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    Clinical Trial Results:
    A Phase 3 prospective, uncontrolled, multicenter study evaluating pharmacokinetics, efficacy, safety, and immunogenicity of BAX 855 (pegylated full-length recombinant FVIII) in previously treated pediatric patients with severe hemophilia A

    Summary
    EudraCT number
    		 2014-000742-30
    Trial protocol
    		 LT   ES   BG   RO   NL   GB  
    Global end of trial date
    23 Oct 2015

    Results information
    Results version number
    		 v1(current)
    This version publication date
    22 Apr 2016
    First version publication date
    22 Apr 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    261202
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02210091
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Baxalta Innovations GmbH
    Sponsor organisation address
    Industriestrasse 67, Vienna, Austria, 1221
    Public contact
    Clinical Trial Registries and Results Disclosure, Baxalta Innovations GmbH, ClinicalTrialsDisclosure@baxalta.com
    Scientific contact
    Clinical Trial Registries and Results Disclosure, Baxalta Innovations GmbH, ClinicalTrialsDisclosure@baxalta.com
    Sponsor organisation name
    Baxalta US Inc.
    Sponsor organisation address
    One Baxter Way, Westlake Village, United States, CA 91362
    Public contact
    Clinical Trial Registries and Results Disclosure, Baxalta US Inc., ClinicalTrialsDisclosure@baxalta.com
    Scientific contact
    Clinical Trial Registries and Results Disclosure, Baxalta US Inc., ClinicalTrialsDisclosure@baxalta.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    		 EMEA-001296-PIP01-12
    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?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    23 Oct 2015
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    23 Oct 2015
    Global end of trial reached?
    Yes
    Global end of trial date
    23 Oct 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To assess the incidence of FVIII inhibitory antibodies (≥0.6 Bethesda units [BU] using the Nijmegen modification of the Bethesda assay).
    Protection of trial subjects
    This study was conducted in accordance with the protocol, the ICH Guideline for Good Clinical Practice E6 (ICH GCP, April 1996), Title 21 of the United States Code of Federal Regulations, the European Clinical Trial Directive (2001/20/EC and 2005/28/EC) and applicable national and local regulatory requirements. Justification for enrollment of pediatric subjects is based on the requirements outlined in the ICH M3 and E11 guidelines. The clinical development program for BAX 855 followed the EMA guidance outlined in EMA/CHMP/BPWP/144533/2009. In line with this guidance the pediatric study did not start before the data of 20 previously treated patients (PTPs) ≥12 years of age that had been treated for at least 50 exposure days (EDs) and the pharmacokinetic (PK) data of at least 12 PTPs ≥12 years of age were available (study 261201), were reviewed by an independent data monitoring committee (DMC) and a decision to start the study was obtained. For the PK evaluation, a population PK approach was used to reduce the number of blood draws: the 3 post-infusion blood draws over 96 hours were randomly selected from 3 choices for each blood draw.
    Background therapy
    		 -
    Evidence for comparator
    		 Prior to receiving prophylactic treatment with BAX 855, a subgroup of subjects within each age cohort underwent PK assessments with ADVATE followed by BAX 855 to compare the PK parameters of BAX 855 with ADVATE.
    Actual start date of recruitment
    31 Oct 2014
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United States: 22
    Country: Number of subjects enrolled
    Malaysia: 9
    Country: Number of subjects enrolled
    Hong Kong: 1
    Country: Number of subjects enrolled
    Taiwan: 1
    Country: Number of subjects enrolled
    Korea, Republic of: 3
    Country: Number of subjects enrolled
    Bulgaria: 3
    Country: Number of subjects enrolled
    Netherlands: 3
    Country: Number of subjects enrolled
    Spain: 5
    Country: Number of subjects enrolled
    Ukraine: 5
    Country: Number of subjects enrolled
    United Kingdom: 8
    Country: Number of subjects enrolled
    Turkey: 6
    Worldwide total number of subjects
    66
    EEA total number of subjects
    19
    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)
    2
    Children (2-11 years)
    64
    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
    		 52 sites participated in this study. 39 study sites enrolled subjects and 13 sites were initiated but were inactive.

    Pre-assignment
    Screening details
    		 A total of 73 subjects provided informed consent and were screened for study participation. There were 9 screen failures. Among these, 2 subjects were screen failures at first screening but entered the study later. 66 subjects were dosed in the prophylactic part of the study, of which 31 subjects were also dosed in the PK part prior to prophylaxis.

    Pre-assignment period milestones
    Number of subjects started
    		 73 [1]
    Number of subjects completed
    		 66

    Pre-assignment subject non-completion reasons
    Reason: Number of subjects
    		 Screen failures: 7
    Notes
    [1] - The number of subjects reported to have started the pre-assignment period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: A total of 73 subjects provided informed consent and were screened for study participation. There were 9 screen failures. Among these, 2 subjects were Screen failures at first screening but entered the study later. 66 subjects were dosed in the prophylactic part of the study, of which 31 subjects were also dosed in the PK part prior to prophylaxis.
    Period 1
    Period 1 title
    Overall trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Pediatric subjects <6 years of age
    Arm description
    		 Subjects were to be treated with prophylactic infusions of BAX 855 at a dose of 50 ±10 IU/kg administered twice weekly (at 3- and 4-day intervals or 3.5-day intervals) for a minimum of 50 exposure days to BAX855 or approximately 6 months, whichever occurred last.
    Arm type
    		 Experimental

    Investigational medicinal product name
    BAX 855
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder and solvent for solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Dose of 50 ±10 IU/kg twice weekly for prophylaxis

    Arm title
    		 Pediatric subjects 6 to <12 years of age
    Arm description
    		 Subjects were to be treated with prophylactic infusions of BAX 855 at a dose of 50 ±10 IU/kg administered twice weekly (at 3- and 4-day intervals or 3.5-day intervals) for a minimum of 50 exposure days to BAX855 or approximately 6 months, whichever occurred last.
    Arm type
    		 Experimental

    Investigational medicinal product name
    BAX 855
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder and solvent for solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Dose of 50 ±10 IU/kg twice weekly for prophylaxis

    Number of subjects in period 1
    		Pediatric subjects <6 years of age Pediatric subjects 6 to <12 years of age
    Started
    32
    34
    Completed
    32
    32
    Not completed
    0
    2
         Physician decision
    -
    1
         Withdrawn by sponsor
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Overall trial
    Reporting group description
    		 Prophylactic Part (main study part)

    Reporting group values
    		 Overall trial Total
    Number of subjects
    		 66 66
    Age categorical
    Units: Subjects
        85 years and over
    		 0 0
        From 65-84 years
    		 0 0
        Adults (18-64 years)
    		 0 0
        Adolescents (12-17 years)
    		 0 0
        Children (2-11 years)
    		 64 64
        Infants and toddlers (28 days-23 months)
    		 2 2
        Newborns (0-27 days)
    		 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0
        In utero
    		 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 6 ( 2.7 ) -
    Gender categorical
    Units:
        Female
    		 1 1
        Male
    		 65 65
    Subject analysis sets

    Subject analysis set title
    Full Analysis Set
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    The full analysis set contains all subjects who received at least one dose of BAX 855 in either the PK part of the study or the prophylaxis part of the study. All efficacy analyses were performed on the full analysis set (FAS). The FAS is the primary analysis set.

