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    Clinical Trial Results:
    BAX326 (recombinant Factor IX): Evaluation of Safety, Immunogenicity, and Hemostatic Efficacy in Previously Treated Patients with Severe (FIX level < 1%) or Moderately Severe (FIX level 1-2 %) Hemophilia B - A Continuation Study

    Summary
    EudraCT number
    2010-022726-33
    Trial protocol
    BG   CZ   GB   DE   SE   PL   ES   IT   IE  
    Global end of trial date
    29 Jun 2017

    Results information
    Results version number
    v1(current)
    This version publication date
    05 Jan 2018
    First version publication date
    05 Jan 2018
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    251001
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01286779
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Baxalta, now part of Shire
    Sponsor organisation address
    Industriestrasse 67, Vienna, Austria, 1221
    Public contact
    Study Physician, Baxalta, now part of Shire, ClinicalTransparency@shire.com
    Scientific contact
    Study Physician, Baxalta, now part of Shire, ClinicalTransparency@shire.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
    29 Jun 2017
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    29 Jun 2017
    Global end of trial reached?
    Yes
    Global end of trial date
    29 Jun 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Further evaluate safety of BAX326 in terms of IP-related AEs as well as clinically significant changes in routine laboratory parameters and vital signs. Further evaluate the hemostatic efficacy of BAX326 in the prevention and routine prophylaxis of acute bleeding episodes using various dose regimens. Further evaluate the hemostatic efficacy of BAX326 in the management of acute bleeding episodes. Further evaluate the immunogenicity of BAX326 for up to 100 exposure days to BAX326. Monitor IR of BAX326 over time. Evaluate changes in health related quality of life (HR QoL), patient activity level and health resource use.
    Protection of trial subjects
    This study was conducted in accordance with the study protocol, the International Conference on Harmonisation 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
    -
    Actual start date of recruitment
    12 Apr 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
    Bulgaria: 10
    Country: Number of subjects enrolled
    Czech Republic: 2
    Country: Number of subjects enrolled
    Ireland: 2
    Country: Number of subjects enrolled
    Italy: 4
    Country: Number of subjects enrolled
    Poland: 22
    Country: Number of subjects enrolled
    Romania: 12
    Country: Number of subjects enrolled
    Sweden: 1
    Country: Number of subjects enrolled
    United Kingdom: 2
    Country: Number of subjects enrolled
    India: 1
    Country: Number of subjects enrolled
    Japan: 3
    Country: Number of subjects enrolled
    Korea, Republic of: 1
    Country: Number of subjects enrolled
    Taiwan: 6
    Country: Number of subjects enrolled
    Argentina: 2
    Country: Number of subjects enrolled
    Brazil: 1
    Country: Number of subjects enrolled
    Chile: 5
    Country: Number of subjects enrolled
    Colombia: 4
    Country: Number of subjects enrolled
    Russian Federation: 18
    Country: Number of subjects enrolled
    Ukraine: 21
    Worldwide total number of subjects
    117
    EEA total number of subjects
    55
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    21
    Adolescents (12-17 years)
    5
    Adults (18-64 years)
    89
    From 65 to 84 years
    2
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    Enrollment was conducted at 40 clinical sites in 18 countries. A total of 117 participants were enrolled. Of these, 65 participants transitioned from BAX326 pivotal study, 20 participants transitioned from BAX326 pediatric study and 32 participant were newly recruited.

    Pre-assignment
    Screening details
    Of 117 enrolled participants, 115 received treatment with IP. All 85 participants who transitioned from the pivotal/pediatric studies continued to receive IP in this study. Of the 32 newly recruited participants, 30 received treatment with IP. 1 participant did not meet the entry criteria and 1 participant discontinued the study prior treatment.

    Pre-assignment period milestones
    Number of subjects started
    117
    Number of subjects completed
    115

    Pre-assignment subject non-completion reasons
    Reason: Number of subjects
    Subject discontinued the study prior treatment: 1
    Reason: Number of subjects
    Screen failure: 1
    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Not applicable
    Blinding used
    Not blinded

    Arms
    Arm title
    Overall study
    Arm description
    Participants treated with BAX 326
    Arm type
    Experimental

    Investigational medicinal product name
    Rixubis
    Investigational medicinal product code
    BAX 326
    Other name
    Pharmaceutical forms
    Powder for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Treatment with BAX326 is at the discretion of the investigator and consists of either prophylaxis or on-demand. Newly recruited subjects receive prophylactic treatment only. Standard Prophylaxis with twice weekly infusions of 50 IU/kg (range 40-60 IU/kg) which may be increased to 75 IU/kg in subjects ≥12 years of age; range 40-80 IU/kg in subjects <12 years of age. Modified Prophylaxis is determined by the investigator and dose can be increased up to 100 IU/kg, if applicable. PK-tailored Prophylaxis is based on subject's individual PK. The maximum dose is 120 IU/kg.

