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    Clinical Trial Results:
    BAX326 (recombinant factor IX): a phase 2/3, prospective, uncontrolled, multicenter study evaluating pharmacokinetics, efficacy, safety, and immunogenicity in previously treated pediatric patients with severe (FIX level <1%) or moderately severe (FIX level 1-2%) hemophilia B

    Summary
    EudraCT number
    2011-002437-19
    Trial protocol
    GB   BG  
    Global end of trial date
    14 May 2013

    Results information
    Results version number
    v1(current)
    This version publication date
    18 Feb 2016
    First version publication date
    06 Aug 2015
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    251101
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01488994
    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
    26 Aug 2013
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    14 May 2013
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate all adverse events possibly or probably related to BAX326
    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. There were 2 age cohorts: <6 years and 6 to <12 years. To reduce the burden of frequent blood sampling on the individual subject for the pharmacokinetic assessment (total of 7 post-infusion sampling time points over 72 hours), subjects within each age cohort were randomized to one of 2 blood sampling sequences of 4 post-infusion blood sampling time points each.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    20 Dec 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: 5
    Country: Number of subjects enrolled
    Romania: 5
    Country: Number of subjects enrolled
    Ukraine: 3
    Country: Number of subjects enrolled
    United Kingdom: 2
    Country: Number of subjects enrolled
    Russian Federation: 7
    Country: Number of subjects enrolled
    India: 1
    Worldwide total number of subjects
    23
    EEA total number of subjects
    12
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    23
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    0
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    Enrollment was conducted at 11 clinical sites in 6 countries (United Kingdom, Poland, Romania, Russian Federation, Ukraine, India). A total of 23 subjects were enrolled in the study. Of these, 11 were <6 years of age and 12 were 6 to <12 years of age.

    Pre-assignment
    Screening details
    -

    Pre-assignment period milestones
    Number of subjects started
    23
    Number of subjects completed
    23

    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
    Paediatric subjects <6 years of age
    Arm description
    Subjects in this cohort had their pharmacokinetic infusion with BAX326 in the morning and were assigned to the following 4 post-infusion blood sampling time points: 15-30 min, 7±1 hour(s), anytime during the 2nd day, anytime during the 3rd day
    Arm type
    Experimental

    Investigational medicinal product name
    BAX326 (recombinant factor IX)
    Investigational medicinal product code
    Other name
    Rixubis
    Pharmaceutical forms
    Powder and solvent for solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects underwent a pharmacokinetic evaluation with BAX326 (1 infusion) which was followed by a twice weekly prophylactic treatment with BAX326. Bleeding episodes were also treated with BAX326.

    Arm title
    Paediatric subjects 6 to <12 years of age
    Arm description
    Subjects in this cohort had their pharmacokinetic infusion with BAX326 in the afternoon and were assigned to the following 4 post-infusion blood sampling time points: 15-30 min, 4±1 hour(s), anytime during the 2nd day, morning of the 4th day
    Arm type
    Experimental

    Investigational medicinal product name
    BAX326 (recombinant factor IX)
    Investigational medicinal product code
    Other name
    Rixubis
    Pharmaceutical forms
    Powder and solvent for solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects underwent a pharmacokinetic evaluation with BAX326 (1 infusion) which was followed by a twice weekly prophylactic treatment with BAX326. Bleeding episodes were also treated with BAX326.

    Number of subjects in period 1
    Paediatric subjects <6 years of age Paediatric subjects 6 to <12 years of age
    Started
    11
    12
    Completed
    11
    11
    Not completed
    0
    1
         Consent withdrawn by subject
             -
             1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Paediatric subjects <6 years of age
    Reporting group description
    Subjects in this cohort had their pharmacokinetic infusion with BAX326 in the morning and were assigned to the following 4 post-infusion blood sampling time points: 15-30 min, 7±1 hour(s), anytime during the 2nd day, anytime during the 3rd day

    Reporting group title
    Paediatric subjects 6 to <12 years of age
    Reporting group description
    Subjects in this cohort had their pharmacokinetic infusion with BAX326 in the afternoon and were assigned to the following 4 post-infusion blood sampling time points: 15-30 min, 4±1 hour(s), anytime during the 2nd day, morning of the 4th day

