion criterion regarding inhibitor testing for MTPs was clarified.
    01 Feb 2019
    Amendment 8 clarified MTP definition, the time in the extension study, and ITI management in the extension study. An additional analysis was added, to be carried out when all PUPs/MTPs completed Part B.

    Interruptions (globally)
    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    16 Dec 2016
    Enrollment in Part B was temporarily suspended in December 2016 to undertake a comprehensive evaluation of a cluster of inhibitor cases that occurred from June to December 2016. After endorsement from the Data Monitoring Committee (DMC), the enrollment was resumed under amendment 7.
    13 Jun 2017

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    Due to the small number of subject per reporting group, all presented summary measures (e.g. mean and proportion) have to be evaluated with caution. If displayed standard deviation should be taken into account.
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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