    Number of subjects in period 1 [1]
    Overall study
    Started
    115
    Completed
    96
    Not completed
    19
         Protocol deviation
    5
         Physician decision
    2
         Participant had scheduled surgery
    1
         Participant moved to another country
    1
         Consent withdrawn by subject
    9
         Discontinued by sponsor
    1
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: Of 117 enrolled participants (who signed informed consent), 115 received treatment with investigational product. 1 participant did not meet the entry criteria and 1 participant discontinued the study prior treatment.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Overall study
    Reporting group description
    Participants treated with BAX 326

    Reporting group values
    Overall study Total
    Number of subjects
    115
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    29.6 ± 16.39 -
    Gender categorical
    Units: Subjects
        Female
    0 0
        Male
    115 115
    Race/Ethnicity, Customized
    Units: Subjects
        Race White
    99 99
        Race Black or African American
    1 1
        Race Asian
    10 10
        Race Other
    5 5
    Subject analysis sets

    Subject analysis set title
    Full analysis set
    Subject analysis set type
    Full analysis
    Subject analysis set description
    Comprises all participants who are exposed to any amount of investigational product.

    Subject analysis set title
    Standard prophylaxis
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Participants treated with BAX 326 with twice weekly prophylactic infusions of 50 IU/kg

    Subject analysis set title
    Modified prophylaxis
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Participants treated with BAX 326 with prophylactic treatment determined by the investigator. The dose could be increased up to 100 IU/kg if indicated.

    Subject analysis set title
    PK-tailored prophylaxis
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Participants treated with BAX 326 with PK tailored prophylaxis based on participant's individual PK with maximum dose of 120 IU/kg.

    Subject analysis set title
    Overall prophylaxis
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    All participants who received BAX 326 as prophylactic regimen (standard prophylaxis, modified prophylaxis and PK-tailored prophylaxis)

    Subject analysis set title
    On-demand
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    All participants who received BAX 326 as on-demand regimen.

    Subject analysis set title
    Pharmacokinetic full analysis set
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Comprises all participants from the full analysis set who underwent an abbreviated PK study.

    Subject analysis sets values
    Full analysis set Standard prophylaxis Modified prophylaxis PK-tailored prophylaxis Overall prophylaxis On-demand Pharmacokinetic full analysis set
    Number of subjects
    115
    108
    26
    3
    110
    13
    6
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    29.6 ± 16.39
    28.9 ± 16.19
    32.3 ± 17.76
    43.0 ± 18.52
    29.1 ± 16.28
    36.6 ± 11.64
    38.5 ± 12.77
    Gender categorical
    Units: Subjects
        Female
    0
    0
    0
    0
    0
    0
    0
        Male
    115
    108
    26
    3
    110
    13
    6
    Race/Ethnicity, Customized
    Units: Subjects
        Race White
    99
    95
    23
    0
    95
    12
    2
        Race Black or African American
    1
    1
    0
    0
    1
    0
    0
        Race Asian
    10
    7
    1
    3
    9
    1
    4
        Race Other
    5
    5
    2
    0
    5
    0
    0

    End points

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    End points reporting groups
    Reporting group title
    Overall study
    Reporting group description
    Participants treated with BAX 326

    Subject analysis set title
    Full analysis set
    Subject analysis set type
    Full analysis
    Subject analysis set description
    Comprises all participants who are exposed to any amount of investigational product.

    Subject analysis set title
    Standard prophylaxis
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Participants treated with BAX 326 with twice weekly prophylactic infusions of 50 IU/kg

    Subject analysis set title
    Modified prophylaxis
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Participants treated with BAX 326 with prophylactic treatment determined by the investigator. The dose could be increased up to 100 IU/kg if indicated.

    Subject analysis set title
    PK-tailored prophylaxis
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Participants treated with BAX 326 with PK tailored prophylaxis based on participant's individual PK with maximum dose of 120 IU/kg.