    Reporting group values
    Paediatric subjects <6 years of age Paediatric subjects 6 to <12 years of age Total
    Number of subjects
    11 12 23
    Age categorical
    Units: Subjects
        <6 years of age
    11 0 11
        6 to <12 years of age
    0 12 12
    Age continuous
    Units: years
        arithmetic mean (full range (min-max))
    3.83 (1.8 to 6) 9.8 (7.1 to 11.8) -
    Gender categorical
    Units:
        Male
    11 12 23
        Female
    0 0 0
    Subject analysis sets

    Subject analysis set title
    Full Analysis Set
    Subject analysis set type
    Full analysis
    Subject analysis set description
    Comprised all subjects who received at least one infusion of investigational product

    Subject analysis set title
    Pharmacokinetic Full Analysis Set
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Comprised all subjects who had at least one plasma factor IX activity level available during post-infusion time points

    Subject analysis sets values
    Full Analysis Set Pharmacokinetic Full Analysis Set
    Number of subjects
    23
    23
    Age categorical
    Units: Subjects
        <6 years of age
    11
    11
        6 to <12 years of age
    12
    12
    Age continuous
    Units: years
        arithmetic mean (full range (min-max))
    6.94 (1.8 to 11.8)
    6.94 (1.8 to 11.8)
    Gender categorical
    Units:
        Male
    23
    23
        Female
    0
    0

    End points

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    End points reporting groups
    Reporting group title
    Paediatric subjects <6 years of age
    Reporting group description
    Subjects in this cohort had their pharmacokinetic infusion with BAX326 in the morning and were assigned to the following 4 post-infusion blood sampling time points: 15-30 min, 7±1 hour(s), anytime during the 2nd day, anytime during the 3rd day

    Reporting group title
    Paediatric subjects 6 to <12 years of age
    Reporting group description
    Subjects in this cohort had their pharmacokinetic infusion with BAX326 in the afternoon and were assigned to the following 4 post-infusion blood sampling time points: 15-30 min, 4±1 hour(s), anytime during the 2nd day, morning of the 4th day

    Subject analysis set title
    Full Analysis Set
    Subject analysis set type
    Full analysis
    Subject analysis set description
    Comprised all subjects who received at least one infusion of investigational product

    Subject analysis set title
    Pharmacokinetic Full Analysis Set
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Comprised all subjects who had at least one plasma factor IX activity level available during post-infusion time points

    Primary: Adverse events (AEs) possibly or probably related to BAX326

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    End point title
    Adverse events (AEs) possibly or probably related to BAX326 [1]
    End point description
    Probable, possible, or unknown causality assessment of an AE were to be counted as “related". AEs that occurred during or after treatment application were presented in summary tables. An overview summary table presented the number (%) of AEs, the number (%) of subjects with AEs by seriousness, severity, and relationship to the study product. Descriptive statistics were presented by age stratum.
    End point type
    Primary
    End point timeframe
    Approximately 7 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, descriptive statistics were collected for this endpoint.
    End point values
    Paediatric subjects <6 years of age Paediatric subjects 6 to <12 years of age Full Analysis Set
    Number of subjects analysed
    11
    12
    23
    Units: possibly or probably related AEs
    0
    0
    0
    No statistical analyses for this end point

    Secondary: Pharmacokinetics (PK): Total Area under the plasma concentration versus time curve per dose (Total AUC/dose)

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    End point title
    Pharmacokinetics (PK): Total Area under the plasma concentration versus time curve per dose (Total AUC/dose)
    End point description
    End point type
    Secondary
    End point timeframe
    72 hours
    End point values
    Paediatric subjects <6 years of age Paediatric subjects 6 to <12 years of age Pharmacokinetic Full Analysis Set
    Number of subjects analysed
    11
    12
    23
    Units: IU•hour (hr)/dL
        arithmetic mean (standard deviation)
    723.7 ± 119
    886 ± 133.66
    808.4 ± 149.14
    No statistical analyses for this end point

    Secondary: PK: Mean residence time (MRT)

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    End point title
    PK: Mean residence time (MRT)
    End point description
    Computed as total area under the first moment curve (total AUMC) divided by the total area under the concentration versus time curve (total AUC)
    End point type
    Secondary
    End point timeframe
    72 hours
    End point values
    Paediatric subjects <6 years of age Paediatric subjects 6 to <12 years of age Pharmacokinetic Full Analysis Set
    Number of subjects analysed
    11
    12
    23
    Units: hours (hr)
        arithmetic mean (standard deviation)
    30.62 ± 3.266
    25.31 ± 1.83
    27.85 ± 3.726
    No statistical analyses for this end point