    Subject analysis set title
    ADVATE Safety Analysis Set
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    The ADVATE safety analysis set contains all subjects who received at least one dose of ADVATE in the PK part of the study.

    Subject analysis set title
    BAX 855 Safety Analysis Set
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    The BAX 855 safety analysis set contains all subjects who received at least one dose of BAX 855.

    Subject analysis set title
    Pharmacokinetic (PK) Full Analysis Set
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    The pharmacokinetic full analysis set (PKFAS) contains all subjects who had been treated with at least 1 dose of ADVATE (60 ±5 IU/kg) and 1 dose of BAX 855 (60 ±5 IU/kg) in the PK part of the study (prior to prophylactic treatment) and had at least 1 PK concentration available for population PK and non-compartmental analysis.

    Subject analysis set title
    Pharmacokinetic (PK) Analysis Set - ADVATE
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    This analysis set contains all subjects who had been treated with at least 1 dose of ADVATE (60 ±5 IU/kg) and 1 dose of BAX 855 (60 ±5 IU/kg) in the PK part of the study (prior to prophylactic treatment) and had at least 1 PK concentration available for population PK and non-compartmental analysis.

    Subject analysis set title
    Pharmacokinetic (PK) Analysis Set - BAX 855
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    This analysis set contains all subjects who had been treated with at least 1 dose of ADVATE (60 ±5 IU/kg) and 1 dose of BAX 855 (60 ±5 IU/kg) in the PK part of the study (prior to prophylactic treatment) and had at least 1 PK concentration available for population PK and non-compartmental analysis.

    Subject analysis set title
    PK Analysis Set - BAX 855 - subjects <6 years of age
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    This analysis set contains all subjects <6 years of age who had been treated with at least 1 dose of ADVATE (60 ±5 IU/kg) and 1 dose of BAX 855 (60 ±5 IU/kg) in the PK part of the study (prior to prophylactic treatment) and had at least 1 PK concentration available for population PK and non-compartmental analysis.

    Subject analysis set title
    PK Analysis Set - BAX 855 - subjects 6 to <12 years of age
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    This analysis set contains all subjects 6 to <12 years of age who had been treated with at least 1 dose of ADVATE (60 ±5 IU/kg) and 1 dose of BAX 855 (60 ±5 IU/kg) in the PK part of the study (prior to prophylactic treatment) and had at least 1 PK concentration available for population PK and non-compartmental analysis.

    Subject analysis set title
    PK Analysis Set - ADVATE - subjects <6 years of age
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    This analysis set contains all subjects <6 years of age who had been treated with at least 1 dose of ADVATE (60 ±5 IU/kg) and 1 dose of BAX 855 (60 ±5 IU/kg) in the PK part of the study (prior to prophylactic treatment) and had at least 1 PK concentration available for population PK and non-compartmental analysis.

    Subject analysis set title
    PK Analysis Set- ADVATE - subjects 6 to <12 years of age
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    This analysis set contains all subjects 6 to <12 years of age who had been treated with at least 1 dose of ADVATE (60 ±5 IU/kg) and 1 dose of BAX 855 (60 ±5 IU/kg) in the PK part of the study (prior to prophylactic treatment) and had at least 1 PK concentration available for population PK and non-compartmental analysis.

    Subject analysis set title
    Per Protocol Analysis Set
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    This analysis set contains all subjects in the Full Analysis Set (FAS) who fulfilled the following compliance criteria for prophylactic treatment: -) Infusion interval of 5 or more days did not occur more than five times in the observation period, -) the dose per infusion was below 40 IU/kg in no more than 10% of the infusions in the observation period, -) the dose per infusion was above 80 IU/kg in no more than 10% of the infusions in the observation period. The Per Protocol Analysis Set was a supportive analysis set.

    Subject analysis sets values
    		 Full Analysis Set ADVATE Safety Analysis Set BAX 855 Safety Analysis Set Pharmacokinetic (PK) Full Analysis Set Pharmacokinetic (PK) Analysis Set - ADVATE Pharmacokinetic (PK) Analysis Set - BAX 855 PK Analysis Set - BAX 855 - subjects <6 years of age PK Analysis Set - BAX 855 - subjects 6 to <12 years of age PK Analysis Set - ADVATE - subjects <6 years of age PK Analysis Set- ADVATE - subjects 6 to <12 years of age Per Protocol Analysis Set
    Number of subjects
    66
    31
    66
    31
    31
    31
    14
    17
    14
    17
    65
    Age categorical
    Units: Subjects
        85 years and over
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
        From 65-84 years
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
        Adults (18-64 years)
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
        Adolescents (12-17 years)
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
        Children (2-11 years)
    64
    30
    64
    30
    30
    30
    13
    17
    13
    17
    63
        Infants and toddlers (28 days-23 months)
    2
    1
    2
    1
    1
    1
    1
    0
    1
    0
    2
        Newborns (0-27 days)
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
        Preterm newborn infants (gestational age < 37 wks)
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
        In utero
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    6 ( 2.7 )
    5.8 ( 2.61 )
    6 ( 2.7 )
    5.8 ( 2.61 )
    5.8 ( 2.61 )
    5.8 ( 2.61 )
    3.7 ( 1.27 )
    7.6 ( 2.06 )
    3.7 ( 1.27 )
    7.6 ( 2.06 )
    6 ( 2.72 )
    Gender categorical
    Units:
        Female
    1
    1
    1
    1
    1
    1
    0
    1
    0
    1
    1
        Male
    65
    30
    65
    30
    30
    30
    14
    16
    14
    16
    64

    End points

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    End points reporting groups
    Reporting group title
    Pediatric subjects <6 years of age
    Reporting group description
    		 Subjects were to be treated with prophylactic infusions of BAX 855 at a dose of 50 ±10 IU/kg administered twice weekly (at 3- and 4-day intervals or 3.5-day intervals) for a minimum of 50 exposure days to BAX855 or approximately 6 months, whichever occurred last.