    Subject analysis set title
    Overall prophylaxis
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    All participants who received BAX 326 as prophylactic regimen (standard prophylaxis, modified prophylaxis and PK-tailored prophylaxis)

    Subject analysis set title
    On-demand
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    All participants who received BAX 326 as on-demand regimen.

    Subject analysis set title
    Pharmacokinetic full analysis set
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Comprises all participants from the full analysis set who underwent an abbreviated PK study.

    Primary: Adverse events possibly or probably related to the investigational product

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    End point title
    Adverse events possibly or probably related to the investigational product [1]
    End point description
    Possibly or probably related adverse events that occurred during or after first BAX326 infusion.
    End point type
    Primary
    End point timeframe
    Assessed (based on patient diary) every 3 months until study completion.
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Per protocol, only descriptive statistics were collected for this endpoint.
    End point values
    Overall study
    Number of subjects analysed
    115
    Units: Adverse Events
        Related adverse events
    2
    No statistical analyses for this end point

    Secondary: Treatment of bleeding episodes: Number of infusions per bleeding episode

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    End point title
    Treatment of bleeding episodes: Number of infusions per bleeding episode
    End point description
    Infusions of BAX326 that were required until bleed resolution.
    End point type
    Secondary
    End point timeframe
    Throughout the study from screening to study completion
    End point values
    Overall study Standard prophylaxis Modified prophylaxis PK-tailored prophylaxis Overall prophylaxis On-demand
    Number of subjects analysed
    115
    108
    26
    3
    110
    13
    Units: Number of infusions
    arithmetic mean (standard deviation)
        Number of infusions
    1.8 ± 1.65
    2.1 ± 2.12
    1.9 ± 1.41
    1.3 ± 0.46
    2.0 ± 2.01
    1.5 ± 0.79
    No statistical analyses for this end point

    Secondary: Treatment of bleeding episodes: Overall hemostatic efficacy rating at resolution of bleed

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    End point title
    Treatment of bleeding episodes: Overall hemostatic efficacy rating at resolution of bleed
    End point description
    Excellent: Full relief of pain and cessation of objective signs of bleeding after a single infusion. No additional infusion is required for the control of bleeding. Administration of further infusion would not affect the 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 a single infusion. Required more than 1 infusion for complete resolution. None: No improvement or condition worsens.
    End point type
    Secondary
    End point timeframe
    Throughout the study from screening to study completion.
    End point values
    Overall study Standard prophylaxis Modified prophylaxis PK-tailored prophylaxis Overall prophylaxis On-demand
    Number of subjects analysed
    115
    108
    26
    3
    110
    13
    Units: Bleeding episodes
        Excellent
    341
    168
    51
    0
    219
    122
        Good
    650
    281
    40
    0
    321
    329
        Fair
    115
    90
    17
    6
    113
    2
        None
    6
    3
    0
    2
    5
    1
    No statistical analyses for this end point

    Secondary: Annualized bleed rate during prophylaxis treatment

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    End point title
    Annualized bleed rate during prophylaxis treatment
    End point description
    Annualized bleed rate (ABR) was calculated as (number of bleeding episodes / observed treatment period in days) * 365.25. The ABR was calculated for participants with an observation period of at least 3 months with BAX326 on the specified treatment regimen.
    End point type
    Secondary
    End point timeframe
    For Prophylactic treatment the period from first to last prophylactic infusion is considered.
    End point values
    Standard prophylaxis Modified prophylaxis PK-tailored prophylaxis Overall prophylaxis
    Number of subjects analysed
    106
    22
    2
    108
    Units: Annualized bleed rate
        median (full range (min-max))
    1.3 (0.0 to 78.7)
    1.4 (0.0 to 34.6)
    1.9 (0.5 to 3.3)
    1.3 (0.0 to 52.2)
    No statistical analyses for this end point

    Secondary: Consumption of BAX 326: Number of infusions per month and per year

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    End point title
    Consumption of BAX 326: Number of infusions per month and per year
    End point description
    The number of infusions consumed per month and per year for the prophylactic and on-demand treatment regimens.
    End point type
    Secondary
    End point timeframe
    Throughout the study from screening to study completion.
    End point values
    Standard prophylaxis Modified prophylaxis PK-tailored prophylaxis Overall prophylaxis On-demand
    Number of subjects analysed
    108
    26
    3
    110
    13
    Units: Number of infusions
    arithmetic mean (standard deviation)
        Number of infusions per month
    8.5 ± 1.25
    10.8 ± 4.34
    4.0 ± 0.60
    8.4 ± 1.38
    3.6 ± 2.44
        Number of infusions per year
    101.8 ± 15.03
    130.2 ± 52.13
    48.3 ± 7.23
    101.1 ± 16.50
    43.1 ± 29.28
    No statistical analyses for this end point

