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    Clinical Trial Results:
    BAX326 (recombinant Factor IX): A Phase 1/3 Prospective, Controlled, Multicenter Study Evaluating Pharmacokinetics, Efficacy, Safety, and Immunogenicity in Previously Treated Patients With Severe (FIX level <1%) or Moderately Severe (FIX level ≤ 2%) Hemophilia B

    Due to the EudraCT – Results system being out of service between 31 July 2015 and 12 January 2016, these results have been published in compliance with revised timelines.
    Summary
    EudraCT number
    2009-016720-31
    Trial protocol
    GB   DE   CZ   ES   BG   SE  
    Global end of trial date
    03 May 2012

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

    Trial information

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    Trial identification
    Sponsor protocol code
    250901
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01174446
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Baxalta US Inc.
    Sponsor organisation address
    One Baxter Way, Westlake Village, United States, CA 91362
    Public contact
    Clinical Trial Registries and Results Disclosure, Baxalta US Inc., ClinicalTrialsDisclosure@baxalta.com
    Scientific contact
    Clinical Trial Registries and Results Disclosure, Baxalta US Inc., ClinicalTrialsDisclosure@baxalta.com
    Sponsor organisation name
    Baxalta Innovations GmbH
    Sponsor organisation address
    Industriestrasse 67, Vienna, Austria, 1221
    Public contact
    Clinical Trial Registries and Results Disclosure, Baxalta Innovations GmbH, ClinicalTrialsDisclosure@baxalta.com
    Scientific contact
    Clinical Trial Registries and Results Disclosure, Baxalta Innovations GmbH, ClinicalTrialsDisclosure@baxalta.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    EMEA-001139-PIP01-11
    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
    11 Sep 2012
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    03 May 2012
    Global end of trial reached?
    Yes
    Global end of trial date
    03 May 2012
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The objective of Part 1 of the study was to compare the PK parameters of BAX326 with those of BeneFIX and to determine pharmacokinetic (PK) equivalence. Part 2 of the study was to assess the hemostatic efficacy, safety, and immunogenicity of BAX326 and health-related quality of life in those subjects receiving BAX326 for prevention and treatment of bleeding episodes. The objective of Part 3 was to re-evaluate the PK parameters for BAX326 after a period of 6 months of treatment, in 27 subjects who had accumulated at least 30 exposure days to BAX326, and to compare them with those determined in the same subjects who participated in Part 1.
    Protection of trial subjects
    This study was conducted in accordance with the clinical protocol, the International Conference on Harmonization Guideline for Good Clinical Practice E6 (ICH GCP, April 1996), Title 21 of the US Code of Federal Regulations (US CFR), the European Clinical Trial Directive (2001/20/EC and 2005/28/EC), and applicable national and local regulatory requirements.
    Background therapy
    -
    Evidence for comparator
    BeneFIX was the comparator product used in Part 1 of this study.The objective was to compare the pharmacokinetic (PK) parameters of BAX326 with BeneFIX and to determine PK equivalence. BeneFIX, manufactured by Wyeth (recently acquired by Pfizer), was the only recombinant FIX product available on the hemophilia B market at the time of the study.
    Actual start date of recruitment
    29 Jul 2011
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Poland: 12
    Country: Number of subjects enrolled
    Russian Federation: 12
    Country: Number of subjects enrolled
    Bulgaria: 10
    Country: Number of subjects enrolled
    Ukraine: 8
    Country: Number of subjects enrolled
    Romania: 8
    Country: Number of subjects enrolled
    Colombia: 5
    Country: Number of subjects enrolled
    Japan: 5
    Country: Number of subjects enrolled
    Chile: 4
    Country: Number of subjects enrolled
    United Kingdom: 2
    Country: Number of subjects enrolled
    Czech Republic: 2
    Country: Number of subjects enrolled
    Argentina: 2
    Country: Number of subjects enrolled
    Spain: 1
    Country: Number of subjects enrolled
    Sweden: 1
    Country: Number of subjects enrolled
    Brazil: 1
    Worldwide total number of subjects
    73
    EEA total number of subjects
    36
    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)
    3
    Adults (18-64 years)
    70
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    Enrollment was conducted at 32 clinical sites in Europe, the United States, South America, and Japan.

    Pre-assignment
    Screening details
    86 subjects were enrolled. 13 subjects discontinued before treatment: 7 withdrew consent, 1 was withdrawn due to an adverse event (suicide attempt), 2 were screen failures, and 3 withdrew due to site closure.

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

    Notes
    [1] - The number of subjects reported to be in the pre-assignment period is not consistent with the number starting period 1. It is expected that the number completing the pre-assignment period are also present in the arms in period 1.
    Justification: 86 subjects were enrolled. 13 subjects discontinued before treatment.
    Period 1
    Period 1 title
    Part 1 -Pharmacokinetic Crossover
    Is this the baseline period?
    No
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator
    Blinding implementation details
    Subjects and investigators in study Part 1 were blinded. To maintain the blind, the investigational products were reconstituted by the hospital pharmacist in the hospital pharmacy who was unblinded.

    Arms
    Arm title
    Pharmacokinetic Crossover with BAX326 and BeneFIX
    Arm description
    In Part 1, randomized subjects received 2 infusions each, 1 infusion with BAX326 and 1 infusion with BeneFIX, at a dose of 75 ± 5 IU/kg, each in a randomized order.
    Arm type
    Experimental

    Investigational medicinal product name
    BAX326
    Investigational medicinal product code
    Recombinant factor IX (rFIX)
    Other name
    Rixubis
    Pharmaceutical forms
    Powder and solvent for solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Study Part 1: PK Crossover with BAX326 and BeneFIX, at a dose of 75 ± 5 IU/kg - Study Part 2: Open-label evaluation of prophylaxis and on-demand - Study Part 3: Open-label repeat of PK evaluation (repeat Study Part 1) with BAX326 only in the same study subjects as in Study Part 1

    Investigational medicinal product name
    BeneFIX
    Investigational medicinal product code
    Recombinant factor IX (rFIX)
    Other name
    Pharmaceutical forms
    Powder and solvent for solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Study Part 1: PK Crossover with BAX326 and BeneFIX, at a dose of 75 ± 5 IU/kg

    Number of subjects in period 1
    Pharmacokinetic Crossover with BAX326 and BeneFIX
    Started
    28
    Completed
    28
    Period 2
    Period 2 title
    Part 2 -BAX326 Prophylaxis and On-demand
    Is this the baseline period?
    Yes [2]
    Allocation method
    Not applicable
    Blinding used
    Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Part 2 Only: BAX326 Prophylaxis
    Arm description
    Participants were only in Study Part 2 (i.e., did not participate in Study Parts 1 and 3)
    Arm type
    Experimental

    Investigational medicinal product name
    BAX326
    Investigational medicinal product code
    Recombinant factor IX (rFIX)
    Other name
    Rixubis
    Pharmaceutical forms
    Powder and solvent for solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Study Part 1: PK Crossover with BAX326 and BeneFIX, at a dose of 75 ± 5 IU/kg - Study Part 2: Open-label evaluation of prophylaxis and on-demand - Study Part 3: Open-label repeat of PK evaluation (repeat Study Part 1) with BAX326 only in the same study subjects as in Study Part 1

    Arm title
    Part 2 Only: BAX326 On-Demand
    Arm description
    Participants were only in Study Part 2 (i.e., did not participate in Study Parts 1 and 3)
    Arm type
    Experimental

    Investigational medicinal product name
    BAX326
    Investigational medicinal product code
    Recombinant factor IX (rFIX)
    Other name
    Rixubis
    Pharmaceutical forms
    Powder and solvent for solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Study Part 1: PK Crossover with BAX326 and BeneFIX, at a dose of 75 ± 5 IU/kg - Study Part 2: Open-label evaluation of prophylaxis and on-demand - Study Part 3: Open-label repeat of PK evaluation (repeat Study Part 1) with BAX326 only in the same study subjects as in Study Part 1

    Arm title
    Part 1: PK crossover - Part 2: Prophylaxis - Part 3: PK BAX326
    Arm description
    -Study Part 1: Pharmacokinetic (PK) Crossover with BeneFIX (75 ± 5 IU/kg) and BAX326 (75 ± 5 IU/kg). -Study Part 2: Open-label evaluation of prophylaxis -Study Part 3: Open-label repeat of PK evaluation (repeat Study Part 1) with BAX326 (75 ± 5 IU/kg) only and same study participants as Study Part 1
    Arm type
    Experimental

    Investigational medicinal product name
    BAX326
    Investigational medicinal product code
    Recombinant factor IX (rFIX)
    Other name
    Rixubis
    Pharmaceutical forms
    Powder and solvent for solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Study Part 1: PK Crossover with BAX326 and BeneFIX, at a dose of 75 ± 5 IU/kg - Study Part 2: Open-label evaluation of prophylaxis and on-demand - Study Part 3: Open-label repeat of PK evaluation (repeat Study Part 1) with BAX326 only in the same study subjects as in Study Part 1

    Notes
    [2] - Period 1 is not the baseline period. It is expected that period 1 will be the baseline period.
    Justification: Period 1 corresponds to Part 1 - Pharmacokinetic Crossover. Randomized subjects received 2 infusions each, 1 infusion with BAX326 and 1 infusion with BeneFIX, at a dose of 75 ± 5 IU/kg, each in a randomized order. All subjects from Part 1 transitioned to Part 2, which is the main part of the study and is defined as the baseline period.
    Number of subjects in period 2
    Part 2 Only: BAX326 Prophylaxis Part 2 Only: BAX326 On-Demand Part 1: PK crossover - Part 2: Prophylaxis - Part 3: PK BAX326
    Started
    31
    14
    28
    Completed
    29
    14
    28
    Not completed
    2
    0
    0
         Physician decision
    1
    -
    -
         Consent withdrawn by subject
    1
    -
    -
    Period 3
    Period 3 title
    Part 3 -Pharmacokinetic BAX326 Only
    Is this the baseline period?
    No
    Allocation method
    Randomised - controlled
    Blinding used
    Not blinded

