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    Clinical Trial Results:
    Phase 3, prospective, randomized, multi-center clinical study comparing the safety and efficacy of BAX 855 following PK-guided prophylaxis targeting two different FVIII trough levels in subjects with severe hemophilia A

    Summary
    EudraCT number
    		 2014-005477-37
    Trial protocol
    		 GB   DE   AT   SE   CZ   ES   HU   BG   PL   IT  
    Global end of trial date
    05 Aug 2018

    Results information
    Results version number
    		 v2(current)
    This version publication date
    13 Nov 2019
    First version publication date
    20 Feb 2019
    Other versions
    		 v1
    Version creation reason

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    261303
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02585960
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Baxalta Innovations GmbH (now part of Shire)
    Sponsor organisation address
    Industriestrasse 67, Vienna, Austria, A-1221
    Public contact
    Study Director, Baxalta Innovations GmbH (now part of Shire), ClinicalTransparency@shire.com
    Scientific contact
    Study Director, Baxalta Innovations GmbH (now part of Shire), ClinicalTransparency@shire.com
    Sponsor organisation name
    Baxalta US Inc. (now part of Shire)
    Sponsor organisation address
    300 Shire Way, Lexington, United States, MA 02421
    Public contact
    Study Director, Baxalta US Inc. (now part of Shire), ClinicalTransparency@shire.com
    Scientific contact
    Study Director, Baxalta US Inc. (now part of Shire), ClinicalTransparency@shire.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
    05 Aug 2018
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    05 Aug 2018
    Global end of trial reached?
    Yes
    Global end of trial date
    05 Aug 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of the study was to compare 2 prophylactic dosing regimens of BAX 855 targeting 2 different FVIII trough levels, by comparing the proportions of subjects achieving a total annualized bleeding rate (ABR) of 0 in the second 6-month study period.
    Protection of trial subjects
    This study was conducted in accordance with the standards of Good Clinical Practice (GCP) in effect at the time of the study. All records have been attached per GCP requirements.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    23 Nov 2015
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Australia: 2
    Country: Number of subjects enrolled
    Austria: 2
    Country: Number of subjects enrolled
    Bulgaria: 5
    Country: Number of subjects enrolled
    Germany: 8
    Country: Number of subjects enrolled
    Spain: 4
    Country: Number of subjects enrolled
    France: 4
    Country: Number of subjects enrolled
    United Kingdom: 7
    Country: Number of subjects enrolled
    Hong Kong: 5
    Country: Number of subjects enrolled
    Hungary: 5
    Country: Number of subjects enrolled
    Israel: 2
    Country: Number of subjects enrolled
    Italy: 4
    Country: Number of subjects enrolled
    Malaysia: 16
    Country: Number of subjects enrolled
    Poland: 16
    Country: Number of subjects enrolled
    Singapore: 7
    Country: Number of subjects enrolled
    Turkey: 8
    Country: Number of subjects enrolled
    Taiwan: 3
    Country: Number of subjects enrolled
    Ukraine: 15
    Country: Number of subjects enrolled
    United States: 8
    Worldwide total number of subjects
    121
    EEA total number of subjects
    55
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    17
    Adults (18-64 years)
    104
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 The study was conducted at 62 study centers in 19 countries between 23 November 2015 (first subject first visit) and 05 August 2018 (last subject last visit).

    Pre-assignment
    Screening details
    		 A total of 135 subjects were enrolled in the study. Of them, 14 subjects were dropped out and did not receive any treatment 121 subjects underwent initial pharmacokinetic (PK) assessment with a single administration of BAX 855 and based on their individual PK values, 115 subjects were randomized to any one of the prophylactic regimens.

    Period 1
    Period 1 title
    Pharmacokinetic (PK) Assessment Period
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 BAX 855-Low Level
    Arm description
    		 Subjects with severe hemophilia A received a single BAX 855 dose of 60 +/- 5 international units per kilogram (IU/kg) intravenous (IV) infusion (PK assessment) followed by a PK-guided dose of BAX 855 twice weekly (Alternating 3 and 4-day infusion intervals or an infusion every 3.5 days), targeting factor VIII (FVIII) trough levels of 1-3%. Depending on subject’s individual PK, more frequent dosing was considered if single doses of greater than (>) 80 IU/kg were required or regular FVIII peak levels of 200% were reached.
    Arm type
    		 Experimental

    Investigational medicinal product name
    BAX 855
    Investigational medicinal product code
    Other name
    Pegylated rFVIII
    Pharmaceutical forms
    Powder and solvent for solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects received IV infusion of BAX 855.

    Arm title
    		 BAX 855-High Level
    Arm description
    		 Subjects with severe hemophilia A received a single BAX 855 dose of 60 +/- 5 IU/kg IV infusion (PK assessment) followed by a PK-guided dose of BAX 855 every other day, targeting FVIII trough levels of 8-12%. Depending on subject’s individual PK, a different dosing interval was considered to prevent regular high FVIII peak levels.
    Arm type
    		 Experimental

    Investigational medicinal product name
    BAX 855
    Investigational medicinal product code
    Other name
    Pegylated rFVIII
    Pharmaceutical forms
    Powder and solvent for solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects received IV infusion of BAX 855.

    Arm title
    		 BAX 855-Non-randomized
    Arm description
    		 Subjects with severe hemophilia A received a single BAX 855 dose of 60 +/- 5 IU/kg IV infusion (PK assessment) and were not randomized to any treatments.
    Arm type
    		 Experimental

    Investigational medicinal product name
    BAX 855
    Investigational medicinal product code
    Other name
    Pegylated rFVIII
    Pharmaceutical forms
    Powder and solvent for solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects received IV infusion of BAX 855.

    Number of subjects in period 1
    		BAX 855-Low Level BAX 855-High Level BAX 855-Non-randomized
    Started
    57
    58
    6
    Completed
    52
    48
    0
    Not completed
    5
    10
    6
         Consent withdrawn by subject
    1
    2
    5
         Physician decision
    -
    1
    -
         Non-compliance to study procedures
    -
    2
    -
         Screen Failure
    -
    -
    1
         Unspecified
    4
    4
    -
         Withdrawn by sponsor
    -
    1
    -
    Period 2
    Period 2 title
    Prophylactic Treatment Period
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 BAX 855-Low Level
    Arm description
    		 Subjects with severe hemophilia A received a single BAX 855 dose of 60 +/- 5 international units per kilogram (IU/kg) intravenous (IV) infusion (PK assessment) followed by a PK-guided dose of BAX 855 twice weekly (Alternating 3 and 4-day infusion intervals or an infusion every 3.5 days), targeting factor VIII (FVIII) trough levels of 1-3%. Depending on subject's individual PK, more frequent dosing was considered if single doses of greater than (>) 80 IU/kg were required or regular FVIII peak levels of 200% were reached.
    Arm type
    		 Experimental

    Investigational medicinal product name
    BAX 855
    Investigational medicinal product code
    Other name
    Pegylated rFVIII
    Pharmaceutical forms
    Powder and solvent for solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects received IV infusion of BAX 855.