    Secondary: Consumption of BAX 326: Weight adjusted consumption per month and per year

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    End point title
    Consumption of BAX 326: Weight adjusted consumption per month and per year
    End point description
    The weight adjusted consumption of BAX 326 per month and per year for the prophylactic and on-demand treatment regimens.
    End point type
    Secondary
    End point timeframe
    Throughout the study from screening to study completion.
    End point values
    Standard prophylaxis Modified prophylaxis PK-tailored prophylaxis Overall prophylaxis On-demand
    Number of subjects analysed
    108
    26
    3
    110
    13
    Units: IU/kg
    arithmetic mean (standard deviation)
        Weight adjusted BAX 326 consumption per month
    462.3 ± 102.05
    684.4 ± 337.70
    250.9 ± 41.37
    464.2 ± 111.46
    199.8 ± 124.18
        Weight adjusted BAX 326 consumption per year
    5547.8 ± 1224.65
    8212.4 ± 4052.36
    3010.3 ± 496.44
    5570.7 ± 1337.53
    2397.4 ± 1490.22
    No statistical analyses for this end point

    Secondary: Consumption of BAX326: Weight adjusted consumption per bleeding episode

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    End point title
    Consumption of BAX326: Weight adjusted consumption per bleeding episode
    End point description
    The weight adjusted consumption of BAX 326 per bleeding episode for the prophylactic and on-demand treatment regimens. Only infusions required until the resolution of bleed are considered.
    End point type
    Secondary
    End point timeframe
    Throughout the study from screening to study completion.
    End point values
    Standard prophylaxis Modified prophylaxis PK-tailored prophylaxis Overall prophylaxis On-demand
    Number of subjects analysed
    108
    26
    3
    110
    13
    Units: IU/kg
    arithmetic mean (standard deviation)
        IU/kg
    124.2 ± 140.70
    114.8 ± 99.41
    67.4 ± 34.39
    122.0 ± 134.02
    82.6 ± 48.21
    No statistical analyses for this end point

    Secondary: Development of inhibitory and total binding antibodies to FIX

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    End point title
    Development of inhibitory and total binding antibodies to FIX
    End point description
    Testing for inhibitory and total binding antibodies to FIX. Development during study means negative at screening and positive at any subsequent visit. Treatment emergent means more than 2-dilution increase as compared to the pre-study titer at screening.
    End point type
    Secondary
    End point timeframe
    Laboratory assessment for immunology were done at screening, at exposure day 1, at week 4 (± 1 week), at month 3 (±1 week), thereafter, every 3 months (± 1 week) and at study completion/termination.
    End point values
    Overall study
    Number of subjects analysed
    115
    Units: Participants
        Inhibitory antibody to FIX
    0
        Total binding antibody to FIX-develop.during study
    0
        Total binding antibody to FIX-treatment emergent
    0
    No statistical analyses for this end point

    Secondary: Development of antibodies to Chinese Hamster Ovary Proteins (CHO proteins) and rFurin

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    End point title
    Development of antibodies to Chinese Hamster Ovary Proteins (CHO proteins) and rFurin
    End point description
    Testing for antibodies to CHO proteins and rFurin. Development during study means negative at screening and positive at any subsequent visit. Treatment emergent means more than 2-dilution increase as compared to the pre-study titer at screening.
    End point type
    Secondary
    End point timeframe
    Laboratory assessment for immunology were done at screening, at exposure day 1, at week 4 (± 1 week), at month 3 (±1 week), thereafter, every 3 months (± 1 week) and at study completion/termination.
    End point values
    Overall study
    Number of subjects analysed
    115
    Units: Participants
        Antibodies to CHO
    0
        Antibodies to rFurin - development during study
    4
        Antibodies to rFurin - treatment emergent
    4
    No statistical analyses for this end point

    Secondary: Occurrence of severe allergic reactions and thrombotic events

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    End point title
    Occurrence of severe allergic reactions and thrombotic events
    End point description
    The occurrence of severe allergic reactions and thrombotic events was assessed.
    End point type
    Secondary
    End point timeframe
    Throughout the study from screening to study completion.
    End point values
    Overall study
    Number of subjects analysed
    115
    Units: Participants
        Severe allergic reactions
    0
        Thrombotic events
    0
    No statistical analyses for this end point