    Arms
    Arm title
    PK BAX326 Only
    Arm description
    Open-label repeat of PK evaluation (repeat Study Part 1) with BAX326 (75 ± 5 IU/kg) only and same study participants as Study Part 1
    Arm type
    Experimental

    Investigational medicinal product name
    BAX326
    Investigational medicinal product code
    Recombinant factor IX (rFIX)
    Other name
    Rixubis
    Pharmaceutical forms
    Powder and solvent for solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Study Part 1: PK Crossover with BAX326 and BeneFIX, at a dose of 75 ± 5 IU/kg - Study Part 2: Open-label evaluation of prophylaxis and on-demand - Study Part 3: Open-label repeat of PK evaluation (repeat Study Part 1) with BAX326 only in the same study subjects as in Study Part 1

    Number of subjects in period 3
    PK BAX326 Only
    Started
    28
    Completed
    25
    Not completed
    3
         Emergency surgery
    1
         Protocol deviation
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Part 2 -BAX326 Prophylaxis and On-demand
    Reporting group description
    Part 2 -BAX326 Prophylaxis and On-demand

    Reporting group values
    Part 2 -BAX326 Prophylaxis and On-demand Total
    Number of subjects
    73
    Age categorical
    Units: Subjects
    Age continuous
    Age continuous description
    Units: years
        arithmetic mean (standard deviation)
    34.5 ± 12.2 -
    Gender categorical
    Gender categorical description
    Units: Subjects
        Female
    0 0
        Male
    73 73
    Region of Enrollment
    Units: Subjects
        Spain
    1 1
        Ukraine
    8 8
        Chile
    4 4
        Russian Federation
    12 12
        Colombia
    5 5
        United Kingdom
    2 2
        Czech Republic
    2 2
        Argentina
    2 2
        Brazil
    1 1
        Poland
    12 12
        Romania
    8 8
        Bulgaria
    10 10
        Japan
    5 5
        Sweden
    1 1
    Subject analysis sets

    Subject analysis set title
    Study Part 1: PK with BAX326
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    In Part 1, randomized subjects received 2 infusions each, 1 infusion with BAX326 and 1 infusion with BeneFIX, at a dose of 75 ± 5 IU/kg, each in a randomized order.

    Subject analysis set title
    Study Part 1: PK with BeneFIX
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    In Part 1, randomized subjects received 2 infusions each, 1 infusion with BAX326 and 1 infusion with BeneFIX, at a dose of 75 ± 5 IU/kg, each in a randomized order.

    Subject analysis set title
    Study Part 2: Prophylactic cohort
    Subject analysis set type
    Full analysis
    Subject analysis set description
    Subjects in the prophylactic cohort were to be treated with a prophylactic regimen of 50 IU/kg BAX326 twice weekly for a period of 6 months or for at least 50 EDs, whichever occurred last. 56 subjects received a minimum of 3 months of prophylactic treatment with BAX326. A further 3 subjects received less than 3 months of prophylactic treatment with BAX326.

    Subject analysis set title
    Study Part 2: On-demand cohort
    Subject analysis set type
    Full analysis
    Subject analysis set description
    Subjects in the on-demand cohort were to receive BAX326 for on-demand treatment.

    Subject analysis set title
    Study Part 3: Repeat PK with BAX326 only
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    In Part 3, subjects who had participated in Part 1 and had a minimum of 30 exposure days to BAX326 in Part 2 underwent a repeat PK with BAX326 only, at a dose of 75 ± 5 IU/kg.

    Subject analysis set title
    Full Analysis Set
    Subject analysis set type
    Full analysis
    Subject analysis set description
    Comprises 73 subjects who were exposed to investigational product.

    Subject analysis sets values
    Study Part 1: PK with BAX326 Study Part 1: PK with BeneFIX Study Part 2: Prophylactic cohort Study Part 2: On-demand cohort Study Part 3: Repeat PK with BAX326 only Full Analysis Set
    Number of subjects
    28
    28
    59
    14
    25
    73
    Age categorical
    Units: Subjects
    Age continuous
    Age continuous description
    Units: years
        arithmetic mean (standard deviation)
    33.9 ± 11.2
    33.9 ± 11.2
    34.7 ± 12
    33.1 ± 12.4
    33.9 ± 11.3
    34.5 ± 12.2
    Gender categorical
    Gender categorical description
    Units: Subjects
        Female
    0
    0
    0
    0
    0
    0
        Male
    28
    28
    59
    14
    25
    73
    Region of Enrollment
    Units: Subjects
        Spain
    0
    0
    1
    0
    0
    1
        Ukraine
    1
    1
    5
    3
    1
    8
        Chile
    0
    0
    4
    0
    0
    4
        Russian Federation
    4
    4
    7
    5
    4
    12
        Colombia
    4
    4
    5
    0
    3
    5
        United Kingdom
    2
    2
    2
    0
    1
    2
        Czech Republic
    0
    0
    1
    1
    0
    2
        Argentina
    1
    1
    2
    0
    1
    2
        Brazil
    0
    0
    1
    0
    0
    1
        Poland
    7
    7
    12
    0
    6
    12
        Romania
    1
    1
    7
    1
    1
    8
        Bulgaria
    6
    6
    6
    4
    6
    10
        Japan
    2
    2
    5
    0
    2
    5
        Sweden
    0
    0
    1
    0
    0
    1

    End points

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    End points reporting groups
    Reporting group title
    Pharmacokinetic Crossover with BAX326 and BeneFIX
    Reporting group description
    In Part 1, randomized subjects received 2 infusions each, 1 infusion with BAX326 and 1 infusion with BeneFIX, at a dose of 75 ± 5 IU/kg, each in a randomized order.
    Reporting group title
    Part 2 Only: BAX326 Prophylaxis
    Reporting group description
    Participants were only in Study Part 2 (i.e., did not participate in Study Parts 1 and 3)

    Reporting group title
    Part 2 Only: BAX326 On-Demand
    Reporting group description
    Participants were only in Study Part 2 (i.e., did not participate in Study Parts 1 and 3)

    Reporting group title
    Part 1: PK crossover - Part 2: Prophylaxis - Part 3: PK BAX326
    Reporting group description
    -Study Part 1: Pharmacokinetic (PK) Crossover with BeneFIX (75 ± 5 IU/kg) and BAX326 (75 ± 5 IU/kg). -Study Part 2: Open-label evaluation of prophylaxis -Study Part 3: Open-label repeat of PK evaluation (repeat Study Part 1) with BAX326 (75 ± 5 IU/kg) only and same study participants as Study Part 1
    Reporting group title
    PK BAX326 Only
    Reporting group description
    Open-label repeat of PK evaluation (repeat Study Part 1) with BAX326 (75 ± 5 IU/kg) only and same study participants as Study Part 1

    Subject analysis set title
    Study Part 1: PK with BAX326
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    In Part 1, randomized subjects received 2 infusions each, 1 infusion with BAX326 and 1 infusion with BeneFIX, at a dose of 75 ± 5 IU/kg, each in a randomized order.

    Subject analysis set title
    Study Part 1: PK with BeneFIX
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    In Part 1, randomized subjects received 2 infusions each, 1 infusion with BAX326 and 1 infusion with BeneFIX, at a dose of 75 ± 5 IU/kg, each in a randomized order.

    Subject analysis set title
    Study Part 2: Prophylactic cohort
    Subject analysis set type
    Full analysis
    Subject analysis set description
    Subjects in the prophylactic cohort were to be treated with a prophylactic regimen of 50 IU/kg BAX326 twice weekly for a period of 6 months or for at least 50 EDs, whichever occurred last. 56 subjects received a minimum of 3 months of prophylactic treatment with BAX326. A further 3 subjects received less than 3 months of prophylactic treatment with BAX326.

    Subject analysis set title
    Study Part 2: On-demand cohort
    Subject analysis set type
    Full analysis
    Subject analysis set description
    Subjects in the on-demand cohort were to receive BAX326 for on-demand treatment.

    Subject analysis set title
    Study Part 3: Repeat PK with BAX326 only
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    In Part 3, subjects who had participated in Part 1 and had a minimum of 30 exposure days to BAX326 in Part 2 underwent a repeat PK with BAX326 only, at a dose of 75 ± 5 IU/kg.

    Subject analysis set title
    Full Analysis Set
    Subject analysis set type
    Full analysis
    Subject analysis set description
    Comprises 73 subjects who were exposed to investigational product.

    Primary: Study Part 1- Area under the plasma concentration versus time curve from 0 to 72 hours per dose

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    End point title
    Study Part 1- Area under the plasma concentration versus time curve from 0 to 72 hours per dose
    End point description
    Computed using the linear trapezoidal method. The concentration at 72 hours was interpolated from the two nearest sampling time points or extrapolated using the last quantifiable concentration and the terminal rate constant λz. λz was estimated from the slope of natural log-linear fitting to latter quantifiable concentrations, with largest adjusted R^2. The pharmacokinetic per-protocol analysis set comprises 25 subjects who participated in Parts 1 and 3 and completed Part 1 without any major protocol deviation.
    End point type
    Primary
    End point timeframe
    72 hours
    End point values
    Study Part 1: PK with BAX326 Study Part 1: PK with BeneFIX
    Number of subjects analysed
    25
    25
    Units: (IU·hr/dL) / (IU/kg)
        median (inter-quartile range (Q1-Q3))
    14.3 (11.2 to 15.95)
    13.42 (11.08 to 15.1)
    Statistical analysis title
    PK equivalence of BAX326 with BeneFIX
    Statistical analysis description
    To assess PK equivalence of BAX326 and BeneFIX, the 90% confidence interval for the difference of the mean natural logarithms of the area under the plasma concentration versus time curve from 0 to 72 hours per dose (AUC0-72h/dose) between the 2 groups was calculated. To establish the equivalence in AUC0-72h /dose with a type I error of 5%, the calculated two-sided 90% confidence interval for the ratio had to be contained completely within the margins of equivalence defined as 80% to 125%.
    Comparison groups
    Study Part 1: PK with BAX326 v Study Part 1: PK with BeneFIX
    Number of subjects included in analysis
    50
    Analysis specification
    Pre-specified
    Analysis type
    equivalence
    Method
    Parameter type
    Ratio of Geometric Means
    Point estimate
    1.063
    Confidence interval
         level
    90%
         sides
    2-sided
         lower limit
    1.03
         upper limit
    1.09