    Secondary: PK: Factor IX (FIX) clearance (CL)

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    End point title
    PK: Factor IX (FIX) clearance (CL)
    End point description
    Computed as the dose divided by total AUC
    End point type
    Secondary
    End point timeframe
    72 hours
    End point values
    Paediatric subjects <6 years of age Paediatric subjects 6 to <12 years of age Pharmacokinetic Full Analysis Set
    Number of subjects analysed
    11
    12
    23
    Units: dL/(kg•hr)
        arithmetic mean (standard deviation)
    0.1058 ± 0.0165
    0.0874 ± 0.01213
    0.0962 ± 0.01689
    No statistical analyses for this end point

    Secondary: PK: Incremental recovery (IR)

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    End point title
    PK: Incremental recovery (IR)
    End point description
    Calculated as follows: (FIX activity at post-infusion minus FIX activity at pre-infusion) divided by weight-adjusted dose
    End point type
    Secondary
    End point timeframe
    30 minutes
    End point values
    Paediatric subjects <6 years of age Paediatric subjects 6 to <12 years of age Pharmacokinetic Full Analysis Set
    Number of subjects analysed
    10 [2]
    12
    22
    Units: IU/dL : IU/kg
        arithmetic mean (standard deviation)
    0.586 ± 0.132
    0.731 ± 0.1615
    0.665 ± 0.1632
    Notes
    [2] - 1 subject <6 yrs had a biologically implausible FIX level at 15-30 min post-infusion -> was excluded
    No statistical analyses for this end point

    Secondary: PK: Elimination phase half-life (T 1/2)

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    End point title
    PK: Elimination phase half-life (T 1/2)
    End point description
    Calculated as log_e2/λ, where λ is the regression slope in the terminal phase of the least absolute deviations regression model
    End point type
    Secondary
    End point timeframe
    72 hours
    End point values
    Paediatric subjects <6 years of age Paediatric subjects 6 to <12 years of age Pharmacokinetic Full Analysis Set
    Number of subjects analysed
    11
    12
    23
    Units: hr
        arithmetic mean (standard deviation)
    27.67 ± 2.658
    23.15 ± 1.582
    25.31 ± 3.13
    No statistical analyses for this end point

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

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    End point title
    PK: Volume of distribution at steady state (Vss)
    End point description
    Computed as Clearance (CL) * Mean residence time (MRT)
    End point type
    Secondary
    End point timeframe
    72 hours
    End point values
    Paediatric subjects <6 years of age Paediatric subjects 6 to <12 years of age Pharmacokinetic Full Analysis Set
    Number of subjects analysed
    11
    12
    23
    Units: dL/kg
        arithmetic mean (standard deviation)
    3.225 ± 0.5233
    2.209 ± 0.3165
    2.695 ± 0.6662
    No statistical analyses for this end point

    Secondary: PK: Incremental recovery (IR) over time

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    End point title
    PK: Incremental recovery (IR) over time
    End point description
    Calculated as follows: (FIX activity at post-infusion minus FIX activity at pre-infusion) divided by weight-adjusted dose
    End point type
    Secondary
    End point timeframe
    Week 5, Week 13, Week 26 and study completion/termination visit (for participants receiving BAX326 beyond Week 26)
    End point values
    Paediatric subjects <6 years of age Paediatric subjects 6 to <12 years of age Pharmacokinetic Full Analysis Set
    Number of subjects analysed
    11 [3]
    12 [4]
    23 [5]
    Units: IU/dL : IU/kg
    arithmetic mean (standard deviation)
        Week 5
    0.63 ± 0.1028
    0.726 ± 0.1291
    0.68 ± 0.1245
        Week 13
    0.676 ± 0.1211
    0.733 ± 0.14
    0.706 ± 0.1313
        Week 26
    0.647 ± 0.1274
    0.795 ± 0.1445
    0.724 ± 0.1533
    Notes
    [3] - Only 10 subjects in the <6-year age group were analyzed for Week 13 and Week 26.
    [4] - Only 11 subjects in the 6-to-<12-year age group were analyzed for Week 13 and Week 26.
    [5] - Only 21 subjects were analyzed for Week 13 and Week 26.
    No statistical analyses for this end point

    Secondary: Haemostatic efficacy: Treatment of bleeding episodes: number of infusions per bleeding episode