    Secondary: Clinical significant changes in routine laboratory parameters and vital signs

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    End point title
    Clinical significant changes in routine laboratory parameters and vital signs
    End point description
    Hematology panel consists of complete blood count (hemoglobin, hematocrit, erythrocytes, leukocytes) with differential (ie, basophils, eosinophils, lymphocytes, monocytes, neutrophils), mean corpuscular volume, mean corpuscular hemoglobin concentration and platelet count. Clinical chemistry panel consists of sodium, potassium, chloride, bicarbonate, total protein, albumin, alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin, alkaline phosphatase, blood urea nitrogen, creatinine and glucose. Vital signs include body temperature, respiratory rate, pulse rate, supine systolic and diastolic blood pressure. CS = clinically significant, NCS = not clinically significant Change from Screening to End of Study is reported.
    End point type
    Secondary
    End point timeframe
    Measurements at screening and at study completion/termination are included in the analysis.
    End point values
    Overall study
    Number of subjects analysed
    115
    Units: Participants
        Hematology: Change from normal to abnormal CS
    2
        Hematology:Change from abnormal NCS to abnormal CS
    1
        Chemistry: Change from normal to abnormal, CS
    1
        Chemistry: Change from abnormal NCS to abnormal CS
    3
        Change in vital signs
    0
    No statistical analyses for this end point

    Secondary: Pharmacokinetics: Incremental Recovery (IR) over time

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    End point title
    Pharmacokinetics: Incremental Recovery (IR) over time
    End point description
    PK infusion with investigational product was administered after a wash out period of at least 5 days. Incremental recovery is calculated as IR30min = (C30min [IU/dL] - Cpre-infusion [IU/dL]) / dose per kg body weight [IU/kg] where C30min and Cpre-infusion relate to the unadjusted concentration values. All subjects treated with investigational product were included in this analysis.
    End point type
    Secondary
    End point timeframe
    IR over time was analysed at Baseline and at Completion/Termination visit within 30 minutes pre-infusion and at 30 (± 5) minutes post-infusion.
    End point values
    Overall study
    Number of subjects analysed
    110 [2]
    Units: (IU/dL)/(IU/kg)
    arithmetic mean (standard deviation)
        Baseline
    0.85 ± 0.207
        End of study
    0.85 ± 0.286
        Change from baseline to end of study
    -0.005 ± 0.259
    Notes
    [2] - n=110 at baseline, n=108 at end of study, n=104 for change
    No statistical analyses for this end point

    Secondary: Pharmacokinetics: Area under the plasma concentration versus time curve from time 0 to infinity (AUC 0-∞)

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    End point title
    Pharmacokinetics: Area under the plasma concentration versus time curve from time 0 to infinity (AUC 0-∞)
    End point description
    After a wash out period of at least 5 days PK infusion with investigational product was administered. AUC 0-∞ is defined as AUC 0-t + Ct/lambda z, where t is the time of last quantifiable concentration, Ct is the last quantifiable concentration.
    End point type
    Secondary
    End point timeframe
    PK assessments were done within 30 minutes pre-infusion and post-infusion at 30 minutes, 9 hours, 24 hours, 48 hours and 72 hours
    End point values
    Pharmacokinetic full analysis set
    Number of subjects analysed
    6
    Units: IU*hr/dL
    arithmetic mean (standard deviation)
        IU*hr/dL
    1335.56 ± 299.83
    No statistical analyses for this end point

    Secondary: Pharmacokinetics: Elimination phase half-life (T1/2)

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    End point title
    Pharmacokinetics: Elimination phase half-life (T1/2)
    End point description
    PK infusion with investigational product was administered after a wash out period of at least 5 days. Elimination phase half-life is calculated as T1/2=log e (2) / lambda z where the elimination rate constant (lambda z) will be obtained by log e - linear fitting using least squares deviation to at least the last 3 quantifiable concentrations above pre-infusion level.
    End point type
    Secondary
    End point timeframe
    PK assessments were done within 30 minutes pre-infusion and post-infusion at 30 minutes, 9 hours, 24 hours, 48 hours and 72 hours
    End point values
    Pharmacokinetic full analysis set
    Number of subjects analysed
    6
    Units: hours
    arithmetic mean (standard deviation)
        hours
    28.52 ± 4.12
    No statistical analyses for this end point