    Secondary: Study Parts 1 and 3: Area under the plasma concentration/time curve from time 0 to infinity per dose (AUC0-∞/ dose)

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    End point title
    Study Parts 1 and 3: Area under the plasma concentration/time curve from time 0 to infinity per dose (AUC0-∞/ dose)
    End point description
    Defined as (AUC0-t + Ct)/ λz/ dose, where t is the time of last quantifiable concentration, Ct is the last quantifiable concentration. λz will be estimated from the slope of natural log-linear fitting to latter quantifiable concentrations, with largest adjusted R^2. The objective of Study Part 3 was to re-evaluate the Pharmacokinetic (PK) parameters for BAX 326 after a period of 6 months of treatment, in participants who accumulated at least 30 EDs to BAX 326, and to compare them with those determined in the same participants participating in Study Part 1. The PK per-protocol analysis set comprises 25 subjects for Part 1 and 23 subjects for Part 3.
    End point type
    Secondary
    End point timeframe
    0-30 minutes before infusion up to 72 hours post-infusion
    End point values
    Study Part 1: PK with BAX326 Study Part 1: PK with BeneFIX Study Part 3: Repeat PK with BAX326 only
    Number of subjects analysed
    25
    25
    23
    Units: (IU·hr)/ dL/ (IU/kg)
        median (inter-quartile range (Q1-Q3))
    16.07 (13.43 to 17.48)
    15.26 (13.71 to 17.05)
    17.38 (14.17 to 20.7)
    No statistical analyses for this end point

    Secondary: Study Parts 1 and 3: Mean residence time (MRT)

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    End point title
    Study Parts 1 and 3: Mean residence time (MRT)
    End point description
    Computed as Area under the moment curve 0-∞ (AUMC0-∞) / AUC0-∞- TI/2, where AUMC0-∞ will be determined in a similar manner as AUC0-∞ and TI represents infusion duration [hr] The objective of Study Part 3 was to re-evaluate the Pharmacokinetic (PK) parameters for BAX 326 after a period of 6 months of treatment, in participants who accumulated at least 30 EDs to BAX 326, and to compare them with those determined in the same participants participating in Study Part 1. The PK per-protocol analysis set comprises 25 subjects for Part 1 and 23 subjects for Part 3.
    End point type
    Secondary
    End point timeframe
    0-30 minutes before infusion up to 72 hours post-infusion
    End point values
    Study Part 1: PK with BAX326 Study Part 1: PK with BeneFIX Study Part 3: Repeat PK with BAX326 only
    Number of subjects analysed
    25
    25
    23
    Units: Hour
        median (inter-quartile range (Q1-Q3))
    28.93 (26.45 to 31.5)
    30.59 (28.13 to 34.84)
    29.04 (28 to 32.31)
    No statistical analyses for this end point

    Secondary: Study Parts 1 and 3: Clearance (CL)

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    End point title
    Study Parts 1 and 3: Clearance (CL)
    End point description
    Computed as Dose/ AUC0-∞. The objective of Study Part 3 was to re-evaluate the Pharmacokinetic (PK) parameters for BAX 326 after a period of 6 months of treatment, in participants who accumulated at least 30 EDs to BAX 326, and to compare them with those determined in the same participants participating in Study Part 1. The pharmacokinetic per-protocol analysis set comprises 25 subjects for Part 1 and 23 subjects for Part 3.
    End point type
    Secondary
    End point timeframe
    0-30 minutes before infusion up to 72 hours post-infusion
    End point values
    Study Part 1: PK with BAX326 Study Part 1: PK with BeneFIX Study Part 3: Repeat PK with BAX326 only
    Number of subjects analysed
    25
    25
    23
    Units: dL/(kg·hr)
        median (inter-quartile range (Q1-Q3))
    0.0622 (0.0572 to 0.0745)
    0.0655 (0.0587 to 0.073)
    0.0576 (0.0483 to 0.0706)
    No statistical analyses for this end point

    Secondary: Study Parts 1 and 3: Incremental Recovery at Cmax (IR at Cmax)

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    End point title
    Study Parts 1 and 3: Incremental Recovery at Cmax (IR at Cmax)
    End point description
    Defined as (Cmax - Cpre-infusion)/Dose, where maximum concentration (Cmax) will be determined as the highest concentration achieved within one hour after infusion. The objective of Study Part 3 was to re-evaluate the Pharmacokinetic (PK) parameters for BAX 326 after a period of 6 months of treatment, in participants who accumulated at least 30 EDs to BAX 326, and to compare them with those determined in the same participants participating in Study Part 1. The pharmacokinetic per-protocol analysis set comprises 25 subjects for Part 1 and 23 subjects for Part 3.
    End point type
    Secondary
    End point timeframe
    0-30 minutes before infusion up to 1 hour post-infusion
    End point values
    Study Part 1: PK with BAX326 Study Part 1: PK with BeneFIX Study Part 3: Repeat PK with BAX326 only
    Number of subjects analysed
    25
    25
    23
    Units: (IU/dL) / (IU/kg)
        median (inter-quartile range (Q1-Q3))
    0.88 (0.79 to 0.98)
    0.73 (0.66 to 0.87)
    0.93 (0.76 to 1.18)
    No statistical analyses for this end point

    Secondary: Incremental Recovery (IR) at 30 Minutes Over Time

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    End point title
    Incremental Recovery (IR) at 30 Minutes Over Time
    End point description
    IR at 30 Minutes was measured at the following time points during the study: - Part 1 or Part 2, Exposure Day (ED) 1. (If participant was present for Study Part 1, then ED 1 from Part 1 was used. If Participant entered study in Study Part 2, then ED 1 from Part 2 was used.) - Part 2: Week 5 - Part 2: Week 13 - Part 2 or Part 3: Week 26 (Week 26 of study participation) - Study Completion or Termination Visit
    End point type
    Secondary
    End point timeframe
    0-30 minutes before infusion and 30 minutes post-infusion
    End point values
    Full Analysis Set
    Number of subjects analysed
    73
    Units: (IU/dL) / (IU/kg)
    median (inter-quartile range (Q1-Q3))
        Part 1 or Part 2, Exposure Day 1 (n=73)
    0.78 (0.7 to 0.91)
        Part 2: Week 5 (n=71)
    0.79 (0.68 to 0.96)
        Part 2: Week 13 (n=68)
    0.83 (0.655 to 1.015)
        Part 2 or 3: Week 26 (n=55)
    0.88 (0.75 to 1.04)
        Study Completion or Termination Visit (n=23)
    0.89 (0.73 to 0.96)
    No statistical analyses for this end point

    Secondary: Change in Incremental Recovery (IR) at 30 Minutes Over Time

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    End point title
    Change in Incremental Recovery (IR) at 30 Minutes Over Time
    End point description
    The median changes in IR at 30 Minutes, calculated as the change in IR value from exposure day 1 (ED1).
    End point type
    Secondary
    End point timeframe
    0-30 minutes before infusion and 30 minutes post-infusion
    End point values
    Full Analysis Set
    Number of subjects analysed
    71
    Units: (IU/dL) / (IU/kg)
    median (inter-quartile range (Q1-Q3))
        Part 2: Week 5 (n=71)
    0.03 (-0.09 to 0.11)
        Part 2: Week 13 (n=68)
    0.075 (-0.07 to 0.17)
        Part 2 or Part 3: Week 26 (n=55)
    0.06 (0.02 to 0.17)
        Study Completion or Termination Visit (n=23)
    0.12 (0 to 0.21)
    No statistical analyses for this end point

    Secondary: Study Parts 1 and 3: Half Life (T 1/2)

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    End point title
    Study Parts 1 and 3: Half Life (T 1/2)
    End point description
    Elimination phase half-life will be determined as ln2/ λz. The objective of Study Part 3 was to re-evaluate the Pharmacokinetic (PK) parameters for BAX 326 after a period of 6 months of treatment, in participants who accumulated at least 30 EDs to BAX 326, and to compare them with those determined in the same participants participating in Study Part 1. The pharmacokinetic per-protocol analysis set comprises 25 subjects for Part 1 and 23 subjects for Part 3.
    End point type
    Secondary
    End point timeframe
    0-30 minutes before infusion up to 72 hours post-infusion
    End point values
    Study Part 1: PK with BAX326 Study Part 1: PK with BeneFIX Study Part 3: Repeat PK with BAX326 only
    Number of subjects analysed
    25
    25
    23
    Units: Hour
        median (inter-quartile range (Q1-Q3))
    24.58 (20.98 to 29.68)
    26.28 (22.51 to 29.46)
    24.59 (19.68 to 29.14)
    No statistical analyses for this end point

    Secondary: Study Parts 1 and 3: Volume of distribution at steady state (Vss)

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    End point title
    Study Parts 1 and 3: Volume of distribution at steady state (Vss)
    End point description
    Vss computed as CL·MRT. The objective of Study Part 3 was to re-evaluate the Pharmacokinetic (PK) parameters for BAX 326 after a period of 6 months of treatment, in participants who accumulated at least 30 EDs to BAX 326, and to compare them with those determined in the same participants participating in Study Part 1. The pharmacokinetic per-protocol analysis set comprises 25 subjects for Part 1 and 23 subjects for Part 3.
    End point type
    Secondary
    End point timeframe
    0-30 minutes before infusion up to 72 hours post-infusion
    End point values
    Study Part 1: PK with BAX326 Study Part 1: PK with BeneFIX Study Part 3: Repeat PK with BAX326 only
    Number of subjects analysed
    25
    25
    23
    Units: dL/kg
        median (inter-quartile range (Q1-Q3))
    1.72 (1.56 to 2.3)
    1.98 (1.76 to 2.51)
    1.74 (1.49 to 2.05)
    No statistical analyses for this end point