    Arm title
    		 BAX 855-High Level
    Arm description
    		 Subjects with severe hemophilia A received a single BAX 855 dose of 60 +/- 5 IU/kg IV infusion (PK assessment) followed by a PK-guided dose of BAX 855 every other day, targeting FVIII trough levels of 8-12%. Depending on subject's individual PK, a different dosing interval was considered to prevent regular high FVIII peak levels.
    Arm type
    		 Experimental

    Investigational medicinal product name
    BAX 855
    Investigational medicinal product code
    Other name
    Pegylated rFVIII
    Pharmaceutical forms
    Powder and solvent for solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects received IV infusion of BAX 855.

    Number of subjects in period 2
    		BAX 855-Low Level BAX 855-High Level
    Started
    52
    48
    Completed
    52
    43
    Not completed
    0
    5
         Subject less than 75% exposed to BAX 855
    -
    1
         Protocol deviation
    -
    4

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    BAX 855-Low Level
    Reporting group description
    		 Subjects with severe hemophilia A received a single BAX 855 dose of 60 +/- 5 international units per kilogram (IU/kg) intravenous (IV) infusion (PK assessment) followed by a PK-guided dose of BAX 855 twice weekly (Alternating 3 and 4-day infusion intervals or an infusion every 3.5 days), targeting factor VIII (FVIII) trough levels of 1-3%. Depending on subject’s individual PK, more frequent dosing was considered if single doses of greater than (>) 80 IU/kg were required or regular FVIII peak levels of 200% were reached.

    Reporting group title
    BAX 855-High Level
    Reporting group description
    		 Subjects with severe hemophilia A received a single BAX 855 dose of 60 +/- 5 IU/kg IV infusion (PK assessment) followed by a PK-guided dose of BAX 855 every other day, targeting FVIII trough levels of 8-12%. Depending on subject’s individual PK, a different dosing interval was considered to prevent regular high FVIII peak levels.

    Reporting group title
    BAX 855-Non-randomized
    Reporting group description
    		 Subjects with severe hemophilia A received a single BAX 855 dose of 60 +/- 5 IU/kg IV infusion (PK assessment) and were not randomized to any treatments.

    Reporting group values
    		 BAX 855-Low Level BAX 855-High Level BAX 855-Non-randomized Total
    Number of subjects
    		 57 58 6
    Age categorical
    Units: Subjects
    Age continuous
    Age at the time of informed consent was reported.
    Units: years
        arithmetic mean (standard deviation)
    		 31.1 ± 13.76 31.2 ± 12.22 25.8 ± 10.03 -
    Gender categorical
    Units: Subjects
        Female
    		 0 0 0 0
        Male
    		 57 58 6 121
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 2 5 2 9
        Not Hispanic or Latino
    		 53 53 4 110
        Unknown or Not Reported
    		 2 0 0 2
    Race/Ethnicity, Customized
    Units: Subjects
        Asian
    		 14 18 2 34
        White
    		 40 36 4 80
        Native Latin American
    		 1 1 0 2
        Mestizo
    		 0 1 0 1
        Other
    		 2 2 0 4

    End points

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    End points reporting groups
    Reporting group title
    BAX 855-Low Level
    Reporting group description
    		 Subjects with severe hemophilia A received a single BAX 855 dose of 60 +/- 5 international units per kilogram (IU/kg) intravenous (IV) infusion (PK assessment) followed by a PK-guided dose of BAX 855 twice weekly (Alternating 3 and 4-day infusion intervals or an infusion every 3.5 days), targeting factor VIII (FVIII) trough levels of 1-3%. Depending on subject’s individual PK, more frequent dosing was considered if single doses of greater than (>) 80 IU/kg were required or regular FVIII peak levels of 200% were reached.

    Reporting group title
    BAX 855-High Level
    Reporting group description
    		 Subjects with severe hemophilia A received a single BAX 855 dose of 60 +/- 5 IU/kg IV infusion (PK assessment) followed by a PK-guided dose of BAX 855 every other day, targeting FVIII trough levels of 8-12%. Depending on subject’s individual PK, a different dosing interval was considered to prevent regular high FVIII peak levels.

    Reporting group title
    BAX 855-Non-randomized
    Reporting group description
    		 Subjects with severe hemophilia A received a single BAX 855 dose of 60 +/- 5 IU/kg IV infusion (PK assessment) and were not randomized to any treatments.
    Reporting group title
    BAX 855-Low Level
    Reporting group description
    		 Subjects with severe hemophilia A received a single BAX 855 dose of 60 +/- 5 international units per kilogram (IU/kg) intravenous (IV) infusion (PK assessment) followed by a PK-guided dose of BAX 855 twice weekly (Alternating 3 and 4-day infusion intervals or an infusion every 3.5 days), targeting factor VIII (FVIII) trough levels of 1-3%. Depending on subject's individual PK, more frequent dosing was considered if single doses of greater than (>) 80 IU/kg were required or regular FVIII peak levels of 200% were reached.

    Reporting group title
    BAX 855-High Level
    Reporting group description
    		 Subjects with severe hemophilia A received a single BAX 855 dose of 60 +/- 5 IU/kg IV infusion (PK assessment) followed by a PK-guided dose of BAX 855 every other day, targeting FVIII trough levels of 8-12%. Depending on subject's individual PK, a different dosing interval was considered to prevent regular high FVIII peak levels.