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    End point title
    Haemostatic efficacy: Treatment of bleeding episodes: number of infusions per bleeding episode
    End point description
    End point type
    Secondary
    End point timeframe
    Approximately 7 months per subject
    End point values
    Paediatric subjects <6 years of age Paediatric subjects 6 to <12 years of age Full Analysis Set
    Number of subjects analysed
    7 [6]
    7 [7]
    14 [8]
    Units: Bleeding episodes
        Controlled with 1 infusion
    9
    6
    15
        Controlled with 2 infusions
    1
    7
    8
        Controlled with 3 or more infusions
    1
    2
    3
    Notes
    [6] - 7 subjects <6 yrs had total of 11 bleeding episodes after first BAX326 exposure which were treated
    [7] - 7 subjects 6 - <12 yrs had 15 bleeding episodes after first BAX326 exposure which were treated
    [8] - 14 subjects in FAS had total of 26 bleeding episodes after first BAX326 exposure which were treated
    No statistical analyses for this end point

    Secondary: Haemostatic efficacy: Treatment of bleeding episodes: overall haemostatic efficacy rating at resolution of bleed

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    End point title
    Haemostatic efficacy: Treatment of bleeding episodes: overall haemostatic efficacy rating at resolution of bleed
    End point description
    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
    Approximately 7 months per subject
    End point values
    Paediatric subjects <6 years of age Paediatric subjects 6 to <12 years of age Full Analysis Set
    Number of subjects analysed
    7 [9]
    7 [10]
    14 [11]
    Units: rating
        Excellent
    9
    4
    13
        Good
    2
    10
    12
        Fair
    0
    1
    1
        None
    0
    0
    0
    Notes
    [9] - 7 subjects <6 yrs had total of 11 bleeding episodes after first BAX326 exposure which were treated
    [10] - 7 subjects 6 - <12 yrs had 15 bleeding episodes after first BAX326 exposure which were treated
    [11] - 14 subjects in FAS had total of 26 bleeding episodes after first BAX326 exposure which were treated
    No statistical analyses for this end point

    Secondary: Haemostatic efficacy: Prophylaxis: annualized bleeding rate (ABR)

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    End point title
    Haemostatic efficacy: Prophylaxis: annualized bleeding rate (ABR)
    End point description
    End point type
    Secondary
    End point timeframe
    Approximately 7 months per subject
    End point values
    Paediatric subjects <6 years of age Paediatric subjects 6 to <12 years of age Full Analysis Set
    Number of subjects analysed
    11 [12]
    12 [13]
    23 [14]
    Units: Annualized bleeding rate (ABR)
        arithmetic mean (standard deviation)
    1.9 ± 1.89
    3.4 ± 3.93
    2.7 ± 3.14
    Notes
    [12] - All 11 subjects <6 yrs had at least 3 months of prophylactic treatment with BAX326
    [13] - All 12 subjects 6 - <12 yrs had at least 3 months of prophylactic treatment with BAX326
    [14] - All 23 subjects in the FAS had at least 3 months of prophylactic treatment with BAX326
    No statistical analyses for this end point

    Secondary: Consumption of BAX326: number of infusions per month and per year (annualized)

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    End point title
    Consumption of BAX326: number of infusions per month and per year (annualized)
    End point description
    End point type
    Secondary
    End point timeframe
    Approximately 7 months per subject
    End point values
    Paediatric subjects <6 years of age Paediatric subjects 6 to <12 years of age Full Analysis Set
    Number of subjects analysed
    11
    12
    23
    Units: infusions
    arithmetic mean (standard deviation)
        Per month
    6.8 ± 0.44
    7.2 ± 0.4
    7 ± 0.44
        Per year
    82.1 ± 5.27
    85.9 ± 4.79
    84.1 ± 5.27
    No statistical analyses for this end point

    Secondary: Consumption of BAX326: weight-adjusted consumption per month and per year (annualized)

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    End point title
    Consumption of BAX326: weight-adjusted consumption per month and per year (annualized)
    End point description
    End point type
    Secondary
    End point timeframe
    Approximately 7 months per subject
    End point values
    Paediatric subjects <6 years of age Paediatric subjects 6 to <12 years of age Full Analysis Set
    Number of subjects analysed
    11
    12
    23
    Units: IU/kg
    arithmetic mean (standard deviation)
        Per month
    393.4 ± 50.53
    414.8 ± 58.44
    404.6 ± 54.66
        Per year
    4720.9 ± 606.31
    4978.2 ± 701.26
    4855.1 ± 655.93
    No statistical analyses for this end point