    Secondary: Study Part 2: Annualized Bleed Rate (ABR) during prophylactic treatment with BAX326

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    End point title
    Study Part 2: Annualized Bleed Rate (ABR) during prophylactic treatment with BAX326
    End point description
    ABR during prophylaxis (twice-weekly) in Part 2 was calculated as (Number of bleeding episodes/observed treatment period in days) * 365.25. The treatment period on prophylaxis was defined as time between the first and the last prophylactic infusions and ABR on prophylaxis was calculated for participants who received a minimum of 3 months of prophylactic treatment with BAX326.
    End point type
    Secondary
    End point timeframe
    Study Part 2 = 26 weeks ± 1 week (Note: Study Part 1 = 2-4 weeks)
    End point values
    Study Part 2: Prophylactic cohort
    Number of subjects analysed
    56
    Units: Bleeds per year
    median (inter-quartile range (Q1-Q3))
        Joint bleeding episode
    0 (0 to 4.5)
        Non-Joint bleeding episode
    0 (0 to 2)
        Spontaneous bleeding episode
    0 (0 to 2)
        Bleeding episode caused by injury
    0 (0 to 2.1)
        Unknown cause of bleeding episode
    0 (0 to 0)
        All bleeding episodes
    1.99 (0 to 6.5)
    No statistical analyses for this end point

    Secondary: Bleeding Episodes Treated With 1, 2 or ≥3 Infusions of BAX326

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    End point title
    Bleeding Episodes Treated With 1, 2 or ≥3 Infusions of BAX326
    End point description
    The number of bleeding episodes treated with 1, 2, or ≥3 infusions of BAX326 to achieve adequate hemostasis. Only infusions required until resolution of bleed were considered. There were a total of 249 bleeding episodes in 47 subjects in the Full Analysis Set (ie, in all 14 on-demand subjects and in 33 of 59 subjects who received prophylaxis).
    End point type
    Secondary
    End point timeframe
    Study Part 2 = 26 weeks ± 1 week (Study Part 2 began at week 3-5)
    End point values
    Full Analysis Set
    Number of subjects analysed
    47
    Units: Bleeding episodes
        1 infusion
    153
        2 infusions
    58
        3 or more infusions
    38
    No statistical analyses for this end point

    Secondary: Hemostatic Efficacy at Resolution of All Bleeding Episodes (BEs) Treated with BAX326

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    End point title
    Hemostatic Efficacy at Resolution of All Bleeding Episodes (BEs) Treated with BAX326
    End point description
    There were a total of 249 bleeding episodes in 47 subjects in the Full Analysis Set (ie, in all 14 on-demand subjects and in 33 of 59 subjects who received prophylaxis). Rating Scale for Treatment of 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
    At bleed resolution throughout the study period of 22 months (Study Parts 1, 2, and 3)
    End point values
    Full Analysis Set
    Number of subjects analysed
    47
    Units: Bleeding episodes
        Excellent
    102
        Good
    137
        Fair
    5
        None
    0
        Not Reported
    5
    No statistical analyses for this end point

    Secondary: Total Weight-adjusted Dose per Bleeding Episode (BEs) of All BEs Treated with BAX326 by Bleeding Site and Cause

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    End point title
    Total Weight-adjusted Dose per Bleeding Episode (BEs) of All BEs Treated with BAX326 by Bleeding Site and Cause
    End point description
    There were a total of 249 bleeding episodes in 47 subjects in the Full Analysis Set (ie, in all 14 on-demand subjects and in 33 of 59 subjects who received prophylaxis).
    End point type
    Secondary
    End point timeframe
    Study Part 2 = 26 weeks ± 1 week (Note: Study Part 1 = 2-4 weeks)
    End point values
    Full Analysis Set
    Number of subjects analysed
    47
    Units: IU/kg
    median (inter-quartile range (Q1-Q3))
        Bleeding Site: Target Joint (107 BEs)
    56.5 (48 to 97)
        Bleeding Site: Non-Target Joint (90 BEs)
    59 (46 to 97)
        Bleeding Site: All Joint (197 BEs)
    56.5 (47 to 97)
        Bleeding Site: Non-Joint (52 BEs)
    68.7 (50 to 130)
        Bleeding Cause: Spontaneous (130 BEs)
    52.3 (45 to 92)
        Bleeding Cause: Inury (90 BEs)
    70 (48 to 116)
        Bleeding Cause: Unknown (29 BEs)
    56.5 (51 to 108)
    No statistical analyses for this end point

    Secondary: Consumption of BAX326 per Event per Subject

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    End point title
    Consumption of BAX326 per Event per Subject
    End point description
    Weight-adjusted consumption of BAX326 by event per participant, i.e., for prophylactic treatment and for treatment of bleeds until resolution of bleed. Includes all participants who received any infusions for bleeding treatment in the Full Analysis Set (ie, includes all on-demand arm (n=14) and 33 subjects from the prophylaxis arm who experienced a bleeding episode).
    End point type
    Secondary
    End point timeframe
    Study Part 2 = 26 weeks ± 1 week (Note: Study Part 1 = 2-4 weeks)
    End point values
    Full Analysis Set
    Number of subjects analysed
    73 [1]
    Units: IU/kg
    median (inter-quartile range (Q1-Q3))
        Prophylactic Treatment (n=59)
    50.5 (46 to 52)
        Bleeding Treatment (n=47)
    87.1 (56 to 125)
    Notes
    [1] - Of 73 subjects in the FAS, 59 had prophylactic treatment and 47 had bleed treatment.
    No statistical analyses for this end point

    Secondary: Consumption of BAX326 per Subject: Median Number of Infusions per Month

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    End point title
    Consumption of BAX326 per Subject: Median Number of Infusions per Month
    End point description
    End point type
    Secondary
    End point timeframe
    Study Part 1 = 2-4 weeks, Study Part 2 = 26 weeks ± 1 week (Prophylaxis and On-Demand period), Study Part 3 = 1 week (Total = 29-31 weeks)
    End point values
    Study Part 2: Prophylactic cohort Study Part 2: On-demand cohort
    Number of subjects analysed
    59
    14
    Units: Infusions
        median (inter-quartile range (Q1-Q3))
    6.7 (6 to 7)
    2.7 (2 to 4)
    No statistical analyses for this end point

    Secondary: Consumption of BAX326 per Subject: Median Weight-adjusted Consumption per Month

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    End point title
    Consumption of BAX326 per Subject: Median Weight-adjusted Consumption per Month
    End point description
    End point type
    Secondary
    End point timeframe
    Study Part 1 = 2-4 weeks, Study Part 2 = 26 weeks ± 1 week (Prophylaxis and On-Demand period), Study Part 3 = 1 week (Total = 29-31 weeks)
    End point values
    Study Part 2: Prophylactic cohort Study Part 2: On-demand cohort
    Number of subjects analysed
    59
    14
    Units: IU/kg
        median (inter-quartile range (Q1-Q3))
    347.8 (320 to 396)
    167.3 (102 to 234)
    No statistical analyses for this end point

    Secondary: Number of Participants Who Developed Inhibitory Antibodies to Factor IX (FIX)

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    End point title
    Number of Participants Who Developed Inhibitory Antibodies to Factor IX (FIX)
    End point description
    End point type
    Secondary
    End point timeframe
    Study Part 1 = 2-4 weeks, Study Part 2 = 26 weeks ± 1 week, Study Part 3 = 1 week (Total = 29-31 weeks)
    End point values
    Full Analysis Set
    Number of subjects analysed
    73
    Units: participants
    0
    No statistical analyses for this end point

    Secondary: Occurrence of total binding antibodies of indeterminate specificity (within assay variability)

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    End point title
    Occurrence of total binding antibodies of indeterminate specificity (within assay variability)
    End point description
    Occurrence of total binding antibodies of indeterminate specificity (within assay variability) to FIX, antibodies to CHO proteins and rFurin is defined by a dilution of 2 or less increase as compared to levels at screening visit (e.g. negative to 1:20 or 1:40).
    End point type
    Secondary
    End point timeframe
    Study Part 1 = 2-4 weeks, Study Part 2 = 26 weeks ± 1 week, Study Part 3 = 1 week (Total = 29-31 weeks)
    End point values
    Full Analysis Set
    Number of subjects analysed
    73
    Units: participants
        Binding Antibody to Factor IX (FIX)
    6
        Antibody to Chinese hamster ovary (CHO) Protein
    0
        Antibody to recombinant Furin (rFurin)
    9
    No statistical analyses for this end point

    Secondary: Occurrence of treatment related total binding antibodies

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    End point title
    Occurrence of treatment related total binding antibodies
    End point description
    Occurrence of treatment related total binding antibodies to Factor IX (FIX), antibodies to Chinese hamster ovary (CHO) proteins, and recombinant furin (rFurin) is defined by more than 2-dilution increase as compared to levels at screening visit and confirmed specificity (e.g. negative to 1:80)
    End point type
    Secondary
    End point timeframe
    Study Part 1 = 2-4 weeks, Study Part 2 = 26 weeks ± 1 week, Study Part 3 = 1 week (Total = 29-31 weeks)
    End point values
    Full Analysis Set
    Number of subjects analysed
    73
    Units: participants
        Treatment Related Binding Antibody to Factor IX
    0
        Treatment Related Antibody to CHO Protein
    0
        Treatment Related Antibody to rFurin
    0
    No statistical analyses for this end point

    Secondary: Number of Subjects Who Experienced Severe Allergic Reactions (e.g. Anaphylaxis)

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    End point title
    Number of Subjects Who Experienced Severe Allergic Reactions (e.g. Anaphylaxis)
    End point description
    End point type
    Secondary
    End point timeframe
    Study Part 1 = 2-4 weeks, Study Part 2 = 26 weeks ± 1 week, Study Part 3 = 1 week (Total = 29-31 weeks)
    End point values
    Full Analysis Set
    Number of subjects analysed
    73
    Units: subjects
    0
    No statistical analyses for this end point