    Primary: Proportion of Subjects with a Total Annualized Bleeding Rate (ABR) of Zero for Second Six Months

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    End point title
    		 Proportion of Subjects with a Total Annualized Bleeding Rate (ABR) of Zero for Second Six Months [1]
    End point description
    Annualized bleeding rate was determined by dividing the number of bleeds by observation period in years. Full analysis set (FAS) included all subjects who were randomized to one of the two prophylactic arms and treated prophylactically for any period of time.
    End point type
    Primary
    End point timeframe
    Day 183 to Day 364 (6 months)
    Notes
    [1] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint was related to subjects randomized to prophylactic treatment, hence not reporting statistics for all the arms in the baseline period
    End point values
    		 BAX 855-Low Level BAX 855-High Level
    Number of subjects analysed
    57
    58
    Units: Percentage of subjects
    number (not applicable)
        Percentage of subjects
    42.1
    62.1
    Statistical analysis title
    		 Statistical analysis 1
    Statistical analysis description
    The proportion of subjects with an ABR of 0 during the second 6-month period on BAX 855 prophylaxis, was compared between the 2 prophylaxis arms using a chi-square test with continuity correction at a 2-sided 5% level of significance.
    Comparison groups
    BAX 855-High Level v BAX 855-Low Level
    Number of subjects included in analysis
    115
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0545
    Method
    		 Chi-squared
    Parameter type
    		 Gaussian Statistic estimate
    Point estimate
    1.96
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.038
         upper limit
    		 3.958

    Secondary: Total Annualized Bleeding Rate for Second Six Months

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    End point title
    		 Total Annualized Bleeding Rate for Second Six Months [2]
    End point description
    Annualized bleeding rate was determined by dividing the number of bleeds by observation period in years. FAS included all subjects who were randomized to one of the two prophylactic arms and treated prophylactically for any period of time. Here "Number of subjects analyzed" refer to number of subjects evaluable for this outcome at specified time point.
    End point type
    Secondary
    End point timeframe
    Day 183 to Day 364 (6 months)
    Notes
    [2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint was related to subjects randomized to prophylactic treatment, hence not reporting statistics for all the arms in the baseline period
    End point values
    		 BAX 855-Low Level BAX 855-High Level
    Number of subjects analysed
    57
    53
    Units: Bleeds per year
    arithmetic mean (standard deviation)
        Bleeds per year
    3.603 ± 7.512
    1.649 ± 3.433
    No statistical analyses for this end point

    Secondary: Annualized Spontaneous Bleeding Rate for Second Six Months

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    End point title
    		 Annualized Spontaneous Bleeding Rate for Second Six Months [3]
    End point description
    Annualized spontaneous bleeding rate was determined by dividing the number of spontaneous bleeds by observation period in years. A bleed was defined as spontaneous if it was not related to injury/trauma. FAS included all subjects who were randomized to one of the two prophylactic arms and treated prophylactically for any period of time. Here "Number of subjects analyzed" refer to number of subjects evaluable for this outcome at specified time point.
    End point type
    Secondary
    End point timeframe
    Day 183 to Day 364 (6 months)
    Notes
    [3] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint was related to subjects randomized to prophylactic treatment, hence not reporting statistics for all the arms in the baseline period
    End point values
    		 BAX 855-Low Level BAX 855-High Level
    Number of subjects analysed
    57
    53
    Units: Bleeds per year
    arithmetic mean (standard deviation)
        Bleeds per year
    2.489 ± 6.554
    0.737 ± 1.738
    No statistical analyses for this end point

    Secondary: Annualized Traumatic Bleeding Rate for Second Six Months

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    End point title
    		 Annualized Traumatic Bleeding Rate for Second Six Months [4]
    End point description
    Annualized traumatic bleeding rate was determined by dividing the number of traumatic bleeds by observation period in years. A bleed was defined as traumatic if it was related to injury/trauma. FAS included all subjects who were randomized to one of the two prophylactic arms and treated prophylactically for any period of time. Here "Number of subjects analyzed" refer to number of subjects evaluable for this outcome at specified time point.
    End point type
    Secondary
    End point timeframe
    Day 183 to Day 364 (6 months)
    Notes
    [4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint was related to subjects randomized to prophylactic treatment, hence not reporting statistics for all the arms in the baseline period
    End point values
    		 BAX 855-Low Level BAX 855-High Level
    Number of subjects analysed
    57
    53
    Units: Bleeds per year
    arithmetic mean (standard deviation)
        Bleeds per year
    1.114 ± 2.037
    0.912 ± 2.647
    No statistical analyses for this end point

    Secondary: Annualized Joint Bleeding Rate (AJBR) for Second Six Months

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    End point title
    		 Annualized Joint Bleeding Rate (AJBR) for Second Six Months [5]
    End point description
    Annualized joint bleeding rate was determined by dividing the number of joint bleeds by observation period in years. An acute joint bleed include some or all of the following: ‘aura’, pain, swelling, warmth of the skin over the joint, decreased range of motion and difficulty in using the limb compared with baseline or loss of function. FAS included all subjects who were randomized to one of the two prophylactic arms and treated prophylactically for any period of time. Here "Number of subjects analyzed" refer to number of subjects evaluable for this outcome at specified time point.
    End point type
    Secondary
    End point timeframe
    Day 183 to Day 364 (6 months)
    Notes
    [5] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint was related to subjects randomized to prophylactic treatment, hence not reporting statistics for all the arms in the baseline period
    End point values
    		 BAX 855-Low Level BAX 855-High Level
    Number of subjects analysed
    57
    53
    Units: Bleeds per year
    arithmetic mean (standard deviation)
        Bleeds per year
    2.617 ± 7.361
    1.079 ± 2.553
    No statistical analyses for this end point

    Secondary: Total Weight-adjusted Consumption of BAX 855

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    End point title
    		 Total Weight-adjusted Consumption of BAX 855 [6]
    End point description
    Total weight-adjusted consumption of BAX 855 was reported. FAS included all subjects who were randomized to one of the two prophylactic arms and treated prophylactically for any period of time.
    End point type
    Secondary
    End point timeframe
    From start of study treatment up to 12 months (completion or termination)
    Notes
    [6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint was related to subjects randomized to prophylactic treatment, hence not reporting statistics for all the arms in the baseline period
    End point values
    		 BAX 855-Low Level BAX 855-High Level
    Number of subjects analysed
    57
    58
    Units: International units per kilogram (IU/kg)
    arithmetic mean (standard deviation)
        International units per kilogram (IU/kg)
    3984.593 ± 1678.461
    7030.714 ± 3208.049
    No statistical analyses for this end point

    Secondary: Number of Bleeding Episodes: Overall Hemostatic Efficacy Rating by Number of Infusions