    Secondary: Consumption of BAX326: weight-adjusted consumption per event

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    End point title
    Consumption of BAX326: weight-adjusted consumption per event
    End point description
    End point type
    Secondary
    End point timeframe
    Approximately 7 months per subject
    End point values
    Paediatric subjects <6 years of age Paediatric subjects 6 to <12 years of age Full Analysis Set
    Number of subjects analysed
    11 [15]
    12 [16]
    23 [17]
    Units: IU/kg
    arithmetic mean (standard deviation)
        Prophylactic Infusions
    56.3 ± 10.29
    56.2 ± 6.55
    56.2 ± 8.34
        Infusions for treatment of bleeding episodes
    57.6 ± 11.87
    62.1 ± 16
    59.9 ± 13.74
    Notes
    [15] - All 11 subjects received prophylactic infusions but only 7 received treatment for bleeding episodes
    [16] - All 12 subjects received prophylactic infusions but only 7 received treatment for bleeding episodes
    [17] - All 23 subjects received prophylactic infusions but only 14 received treatment for bleeding episodes
    No statistical analyses for this end point

    Secondary: Safety and Immunogenicity: Development of inhibitory antibodies to factor IX (FIX)

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    End point title
    Safety and Immunogenicity: Development of inhibitory antibodies to factor IX (FIX)
    End point description
    End point type
    Secondary
    End point timeframe
    Approximately 7 months per subject
    End point values
    Paediatric subjects <6 years of age Paediatric subjects 6 to <12 years of age Full Analysis Set
    Number of subjects analysed
    11
    12
    23
    Units: subjects
    0
    0
    0
    No statistical analyses for this end point

    Secondary: Safety and Immunogenicity: Development of total binding antibodies to FIX

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    End point title
    Safety and Immunogenicity: Development of total binding antibodies to FIX
    End point description
    If more than 2-dilution increase as compared to pre-study level at screening and titers verified for specificity in the confirmatory assay
    End point type
    Secondary
    End point timeframe
    Approximately 7 months per subject
    End point values
    Paediatric subjects <6 years of age Paediatric subjects 6 to <12 years of age Full Analysis Set
    Number of subjects analysed
    11
    12
    23
    Units: subjects
    0
    0
    0
    No statistical analyses for this end point

    Secondary: Safety: Occurrence of severe allergic reactions (eg, anaphylaxis)

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    End point title
    Safety: Occurrence of severe allergic reactions (eg, anaphylaxis)
    End point description
    End point type
    Secondary
    End point timeframe
    Approximately 7 months per subject
    End point values
    Paediatric subjects <6 years of age Paediatric subjects 6 to <12 years of age Full Analysis Set
    Number of subjects analysed
    11
    12
    23
    Units: severe allergic reactions
    0
    0
    0
    No statistical analyses for this end point

    Secondary: Safety: Occurrence of thrombotic events

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    End point title
    Safety: Occurrence of thrombotic events
    End point description
    End point type
    Secondary
    End point timeframe
    Approximately 7 months per subject
    End point values
    Paediatric subjects <6 years of age Paediatric subjects 6 to <12 years of age Full Analysis Set
    Number of subjects analysed
    11
    12
    23
    Units: thrombotic events
    0
    0
    0
    No statistical analyses for this end point

    Secondary: Safety: Clinically significant (CS) changes in routine laboratory parameters (haematology and clinical chemistry), and vital signs

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    End point title
    Safety: Clinically significant (CS) changes in routine laboratory parameters (haematology and clinical chemistry), and vital signs
    End point description
    End point type
    Secondary
    End point timeframe
    Approximately 7 months per subject
    End point values
    Paediatric subjects <6 years of age Paediatric subjects 6 to <12 years of age Full Analysis Set
    Number of subjects analysed
    11
    12
    23
    Units: subjects
        CS changes in haematology parameters
    0
    2
    2
        CS changes in clinical chemistry parameters
    0
    0
    0
        CS changes in vital signs
    0
    0
    0
    No statistical analyses for this end point

    Secondary: Safety and Immunogenicity: Development of antibodies to Chinese hamster ovary (CHO) proteins and recombinant furin (rFurin)