    Secondary: Number of Subjects Who Experienced Thrombotic Events

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    End point title
    Number of Subjects Who Experienced Thrombotic Events
    End point description
    End point type
    Secondary
    End point timeframe
    Study Part 1 = 2-4 weeks, Study Part 2 = 26 weeks ± 1 week, Study Part 3 = 1 week (Total = 29-31 weeks)
    End point values
    Full Analysis Set
    Number of subjects analysed
    73
    Units: subjects
    0
    No statistical analyses for this end point

    Secondary: Number of subjects with clinically significant changes in laboratory parameters: clinical chemistry

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    End point title
    Number of subjects with clinically significant changes in laboratory parameters: clinical chemistry
    End point description
    Clinically significant changes in chemistry assessments for Alanine Aminotransferase, Albumin, Alkaline Phosphatase, Aspartate Aminotransferase, Bicarbonate, Bilirubin, Blood Urea Nitrogen, Chloride, Glucose, Potassium, Protein (Serum), Sodium. Clinically Significant (CS) defined as: -1. The abnormal value constitutes an adverse event (AE) and, -2. The abnormal value is a symptom of or related to a disease that is already recorded as an AE in Case Report Form (CRF).
    End point type
    Secondary
    End point timeframe
    Study Part 1 = 2-4 weeks, Study Part 2 = 26 weeks ± 1 week, Study Part 3 = 1 week (Total = 29-31 weeks)
    End point values
    Full Analysis Set
    Number of subjects analysed
    73
    Units: subjects
    0
    No statistical analyses for this end point

    Secondary: Number of subjects with clinically significant changes in laboratory parameters: hematology

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    End point title
    Number of subjects with clinically significant changes in laboratory parameters: hematology
    End point description
    Clinically significant changes in hematology assessments for Basophils, Basophils/Leukocytes, Eosinophils, Eosinophils/Leukocytes, Erythrocyte Mean Corpuscular Hemoglobin Concentration, Erythrocyte Mean Corpuscular Volume, Erythrocytes, Hematocrit, Hemoglobin, Leukocytes, Lymphocytes, Lymphocytes/Leukocytes, Monocytes, Monocytes/Leukocytes, Neutrophils, Neutrophils/Leukocytes, Platelets,
    End point type
    Secondary
    End point timeframe
    Study Part 1 = 2-4 weeks, Study Part 2 = 26 weeks ± 1 week, Study Part 3 = 1 week (Total = 29-31 weeks)
    End point values
    Full Analysis Set
    Number of subjects analysed
    73
    Units: subjects
    0
    No statistical analyses for this end point

    Secondary: Number of Subjects With Clinically significant changes in laboratory parameters: thrombogenic markers

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    End point title
    Number of Subjects With Clinically significant changes in laboratory parameters: thrombogenic markers
    End point description
    Clinically significant changes in thrombogenic markers assessments for thrombin-antithrombin (TAT), prothrombin fragment 1.2, and D-dimer as evaluated by an independent Data Monitoring Committee (DMC)
    End point type
    Secondary
    End point timeframe
    Study Part 1 = 2-4 weeks, Study Part 2 = 26 weeks ± 1 week, Study Part 3 = 1 week (Total = 29-31 weeks)
    End point values
    Full Analysis Set
    Number of subjects analysed
    73
    Units: subjects
    0
    No statistical analyses for this end point

    Secondary: Number of Subjects With Clinically significant changes in laboratory parameters: vital signs

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    End point title
    Number of Subjects With Clinically significant changes in laboratory parameters: vital signs
    End point description
    Clinically significant changes in vital signs assessments for pulse rate, systolic/diastolic blood pressure, respiratory rate, body temperature
    End point type
    Secondary
    End point timeframe
    Study Part 1 = 2-4 weeks, Study Part 2 = 26 weeks ± 1 week, Study Part 3 = 1 week (Total = 29-31 weeks)
    End point values
    Full Analysis Set
    Number of subjects analysed
    73
    Units: subjects
    0
    No statistical analyses for this end point

    Secondary: Number of Adverse Events (AEs) Considered Related to BAX326 Treatment

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    End point title
    Number of Adverse Events (AEs) Considered Related to BAX326 Treatment
    End point description
    Probable, possible, or unknown causality assessment of an AE was to be counted as "related".
    End point type
    Secondary
    End point timeframe
    Study Part 1 = 2-4 weeks, Study Part 2 = 26 weeks ± 1 week, and Study Part 3 = 1 week (Total = 29-31 weeks)
    End point values
    Full Analysis Set
    Number of subjects analysed
    73
    Units: related adverse events
        Serious- Mild
    0
        Serious- Moderate
    0
        Serious- Severe
    0
        Serious- Unknown
    0
        Non-Serious- Mild
    2
        Non-Serious- Moderate
    0
        Non-Serious- Severe
    0
        Non-Serious- Unknown
    1
    No statistical analyses for this end point

    Secondary: Number of Subjects with Adverse Events (AEs) Considered Related to BAX326 Treatment

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    End point title
    Number of Subjects with Adverse Events (AEs) Considered Related to BAX326 Treatment
    End point description
    End point type
    Secondary
    End point timeframe
    Study Part 1 = 2-4 weeks, Study Part 2 = 26 weeks ± 1 week, and Study Part 3 = 1 week (Total = 29-31 weeks)
    End point values
    Full Analysis Set
    Number of subjects analysed
    73
    Units: subjects
        Serious- Mild
    0
        Serious- Moderate
    0
        Serious- Severe
    0
        Serious- Unknown
    0
        Non-Serious- Mild
    1
        Non-Serious- Moderate
    0
        Non-Serious- Severe
    0
        Non-Serious- Unknown
    1
    No statistical analyses for this end point

    Secondary: EuroQoL (Quality of Life)-5 Dimensions (EQ-5D) Total Index Scores

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    End point title
    EuroQoL (Quality of Life)-5 Dimensions (EQ-5D) Total Index Scores
    End point description
    EQ-5D is a subject answered questionnaire scoring 5 dimensions - mobility, self-care, usual activities, pain/discomfort and anxiety/depression. The EQ-5D total score ranges from 0 (worst health state) to 1 (perfect health state) and 1 reflects the best outcome.
    End point type
    Secondary
    End point timeframe
    Baseline at either Study Part 1, or Study Part 2, and End of Study (study weeks 29-31)
    End point values
    Study Part 2: Prophylactic cohort Study Part 2: On-demand cohort
    Number of subjects analysed
    55 [2]
    14
    Units: Score on a scale
    arithmetic mean (standard deviation)
        Part 1 or Part 2, Exposure Day 1 (Baseline)
    0.75 ± 0.16
    0.72 ± 0.14
        End of Study
    0.75 ± 0.16
    0.73 ± 0.09
        Change from Baseline
    0.01 ± 0.18
    0 ± 0.13
    Notes
    [2] - N=56 at baseline, N=55 at end of study
    No statistical analyses for this end point

    Secondary: EuroQoL (Quality of Life)-5 Dimensions Visual Analogue Scale (EQ-5D VAS) Scores

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    End point title
    EuroQoL (Quality of Life)-5 Dimensions Visual Analogue Scale (EQ-5D VAS) Scores
    End point description
    Subject rated questionnaire to assess health-related quality of life in terms of a single index value. The VAS component rates current health state on a scale from 0 (worst imaginable health state) to 100 (best imaginable health state); higher scores indicate a better quality of life.
    End point type
    Secondary
    End point timeframe
    Baseline at either Study Part 1, or Study Part 2, and End of Study (study weeks 29-31)
    End point values
    Study Part 2: Prophylactic cohort Study Part 2: On-demand cohort
    Number of subjects analysed
    54 [3]
    14
    Units: Score on a scale
    arithmetic mean (standard deviation)
        Part 1 or Part 2, Exposure Day 1 (Baseline)
    58.75 ± 24.89
    56.64 ± 25.97
        End of Study
    68.22 ± 22.78
    62.07 ± 19
        Change from Baseline
    9.98 ± 25.41
    5.43 ± 24.02
    Notes
    [3] - N=56 at baseline, N=54 at end of study
    No statistical analyses for this end point

    Secondary: General pain assessment through a visual analog scale (VAS)

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    End point title
    General pain assessment through a visual analog scale (VAS)
    End point description
    Participant rated assessment of health-related quality of life. The VAS Pain Scale rates current health state on a scale from 0 (no pain) to 100 (worst imaginable pain). For the pain scale, a higher score indicates worse pain.
    End point type
    Secondary
    End point timeframe
    Baseline at either Study Part 1, or Study Part 2, and End of Study (study weeks 29-31)
    End point values
    Study Part 2: Prophylactic cohort Study Part 2: On-demand cohort
    Number of subjects analysed
    54 [4]
    14
    Units: Score on a scale
    arithmetic mean (standard deviation)
        Part 1 or Part 2, Exposure Day 1 (Baseline)
    32.67 ± 26.62
    47.57 ± 30.82
        End of Study
    33.09 ± 25.9
    39.93 ± 22.57
        Change from Baseline
    0.35 ± 21.77
    -7.64 ± 33.58
    Notes
    [4] - N=55 at baseline, N=54 at end of study
    No statistical analyses for this end point

    Secondary: Short Form (36) Health Survey (SF-36): HRQoL 'Physical Component Score' (PCS)

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    End point title
    Short Form (36) Health Survey (SF-36): HRQoL 'Physical Component Score' (PCS)
    End point description
    The 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 subscores and summary scores.
    End point type
    Secondary
    End point timeframe
    Baseline at either Study Part 1, or Study Part 2, and End of Study (study weeks 29-31)
    End point values
    Study Part 2: Prophylactic cohort Study Part 2: On-demand cohort
    Number of subjects analysed
    52 [5]
    13
    Units: Score on a scale
    arithmetic mean (standard deviation)
        Part 1 or Part 2, Exposure Day 1 (Baseline)
    39.08 ± 9.39
    37.38 ± 7.2
        End of Study
    41.35 ± 8.73
    38.92 ± 8.53
        Change from Baseline
    2.6 ± 7.72
    1.54 ± 5.11
    Notes
    [5] - N=54 at baseline, N=52 at end of study
    No statistical analyses for this end point