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    End point title
    		 Number of Bleeding Episodes: Overall Hemostatic Efficacy Rating by Number of Infusions [7]
    End point description
    The subject or caregiver rated overall treatment response using a 4-point efficacy rating scale as Excellent: Full relief of pain and cessation of objective signs of bleeding after a single infusion and no additional infusion is required for the control of bleeding; Good: Definite pain relief and/or improvement in signs of bleeding after a single infusion and possibly requires more than 1 infusion for complete resolution; Fair: Probable and/or slight relief of pain and slight improvement in signs of bleeding after a single infusion and required more than 1 infusion for complete resolution and None: No improvement or condition worsens. FAS included all subjects who were randomized to one of the two prophylactic arms and treated prophylactically for any period of time. Here "Number of subjects analyzed" refer to number of subjects evaluable for this outcome at specified time point and "n" refer to total number of bleeds in infusion category with available hemostatic efficacy rating.
    End point type
    Secondary
    End point timeframe
    8 +/- 1 hours after study drug administration
    Notes
    [7] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint was related to subjects randomized to prophylactic treatment, hence not reporting statistics for all the arms in the baseline period
    End point values
    		 BAX 855-Low Level BAX 855-High Level
    Number of subjects analysed
    28
    19
    Units: Bleeds
        Excellent:Bleeds treated with 1 infusion (n=58,33)
    19
    17
        Excellent:Bleeds treated with 2 infusions (n=27,7)
    3
    1
        Excellent:Bleeds treated with 3 infusions (n=9,3)
    0
    1
        Excellent: Bleeds treated with>=4 infusions(n=3,3)
    0
    0
        Good:Bleeds treated with 1 infusion (n=58,33)
    36
    16
        Good:Bleeds treated with 2 infusions (n=27,7)
    16
    6
        Good:Bleeds treated with 3 infusions (n=9,3)
    5
    1
        Good:leeds treated with >= 4 infusion (n=3,3)
    2
    2
        Fair:Bleeds treated with 1 infusion (n=58,33)
    2
    0
        Fair:Bleeds treated with 2 infusions (n=27,7)
    7
    0
        Fair:Bleeds treated with 3 infusions (n=9,3)
    4
    0
        Fair:Bleeds treated with >= 4 infusions (n=3,3)
    1
    0
        None:Bleeds treated with 1 infusion (n=58,33)
    1
    0
        None:Bleeds treated with 2 infusions (n=27,7)
    1
    0
        None:Bleeds treated with 3 infusions (n=9,3)
    0
    1
        None:Bleeds treated with >= 4 infusions (n=3,3)
    0
    1
    No statistical analyses for this end point

    Secondary: Number of Bleeding Episodes: Overall Hemostatic Efficacy Rating at Bleed Resolution

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    End point title
    		 Number of Bleeding Episodes: Overall Hemostatic Efficacy Rating at Bleed Resolution
    End point description
    The subject or caregiver rated the treatment response using a 4-point efficacy rating scale as Excellent: Full relief of pain and cessation of objective signs of bleeding after a single infusion and no additional infusion is required for the control of bleeding; Good: Definite pain relief and/or improvement in signs of bleeding after a single infusion and possibly requires more than 1 infusion for complete resolution; Fair: Probable and/or slight relief of pain and slight improvement in signs of bleeding after a single infusion and required more than 1 infusion for complete resolution and None: No improvement or condition worsens. FAS included all subjects who were randomized to one of the two prophylactic arms and treated prophylactically for any period of time. Here "Number of subjects analyzed" refer to number of subjects evaluable for this outcome at specified time point and "n" refer to total number of bleeds in infusion category with available hemostatic efficacy rating.
    End point type
    Secondary
    End point timeframe
    From start of study treatment up to bleed resolution (up to 12 months)
    End point values
    		 BAX 855-Low Level BAX 855-High Level
    Number of subjects analysed
    39
    26
    Units: Bleeds
        Excellent:Bleeds treated with 1 infusion(n=100,58)
    50
    34
        Excellent:Bleeds treated with 2 infusions(n=29,10)
    4
    2
        Good:Bleeds treated with 1 infusion(n=100,58)
    47
    24
        Good:Bleeds treated with 2 infusions(n=29,10)
    19
    7
        Good:Bleeds treated with 3 infusions (n=13,4)
    6
    3
        Good:Bleeds treated with >= 4 infusions (n=6,6)
    3
    6
        Fair:Bleeds treated with 1 infusion(n=100,58)
    3
    0
        Fair:Bleeds treated with 2 infusions(n=29,10)
    5
    1
        Fair:Bleeds treated with 3 infusions (n=13,4)
    7
    0
        Fair:Bleeds treated with >= 4 infusions (n=6,6)
    3
    0
        None:Bleeds treated with 2 infusions(n=29,10)
    1
    0
        None:Bleeds treated with 3 infusions (n=13,4)
    0
    1
    No statistical analyses for this end point

    Secondary: Treatment of Bleeding Episodes: Number of BAX 855 Infusions per Bleeding Episode Required Until Bleed Resolution

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    End point title
    		 Treatment of Bleeding Episodes: Number of BAX 855 Infusions per Bleeding Episode Required Until Bleed Resolution [8]
    End point description
    Infusions of BAX 855 that were required until bleed resolution were reported. FAS included all subjects who were randomized to one of the two prophylactic arms and treated prophylactically for any period of time. Here "Number of subjects analyzed" refer to number of subjects evaluable for this outcome at specified time point.
    End point type
    Secondary
    End point timeframe
    From start of study treatment up to 12 months (completion or termination)
    Notes
    [8] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint was related to subjects randomized to prophylactic treatment, hence not reporting statistics for all the arms in the baseline period
    End point values
    		 BAX 855-Low Level BAX 855-High Level
    Number of subjects analysed
    41
    26
    Units: Infusions
    arithmetic mean (standard deviation)
        Infusions
    1.6 ± 1.19
    1.6 ± 1.36
    No statistical analyses for this end point

    Secondary: Change From Baseline in Hemophilia Joint Health Score (HJHS)- Total Score

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    End point title
    		 Change From Baseline in Hemophilia Joint Health Score (HJHS)- Total Score [9]
    End point description
    HJHS was assessed based on the following components of the elbow, knee, and ankle joints: swelling, duration of swelling, muscle atrophy, crepitus on motion, flexion loss, extension loss, joint pain, and strength, together with an assessment of the global gait. The HJHS is a validated 11-item scoring tool based on radiologic and clinical evaluation, sensitive to detect early signs and minor changes. HJHS ranges from 0 to 124. Higher values in the HJHS represent worse situation for the subject. FAS included all subjects who were randomized to one of the two prophylactic arms and treated prophylactically for any period of time. Here "Number of subjects analyzed" refer to number of subjects evaluable for this outcome at specified time point.
    End point type
    Secondary
    End point timeframe
    Baseline, Month 12
    Notes
    [9] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint was related to subjects randomized to prophylactic treatment, hence not reporting statistics for all the arms in the baseline period
    End point values
    		 BAX 855-Low Level BAX 855-High Level
    Number of subjects analysed
    57
    54
    Units: Score on a scale
    arithmetic mean (standard deviation)
        Score on a scale
    -1.9 ± 5.25
    -1.1 ± 7.77
    No statistical analyses for this end point