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    End point title
    Safety and Immunogenicity: Development of antibodies to Chinese hamster ovary (CHO) proteins and recombinant furin (rFurin)
    End point description
    End point type
    Secondary
    End point timeframe
    Approximately 7 months per subject
    End point values
    Paediatric subjects <6 years of age Paediatric subjects 6 to <12 years of age Full Analysis Set
    Number of subjects analysed
    11
    12
    23
    Units: subjects
        Treatment-related Antibodies to CHO proteins
    0
    0
    0
        Treatment-related Antibodies to rFurin
    0
    0
    0
    No statistical analyses for this end point

    Secondary: Health-related Quality of Life (HRQoL): Peds-QL: Change from baseline in total score

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    End point title
    Health-related Quality of Life (HRQoL): Peds-QL: Change from baseline in total score
    End point description
    The Peds-QL is a generic HR QoL instrument designed specifically for a paediatric population. It captures the following domains: general health/activities, feelings/emotional, social functioning, school functioning. For this study, the Peds-QL questionnaires for subjects 2 to 7 years of age (parent-proxy versions for age groups 2-4 years and 5-7 years) and for subjects 8 to 12 years of age were used. Higher scores indicate better quality of life for all domains of the Peds-QL.
    End point type
    Secondary
    End point timeframe
    Approximately 6 months per subject
    End point values
    Full Analysis Set
    Number of subjects analysed
    23 [18]
    Units: score
    arithmetic mean (standard deviation)
        Peds-QL 2-4
    3.27 ± 10.119
        Peds-QL 5-7
    -7.07 ± 6.917
        PedsQL 8-12
    4.02 ± 11.038
    Notes
    [18] - Results for 4 subjects 2-4 years, 2 subjects 5-7 years and 10 subjects 8-12 years
    No statistical analyses for this end point

    Secondary: HRQoL: Haemo-QoL (short version): Change from baseline in total score

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    End point title
    HRQoL: Haemo-QoL (short version): Change from baseline in total score
    End point description
    The Haemo-QOL instrument assesses specific aspects of dealing with haemophilia. The areas covered by this instrument are: physical health, sports/leisure, school, dealing with haemophilia, and outlook for the future. For this study, the Haemo-QoL for subjects 8-16 years of age was used. Higher scores indicate worse quality of life.
    End point type
    Secondary
    End point timeframe
    Approximately 6 months per subject
    End point values
    Full Analysis Set
    Number of subjects analysed
    23 [19]
    Units: score
        arithmetic mean (standard deviation)
    -0.18 ± 0.456
    Notes
    [19] - Results are only available for 10 subjects >8 years of age.
    No statistical analyses for this end point

    Secondary: HRQoL: Number of hospitalizations

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    End point title
    HRQoL: Number of hospitalizations
    End point description
    End point type
    Secondary
    End point timeframe
    Approximately 6 months per subject
    End point values
    Paediatric subjects <6 years of age Paediatric subjects 6 to <12 years of age Full Analysis Set
    Number of subjects analysed
    11
    12
    23
    Units: subjects who were hospitalized
    1
    2
    3
    No statistical analyses for this end point

    Secondary: HRQoL: Length of hospitalization

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    End point title
    HRQoL: Length of hospitalization
    End point description
    End point type
    Secondary
    End point timeframe
    Approximately 6 months per subject
    End point values
    Paediatric subjects <6 years of age Paediatric subjects 6 to <12 years of age Full Analysis Set
    Number of subjects analysed
    11 [20]
    12 [21]
    23
    Units: days in hospital
    median (full range (min-max))
        Week 13
    2 (2 to 2)
    4 (4 to 4)
    3 (2 to 4)
        Week 26
    0 (0 to 0)
    13 (13 to 13)
    13 (13 to 13)
    Notes
    [20] - One subject in the <6-year age group underwent hospitalization by Week 13.
    [21] - Of 2 subjects 6 - <12 yrs who were hospitalized, 1 had data for Week 13 and the other for Week 26
    No statistical analyses for this end point

    Secondary: HRQoL: Unscheduled visits to a doctor´s office

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    End point title
    HRQoL: Unscheduled visits to a doctor´s office
    End point description
    End point type
    Secondary
    End point timeframe
    Approximately 6 months per subject
    End point values
    Paediatric subjects <6 years of age Paediatric subjects 6 to <12 years of age Full Analysis Set
    Number of subjects analysed
    11
    12
    23
    Units: Visits to a doctor´s office
    9
    5
    14
    No statistical analyses for this end point