    Reporting group title
    Pediatric subjects 6 to <12 years of age
    Reporting group description
    		 Subjects were to be treated with prophylactic infusions of BAX 855 at a dose of 50 ±10 IU/kg administered twice weekly (at 3- and 4-day intervals or 3.5-day intervals) for a minimum of 50 exposure days to BAX855 or approximately 6 months, whichever occurred last.

    Subject analysis set title
    Full Analysis Set
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    The full analysis set contains all subjects who received at least one dose of BAX 855 in either the PK part of the study or the prophylaxis part of the study. All efficacy analyses were performed on the full analysis set (FAS). The FAS is the primary analysis set.

    Subject analysis set title
    ADVATE Safety Analysis Set
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    The ADVATE safety analysis set contains all subjects who received at least one dose of ADVATE in the PK part of the study.

    Subject analysis set title
    BAX 855 Safety Analysis Set
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    The BAX 855 safety analysis set contains all subjects who received at least one dose of BAX 855.

    Subject analysis set title
    Pharmacokinetic (PK) Full Analysis Set
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    The pharmacokinetic full analysis set (PKFAS) contains all subjects who had been treated with at least 1 dose of ADVATE (60 ±5 IU/kg) and 1 dose of BAX 855 (60 ±5 IU/kg) in the PK part of the study (prior to prophylactic treatment) and had at least 1 PK concentration available for population PK and non-compartmental analysis.

    Subject analysis set title
    Pharmacokinetic (PK) Analysis Set - ADVATE
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    This analysis set contains all subjects who had been treated with at least 1 dose of ADVATE (60 ±5 IU/kg) and 1 dose of BAX 855 (60 ±5 IU/kg) in the PK part of the study (prior to prophylactic treatment) and had at least 1 PK concentration available for population PK and non-compartmental analysis.

    Subject analysis set title
    Pharmacokinetic (PK) Analysis Set - BAX 855
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    This analysis set contains all subjects who had been treated with at least 1 dose of ADVATE (60 ±5 IU/kg) and 1 dose of BAX 855 (60 ±5 IU/kg) in the PK part of the study (prior to prophylactic treatment) and had at least 1 PK concentration available for population PK and non-compartmental analysis.

    Subject analysis set title
    PK Analysis Set - BAX 855 - subjects <6 years of age
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    This analysis set contains all subjects <6 years of age who had been treated with at least 1 dose of ADVATE (60 ±5 IU/kg) and 1 dose of BAX 855 (60 ±5 IU/kg) in the PK part of the study (prior to prophylactic treatment) and had at least 1 PK concentration available for population PK and non-compartmental analysis.

    Subject analysis set title
    PK Analysis Set - BAX 855 - subjects 6 to <12 years of age
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    This analysis set contains all subjects 6 to <12 years of age who had been treated with at least 1 dose of ADVATE (60 ±5 IU/kg) and 1 dose of BAX 855 (60 ±5 IU/kg) in the PK part of the study (prior to prophylactic treatment) and had at least 1 PK concentration available for population PK and non-compartmental analysis.

    Subject analysis set title
    PK Analysis Set - ADVATE - subjects <6 years of age
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    This analysis set contains all subjects <6 years of age who had been treated with at least 1 dose of ADVATE (60 ±5 IU/kg) and 1 dose of BAX 855 (60 ±5 IU/kg) in the PK part of the study (prior to prophylactic treatment) and had at least 1 PK concentration available for population PK and non-compartmental analysis.

    Subject analysis set title
    PK Analysis Set- ADVATE - subjects 6 to <12 years of age
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    This analysis set contains all subjects 6 to <12 years of age who had been treated with at least 1 dose of ADVATE (60 ±5 IU/kg) and 1 dose of BAX 855 (60 ±5 IU/kg) in the PK part of the study (prior to prophylactic treatment) and had at least 1 PK concentration available for population PK and non-compartmental analysis.

    Subject analysis set title
    Per Protocol Analysis Set
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    This analysis set contains all subjects in the Full Analysis Set (FAS) who fulfilled the following compliance criteria for prophylactic treatment: -) Infusion interval of 5 or more days did not occur more than five times in the observation period, -) the dose per infusion was below 40 IU/kg in no more than 10% of the infusions in the observation period, -) the dose per infusion was above 80 IU/kg in no more than 10% of the infusions in the observation period. The Per Protocol Analysis Set was a supportive analysis set.

    Primary: Incidence of FVIII inhibitory antibodies (≥0.6 Bethesda units [BU] using the Nijmegen modification of the Bethesda assay)

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    End point title
    		 Incidence of FVIII inhibitory antibodies (≥0.6 Bethesda units [BU] using the Nijmegen modification of the Bethesda assay) [1]
    End point description
    Inhibitory antibodies were measured by the Nijmegen modification of the Bethesda assay at each study visit. The number of subjects included in the analysis was the sum of subjects that developed inhibitory antibodies to FVIII and the number of subjects that did not develop inhibitory antibodies to FVIII, had 50 or more exposure days and had a FVIII inhibitory test result after 50 exposure days. Per protocol, descriptive statistics were collected for this endpoint.
    End point type
    Primary
    End point timeframe
    Throughout the study period (1 year), approximately 6 months per subject
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Per protocol, only descriptive statistics were collected for this endpoint.
    End point values
    		 Pediatric subjects <6 years of age Pediatric subjects 6 to <12 years of age Full Analysis Set
    Number of subjects analysed
    29 [2]
    28 [3]
    57 [4]
    Units: subjects
    0
    0
    0
    Notes
    [2] - 29 subjects <6 years of age included in this analysis
    [3] - 28 subjects 6 to <12 years of age included in this analysis
    [4] - 57 subjects included in this analysis
    No statistical analyses for this end point