    Secondary: Number of Subjects With Hemostatic Efficacy Ratings for BAX 855 Treatment of Operative Bleeds

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    End point title
    		 Number of Subjects With Hemostatic Efficacy Ratings for BAX 855 Treatment of Operative Bleeds [10]
    End point description
    The operating surgeon rated hemostatic efficacy compared to that expected for the type of procedure performed using a 4-point efficacy rating scale as Excellent: blood loss was less than or equal to that expected (<=100%); Good: blood loss was up to 50% more than expected (101-150%); Fair: blood loss was more than 50% of that expected (>150%) and None: Uncontrolled hemorrhage/ Significant postoperative bleeding/ Significant perioperative bleeding that was the result of inadequate therapeutic response despite proper dosing, necessitating rescue therapy. Hemostatic efficacy was evaluated intra-operatively (from start to end of the procedure), post-operatively (from the end of procedure up to 24 h post procedure), and perioperatively (from the start of procedure to subject discharge from hospital or 14 days after completion of procedure; whichever was first). FAS with evaluable subjects were analyzed.
    End point type
    Secondary
    End point timeframe
    Day 0 through discharge or 14 days post-surgery
    Notes
    [10] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint was related to subjects randomized to prophylactic treatment, hence not reporting statistics for all the arms in the baseline period
    End point values
    		 BAX 855-Low Level BAX 855-High Level
    Number of subjects analysed
    3
    4
    Units: Subjects
        Excellent: Intra-operative
    1
    3
        Excellent: Post-operative
    3
    4
        Excellent: Peri-operative
    2
    4
        Good: Intra-operative
    0
    0
        Good: Post-operative
    0
    0
        Good: Peri-operative
    0
    0
        Fair: Intra-operative
    0
    1
        Fair: Post-operative
    0
    0
        Fair: Peri-operative
    0
    0
        None: Intra-operative
    0
    0
        None: Post-operative
    0
    0
        None: Peri-operative
    0
    0
        Unknown: Intra-operative
    2
    0
        Unknown: Post-operative
    0
    0
        Unknown: Peri-operative
    1
    0
    No statistical analyses for this end point

    Secondary: Blood Loss per Subject in Case of Surgery

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    End point title
    		 Blood Loss per Subject in Case of Surgery [11]
    End point description
    Intraoperative blood loss was measured by determining volume of blood and fluid removal through suction into collection container and estimated blood loss into swabs and towels during procedure, per anesthesiologist’s record. Postoperatively, blood loss was determined by drainage volume collected (via vacuum or gravity drain). In cases where no drain was present, blood loss was determined by surgeon’s clinical judgment, as applicable or entered as “not available”. Blood loss was evaluated intra-operatively (from start to end of the procedure), post-operatively (from the end of procedure up to 24 h post procedure), and perioperatively (from the start of procedure to subject discharge or 14 days after completion of procedure; whichever was first). Surgery analysis set included all subjects in FAS who underwent some form of surgery during the study participation. Blood loss per subject was reported. "99999" indicates data was not calculated.
    End point type
    Secondary
    End point timeframe
    Day 0 through discharge or 14 days post-surgery
    Notes
    [11] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint was related to subjects randomized to prophylactic treatment, hence not reporting statistics for all the arms in the baseline period
    End point values
    		 BAX 855-Low Level BAX 855-High Level
    Number of subjects analysed
    3
    4
    Units: Milliliters (mL)
    arithmetic mean (standard deviation)
        Intra-operative: Observed (n=3,4)
    4.400 ± 4.017
    72.000 ± 160.741
        Intra-operative: Predicted Average (n=3,4)
    10.600 ± 9.227
    65.833 ± 139.290
        Intra-operative: Predicted Maximum (n=3,4)
    20.800 ± 18.089
    128.333 ± 231.790
        Post-operative: Observed (n=0,1)
    99999 ± 99999
    820.000 ± 99999
        Post-operative: Predicted Average (n=3,4)
    10.000 ± 9.129
    145.000 ± 320.967
        Post-operative: Predicted Maximum (n=3,4)
    20.200 ± 17.987
    230.000 ± 475.563
    No statistical analyses for this end point

    Secondary: Number of Subjects With Adverse Events (AEs) and Serious Adverse Events (SAEs)

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    End point title
    		 Number of Subjects With Adverse Events (AEs) and Serious Adverse Events (SAEs)
    End point description
    An AE was any unfavorable and unintended sign, symptom (rash, pain, discomfort, fever, dizziness, etc.), disease (peritonitis, bacteremia, etc.), or outcome of death temporally associated with the use of an investigational product (IP), whether or not considered causally related to the IP. A SAE was defined as an untoward medical occurrence that at any dose met one or more of the following criteria: outcome was fatal/results in death, life-threatening, required in-patient hospitalization or resulted in prolongation of an existing hospitalization, resulted in persistent or significant disability/incapacity, was a congenital anomaly/birth defect, was a medically important event that was not immediately life-threatening or resulted in death or required hospitalization but jeopardize the subject or required medical or surgical intervention to prevent any of the above outcomes. Safety analysis set (SAS) included all subjects enrolled who had at least one BAX 855 infusion.
    End point type
    Secondary
    End point timeframe
    From start of study treatment up to 12 months (completion or termination)
    End point values
    		 BAX 855-Low Level BAX 855-High Level BAX 855-Non-randomized
    Number of subjects analysed
    57
    58
    6
    Units: Subjects
        Number of Subjects with SAE
    5
    5
    0
        Number of Subjects with AE
    35
    38
    0
    No statistical analyses for this end point

    Secondary: Number of Subjects With Clinically Significant Changes in Vital Signs Reported as Treatment Related Adverse Events

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    End point title
    		 Number of Subjects With Clinically Significant Changes in Vital Signs Reported as Treatment Related Adverse Events
    End point description
    Vital signs included systolic and diastolic blood pressure, pulse rate, respiratory rate, body temperature. SAS included all subjects enrolled who had at least one BAX 855 infusion.
    End point type
    Secondary
    End point timeframe
    From start of study treatment up to 12 months (completion or termination)
    End point values
    		 BAX 855-Low Level BAX 855-High Level BAX 855-Non-randomized
    Number of subjects analysed
    57
    58
    6
    Units: Subjects
        Subjects
    0
    0
    0
    No statistical analyses for this end point