    Secondary: SF-36: HRQoL 'Mental Health' (MH)

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    End point title
    SF-36: HRQoL 'Mental Health' (MH)
    End point description
    Quality of life survey response as measured using the SF-36 questionnaire. Scores range from 0 to 100 with higher scores representing better health. There is no total overall score; scoring is done for both subscores and summary scores. The raw data from the SF-36 items were transformed to norm based scores for each of the 8 HRQoL/SF-36 health domain scores.
    End point type
    Secondary
    End point timeframe
    Baseline at either Study Part 1, or Study Part 2, and End of Study (study weeks 29-31)
    End point values
    Study Part 2: Prophylactic cohort Study Part 2: On-demand cohort
    Number of subjects analysed
    52 [6]
    13
    Units: Score on a scale
    arithmetic mean (standard deviation)
        Part 1 or Part 2, Exposure Day 1 (Baseline)
    47.53 ± 9.46
    47.24 ± 8.8
        End of Study
    49.67 ± 9.3
    45.03 ± 9.96
        Change from Baseline
    2.01 ± 11.17
    -2.21 ± 8.28
    Notes
    [6] - N=54 at baseline, N=52 at end of study
    No statistical analyses for this end point

    Secondary: SF-36: HRQoL Physical Functioning' (PF)

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    End point title
    SF-36: HRQoL Physical Functioning' (PF)
    End point description
    Quality of life survey response as measured using the SF-36 questionnaire. Scores range from 0 to 100 with higher scores representing better health. There is no total overall score; scoring is done for both subscores and summary scores. The raw data from the SF-36 items were transformed to norm based scores for each of the 8 HRQoL/SF-36 health domain scores.
    End point type
    Secondary
    End point timeframe
    Baseline at either Study Part 1, or Study Part 2, and End of Study (study weeks 29-31)
    End point values
    Study Part 2: Prophylactic cohort Study Part 2: On-demand cohort
    Number of subjects analysed
    53 [7]
    13
    Units: Score on a scale
    arithmetic mean (standard deviation)
        Part 1 or Part 2, Exposure Day 1 (Baseline) vs. En
    40.2 ± 10.57
    40.04 ± 10.57
        End of Study
    40.75 ± 10.14
    39.87 ± 10.55
        Change from Baseline
    0.68 ± 7.48
    -0.16 ± 5.86
    Notes
    [7] - N=54 at baseline, N=53 at end of study
    No statistical analyses for this end point

    Secondary: SF-36: HRQoL Role-Physical (RP)

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    End point title
    SF-36: HRQoL Role-Physical (RP)
    End point description
    Quality of life survey response as measured using the SF-36 questionnaire. Scores range from 0 to 100 with higher scores representing better health. There is no total overall score; scoring is done for both subscores and summary scores. The raw data from the SF-36 items were transformed to norm based scores for each of the 8 HRQoL/SF-36 health domain scores.
    End point type
    Secondary
    End point timeframe
    Baseline at either Study Part 1, or Study Part 2, and End of Study (study weeks 29-31)
    End point values
    Study Part 2: Prophylactic cohort Study Part 2: On-demand cohort
    Number of subjects analysed
    53 [8]
    13
    Units: Score on a scale
    arithmetic mean (standard deviation)
        Part 1 or Part 2, Exposure Day 1 (Baseline)
    40.39 ± 10.7
    39.15 ± 8.13
        End of Study
    43.82 ± 8.67
    37.45 ± 10.12
        Change from Baseline
    3.47 ± 10.15
    -1.7 ± 5.86
    Notes
    [8] - N=54 at baseline, N=53 at end of study
    No statistical analyses for this end point

    Secondary: SF-36: HRQoL Role-Emotional

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    End point title
    SF-36: HRQoL Role-Emotional
    End point description
    Quality of life survey response as measured using the SF-36 questionnaire. Scores range from 0 to 100 with higher scores representing better health. There is no total overall score; scoring is done for both subscores and summary scores. The raw data from the SF-36 items were transformed to norm based scores for each of the 8 HRQoL/SF-36 health domain scores.
    End point type
    Secondary
    End point timeframe
    Baseline at either Study Part 1, or Study Part 2, and End of Study (study weeks 29-31)
    End point values
    Study Part 2: Prophylactic cohort Study Part 2: On-demand cohort
    Number of subjects analysed
    53 [9]
    13
    Units: Score on a scale
    arithmetic mean (standard deviation)
        Part 1 or Part 2, Exposure Day 1 (Baseline)
    44.22 ± 11.45
    40.93 ± 9.1
        End of Study
    44.8 ± 10.15
    39.43 ± 11.57
        Change from Baseline
    0.37 ± 11.74
    -1.5 ± 8.91
    Notes
    [9] - N=54 at baseline, N=53 at end of study
    No statistical analyses for this end point

    Secondary: SF-36: HRQoL Bodily Pain

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    End point title
    SF-36: HRQoL Bodily Pain
    End point description
    Quality of life survey response as measured using the SF-36 questionnaire. Scores range from 0 to 100 with higher scores representing better health. There is no total overall score; scoring is done for both subscores and summary scores. The raw data from the SF-36 items were transformed to norm based scores for each of the 8 HRQoL/SF-36 health domain scores.
    End point type
    Secondary
    End point timeframe
    Baseline at either Study Part 1, or Study Part 2, and End of Study (study weeks 29-31)
    End point values
    Study Part 2: Prophylactic cohort Study Part 2: On-demand cohort
    Number of subjects analysed
    53 [10]
    13
    Units: Score on a scale
    arithmetic mean (standard deviation)
        Part 1 or Part 2, Exposure Day 1 (Baseline)
    42.09 ± 10.21
    36.89 ± 7.84
        End of Study
    45.72 ± 8.68
    39.33 ± 8.91
        Change from Baseline
    3.45 ± 9.95
    2.44 ± 10.18
    Notes
    [10] - N=54 at baseline, N=53 at end of study
    No statistical analyses for this end point

    Secondary: SF-36: HRQoL Mental Health

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    End point title
    SF-36: HRQoL Mental Health
    End point description
    Quality of life survey response as measured using the SF-36 questionnaire. Scores range from 0 to 100 with higher scores representing better health. There is no total overall score; scoring is done for both subscores and summary scores. The raw data from the SF-36 items were transformed to norm based scores for each of the 8 HRQoL/SF-36 health domain scores.
    End point type
    Secondary
    End point timeframe
    Baseline at either Study Part 1, or Study Part 2, and End of Study (study weeks 29-31)
    End point values
    Study Part 2: Prophylactic cohort Study Part 2: On-demand cohort
    Number of subjects analysed
    52 [11]
    13
    Units: Score on a scale
    arithmetic mean (standard deviation)
        Part 1 or Part 2, Exposure Day 1 (Baseline)
    45.52 ± 8.78
    45.46 ± 10.57
        End of Study
    47.95 ± 8.84
    42.64 ± 10.63
        Change from Baseline
    2.44 ± 11.29
    -2.82 ± 8.53
    Notes
    [11] - N=54 at baseline, N=52 at end of study
    No statistical analyses for this end point

    Secondary: SF-36: HRQoL Vitality

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    End point title
    SF-36: HRQoL Vitality
    End point description
    Quality of life survey response as measured using the SF-36 questionnaire. Scores range from 0 to 100 with higher scores representing better health. There is no total overall score; scoring is done for both subscores and summary scores. The raw data from the SF-36 items were transformed to norm based scores for each of the 8 HRQoL/SF-36 health domain scores.
    End point type
    Secondary
    End point timeframe
    Baseline at either Study Part 1, or Study Part 2, and End of Study (study weeks 29-31)
    End point values
    Study Part 2: Prophylactic cohort Study Part 2: On-demand cohort
    Number of subjects analysed
    52 [12]
    13
    Units: Score on a scale
    arithmetic mean (standard deviation)
        Part 1 or Part 2, Exposure Day 1 (Baseline)
    50.07 ± 8.47
    50.17 ± 5.63
        End of Study
    52.75 ± 8.88
    50.89 ± 6.81
        Change from Baseline
    2.46 ± 10.75
    0.72 ± 5.43
    Notes
    [12] - N=54 at baseline, N=52 at end of study
    No statistical analyses for this end point

    Secondary: SF-36: HRQoL Social Functioning

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    End point title
    SF-36: HRQoL Social Functioning
    End point description
    Quality of life survey response as measured using the SF-36 questionnaire. Scores range from 0 to 100 with higher scores representing better health. There is no total overall score; scoring is done for both subscores and summary scores. The raw data from the SF-36 items were transformed to norm based scores for each of the 8 HRQoL/SF-36 health domain scores.
    End point type
    Secondary
    End point timeframe
    Baseline at either Study Part 1, or Study Part 2, and End of Study (study weeks 29-31)
    End point values
    Study Part 2: Prophylactic cohort Study Part 2: On-demand cohort
    Number of subjects analysed
    53 [13]
    13
    Units: Score on a scale
    arithmetic mean (standard deviation)
        Part 1 or Part 2, Exposure Day 1 (Baseline)
    41.8 ± 10.54
    43.42 ± 9.61
        End of Study
    44.6 ± 8.94
    42.17 ± 9.8
        Change from Baseline
    2.78 ± 10.78
    -1.26 ± 6.36
    Notes
    [13] - N=54 at baseline, N=53 at end of study
    No statistical analyses for this end point

    Secondary: SF-36: HRQoL General Health

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    End point title
    SF-36: HRQoL General Health
    End point description
    Quality of life survey response as measured using the SF-36 questionnaire. Scores range from 0 to 100 with higher scores representing better health. There is no total overall score; scoring is done for both subscores and summary scores. The raw data from the SF-36 items were transformed to norm based scores for each of the 8 HRQoL/SF-36 health domain scores.
    End point type
    Secondary
    End point timeframe
    Baseline at either Study Part 1, or Study Part 2, and End of Study (study weeks 29-31)
    End point values
    Study Part 2: Prophylactic cohort Study Part 2: On-demand cohort
    Number of subjects analysed
    53 [14]
    13
    Units: Score on a scale
    arithmetic mean (standard deviation)
        Part 1 or Part 2, Exposure Day 1 (Baseline)
    37.84 ± 8.38
    37.09 ± 10.47
        End of Study
    39.98 ± 9.03
    39.07 ± 8.88
        Change from Baseline
    2.2 ± 8.22
    1.98 ± 7.94
    Notes
    [14] - N=54 at baseline, N=53 at end of study
    No statistical analyses for this end point