    Secondary: Annualized bleeding rate

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    End point title
    		 Annualized bleeding rate
    End point description
    The annualized bleeding rate (ABR) was assessed based upon each individual bleeding episode, spontaneous or traumatic, recorded in the subject´s diary and/or recorded in the physician/nurse/study site notes. In the Full Analysis Set (n=66), the point estimate for the overall mean ABR was 3.04 (95% confidence interval [CI] 2.208 – 4.186). Point estimates for the mean ABR were 2.37 (95% CI 1.486 – 3.778) in subjects <6 years of age (n=32) and 3.75 (95% CI 2.429 –5.781) in subjects 6 to <12 years of age (n=34). Point estimates for the mean annualized spontaneous bleeding rate were 1.164 (95% CI 0.740 - 1.832) in the FAS (n=66), 1.018 (95% CI 0.523 - 1.978) in the younger (n=32) and 1.316 (95% CI 0.710 - 2.438) in the older (n=34) age cohort. Point estimates for the mean annualized rate of joint bleeds were 1.103 (95% CI 0.637 - 1.910) in the FAS (n=66), 0.862 (95% CI 0.381 - 1.946) in the younger (n=32) and 1.355 (95% CI 0.648 - 2.833) in the older age cohort (n=34).
    End point type
    Secondary
    End point timeframe
    During prophylactic treatment: approx. 6 months per subject
    End point values
    		 Pediatric subjects <6 years of age Pediatric subjects 6 to <12 years of age Full Analysis Set
    Number of subjects analysed
    32
    34
    66
    Units: Annualized bleeding rate
    arithmetic mean (standard deviation)
        Overall annualized bleeding rate
    2.4 ( 3.508 )
    4.76 ( 9.046 )
    3.61 ( 6.988 )
        Annualized rate of joint bleeds
    0.87 ( 2.622 )
    1.36 ( 2.59 )
    1.12 ( 2.597 )
        Annualized rate of target joint bleeds
    0.06 ( 0.354 )
    0.36 ( 1.146 )
    0.21 ( 0.865 )
        Annualized rate of non-target joint bleeds
    0.81 ( 2.618 )
    1 ( 2.253 )
    0.91 ( 2.42 )
        Annualized spontaneous bleeding rate
    1.05 ( 2.048 )
    1.31 ( 2.467 )
    1.18 ( 2.26 )
        Annualized rate of injury-related bleeds
    1.63 ( 2.308 )
    3.71 ( 8.678 )
    2.71 ( 6.471 )
    No statistical analyses for this end point

    Secondary: Consumption of BAX 855: number of prophylactic infusions per month and per year (annualized) per subject

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    End point title
    		 Consumption of BAX 855: number of prophylactic infusions per month and per year (annualized) per subject
    End point description
    End point type
    Secondary
    End point timeframe
    During prophylactic treatment: approx. 6 months per subject
    End point values
    		 Pediatric subjects <6 years of age Pediatric subjects 6 to <12 years of age BAX 855 Safety Analysis Set
    Number of subjects analysed
    32
    34
    66
    Units: Prophylactic infusions
    arithmetic mean (standard deviation)
        Per month
    8.07 ( 0.245 )
    7.72 ( 0.974 )
    7.89 ( 0.736 )
        Per year
    96.82 ( 2.942 )
    92.61 ( 11.693 )
    94.65 ( 8.834 )
    No statistical analyses for this end point

    Secondary: Consumption of BAX 855: weight-adjusted dose of prophylactic infusions per month and per year (annualized) per subject

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    End point title
    		 Consumption of BAX 855: weight-adjusted dose of prophylactic infusions per month and per year (annualized) per subject
    End point description
    End point type
    Secondary
    End point timeframe
    During prophylactic treatment: approx. 6 months per subject
    End point values
    		 Pediatric subjects <6 years of age Pediatric subjects 6 to <12 years of age BAX 855 Safety Analysis Set
    Number of subjects analysed
    32
    34
    66
    Units: IU/kg
    arithmetic mean (standard deviation)
        Per month
    458.93 ( 46.161 )
    455.86 ( 76.101 )
    457.35 ( 62.919 )
        Per year
    5507.2 ( 553.931 )
    5470.32 ( 913.21 )
    5488.2 ( 755.033 )
    No statistical analyses for this end point

    Secondary: Consumption of BAX 855: number of infusions per bleeding episode

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    End point title
    		 Consumption of BAX 855: number of infusions per bleeding episode
    End point description
    Of 66 subjects in the BAX855 Safety Analysis Set, 34 experienced bleeding episodes which were treated, 15 in the <6 year age group, 19 in the 6 to <12 year age group.
    End point type
    Secondary
    End point timeframe
    During prophylactic treatment: approx. 6 months per subject
    End point values
    		 Pediatric subjects <6 years of age Pediatric subjects 6 to <12 years of age BAX 855 Safety Analysis Set
    Number of subjects analysed
    15
    19
    34
    Units: infusions
        arithmetic mean (standard deviation)
    1.17 ( 0.362 )
    1.4 ( 0.655 )
    1.3 ( 0.551 )
    No statistical analyses for this end point

    Secondary: Consumption of BAX 855: weight-adjusted dose per bleeding episode

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    End point title
    		 Consumption of BAX 855: weight-adjusted dose per bleeding episode
    End point description
    Of 66 subjects in the BAX855 Safety Analysis Set, 34 experienced bleeding episodes which were treated, 15 in the <6 year age group, 19 in the 6 to <12 year age group.
    End point type
    Secondary
    End point timeframe
    During prophylactic treatment: approx. 6 months per subject
    End point values
    		 Pediatric subjects <6 years of age Pediatric subjects 6 to <12 years of age BAX 855 Safety Analysis Set
    Number of subjects analysed
    15
    19
    34
    Units: IU/kg
        arithmetic mean (standard deviation)
    52.21 ( 16.681 )
    62.31 ( 38.764 )
    57.85 ( 31.041 )
    No statistical analyses for this end point

    Secondary: Hemostatic efficacy at resolution of bleed

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    End point title
    		 Hemostatic efficacy at resolution of bleed
    End point description
    A total of 70 treated bleeding episodes occurred in 34 subjects: 25 treated bleeding episodes in 15 subjects <6 years of age and 45 treated bleeding episodes in 19 subjects 6 to <12 years of age. Rating Scale for Treatment of Bleeding Episodes (BEs) (4-point ordinal scale): EXCELLENT: Full relief of pain and cessation of objective signs of bleeding (eg, swelling, tenderness, and decreased range of motion in the case of musculoskeletal hemorrhage) after a single infusion. No additional infusion required for the control of bleeding. Administration of further infusions to maintain hemostasis did not affect this scoring. GOOD: Definite pain relief and/or improvement in signs of bleeding after a single infusion. 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 single infusion. Required more than 1 infusion for complete resolution. NONE: No improvement or condition worsens.
    End point type
    Secondary
    End point timeframe
    During prophylactic treatment: approx. 6 months per subject
    End point values
    		 Pediatric subjects <6 years of age Pediatric subjects 6 to <12 years of age Full Analysis Set
    Number of subjects analysed
    15 [5]
    19 [6]
    34 [7]
    Units: bleeding episodes
        Excellent
    15
    19
    34
        Good
    9
    20
    29
        Fair
    1
    3
    4
        Not reported
    0
    3
    3
    Notes
    [5] - 15 subjects <6 years of age had 25 bleeding episodes which were treated.
    [6] - 19 subjects 6 to <12 years of age had 45 bleeding episodes which were treated.
    [7] - A total of 70 treated bleeding episodes occurred in 34 of 66 subjects in the FAS.
    No statistical analyses for this end point