    Secondary: HRQoL: Emergency Room (ER) visits

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    End point title
    HRQoL: Emergency Room (ER) visits
    End point description
    End point type
    Secondary
    End point timeframe
    Approximately 6 months per subject
    End point values
    Paediatric subjects <6 years of age Paediatric subjects 6 to <12 years of age Full Analysis Set
    Number of subjects analysed
    11 [22]
    12 [23]
    23 [24]
    Units: ER visits
    8
    3
    11
    Notes
    [22] - ER visits were recorded for 3 subjects in the <6-year age cohort.
    [23] - ER visits were recorded for 3 subjects in the 6-to-<12-year age cohort.
    [24] - ER visits were recorded for a total of 6 subjects.
    No statistical analyses for this end point

    Secondary: HRQoL: Days lost from school

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    End point title
    HRQoL: Days lost from school
    End point description
    End point type
    Secondary
    End point timeframe
    Approximately 6 months per subject
    End point values
    Paediatric subjects <6 years of age Paediatric subjects 6 to <12 years of age Full Analysis Set
    Number of subjects analysed
    11 [25]
    12 [26]
    23 [27]
    Units: days
    29
    53
    82
    Notes
    [25] - 2 subjects in the <6-year age group missed days from school.
    [26] - 8 subjects in the 6-to-<12-year age group missed days from school.
    [27] - A total of 10 subjects missed days from school.
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Approximately 7 months per subject
    Assessment type
    Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    N/A
    Reporting groups
    Reporting group title
    Paediatric subjects less than 6 years of age
    Reporting group description
    Subjects in this cohort had their pharmacokinetic infusion with BAX326 in the morning and were assigned to the following 4 post-infusion blood sampling time points: 15-30 min, 7±1 hour(s), anytime during the 2nd day, anytime during the 3rd day

    Reporting group title
    Paediatric subjects between 6 and less than 12 years of age
    Reporting group description
    Subjects in this cohort had their pharmacokinetic infusion with BAX326 in the afternoon and were assigned to the following 4 post-infusion blood sampling time points: 15-30 min, 4±1 hour(s), anytime during the 2nd day, anytime during the 3rd day

    Serious adverse events
    Paediatric subjects less than 6 years of age Paediatric subjects between 6 and less than 12 years of age
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 11 (0.00%)
    3 / 12 (25.00%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Injury, poisoning and procedural complications
    Humerus fracture
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Haemorrhage subcutaneous
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Haemarthrosis
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Device related infection
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Paediatric subjects less than 6 years of age Paediatric subjects between 6 and less than 12 years of age
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    7 / 11 (63.64%)
    9 / 12 (75.00%)
    Investigations
    Immunology test abnormal
    Additional description: The abnormal test results refer to total binding antibodies to FIX and/or rFurin of indeterminate specificity (titers of 1:20 or 1:40, ie, <2-dilution steps) which could not be verified in the confirmatory assay.
         subjects affected / exposed
    1 / 11 (9.09%)
    5 / 12 (41.67%)
         occurrences all number
    1
    7
    Nervous system disorders
    Headache
         subjects affected / exposed
    1 / 11 (9.09%)
    1 / 12 (8.33%)
         occurrences all number
    1
    1
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    1 / 11 (9.09%)
    1 / 12 (8.33%)
         occurrences all number
    1
    1
    Toothache
         subjects affected / exposed
    0 / 11 (0.00%)
    2 / 12 (16.67%)
         occurrences all number
    0
    2
    Infections and infestations
    Respiratory tract infection viral
         subjects affected / exposed
    0 / 11 (0.00%)
    2 / 12 (16.67%)
         occurrences all number
    0
    2
    Rhinitis
         subjects affected / exposed
    2 / 11 (18.18%)
    0 / 12 (0.00%)
         occurrences all number
    4
    0
    Bronchitis
         subjects affected / exposed
    1 / 11 (9.09%)
    1 / 12 (8.33%)
         occurrences all number
    1
    1
    Nasopharyngitis
         subjects affected / exposed
    1 / 11 (9.09%)
    1 / 12 (8.33%)
         occurrences all number
    1
    2
    Upper respiratory tract infection
         subjects affected / exposed
    2 / 11 (18.18%)
    1 / 12 (8.33%)
         occurrences all number
    2
    1

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? No

    Interruptions (globally)

    Were there any global interruptions to the trial? No

    Limitations and caveats

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