    Secondary: Number of Subjects With Clinically Significant Changes in Clinical Laboratory Parameters Reported as Treatment Related Adverse Events

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    End point title
    		 Number of Subjects With Clinically Significant Changes in Clinical Laboratory Parameters Reported as Treatment Related Adverse Events
    End point description
    Clinical laboratory assessments included clinical chemistry, hematology, lipid panel, genetics, T-cell, B-cell and NK cell (TBNK) and viral serology. SAS included all subjects enrolled who had at least one BAX 855 infusion.
    End point type
    Secondary
    End point timeframe
    From start of study treatment up to 12 months (completion or termination)
    End point values
    		 BAX 855-Low Level BAX 855-High Level BAX 855-Non-randomized
    Number of subjects analysed
    57
    58
    6
    Units: Subjects
        Subjects
    2
    1
    0
    No statistical analyses for this end point

    Secondary: Number of Subjects With Positive Inhibitory Antibodies and Binding Antibodies to Factor VIII (FVIII), BAX 855, Polyethylene Glycol (PEG), and Chinese Hamster Ovary (CHO) Protein were reported here.

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    End point title
    		 Number of Subjects With Positive Inhibitory Antibodies and Binding Antibodies to Factor VIII (FVIII), BAX 855, Polyethylene Glycol (PEG), and Chinese Hamster Ovary (CHO) Protein were reported here. [12]
    End point description
    Positive Inhibitory Antibodies and Binding Antibodies to Factor VIII (FVIII), BAX 855, Polyethylene Glycol (PEG), and Chinese Hamster Ovary (CHO) Protein were reported.
    End point type
    Secondary
    End point timeframe
    From start of study treatment up to 12 months (completion or termination)
    Notes
    [12] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint was related to subjects randomized to prophylactic treatment, hence not reporting statistics for all the arms in the baseline period
    End point values
    		 BAX 855-Low Level BAX 855-High Level
    Number of subjects analysed
    57
    58
    Units: Subjects
        Binding IgG antibodies to FVIII
    0
    3
        Binding IgM antibodies to FVIII
    0
    0
        Binding IgG antibodies to PEG-FVIII
    2
    7
        Binding IgM antibodies to PEG-FVIII
    0
    1
        Binding IgG antibodies to PEG
    0
    0
        Binding IgM antibodies to PEG
    1
    3
        Binding Ig antibodies to CHO
    0
    0
        Inhibitory antibodies to FVIII
    0
    1
    No statistical analyses for this end point

    Secondary: Change from Baseline in Physical Component Scores (PCS) of the Short Form-36 (SF-36) Health Survey

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    End point title
    		 Change from Baseline in Physical Component Scores (PCS) of the Short Form-36 (SF-36) Health Survey [13]
    End point description
    Short Form (36) Health Survey (SF-36) is a 36-item validated, generic health related quality of life (HR QoL) instrument. PCS is a summary scale of the dimensions physical functioning, role physical, bodily pain, and general health. The component score is normalized to a standard population. Scores range from 0 to 100 with higher scores representing better health. There is no total overall score; scoring is done for both sub-scores and summary scores. FAS included all subjects who were randomized to one of the two prophylactic arms and treated prophylactically for any period of time. Here "Number of subjects analyzed" refer to number of subjects evaluable for this outcome at specified time points.
    End point type
    Secondary
    End point timeframe
    Baseline, Month 12 (completion or termination)
    Notes
    [13] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint was related to subjects randomized to prophylactic treatment, hence not reporting statistics for all the arms in the baseline period
    End point values
    		 BAX 855-Low Level BAX 855-High Level
    Number of subjects analysed
    47
    48
    Units: Score on a scale
    arithmetic mean (standard deviation)
        Score on a scale
    3.551 ± 8.351
    2.846 ± 8.658
    No statistical analyses for this end point

    Secondary: Area Under the Plasma Concentration of BAX 855 From Zero to Infinity (AUC0-inf)

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    End point title
    		 Area Under the Plasma Concentration of BAX 855 From Zero to Infinity (AUC0-inf)
    End point description
    Area under the plasma concentration versus time curve from time 0 to infinity of BAX 855 was reported. Pharmacokinetic analysis set (PKAS) included all subjects in the SAS that had at least one quantifiable post-dose FVIII activity level without major protocol deviations or events with potential to affect the PK analysis. Here "Number of subjects analyzed" refer to number of subjects evaluable for this outcome at specified time points.
    End point type
    Secondary
    End point timeframe
    Pre-infusion, 15 - 30 minutes, 3, 8, 24, 48, 72 and 96 hours post-infusion
    End point values
    		 BAX 855-Low Level BAX 855-High Level BAX 855-Non-randomized
    Number of subjects analysed
    54
    57
    5
    Units: International units*hour per deciliter
    arithmetic mean (standard deviation)
        International units*hour per deciliter
    2673 ± 877.3
    2659 ± 1041
    2214 ± 355.8
    No statistical analyses for this end point

    Secondary: Incremental Recovery (IR) at Maximum Plasma Concentration (Cmax) of BAX 855

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    End point title
    		 Incremental Recovery (IR) at Maximum Plasma Concentration (Cmax) of BAX 855
    End point description
    IR at Cmax of BAX 855 was reported. PKAS included all subjects in the SAS that had at least one quantifiable post-dose FVIII activity level without major protocol deviations or events with potential to affect the PK analysis.
    End point type
    Secondary
    End point timeframe
    Pre-infusion, 15 - 30 minutes, 3, 8, 24, 48, 72 and 96 hours post-infusion
    End point values
    		 BAX 855-Low Level BAX 855-High Level BAX 855-Non-randomized
    Number of subjects analysed
    57
    58
    5
    Units: (IU/dL) / (IU/kg)
    arithmetic mean (standard deviation)
        (IU/dL) / (IU/kg)
    2.227 ± 0.5201
    2.231 ± 0.5451
    2.478 ± 0.2016
    No statistical analyses for this end point