    Secondary: Serious adverse events (SAEs) possibly or probably related to BAX 855

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    End point title
    		 Serious adverse events (SAEs) possibly or probably related to BAX 855
    End point description
    End point type
    Secondary
    End point timeframe
    Throughout the study period (1 year), approximately 6 months per subject
    End point values
    		 Pediatric subjects <6 years of age Pediatric subjects 6 to <12 years of age BAX 855 Safety Analysis Set
    Number of subjects analysed
    32
    34
    66
    Units: subjects
        Investigator assessment
    0
    0
    0
        Sponsor assessment
    0
    0
    0
    No statistical analyses for this end point

    Secondary: Non-serious AEs possibly or probably related to BAX 855

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    End point title
    		 Non-serious AEs possibly or probably related to BAX 855
    End point description
    End point type
    Secondary
    End point timeframe
    Throughout the study period (1 year), approximately 6 months per subject
    End point values
    		 Pediatric subjects <6 years of age Pediatric subjects 6 to <12 years of age BAX 855 Safety Analysis Set
    Number of subjects analysed
    32
    34
    66
    Units: subjects
        Investigator assessment
    1
    0
    1
        Sponsor assessment
    0
    0
    0
    No statistical analyses for this end point

    Secondary: Clinically significant changes in vital signs

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    End point title
    		 Clinically significant changes in vital signs
    End point description
    Vital signs: body temperature, respiratory rate (breaths/min), pulse rate (beats/min), and systolic and diastolic blood pressure (mmHg). For each abnormal vital sign value, the investigator had to decide if he/she deemed this to be an AE.
    End point type
    Secondary
    End point timeframe
    Throughout the study period (1 year), approximately 6 months per subject
    End point values
    		 Pediatric subjects <6 years of age Pediatric subjects 6 to <12 years of age BAX 855 Safety Analysis Set
    Number of subjects analysed
    32
    34
    66
    Units: subjects
    0
    0
    0
    No statistical analyses for this end point

    Secondary: Clinically significant changes in clinical laboratory parameters (hematology, clinical chemistry, lipids)

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    End point title
    		 Clinically significant changes in clinical laboratory parameters (hematology, clinical chemistry, lipids)
    End point description
    The HEMATOLOGY PANEL consisted of complete blood count: hemoglobin, hematocrit, erythrocytes (ie, red blood cell count), leukocytes (ie, white blood cell count) with differential (ie, basophils, eosinophils, lymphocytes, monocytes, and neutrophils), mean corpuscular volume, mean corpuscular hemoglobin concentration, and platelet count. The CLINICAL CHEMISTRY PANEL consisted of sodium, potassium, chloride, bicarbonate, total protein, albumin, ALT, aspartate aminotransferase (AST), total bilirubin, alkaline phosphatase, blood urea nitrogen, creatinine, and glucose. The LIPID PANEL consisted of cholesterol, very low density lipoprotein, low density lipoprotein, high density lipoprotein, and triglycerides.
    End point type
    Secondary
    End point timeframe
    Throughout the study period (1 year), approximately 6 months per subject
    End point values
    		 Pediatric subjects <6 years of age Pediatric subjects 6 to <12 years of age BAX 855 Safety Analysis Set
    Number of subjects analysed
    32
    34
    66
    Units: subjects
        Hematology panel
    1
    0
    1
        Clinical chemistry panel
    1
    0
    1
        Lipid panel
    0
    0
    0
    No statistical analyses for this end point

    Secondary: Positive post-baseline binding antibodies to FVIII, PEG-FVIII, polyethylene glycol (PEG), and Chinese hamster ovary (CHO) proteins

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    End point title
    		 Positive post-baseline binding antibodies to FVIII, PEG-FVIII, polyethylene glycol (PEG), and Chinese hamster ovary (CHO) proteins
    End point description
    Binding antibodies to FVIII and PEG-FVIII, as well as to PEG, were measured using enzyme-linked immunosorbent assay (ELISA). Both immunoglobulin G (IgG) and immunoglobulin M (IgM) binding antibodies for FVIII, BAX 855, and PEG were routinely tested. Based on the variability of these tests, only samples with titers ≥1:80 could be confirmed and were evaluated as positive. Furthermore, only increases of more than 2 titer steps between pre- and post-treatment samples were considered positive for treatment-related antibody development.
    End point type
    Secondary
    End point timeframe
    Throughout the study period (1 year), approximately 6 months per subject
    End point values
    		 Pediatric subjects <6 years of age Pediatric subjects 6 to <12 years of age BAX 855 Safety Analysis Set
    Number of subjects analysed
    32
    33 [8]
    65 [9]
    Units: subjects
        Positive binding IgG antibodies to FVIII
    0
    0
    0
        Positive binding IgM antibodies to FVIII
    0
    0
    0
        Positive binding IgG antibodies to PEG-FVIII
    3
    4
    7
        Positive binding IgM antibodies to PEG-FVIII
    0
    0
    0
        Positive binding IgG antibodies to PEG
    0
    0
    0
        Positive binding IgM antibodies to PEG
    0
    0
    0
        Positive binding Ig antibodies to CHO
    0
    0
    0
    Notes
    [8] - For 1 of 34 subjects in the 6 to <12 year age group of the SAS, no data are available.
    [9] - For 1 of 66 subjects in the SAS (6 to <12 year age group), no data are available.
    No statistical analyses for this end point

    Secondary: Pharmacokinetics (PK): Area under the plasma concentration versus time curve from 0 to ∞ hours post-infusion (AUC0-∞)