    Secondary: Pediatric Quality of Life Questionnaire (PedsQL) Physical Health Summary Score (Ages 12-16)

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    End point title
    Pediatric Quality of Life Questionnaire (PedsQL) Physical Health Summary Score (Ages 12-16)
    End point description
    The Peds-QL is a generic Health-Related Quality of Life (HR QoL) instrument designed specifically for a pediatric population. It captures the following domains: general health/activities, feelings/emotional, social functioning, school functioning. For this study, the Peds-QL for 12 to 16-year-old subjects was used. Higher scores indicate better quality of life (QOL) for all domains of the Peds-QL. This modular instrument uses a 5-point scale: from 0 (never) to 4 (almost always). Items are reversed scored and linearly transformed to a 0-100 scale as follows: 0=100, 1=75, 2=50, 3=25, 4=0. 4 dimensions (physical, emotional, social, & school functioning) are scored.
    End point type
    Secondary
    End point timeframe
    Baseline at either Study Part 1, or Study Part 2, and End of Study (study weeks 29-31)
    End point values
    Study Part 2: Prophylactic cohort Study Part 2: On-demand cohort
    Number of subjects analysed
    2
    1
    Units: Score on a scale
    arithmetic mean (standard deviation)
        Part 1 or Part 2, Exposure Day 1 (Baseline)
    65.63 ± 13.26
    65.63 ± 0
        End of Study
    54.69 ± 6.63
    65.63 ± 0
        Change from Baseline
    -10.94 ± 19.89
    0 ± 0
    No statistical analyses for this end point

    Secondary: Pediatric Quality of Life Questionnaire (PedsQL) Psychosocial Health Summary Score (Ages 12-16)

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    End point title
    Pediatric Quality of Life Questionnaire (PedsQL) Psychosocial Health Summary Score (Ages 12-16)
    End point description
    The Peds-QL is a generic Health-Related Quality of Life (HR QoL) instrument designed specifically for a pediatric population. It captures the following domains: general health/activities, feelings/emotional, social functioning, school functioning. For this study, the Peds-QL for 12 to 16-year-old subjects was used. Higher scores indicate better quality of life (QOL) for all domains of the Peds-QL. This modular instrument uses a 5-point scale: from 0 (never) to 4 (almost always). Items are reversed scored and linearly transformed to a 0-100 scale as follows: 0=100, 1=75, 2=50, 3=25, 4=0. 4 dimensions (physical, emotional, social, & school functioning) are scored.
    End point type
    Secondary
    End point timeframe
    Baseline at either Study Part 1, or Study Part 2, and End of Study (study weeks 29-31)
    End point values
    Study Part 2: Prophylactic cohort Study Part 2: On-demand cohort
    Number of subjects analysed
    2
    1
    Units: Score on a scale
    arithmetic mean (standard deviation)
        Part 1 or Part 2, Exposure Day 1 (Baseline)
    63.33 ± 11.79
    88.33 ± 0
        End of Study
    55.83 ± 3.54
    86.67 ± 0
        Change from Baseline
    -7.5 ± 8.25
    -1.67 ± 0
    No statistical analyses for this end point

    Secondary: Pediatric Quality of Life Questionnaire (PedsQL) Total Score (Ages 12-16)

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    End point title
    Pediatric Quality of Life Questionnaire (PedsQL) Total Score (Ages 12-16)
    End point description
    The Peds-QL is a generic Health-Related Quality of Life (HR QoL) instrument designed specifically for a pediatric population. It captures the following domains: general health/activities, feelings/emotional, social functioning, school functioning. For this study, the Peds-QL for 12 to 16-year-old subjects was used. Higher scores indicate better quality of life (QOL) for all domains of the Peds-QL. This modular instrument uses a 5-point scale: from 0 (never) to 4 (almost always). Items are reversed scored and linearly transformed to a 0-100 scale as follows: 0=100, 1=75, 2=50, 3=25, 4=0. 4 dimensions (physical, emotional, social, & school functioning) are scored.
    End point type
    Secondary
    End point timeframe
    Baseline at either Study Part 1, or Study Part 2, and End of Study (study weeks 29-31)
    End point values
    Study Part 2: Prophylactic cohort Study Part 2: On-demand cohort
    Number of subjects analysed
    2
    1
    Units: Score on a scale
    arithmetic mean (standard deviation)
        Part 1 or Part 2, Exposure Day 1 (Baseline)
    64.13 ± 12.3
    80.43 ± 0
        End of Study
    55.43 ± 0
    79.35 ± 0
        Change from Baseline
    -8.7 ± 12.3
    -1.09 ± 0
    No statistical analyses for this end point

    Secondary: Health-Related Quality of Life (HRQoL) Disease-specific: Haem-A-QoL

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    End point title
    Health-Related Quality of Life (HRQoL) Disease-specific: Haem-A-QoL
    End point description
    The Haem-A-QOL instrument has been developed and used in hemophilia A patients. As a hemophilia-specific instrument, this measure assesses very specific aspects of dealing with hemophilia. The areas covered by this instrument are: physical health, sports/leisure, school/work, dealing with hemophilia, and outlook for the future. For the Haem-A-QOL, higher scores indicate a worse quality of life. Scores on a scale range between 0 and 100.
    End point type
    Secondary
    End point timeframe
    Baseline at either Study Part 1, or Study Part 2, and End of Study (study weeks 29-31)
    End point values
    Study Part 2: Prophylactic cohort Study Part 2: On-demand cohort
    Number of subjects analysed
    48 [15]
    13
    Units: Score on a scale
    arithmetic mean (standard deviation)
        Part 1 or Part 2, Exposure Day 1 (Baseline)
    40.68 ± 15.33
    41.65 ± 15.19
        End of Study
    37.85 ± 16.57
    41.37 ± 16.64
        Change from Baseline
    -3.52 ± 12.81
    -0.28 ± 12.18
    Notes
    [15] - N=51 at baseline, N=50 at end of study, N=48 for change from baseline
    No statistical analyses for this end point

    Secondary: Health-Related Quality of Life (HRQoL) Disease-specific: Haemo-QoL - Participants On-Demand (Ages 12-16)

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    End point title
    Health-Related Quality of Life (HRQoL) Disease-specific: Haemo-QoL - Participants On-Demand (Ages 12-16)
    End point description
    The Haemo-QoL is a quality of life (QoL) assessment instrument for children and adolescents with haemophilia. As a hemophilia-specific instrument, this measure assesses very specific aspects of dealing with hemophilia. For the Haemo-QoL, higher scores indicate a worse quality of life. Scores on a scale range between 0 and 100.
    End point type
    Secondary
    End point timeframe
    Baseline at either Study Part 1, or Study Part 2, and End of Study (study weeks 29-31)
    End point values
    Study Part 2: On-demand cohort
    Number of subjects analysed
    1
    Units: Score on a scale
    arithmetic mean (standard deviation)
        Part 1 or Part 2, Exposure Day 1 (Baseline)
    40 ± 0
        End of Study
    40 ± 0
        Change from Baseline
    0 ± 0
    No statistical analyses for this end point

    Secondary: Health Resource Use - Number of Hospitalizations

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    End point title
    Health Resource Use - Number of Hospitalizations
    End point description
    End point type
    Secondary
    End point timeframe
    Study Part 1 = 2-4 weeks, Study Part 2 = 26 weeks ± 1 week, Study Part 3 = 1 week (Total = 29-31 weeks)
    End point values
    Study Part 2: Prophylactic cohort Study Part 2: On-demand cohort
    Number of subjects analysed
    57
    14 [16]
    Units: Hospitalizations
    median (full range (min-max))
        Part 1 - PK (N= 28/prophy; NA/on-demand)
    0 (0 to 0)
    0 (0 to 0)
        Part 2: Exp Day 1 (N= 31/prophy, 14/on-demand)
    0 (0 to 0)
    0 (0 to 0)
        Part 2: Week 5 (N= 57/prophy, 14/on-demand)
    0 (0 to 1)
    0 (0 to 0)
        Part 2: Week 13 (N= 56/prophy, 12/on-demand)
    0 (0 to 0)
    0 (0 to 0)
        Part 2: Week 26 (N= 30/prophy, NA/on-demand)
    0 (0 to 0)
    0 (0 to 0)
        Part 3 (N= 25/prophy, NA/on-demand)
    0 (0 to 3)
    0 (0 to 0)
        Completion/Termination (N= 20 /prophy, 9/on-dem)
    0 (0 to 1)
    0 (0 to 0)
        Unscheduled Study Visit (N= 1/prophy, NA/on-dem)
    0 (0 to 0)
    0 (0 to 0)
    Notes
    [16] - No on-demand subjects in Part 1, in Part 2 at Week 26, in Part 3, and with an unscheduled visit.
    No statistical analyses for this end point

    Secondary: Health Resource Use - Total Days of Hospital Stay

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    End point title
    Health Resource Use - Total Days of Hospital Stay
    End point description
    This endpoint is only applicable to 4 subjects in the propyhlactic cohort who were hospitalized.
    End point type
    Secondary
    End point timeframe
    Study Part 1 = 2-4 weeks, Study Part 2 = 26 weeks ± 1 week, Study Part 3 = 1 week (Total = 29-31 weeks)
    End point values
    Study Part 2: Prophylactic cohort
    Number of subjects analysed
    4
    Units: Days
    median (full range (min-max))
        Part 2: Week 5 (N= 1)
    46 (46 to 46)
        Part 2: Week 13 (N= 1)
    23 (23 to 23)
        Part 3 (N= 3)
    2 (1 to 16)
        Completion/Termination (N= 2)
    5.5 (2 to 9)
    No statistical analyses for this end point