    Secondary: Plasma Half-life (T1/2) of BAX 855

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    End point title
    		 Plasma Half-life (T1/2) of BAX 855
    End point description
    T1/2 of BAX 855 in plasma was reported. PKAS included all subjects in the SAS that had at least one quantifiable post-dose FVIII activity level without major protocol deviations or events with potential to affect the PK analysis.
    End point type
    Secondary
    End point timeframe
    Pre-infusion, 15 - 30 minutes, 3, 8, 24, 48, 72 and 96 hours post-infusion
    End point values
    		 BAX 855-Low Level BAX 855-High Level BAX 855-Non-randomized
    Number of subjects analysed
    57
    58
    5
    Units: hour (h)
    median (full range (min-max))
        hour (h)
    15.28 (8.77 to 31.9)
    14.66 (6.78 to 35.8)
    10.97 (8.67 to 12.5)
    No statistical analyses for this end point

    Secondary: Mean Residence Time (MRT) of BAX 855

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    End point title
    		 Mean Residence Time (MRT) of BAX 855
    End point description
    MRT of BAX 855 was reported. PKAS included all subjects in the SAS that had at least one quantifiable post-dose FVIII activity level without major protocol deviations or events with potential to affect the PK analysis.
    End point type
    Secondary
    End point timeframe
    Pre-infusion, 15 - 30 minutes, 3, 8, 24, 48, 72 and 96 hours post-infusion
    End point values
    		 BAX 855-Low Level BAX 855-High Level BAX 855-Non-randomized
    Number of subjects analysed
    57
    58
    5
    Units: hour (h)
    median (full range (min-max))
        hour (h)
    22.77 (12.6 to 41.7)
    21.50 (10.1 to 52.5)
    16.18 (12.6 to 18.2)
    No statistical analyses for this end point

    Secondary: Maximum Plasma Concentration (Cmax) of BAX 855

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    End point title
    		 Maximum Plasma Concentration (Cmax) of BAX 855
    End point description
    Cmax of BAX 855 was reported. PKAS included all subjects in the SAS that had at least one quantifiable post-dose FVIII activity level without major protocol deviations or events with potential to affect the PK analysis. Here "Number of subjects analyzed" refer to number of subjects evaluable for this outcome at specified time points.
    End point type
    Secondary
    End point timeframe
    Pre-infusion, 15 - 30 minutes, 3, 8, 24, 48, 72 and 96 hours post-infusion
    End point values
    		 BAX 855-Low Level BAX 855-High Level BAX 855-Non-randomized
    Number of subjects analysed
    54
    57
    5
    Units: International units per deciliter(IU/dL)
    arithmetic mean (standard deviation)
        International units per deciliter(IU/dL)
    132.54 ± 31.83
    135.65 ± 33.10
    149.18 ± 12.86
    No statistical analyses for this end point

    Secondary: Time to Maximum Concentration of BAX 855 in Plasma (Tmax)

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    End point title
    		 Time to Maximum Concentration of BAX 855 in Plasma (Tmax)
    End point description
    Tmax of BAX 855 was reported. PKAS included all subjects in the SAS that had at least one quantifiable post-dose FVIII activity level without major protocol deviations or events with potential to affect the PK analysis.
    End point type
    Secondary
    End point timeframe
    Pre-infusion, 15 - 30 minutes, 3, 8, 24, 48, 72 and 96 hours post-infusion
    End point values
    		 BAX 855-Low Level BAX 855-High Level BAX 855-Non-randomized
    Number of subjects analysed
    57
    58
    5
    Units: hour (h)
    median (full range (min-max))
        hour (h)
    0.467 (0.30 to 3.08)
    0.475 (0.25 to 3.25)
    0.417 (0.38 to 0.53)
    No statistical analyses for this end point

    Secondary: Total Body Clearance (CL) of BAX 855

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    End point title
    		 Total Body Clearance (CL) of BAX 855
    End point description
    Total body clearance of BAX 855 from blood by the kidney was reported. PKAS included all subjects in the SAS that had at least one quantifiable post-dose FVIII activity level without major protocol deviations or events with potential to affect the PK analysis.
    End point type
    Secondary
    End point timeframe
    Pre-infusion, 15 - 30 minutes, 3, 8, 24, 48, 72 and 96 hours post-infusion
    End point values
    		 BAX 855-Low Level BAX 855-High Level BAX 855-Non-randomized
    Number of subjects analysed
    57
    58
    5
    Units: Deciliters per kilogram * hour (dL/kg*h)
    arithmetic mean (standard deviation)
        Deciliters per kilogram * hour (dL/kg*h)
    0.02477 ± 0.009580
    0.02624 ± 0.009333
    0.02774 ± 0.004385
    No statistical analyses for this end point

    Secondary: Volume of Distribution at steady state (Vss)

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    End point title
    		 Volume of Distribution at steady state (Vss)
    End point description
    Volume of distribution was defined as the theoretical volume in which the total amount of drug was uniformly distributed to produce the desired blood concentration of a drug. Vss is the apparent volume of distribution at steadystate. PKAS included all subjects in the SAS that had at least one quantifiable post-dose FVIII activity level without major protocol deviations or events with potential to affect the PK analysis.
    End point type
    Secondary
    End point timeframe
    Pre-infusion, 15 - 30 minutes, 3, 8, 24, 48, 72 and 96 hours post-infusion
    End point values
    		 BAX 855-Low Level BAX 855-High Level BAX 855-Non-randomized
    Number of subjects analysed
    57
    58
    5
    Units: Deciliters per kilogram (dL/kg)
    arithmetic mean (standard deviation)
        Deciliters per kilogram (dL/kg)
    0.5147 ± 0.1209
    0.5158 ± 0.1062
    149.18 ± 12.86
    No statistical analyses for this end point