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    End point title
    		 Pharmacokinetics (PK): Area under the plasma concentration versus time curve from 0 to ∞ hours post-infusion (AUC0-∞)
    End point description
    The first infusion given for PK assessment was ADVATE and the second infusion was BAX 855. All subjects undergoing PK assessment were to have a 72-hour washout period prior to administration of ADVATE or BAX 855. The timing of the infusion (morning or afternoon) and the timing of the second and third post-infusion blood draws were to be determined at randomization. All subjects had samples drawn at 15-30 minutes post-infusion. The second post-infusion sample was either 7 hours (if am PK dose) or 4 hours post infusion (if pm PK dose), or on Day 1 in the morning or Day 1 in the afternoon. The third post-infusion sample was either on Day 2, Day 3 or Day 4. A nonlinear mixed effects model approach (population PK) was implemented to analyze PK data.
    End point type
    Secondary
    End point timeframe
    (1) up to 30 minutes pre-infusion; (2) up to 30 min post-infusion, (3) Day 0 either 4 or 7 hours post infusion or Day 1; (4) Either Day 2, Day 3, or Day 4
    End point values
    		 Pharmacokinetic (PK) Analysis Set - ADVATE Pharmacokinetic (PK) Analysis Set - BAX 855 PK Analysis Set - BAX 855 - subjects <6 years of age PK Analysis Set - BAX 855 - subjects 6 to <12 years of age PK Analysis Set - ADVATE - subjects <6 years of age PK Analysis Set- ADVATE - subjects 6 to <12 years of age
    Number of subjects analysed
    31
    31
    14
    17
    14
    17
    Units: IU•hr/L
    arithmetic mean (standard deviation)
        One stage clotting assay
    14200 ( 2420 )
    19800 ( 6160 )
    19500 ( 7580 )
    20100 ( 4930 )
    14000 ( 3070 )
    14400 ( 1800 )
        Chromogenic assay
    14400 ( 4040 )
    22300 ( 11200 )
    21900 ( 15900 )
    22600 ( 5140 )
    11600 ( 3070 )
    16600 ( 3290 )
    No statistical analyses for this end point

    Secondary: Pharmacokinetics (PK): Mean residence time (MRT)

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    End point title
    		 Pharmacokinetics (PK): Mean residence time (MRT)
    End point description
    The first infusion given for PK assessment was ADVATE and the second infusion was BAX 855. All subjects undergoing PK assessment were to have a 72-hour washout period prior to administration of ADVATE or BAX 855. The timing of the infusion (morning or afternoon) and the timing of the second and third post-infusion blood draws were to be determined at randomization. All subjects had samples drawn at 15-30 minutes post-infusion. The second post-infusion sample was either 7 hours (if am PK dose) or 4 hours post infusion (if pm PK dose), or on Day 1 in the morning or Day 1 in the afternoon. The third post-infusion sample was either on Day 2, Day 3 or Day 4. A nonlinear mixed effects model approach (population PK) was implemented to analyze PK data.
    End point type
    Secondary
    End point timeframe
    (1) up to 30 minutes pre-infusion; (2) up to 30 min post-infusion, (3) Day 0 either 4 or 7 hours post infusion or Day 1; (4) Either Day 2, Day 3, or Day 4
    End point values
    		 Pharmacokinetic (PK) Analysis Set - ADVATE Pharmacokinetic (PK) Analysis Set - BAX 855 PK Analysis Set - BAX 855 - subjects <6 years of age PK Analysis Set - BAX 855 - subjects 6 to <12 years of age PK Analysis Set - ADVATE - subjects <6 years of age PK Analysis Set- ADVATE - subjects 6 to <12 years of age
    Number of subjects analysed
    31
    31
    14
    17
    14
    17
    Units: hour (hr)
    arithmetic mean (standard deviation)
        One stage clotting assay
    13.8 ( 3.27 )
    17.5 ( 2.93 )
    17 ( 3.51 )
    17.8 ( 2.4 )
    13.3 ( 3.95 )
    14.2 ( 2.64 )
        Chromogenic assay
    12 ( 1.93 )
    17.9 ( 8.76 )
    18.7 ( 12.6 )
    17.2 ( 3.72 )
    12.5 ( 2.52 )
    11.6 ( 1.2 )
    No statistical analyses for this end point

    Secondary: Pharmacokinetics (PK): Clearance (CL)

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    End point title
    		 Pharmacokinetics (PK): Clearance (CL)
    End point description
    The first infusion given for PK assessment was ADVATE and the second infusion was BAX 855. All subjects undergoing PK assessment were to have a 72-hour washout period prior to administration of ADVATE or BAX 855. The timing of the infusion (morning or afternoon) and the timing of the second and third post-infusion blood draws were to be determined at randomization. All subjects had samples drawn at 15-30 minutes post-infusion. The second post-infusion sample was either 7 hours (if am PK dose) or 4 hours post infusion (if pm PK dose), or on Day 1 in the morning or Day 1 in the afternoon. The third post-infusion sample was either on Day 2, Day 3 or Day 4. A nonlinear mixed effects model approach (population PK) was implemented to analyze PK data.
    End point type
    Secondary
    End point timeframe
    (1) up to 30 minutes pre-infusion; (2) up to 30 min post-infusion, (3) Day 0 either 4 or 7 hours post infusion or Day 1; (4) Either Day 2, Day 3, or Day 4
    End point values
    		 Pharmacokinetic (PK) Analysis Set - ADVATE Pharmacokinetic (PK) Analysis Set - BAX 855 PK Analysis Set - BAX 855 - subjects <6 years of age PK Analysis Set - BAX 855 - subjects 6 to <12 years of age PK Analysis Set - ADVATE - subjects <6 years of age PK Analysis Set- ADVATE - subjects 6 to <12 years of age
    Number of subjects analysed
    31
    31
    14
    17
    14
    17
    Units: L/hr
    arithmetic mean (standard deviation)
        One stage clotting assay
    0.103 ( 0.0398 )
    0.77 ( 0.0286 )
    0.0596 ( 0.019 )
    0.0913 ( 0.0276 )
    0.0775 ( 0.0132 )
    0.125 ( 0.042 )
        Chromogenic assay
    0.0994 ( 0.011 )
    0.0704 ( 0.0246 )
    0.0574 ( 0.0174 )
    0.0812 ( 0.0248 )
    0.0933 ( 0.0106 )
    0.104 ( 0.00875 )
    No statistical analyses for this end point

    Secondary: Pharmacokinetics (PK): Incremental recovery (IR)