    Secondary: Health Resource Use - Emergency Room Visits

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    End point title
    Health Resource Use - Emergency Room Visits
    End point description
    End point type
    Secondary
    End point timeframe
    Study Part 1 = 2-4 weeks, Study Part 2 = 26 weeks ± 1 week, Study Part 3 = 1 week (Total = 29-31 weeks)
    End point values
    Study Part 2: Prophylactic cohort Study Part 2: On-demand cohort
    Number of subjects analysed
    57
    14 [17]
    Units: Visits
    median (full range (min-max))
        Part 1 - PK (N= 28/prophy, NA/on-demand)
    0 (0 to 0)
    0 (0 to 0)
        Part 2: Exp Day 1 (N= 31/prophy, 14/on-demand)
    0 (0 to 10)
    0 (0 to 0)
        Part 2: Week 5 (N= 57/prophy, 14/on-demand)
    0 (0 to 1)
    0 (0 to 0)
        Part 2: Week 13 (N= 56/prophy, 12/on-demand)
    0 (0 to 1)
    0 (0 to 0)
        Part 2: Week 26 (N= 30/prophy, NA/on-demand)
    0 (0 to 0)
    0 (0 to 0)
        Part 3 (N= 25/prophy, NA/on-demand)
    0 (0 to 0)
    0 (0 to 0)
        Completion/Termination (N= 20/prophy, 9/on-demand)
    0 (0 to 1)
    0 (0 to 0)
        Unscheduled Study Visit (N= 1/prophy, NA/on-dem)
    0 (0 to 0)
    0 (0 to 0)
    Notes
    [17] - No on-demand subjects in Part 1, in Part 2 at Week 26, in Part 3, and with an unscheduled visit.
    No statistical analyses for this end point

    Secondary: Health Resource Use - Unscheduled Doctor's Office Visits

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    End point title
    Health Resource Use - Unscheduled Doctor's Office Visits
    End point description
    End point type
    Secondary
    End point timeframe
    Study Part 1 = 2-4 weeks, Study Part 2 = 26 weeks ± 1 week, Study Part 3 = 1 week (Total = 29-31 weeks)
    End point values
    Study Part 2: Prophylactic cohort Study Part 2: On-demand cohort
    Number of subjects analysed
    57
    14 [18]
    Units: Visits
    median (full range (min-max))
        Part 1 - PK (N= 28/prophy, NA/on-demand)
    0 (0 to 1)
    0 (0 to 0)
        Part 2: Exp Day 1 (N= 31/prophy, 14/on-demand)
    0 (0 to 0)
    0 (0 to 0)
        Part 2: Week 5 (N= 57/prophy, 14/on-demand)
    0 (0 to 3)
    0 (0 to 0)
        Part 2: Week 13 (N= 56/prophy, 12/on-demand)
    0 (0 to 2)
    0 (0 to 0)
        Part 2: Week 26 (N= 30/prophy, NA/on-demand)
    0 (0 to 1)
    0 (0 to 0)
        Part 3 (N= 25/prophy, NA/on-demand)
    0 (0 to 1)
    0 (0 to 0)
        Completion/Termination (N= 20/prophy, 9/on-demand)
    0 (0 to 2)
    0 (0 to 1)
        Unscheduled Study Visit (N= 1/prophy, NA/on-dem)
    1 (1 to 1)
    0 (0 to 0)
    Notes
    [18] - No on-demand subjects in Part 1, in Part 2 at Week 26, in Part 3, and with an unscheduled visit.
    No statistical analyses for this end point

    Secondary: Health Resource Use - Days Lost from Work or School

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    End point title
    Health Resource Use - Days Lost from Work or School
    End point description
    End point type
    Secondary
    End point timeframe
    Study Part 1 = 2-4 weeks, Study Part 2 = 26 weeks ± 1 week, Study Part 3 = 1 week (Total = 29-31 weeks)
    End point values
    Study Part 2: Prophylactic cohort Study Part 2: On-demand cohort
    Number of subjects analysed
    57
    14 [19]
    Units: Days
    median (full range (min-max))
        Part 1 - PK (N= 28/prophy, NA/on-demand)
    0 (0 to 10)
    0 (0 to 0)
        Part 2: Exp Day 1 (N= 31/prophy, 14/on-demand)
    0 (0 to 2)
    0 (0 to 0)
        Part 2: Week 5 (N= 57/prophy, 14/on-demand)
    0 (0 to 8)
    0 (0 to 4)
        Part 2: Week 13 (N= 56/prophy, 12/on-demand)
    0 (0 to 7)
    0 (0 to 0)
        Part 2: Week 26 (N= 30/prophy, NA/on-demand)
    0 (0 to 5)
    0 (0 to 0)
        Part 3 (N= 25/prophy, NA/on-demand)
    0 (0 to 1)
    0 (0 to 0)
        Completion/Termination (N= 20/prophy, 9/on-demand)
    0 (0 to 24)
    0 (0 to 0)
        Unscheduled Study Visit (N= 1/prophy, NA/on-dem)
    0 (0 to 0)
    0 (0 to 0)
    Notes
    [19] - No on-demand subjects in Part 1, in Part 2 at Week 26, in Part 3, and with an unscheduled visit.
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Study Part 1 = 2-4 weeks, Study Part 2 = 26 weeks ± 1 week, Study Part 3 = 1 week (Total = 29-31 weeks)
    Assessment type
    Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    N/A
    Reporting groups
    Reporting group title
    BAX326
    Reporting group description
    BAX326: -Study Part 1: Pharmacokinetic (PK) Crossover with BAX326 and BeneFIX •Study Part 2: Open-label evaluation of prophylaxis and on-demand BAX326 only •Study Part 3: Open-label repeat of PK evaluation (repeat Study Part 1) with BAX326 only and same study participants as Study Part 1

    Serious adverse events
    BAX326
    Total subjects affected by serious adverse events
         subjects affected / exposed
    4 / 73 (5.48%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Injury, poisoning and procedural complications
    Cervical Vertebral Fracture
         subjects affected / exposed
    1 / 73 (1.37%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Traumatic Haematoma
         subjects affected / exposed
    1 / 73 (1.37%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Investigations
    Hepatitis B Core Antibody Positive
    Additional description: The subject´s medical history included chronic hepatitis B.
         subjects affected / exposed
    1 / 73 (1.37%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Nervous system disorders
    Convulsion
         subjects affected / exposed
    1 / 73 (1.37%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorders
    Intestinal Obstruction
         subjects affected / exposed
    1 / 73 (1.37%)
         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
    BAX326
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    15 / 73 (20.55%)
    Investigations
    Immunology Test Abnormal
         subjects affected / exposed
    12 / 73 (16.44%)
         occurrences all number
    12
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    6 / 73 (8.22%)
         occurrences all number
    8

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    05 Jul 2010
    - In the eligibility criteria, the acceptable upper limit of normal for ALT and AST was increased from ≥2 times to >5 times. - To ensure that subject weight is within a reasonable range, the following exclusion criterion was added: The subject´s weight is < 35 kg or > 120 kg. - It was clarified that hospitalization for elective surgery would not be considered a serious adverse event (SAE). - It was clarified that in Part 1 thrombotic markers would not only be assessed prior to and following the BAX326 infusion but also prior to and following the BeneFIX infusion. - The number of bleeding episodes (BEs) beginning within 24 and 48 hours of an infusion was added as an exploratory endpoint (per request of FDA). - The assessment time point for the main overall hemostatic efficacy rating for the treatment of BEs was set at “resolution of bleed” to be consistent with previous hemophilia studies. Overall hemostatic efficacy ratings performed at 12 ± 1 and 24 ± 1 h time points were added as exploratory endpoints. - It was emphasized that in case of inadequate response to BAX326, the subject should be managed according to the clinical judgment of the Investigator. - A third interim safety review was added which was to be performed after 24 subjects (20 evaluable) had completed Part 2 of whom 16 subjects had also completed Parts 1 and 3, and had been evaluated for hemostatic efficacy, safety, and immunogenicity for a period 50 EDs or 6 months, whichever occurred last.
    03 May 2011
    - An additional on-demand cohort of 15 to 20 subjects was added to Part 2 of the study. The total sample size was therefore increased from 60 up to 75-80 PTPs. The 2 cohorts are described as ‘prophylactic cohort’ and ‘on-demand cohort’. The reason for adding an on-demand cohort was to ensure sufficient data on the hemostatic efficacy of BAX326 in the treatment of BEs. It was specified that the decision regarding the type of treatment regimen was at the discretion of the Investigator and subject. However, once enrollment in the prophylactic cohort was completed (n = 60), only subjects willing to receive on-demand treatment would be recruited. The on-demand cohort would basically follow the same study schedule as the prophylactic cohort, except that they would only receive BAX326 to treat BEs and to determine IR at the scheduled study visits. - The following subject participation periods for the respective cohorts (prophylactic and on-demand) were added: a) Prophylactic cohort: 8-12 months for subjects taking part in Parts 1, 2 and 3; approximately 7-10 months for subject taking part in Part 2 only (unless prematurely discontinued) b) On-demand cohort: approximately 2-10 months, depending on when the subject is enrolled. - The upper acceptable limit of the International Normalized Ratio (INR) in the eligibility criteria was increased from 1.2 (upper limit of normal as defined by the central laboratory) to 1.4 to account for the fluctuating INR values between 1.1 and 1.4, in particular in subjects with hepatitis. - It was clarified that only vials with a nominal potency of 500 IU could be used for the PK parts and the determination of IR. - Although the required minimum wash-out period prior to the PK infusions in Parts 1 and 3 and prior to all study visits in Part 2 was 5 days, it was added that a wash-out period of 7 days would be preferable to ensure that the baseline FIX activity level was reached.
    02 Mar 2012
    The sample size for the third interim safety review was increased from 24 to 50 subjects (as suggested by FDA).

    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

    Online references

    http://www.ncbi.nlm.nih.gov/pubmed/24832133
    http://www.ncbi.nlm.nih.gov/pubmed/23834666
    http://www.ncbi.nlm.nih.gov/pubmed/24251442
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