    Secondary: Incremental recovery (IR) Over Time

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    End point title
    		 Incremental recovery (IR) Over Time [14]
    End point description
    Incremental recovery was calculated by BAX 855 increment (IU/dL) / BAX 855 dose (IU/kg). PKAS included all subjects in the SAS that had at least one quantifiable post-dose FVIII activity level without major protocol deviations or events with potential to affect the PK analysis. Here "n" refer to number of subjects evaluable for this outcome at specified time points.
    End point type
    Secondary
    End point timeframe
    Baseline, Month 3, 6, 7.5, 9, 10.5, 12 (Completion or termination)
    Notes
    [14] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint was related to subjects randomized to prophylactic treatment, hence not reporting statistics for all the arms in the baseline period
    End point values
    		 BAX 855-Low Level BAX 855-High Level
    Number of subjects analysed
    57
    58
    Units: IU/dL per IU/kg
    arithmetic mean (standard deviation)
        Baseline (n=53,54)
    2.68 ± 0.513
    2.70 ± 0.450
        Month 3 (n=56,54)
    2.68 ± 0.515
    2.66 ± 0.459
        Month 6 (n=51,49)
    2.62 ± 0.585
    2.76 ± 0.552
        Month 7.5 (n=13,11)
    2.53 ± 0.360
    2.71 ± 0.545
        Month 9 (n=55,52)
    2.65 ± 0.511
    2.68 ± 0.545
        Month 10.5 (n=12,5)
    2.61 ± 0.467
    2.58 ± 0.584
        Completion/ Termination (n=56,53)
    2.71 ± 0.553
    2.73 ± 0.689
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From start of study treatment up to 12 months (completion or termination)
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    21.0
    Reporting groups
    Reporting group title
    BAX 855-Low Level
    Reporting group description
    		 Subjects with severe hemophilia A received a single BAX 855 dose of 60 +/- 5 IU/kg IV infusion (PK assessment) followed by a PK-guided dose of BAX 855 twice weekly (Alternating 3 and 4-day infusion intervals or an infusion every 3.5 days), FVIII trough levels of 1-3%. Depending on subject’s individual PK, more frequent dosing was considered if single doses of > 80 IU/kg were required or regular FVIII peak levels of 200% were reached.

    Reporting group title
    BAX 855-High Level
    Reporting group description
    		 Subjects with severe hemophilia A received a single BAX 855 dose of 60 +/- 5 IU/kg IV infusion (PK assessment) followed by a PK-guided dose of BAX 855 every other day, targeting FVIII trough levels of 8-12%. Depending on subject’s individual PK, a different dosing interval was considered to prevent regular high FVIII peak levels.

    Reporting group title
    BAX 855-Non-randomized
    Reporting group description
    		 Subjects with severe hemophilia A received a single BAX 855 dose of 60 +/- 5 IU/kg IV infusion (PK assessment) and were not randomized to any treatments.

    Serious adverse events
    		 BAX 855-Low Level BAX 855-High Level BAX 855-Non-randomized
    Total subjects affected by serious adverse events
         subjects affected / exposed
    5 / 57 (8.77%)
    5 / 58 (8.62%)
    0 / 6 (0.00%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Injury, poisoning and procedural complications
    Hand fracture
         subjects affected / exposed
    0 / 57 (0.00%)
    1 / 58 (1.72%)
    0 / 6 (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
    Head injury
         subjects affected / exposed
    1 / 57 (1.75%)
    1 / 58 (1.72%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Laceration
         subjects affected / exposed
    0 / 57 (0.00%)
    1 / 58 (1.72%)
    0 / 6 (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
    Multiple injuries
         subjects affected / exposed
    0 / 57 (0.00%)
    1 / 58 (1.72%)
    0 / 6 (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
    Radius fracture
         subjects affected / exposed
    1 / 57 (1.75%)
    0 / 58 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebellar haematoma
         subjects affected / exposed
    0 / 57 (0.00%)
    1 / 58 (1.72%)
    0 / 6 (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
    Blood and lymphatic system disorders
    Factor VIII inhibition
         subjects affected / exposed
    0 / 57 (0.00%)
    1 / 58 (1.72%)
    0 / 6 (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
    Musculoskeletal and connective tissue disorders
    Synovitis
         subjects affected / exposed
    1 / 57 (1.75%)
    0 / 58 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Abscess limb
         subjects affected / exposed
    1 / 57 (1.75%)
    0 / 58 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Appendicitis
         subjects affected / exposed
    1 / 57 (1.75%)
    0 / 58 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    1 / 57 (1.75%)
    0 / 58 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 BAX 855-Low Level BAX 855-High Level BAX 855-Non-randomized
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    25 / 57 (43.86%)
    25 / 58 (43.10%)
    0 / 6 (0.00%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    5 / 57 (8.77%)
    6 / 58 (10.34%)
    0 / 6 (0.00%)
         occurrences all number
    7
    7
    0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    2 / 57 (3.51%)
    3 / 58 (5.17%)
    0 / 6 (0.00%)
         occurrences all number
    2
    3
    0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    3 / 57 (5.26%)
    2 / 58 (3.45%)
    0 / 6 (0.00%)
         occurrences all number
    3
    2
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    6 / 57 (10.53%)
    5 / 58 (8.62%)
    0 / 6 (0.00%)
         occurrences all number
    7
    5
    0
    Back pain
         subjects affected / exposed
    1 / 57 (1.75%)
    3 / 58 (5.17%)
    0 / 6 (0.00%)
         occurrences all number
    2
    3
    0
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    6 / 57 (10.53%)
    5 / 58 (8.62%)
    0 / 6 (0.00%)
         occurrences all number
    8
    6
    0
    Rhinitis
         subjects affected / exposed
    3 / 57 (5.26%)
    3 / 58 (5.17%)
    0 / 6 (0.00%)
         occurrences all number
    3
    3
    0
    Sinusitis
         subjects affected / exposed
    3 / 57 (5.26%)
    0 / 58 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    3
    0
    0
    Upper respiratory tract infection
         subjects affected / exposed
    6 / 57 (10.53%)
    12 / 58 (20.69%)
    0 / 6 (0.00%)
         occurrences all number
    11
    16
    0

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    12 May 2015
    1) The Chi-squared test with continuity correction is used which results in a lower but acceptable power of 80%. 2) The blood sampling time points for PK study were modified as follows: Postinfusion at 15-30 minutes and at 3, 8, 24, 48, 72 and 96 hours.
    03 Sep 2015
    1) The term for the primary outcome measure was changed from “total ABR” to “Presence or absence of any bleedings in the second 6- month study period”. 2) SF-36 Physical activity level was replaced by SF-36 Health Survey. 3) HrQoL including SF-36, EQ-5D, Haemo-SYM and healthcare resource utilization was added to pharmacoeconomic outcomes. 4) The time point for the initial hemostatic efficacy rating for treatment of bleeding episodes was changed from 24±2 hours to 8+/-1 hours. 5) It was made clear that the second 6-month study period will consist of at least 26 weeks following the 6 month-study visit scheduled at 26 (+/-1) weeks and that the subject will have received his PK-tailored dosing regimen for at least 52 weeks.
    18 Oct 2016
    1) The washout periods have been revised to be consistent with the infusion interval according to the treatment regimen provided to the subject. 2) The dose to determine IR has been revised. Instead of a set dose of 60 +/- 5 IU, the PK-guided prophylactic dose of BAX 855 will be used. 3) Description of EQ-5D questionnaire amended to reflect 3 levels for each of the 5 measured dimensions.

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

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