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    End point title
    		 Pharmacokinetics (PK): Incremental recovery (IR)
    End point description
    The first infusion given for PK assessment was ADVATE and the second infusion was BAX 855. All subjects undergoing PK assessment were to have a 72-hour washout period prior to administration of ADVATE or BAX 855. The timing of the infusion (morning or afternoon) and the timing of the second and third post-infusion blood draws were to be determined at randomization. All subjects had samples drawn at 15-30 minutes post-infusion. The second post-infusion sample was either 7 hours (if am PK dose) or 4 hours post infusion (if pm PK dose), or on Day 1 in the morning or Day 1 in the afternoon. The third post-infusion sample was either on Day 2, Day 3 or Day 4. A nonlinear mixed effects model approach (population PK) was implemented to analyze PK data.
    End point type
    Secondary
    End point timeframe
    (1) up to 30 minutes pre-infusion; (2) up to 30 min post-infusion, (3) Day 0 either 4 or 7 hours post infusion or Day 1; (4) Either Day 2, Day 3, or Day 4
    End point values
    		 Pharmacokinetic (PK) Analysis Set - ADVATE Pharmacokinetic (PK) Analysis Set - BAX 855 PK Analysis Set - BAX 855 - subjects <6 years of age PK Analysis Set - BAX 855 - subjects 6 to <12 years of age PK Analysis Set - ADVATE - subjects <6 years of age PK Analysis Set- ADVATE - subjects 6 to <12 years of age
    Number of subjects analysed
    31
    31
    14
    17
    14
    17
    Units: IU/dL : IU/kg
    arithmetic mean (standard deviation)
        One stage clotting assay
    1.8636 ( 0.53481 )
    1.9101 ( 0.47371 )
    1.8809 ( 0.48894 )
    1.9342 ( 0.47451 )
    1.8563 ( 0.76004 )
    1.8696 ( 0.25856 )
        Chromogenic assay
    1.9065 ( 0.33879 )
    2.0402 ( 0.36355 )
    1.8813 ( 0.27069 )
    2.171 ( 0.38472 )
    1.7374 ( 0.2911 )
    2.0458 ( 0.31739 )
    No statistical analyses for this end point

    Secondary: Pharmacokinetics (PK): Incremental recovery (IR) of BAX 855 over time - one stage clotting assay

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    End point title
    		 Pharmacokinetics (PK): Incremental recovery (IR) of BAX 855 over time - one stage clotting assay
    End point description
    Pre- and post-infusion levels of Factor VIII (FVIII) following infusion of BAX 855 were used to determine IR.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 5 (or 10-15 EDs, whichever occurs last), Week 12, and Month 6 (Completion/Termination)
    End point values
    		 Pediatric subjects <6 years of age Pediatric subjects 6 to <12 years of age Full Analysis Set
    Number of subjects analysed
    27 [10]
    30 [11]
    57 [12]
    Units: IU/dL : IU/kg
    arithmetic mean (standard deviation)
        Baseline
    1.6889 ( 0.2761 )
    1.7843 ( 0.35942 )
    1.7381 ( 0.32017 )
        Week 5 (or after 10-15 EDs)
    1.8952 ( 0.55483 )
    1.8661 ( 0.49785 )
    1.8799 ( 0.52105 )
        Week 12
    1.6818 ( 0.23069 )
    1.9212 ( 0.42496 )
    1.812 ( 0.36738 )
        Month 6 (Completion/Termination)
    1.5801 ( 0.31568 )
    1.712 ( 0.36588 )
    1.6472 ( 0.34546 )
    Notes
    [10] - Baseline: n=15, Week 5: n=27, Week 12: n=26, Month 6: n=27
    [11] - Baseline: n=16, Week 5: n=30, Week 12: n=31, Month 6: n=28
    [12] - Baseline: n=31, Week 5: n=57, Week 12: n=57, Month 6: n=55
    No statistical analyses for this end point

    Secondary: Pharmacokinetics (PK): Incremental recovery (IR) of BAX 855 over time - chromogenic assay

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    End point title
    		 Pharmacokinetics (PK): Incremental recovery (IR) of BAX 855 over time - chromogenic assay
    End point description
    Pre- and post-infusion levels of Factor VIII (FVIII) following infusion of BAX 855 were used to determine IR.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 5 (or 10-15 EDs, whichever occurs last), Week 12, and Month 6 (Completion/Termination)
    End point values
    		 Pediatric subjects <6 years of age Pediatric subjects 6 to <12 years of age Full Analysis Set
    Number of subjects analysed
    27 [13]
    30 [14]
    57 [15]
    Units: IU/dL : IU/kg
    arithmetic mean (standard deviation)
        Baseline
    1.7675 ( 0.34998 )
    1.9334 ( 0.3 )
    1.8532 ( 0.33055 )
        Week 5 (or after 10-15 EDs)
    1.9273 ( 0.324 )
    1.996 ( 0.39258 )
    1.9635 ( 0.36021 )
        Week 12
    1.8794 ( 0.24281 )
    1.9869 ( 0.423 )
    1.9379 ( 0.35368 )
        Month 6 (Completion/Termination)
    1.8359 ( 0.29188 )
    2.0659 ( 0.45723 )
    1.953 ( 0.39876 )
    Notes
    [13] - Baseline: n=15, Week 5: n=27, Week 12: n=26, Month 6: n=27
    [14] - Baseline: n=16, Week 5: n=30, Week 12: n=31, Month 6: n=28
    [15] - Baseline: n=31, Week 5: n=57, Week 12: n=57, Month 6: n=55
    No statistical analyses for this end point

    Secondary: Pharmacokinetics (PK): Plasma half-life (T 1/2)

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    End point title
    		 Pharmacokinetics (PK): Plasma half-life (T 1/2)
    End point description
    The first infusion given for PK assessment was ADVATE and the second infusion was BAX 855. All subjects undergoing PK assessment were to have a 72-hour washout period prior to administration of ADVATE or BAX 855. The timing of the infusion (morning or afternoon) and the timing of the second and third post-infusion blood draws were to be determined at randomization. All subjects had samples drawn at 15-30 minutes post-infusion. The second post-infusion sample was either 7 hours (if am PK dose) or 4 hours post infusion (if pm PK dose), or on Day 1 in the morning or Day 1 in the afternoon. The third post-infusion sample was either on Day 2, Day 3 or Day 4. A nonlinear mixed effects model approach (population PK) was implemented to analyze PK data.
    End point type
    Secondary
    End point timeframe
    (1) up to 30 minutes pre-infusion; (2) up to 30 min post-infusion, (3) Day 0 either 4 or 7 hours post infusion or Day 1; (4) Either Day 2, Day 3, or Day 4
    End point values
    		 Pharmacokinetic (PK) Analysis Set - ADVATE Pharmacokinetic (PK) Analysis Set - BAX 855 PK Analysis Set - BAX 855 - subjects <6 years of age PK Analysis Set - BAX 855 - subjects 6 to <12 years of age PK Analysis Set - ADVATE - subjects <6 years of age PK Analysis Set- ADVATE - subjects 6 to <12 years of age
    Number of subjects analysed
    31
    31
    14
    17
    14
    17
    Units: hr
    arithmetic mean (standard deviation)
        One stage clotting assay
    9.56 ( 2.26 )
    12.1 ( 2.03 )
    11.8 ( 2.43 )
    12.4 ( 1.67 )
    9.24 ( 2.74 )
    9.82 ( 1.83 )
        Chromogenic assay
    8.33 ( 1.34 )
    12.4 ( 6.07 )
    13 ( 8.74 )
    11.9 ( 2.58 )
    8.68 ( 1.75 )
    8.04 ( 0.83 )
    No statistical analyses for this end point