    Secondary: Pharmacokinetics: Mean residence time (MRT)

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    End point title
    Pharmacokinetics: Mean residence time (MRT)
    End point description
    PK infusion with investigational product was administered after a wash out period of at least 5 days. Mean residence time is calculated as total area under the moment curve divided by the total area under the curve. MRT=(AUMC0-∞[h2*IU/dL])/(AUC0-∞[h*IU/dL]) - TI/2 where AUMC0-∞ is determined in a similar manner as AUC0-∞ and TI represents infusion duration in hours.
    End point type
    Secondary
    End point timeframe
    PK assessments were done within 30 minutes pre-infusion and post-infusion at 30 minutes, 9 hours, 24 hours, 48 hours and 72 hours
    End point values
    Pharmacokinetic full analysis set
    Number of subjects analysed
    6
    Units: hours
    arithmetic mean (standard deviation)
        hours
    29.97 ± 2.72
    No statistical analyses for this end point

    Secondary: Pharmacokinetics: Systemic Clearance (CL)

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    End point title
    Pharmacokinetics: Systemic Clearance (CL)
    End point description
    PK infusion with investigational product was administered after a wash out period of at least 5 days. Systemic clearance is calculated as the dose in IU/kg divided by the total AUC. CL= Dose[IU/kg] / AUC0-∞[h*IU/dL]
    End point type
    Secondary
    End point timeframe
    PK assessments were done within 30 minutes pre-infusion and post-infusion at 30 minutes, 9 hours, 24 hours, 48 hours and 72 hours
    End point values
    Pharmacokinetic full analysis set
    Number of subjects analysed
    6
    Units: dL/kg/hours
    arithmetic mean (standard deviation)
        dL/kg/hours
    0.06 ± 0.014
    No statistical analyses for this end point

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

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    End point title
    Pharmacokinetics: Volume of distribution at steady state (Vss)
    End point description
    PK infusion with investigational product was administered after a wash out period of at least 5 days. Apparent steady state volume of distribution is calculated as Vss = CL * MRT CL=Systemic Clearance and MRT=Mean residence time
    End point type
    Secondary
    End point timeframe
    PK assessments were done within 30 minutes pre-infusion and post-infusion at 30 minutes, 9 hours, 24 hours, 48 hours and 72 hours
    End point values
    Pharmacokinetic full analysis set
    Number of subjects analysed
    6
    Units: dL/kg
    arithmetic mean (standard deviation)
        dL/kg
    1.78 ± 0.42
    No statistical analyses for this end point

    Secondary: Pharmacokinetics: Incremental recovery (IR)

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    End point title
    Pharmacokinetics: Incremental recovery (IR)
    End point description
    PK infusion with investigational product was administered after a wash out period of at least 5 days. Incremental recovery is calculated as IR30min = (C30min [IU/dL] - Cpre-infusion [IU/dL]) / dose per kg body weight [IU/kg] where C30min and Cpre-infusion relate to the unadjusted concentration values.
    End point type
    Secondary
    End point timeframe
    IR assessments were done within 30 minutes pre-infusion and post-infusion at 30 (± 5) minutes.
    End point values
    Pharmacokinetic full analysis set
    Number of subjects analysed
    6
    Units: (IU/dL)/(IU/kg)
    arithmetic mean (standard deviation)
        (IU/dL)/(IU/kg)
    0.85 ± 0.196
    No statistical analyses for this end point

    Secondary: Changes in health related quality of life (HR QoL) based on questionnaire SF-36

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    End point title
    Changes in health related quality of life (HR QoL) based on questionnaire SF-36
    End point description
    The SF-36 is a validated, generic HR QoL instrument, measuring physical, emotional, social functioning as well as overall general health, suitable for subjects of 17 years of age or older. Higher scores indicate better health status. The Change in health related quality of life is analyzed from baseline to study completion. Only newly recruited subjects are included in the analysis of change as baseline values were not reported for transitioning subjects. Only subjects who received prophylaxis treatment are included.
    End point type
    Secondary
    End point timeframe
    Baseline at exposure day 1 and at study completion/termination.
    End point values
    Overall prophylaxis
    Number of subjects analysed
    24
    Units: Score
    arithmetic mean (standard deviation)
        SF-36 Bodily Pain
    6.7 ± 12.66
        SF-36 General Health
    3.2 ± 9.32
        SF-36 Mental Health
    0.7 ± 14.72
        SF-36 Mental Health Component Score
    0.8 ± 12.08
        SF-36 Physical Funcioning
    4.2 ± 10.46
        SF-36 Physical Health Component Score
    5.7 ± 8.43
        SF-36 Role-Emotional
    2.3 ± 11.57
        SF-36 Role-Physical
    4.5 ± 10.28
        SF-36 Social Functioning
    4.5 ± 11.67
        SF-36 Vitality
    2.0 ± 8.87
    No statistical analyses for this end point