    Secondary: Pharmacokinetics (PK): Volume of distribution at steady state (Vss)

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    End point title
    		 Pharmacokinetics (PK): Volume of distribution at steady state (Vss)
    End point description
    The first infusion given for PK assessment was ADVATE and the second infusion was BAX 855. All subjects undergoing PK assessment were to have a 72-hour washout period prior to administration of ADVATE or BAX 855. The timing of the infusion (morning or afternoon) and the timing of the second and third post-infusion blood draws were to be determined at randomization. All subjects had samples drawn at 15-30 minutes post-infusion. The second post-infusion sample was either 7 hours (if am PK dose) or 4 hours post infusion (if pm PK dose), or on Day 1 in the morning or Day 1 in the afternoon. The third post-infusion sample was either on Day 2, Day 3 or Day 4. A nonlinear mixed effects model approach (population PK) was implemented to analyze PK data.
    End point type
    Secondary
    End point timeframe
    (1) up to 30 minutes pre-infusion; (2) up to 30 min post-infusion, (3) Day 0 either 4 or 7 hours post infusion or Day 1; (4) Either Day 2, Day 3, or Day 4
    End point values
    		 Pharmacokinetic (PK) Analysis Set - ADVATE Pharmacokinetic (PK) Analysis Set - BAX 855 PK Analysis Set - BAX 855 - subjects <6 years of age PK Analysis Set - BAX 855 - subjects 6 to <12 years of age PK Analysis Set - ADVATE - subjects <6 years of age PK Analysis Set- ADVATE - subjects 6 to <12 years of age
    Number of subjects analysed
    31
    31
    14
    17
    14
    17
    Units: litre (L)
    arithmetic mean (standard deviation)
        One stage clotting assay
    1.39 ( 0.47 )
    1.31 ( 0.427 )
    0.97 ( 0.23 )
    1.59 ( 0.343 )
    1.02 ( 0.302 )
    1.69 ( 0.35 )
        Chromogenic assay
    1.18 ( 0.0857 )
    1.14 ( 0.285 )
    0.907 ( 0.124 )
    1.33 ( 0.233 )
    1.14 ( 0.107 )
    1.2 ( 0.0548 )
    No statistical analyses for this end point

    Post-hoc: Pharmacokinetics (PK): Plasma half-life ratio of BAX 855 to ADVATE

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    End point title
    		 Pharmacokinetics (PK): Plasma half-life ratio of BAX 855 to ADVATE
    End point description
    This is a descriptive summary of the ratio of plasma half-life in the same subject for BAX 855 compared to ADVATE based on the final covariate model (first observation tabulation). In the one-stage clotting assay, the mean half-life of BAX 855 was 1.30 times longer compared to ADVATE. In the chromogenic assay, the mean half-life of BAX 855 was 1.50 times longer compared to ADVATE.
    End point type
    Post-hoc
    End point timeframe
    (1) up to 30 minutes pre-infusion; (2) up to 30 min post-infusion, (3) Day 0 either 4 or 7 hours post infusion or Day 1; (4) Either Day 2, Day 3, or Day 4
    End point values
    		 Pharmacokinetic (PK) Full Analysis Set
    Number of subjects analysed
    31
    Units: hr
    arithmetic mean (full range (min-max))
        One stage clotting assay
    1.3 (0.944 to 2)
        Chromogenic assay
    1.5 (0.894 to 4.81)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Throughout the study period (1 year), approximately 6 months per subject
    Adverse event reporting additional description
    AEs were continuously monitored but specifically discussed and reviewed at these time points: pre- and post-PK infusion, at the baseline visit, during prophylactic treatment at these visits: Week 5 (or 10-15 exposure days (EDs)), Week 12, Week 20 (by phone); at the study completion visit at Month 6 or after at least 50 EDs, whichever occurred last
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    18.1
    Reporting groups
    Reporting group title
    BAX 855 Safety Analysis Set (n=66)
    Reporting group description
    		 The BAX 855 safety analysis set contains all subjects who received at least one dose of BAX 855.

    Serious adverse events
    		 BAX 855 Safety Analysis Set (n=66)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    3 / 66 (4.55%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Blood and lymphatic system disorders
    Febrile neutropenia
         subjects affected / exposed
    1 / 66 (1.52%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pancytopenia
         subjects affected / exposed
    1 / 66 (1.52%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    1 / 66 (1.52%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastritis
         subjects affected / exposed
    1 / 66 (1.52%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 BAX 855 Safety Analysis Set (n=66)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    43 / 66 (65.15%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    5 / 66 (7.58%)
         occurrences all number
    7
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    13 / 66 (19.70%)
         occurrences all number
    20
    Gastrointestinal disorders
    Diarrhea
         subjects affected / exposed
    5 / 66 (7.58%)
         occurrences all number
    5
    Vomiting
         subjects affected / exposed
    5 / 66 (7.58%)
         occurrences all number
    6
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    4 / 66 (6.06%)
         occurrences all number
    8
    Infections and infestations
    Upper respiratory tract infection
         subjects affected / exposed
    9 / 66 (13.64%)
         occurrences all number
    9
    Nasopharyngitis
         subjects affected / exposed
    5 / 66 (7.58%)
         occurrences all number
    5

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    18 Nov 2014
    -) The inclusion criterion “The subject has severe hemophilia A (FVIII <1%) as determined by the central laboratory” was amended to: “The subject has severe hemophilia A (FVIII <1%) as determined by the central laboratory, or a historical FVIII level <1% as determined at any local laboratory and/or a FVIII gene mutation consistent with severe hemophilia A”. Reason for change: To avoid potential risk of bleeding episodes in the washout period. -) Text regarding dose adjustment of BAX 855 for prophylactic treatment was amended as follows: Original text: “Based on the Investigator’s clinical evaluation, the dose may be increased for subjects receiving prophylactic treatment at any time to ensure patient safety is adequately managed.” Revised text: “Based on the Investigator’s clinical evaluation, the dose may be increased up to a maximum of 80 IU/kg but not exceeding plasmatic FVIII peak levels of 200% for subjects receiving prophylactic treatment at any time to ensure patient safety is adequately managed.” Reason for change: To provide a maximum dose for prophylactic treatment. -) Addition of the following serious adverse event (SAE) criterion: “Hospitalization for planned port placement or removal is not considered an SAE, however, any hospitalization required for an emergency port removal is considered an SAE”.

    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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