    Secondary: Changes in health related quality of life using the Peds QL

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    End point title
    Changes in health related quality of life using the Peds QL
    End point description
    The Peds QL is a generic HR QoL instrument designed specifically for a pediatric population. It captures following domains: general health/activities, feelings/emotional, social functioning, school functioning. Higher scores indicate better quality of life. The Change in health related quality of life is analyzed from baseline to study completion. Only newly recruited subjects are included in the analysis of change as baseline values were not reported for transitioning subjects. Only subjects who received prophylaxis treatment are included.
    End point type
    Secondary
    End point timeframe
    Baseline at exposure day 1 and at study completion/termination.
    End point values
    Overall prophylaxis
    Number of subjects analysed
    4
    Units: Change from baseline to end of study
    arithmetic mean (standard deviation)
        Peds-QL Physical Health Summary Score
    -2.3 ± 18.47
        Peds-QL Psychosocial Health Summary Score
    3.8 ± 5.99
        Peds-QL Total Score
    1.6 ± 10.14
    No statistical analyses for this end point

    Secondary: Changes in health related quality of life (HR QoL) based on questionnaire Haemo-QoL and Haem-A-QoL

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    End point title
    Changes in health related quality of life (HR QoL) based on questionnaire Haemo-QoL and Haem-A-QoL
    End point description
    The Haemo-QoL and Haem-A-Qol instruments have 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 both instruments higher scores indicate worse quality of life. The Change in health related quality of life is analyzed from baseline to study completion. Only newly recruited subjects are included in the analysis of change as baseline values were not reported for transitioning subjects. Only subjects who received prophylaxis treatment are included.
    End point type
    Secondary
    End point timeframe
    Baseline at exposure day 1 and at study completion/termination.
    End point values
    Overall prophylaxis
    Number of subjects analysed
    16 [3]
    Units: Change from baseline to end of study
    arithmetic mean (standard deviation)
        Haem-A-QoL Total Score
    -3.0 ± 9.45
        Haemo-QoL Total Score
    -0.7 ± 99.999
    Notes
    [3] - n=16 for Haem-A-QoL and n=1 for Haemo-Qol - Dispersion not applicable as n=1, entered as 99.999
    No statistical analyses for this end point

    Secondary: Changes in health related quality of life (HR QoL) based on questionnaire EQ-5D and pain score.

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    End point title
    Changes in health related quality of life (HR QoL) based on questionnaire EQ-5D and pain score.
    End point description
    The EQ-5D captures overall HR QoL (phyiscal, mental and social functioning). A health utility score can be calculated from this measure, adult and proxy versions available. General pain assessment are done through a visual analog scale (VAS). For the EQ-5D Index score and EQ-5D VAS score, a higher score represents better quality of life. For the pain scale, a higher score indicates worse pain. The Change in health related quality of life is analyzed from baseline to study completion. Only newly recruited subjects are included in the analysis of change as baseline values were not reported for transitioning subjects. Only subjects who received prophylaxis treatment are included.
    End point type
    Secondary
    End point timeframe
    Baseline at exposure day 1 and at study completion/termination.
    End point values
    Overall prophylaxis
    Number of subjects analysed
    26 [4]
    Units: Change from baseline to end of study
    arithmetic mean (standard deviation)
        EQ-5D Total Index
    0.0 ± 0.13
        EQ-5D VAS
    5.1 ± 21.75
        Pain Score
    -8.0 ± 36.62
    Notes
    [4] - n=26 for EQ-5D Total Index, n=25 for EQ-5D VAS, n=24 for Pain Score
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Throughout the entire study period from screening to completion/termination. Overall 6 years and 2 months.
    Assessment type
    Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    N/A
    Reporting groups
    Reporting group title
    BAX 326
    Reporting group description
    Participants treated with BAX 326

    Serious adverse events
    BAX 326
    Total subjects affected by serious adverse events
         subjects affected / exposed
    9 / 115 (7.83%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Injury, poisoning and procedural complications
    Brain contusion
         subjects affected / exposed
    1 / 115 (0.87%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Extradural hematoma
         subjects affected / exposed
    1 / 115 (0.87%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Head injury
         subjects affected / exposed
    1 / 115 (0.87%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Scroctal haematoma
         subjects affected / exposed
    1 / 115 (0.87%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Nervous system disorders
    Seizure
         subjects affected / exposed
    1 / 115 (0.87%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    1 / 115 (0.87%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    1 / 115 (0.87%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Duodenal ulcer hemorrhage
         subjects affected / exposed
    1 / 115 (0.87%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Reproductive system and breast disorders
    Testicular appendage torsion
         subjects affected / exposed
    1 / 115 (0.87%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Renal and urinary disorders
    Haematuria
         subjects affected / exposed
    1 / 115 (0.87%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Renal colic
         subjects affected / exposed
    2 / 115 (1.74%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Corneal abscess
         subjects affected / exposed
    1 / 115 (0.87%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    BAX 326
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    63 / 115 (54.78%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    6 / 115 (5.22%)
         occurrences all number
    6
    Respiratory, thoracic and mediastinal disorders
    Oropharyngeal pain
         subjects affected / exposed
    6 / 115 (5.22%)
         occurrences all number
    6
    Cough
         subjects affected / exposed
    11 / 115 (9.57%)
         occurrences all number
    15
    Nervous system disorders
    Headache
         subjects affected / exposed
    8 / 115 (6.96%)
         occurrences all number
    20
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    14 / 115 (12.17%)
         occurrences all number
    23
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    15 / 115 (13.04%)
         occurrences all number
    48
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    25 / 115 (21.74%)
         occurrences all number
    55
    Bronchhitis
         subjects affected / exposed
    6 / 115 (5.22%)
         occurrences all number
    8
    Influenza
         subjects affected / exposed
    8 / 115 (6.96%)
         occurrences all number
    8
    Pharyngitis
         subjects affected / exposed
    6 / 115 (5.22%)
         occurrences all number
    8
    Rhinitis
         subjects affected / exposed
    8 / 115 (6.96%)
         occurrences all number
    15
    Upper respiratory tract infection
         subjects affected / exposed
    11 / 115 (9.57%)
         occurrences all number
    17

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    07 Dec 2011
    Enrollment opened to pediatric subjects who participated in BAX326 pediatric study 251101 (to enable pediatric subjects to continue to receive BAX326 after completion of the pediatric study ); other changes made due to the inclusion of pediatric subjects: - 80 IU/kg stated as upper end of dose range for pediatric subjects - Anticipated IR of 0.7 [IU/dL]/[IU/kg] stated for pediatric subjects for calculation of the required number of units to treat a bleeding episode - Separate analyses between adult and pediatric subjects, if applicable
    31 Jul 2013
    - Enrollment opened to at least 25 subjects naïve to BAX326 (per regulatory authority request). - Addition of PK-tailored prophylactic administration of BAX326 as an additional prophylactic treatment option. - Clarification provided that newly recruited subjects had to receive prophylactic treatment. - IR for calculating dose for subjects ≥ 12 years of age updated from 0.8 to 0.9 (based on PK data of BAX326 pivotal protocol 250901) -> Formula changed to: ‘body weight (kg) x desired FIX rise (% or (IU/dL)) x 1.1 IU/kg’ (previously 1.3 IU/kg) - Addition of TGA testing for the following new exploratory objective: “To correlate pre-infusion TGA parameters with pre-infusion FIX levels and spontaneous breakthrough bleeds in a subset of subjects receiving twice weekly standard or modified prophylactic treatment, including PK-tailored prophylaxis” (to evaluate whether and which TGA parameters, in particular endogenous thrombin potential (ETP) and/or peak thrombin generation may be a better parameter to monitor the adequacy of prophylactic treatment instead of FIX activity trough levels and/or clinical outcome); TGA testing was only to be performed in subjects ≥ 12 years of age
    19 Oct 2015
    - Term “Cohort 1” introduced for subjects who were previously treated in BAX326 Studies 250901 or 251101; term “Cohort 2” introduced for newly recruited, BAX326 naïve subjects - Maximum dose of 120 IU/kg introduced for PK-tailored prophylaxis

    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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