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    Clinical Trial Results:
    A Phase 2/3, Multi-Center, Open Label Study of Efficacy, Safety, and Pharmacokinetics of PEGylated Recombinant Factor VIII (BAX 855) Administered for Prophylaxis and Treatment of Bleeding in Previously Treated Patients with Severe Hemophilia A

    Summary
    EudraCT number
    2012-003599-38
    Trial protocol
    DE   GB   AT   LT   CZ   SE   ES   BE   NL   BG   PL   HU   RO  
    Global end of trial date
    17 Jul 2014

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

    Trial information

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    Trial identification
    Sponsor protocol code
    261201
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    -
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Baxalta Innovations GmbH
    Sponsor organisation address
    Industriestrasse 67, Vienna, Austria, 1221
    Public contact
    Clinical Trial Registries and Results Disclosure, Baxalta Innovations GmbH, ClinicalTrialsDisclosure@baxalta.com
    Scientific contact
    Clinical Trial Registries and Results Disclosure, Baxalta Innovations GmbH, ClinicalTrialsDisclosure@baxalta.com
    Sponsor organisation name
    Baxalta US Inc
    Sponsor organisation address
    One Baxter Way, Westlake Village CA, United States, 91362-3811
    Public contact
    Clinical Trial Registries and Results Disclosure, Baxalta US Inc, ClinicalTrialsDisclosure@baxalta.com
    Scientific contact
    Clinical Trial Registries and Results Disclosure, Baxalta US Inc, ClinicalTrialsDisclosure@baxalta.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    EMEA-001296-PIP01-12
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    17 Jul 2014
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    17 Jul 2014
    Global end of trial reached?
    Yes
    Global end of trial date
    17 Jul 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Compare the annualized rates of bleeding episodes (ABR) between subjects who received a prophylactic dosing regimen of BAX 855 with those who received an on-demand treatment regimen
    Protection of trial subjects
    This study was conducted in accordance with the standards of Good Clinical Practice (GCP) in effect at the time of the study. Justification for enrollment of adolescent subjects was based on requirements outlined in the ICH M3 Guideline, Section 12 as well as the ICH E11 Guideline on clinical investigation of medicinal products in the pediatric population.Baxalta follows a stepwise approach and starts the clinical investigation of efficacy and safety in patients ≥12 years before starting studies in patients < 12 years.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    31 Jan 2013
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United States: 32
    Country: Number of subjects enrolled
    Australia: 6
    Country: Number of subjects enrolled
    Japan: 11
    Country: Number of subjects enrolled
    Malaysia: 9
    Country: Number of subjects enrolled
    Korea, Republic of: 10
    Country: Number of subjects enrolled
    Taiwan: 1
    Country: Number of subjects enrolled
    Austria: 7
    Country: Number of subjects enrolled
    Bulgaria: 1
    Country: Number of subjects enrolled
    Czech Republic: 7
    Country: Number of subjects enrolled
    Germany: 5
    Country: Number of subjects enrolled
    Israel: 4
    Country: Number of subjects enrolled
    Lithuania: 6
    Country: Number of subjects enrolled
    Netherlands: 1
    Country: Number of subjects enrolled
    Poland: 6
    Country: Number of subjects enrolled
    Romania: 2
    Country: Number of subjects enrolled
    Spain: 8
    Country: Number of subjects enrolled
    Sweden: 3
    Country: Number of subjects enrolled
    Switzerland: 2
    Country: Number of subjects enrolled
    Ukraine: 9
    Country: Number of subjects enrolled
    United Kingdom: 8
    Worldwide total number of subjects
    138
    EEA total number of subjects
    54
    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)
    25
    Adults (18-64 years)
    113
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    Subjects were enrolled (signed informed consent) from 72 sites.

    Pre-assignment
    Screening details
    A total of 159 subjects provided informed consent and were screened for study participation, of which there were 21 screen failures. 138 subjects were assigned to the prophylactic arm or the on-demand treatment regimen.

    Pre-assignment period milestones
    Number of subjects started
    159 [1]
    Number of subjects completed
    138

    Pre-assignment subject non-completion reasons
    Reason: Number of subjects
    Screen failures: 21
    Notes
    [1] - The number of subjects reported to have started the pre-assignment period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: A total of 159 subjects provided informed consent and were screened for study participation, of which there were 21 screen failures. 138 subjects were assigned to the prophylactic arm or the on-demand treatment regimen.
    Period 1
    Period 1 title
    Overall Trial (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Non-randomised - controlled
    Blinding used
    Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Arm A: Prophylactic treatment
    Arm description
    Prophylactic treatment with BAX 855 at a dose of 45 ± 5 IU/kg twice weekly
    Arm type
    Experimental

    Investigational medicinal product name
    BAX 855
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous bolus use
    Dosage and administration details
    45 ± 5 IU/kg twice weekly

    Arm title
    Arm B: On-demand treatment
    Arm description
    On-demand therapy with BAX 855 at a dose of 10 to 60 IU/kg dose
    Arm type
    Experimental

    Investigational medicinal product name
    BAX 855
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous bolus use
    Dosage and administration details
    10 to 60 IU/kg dose

    Number of subjects in period 1
    Arm A: Prophylactic treatment Arm B: On-demand treatment
    Started
    121
    17
    Completed
    109
    17
    Not completed
    12
    0
         Protocol deviation
    4
    -
         Screen failure -1; surgical procedure -1
    2
    -
         Adverse event, non-fatal
    4
    -
         Consent withdrawn by subject
    2
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Arm A: Prophylactic treatment
    Reporting group description
    Prophylactic treatment with BAX 855 at a dose of 45 ± 5 IU/kg twice weekly

    Reporting group title
    Arm B: On-demand treatment
    Reporting group description
    On-demand therapy with BAX 855 at a dose of 10 to 60 IU/kg dose

    Reporting group values
    Arm A: Prophylactic treatment Arm B: On-demand treatment Total
    Number of subjects
    121 17 138
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    98 15 113
        Adolescents (12-17 years)
    23 2 25
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    29.8 ± 12.53 31.5 ± 11.05 -
    Gender categorical
    Units:
        Female
    0 0 0
        Male
    121 17 138
    Subject analysis sets

    Subject analysis set title
    Full Analysis Set
    Subject analysis set type
    Full analysis
    Subject analysis set description
    Comprised all subjects who were assigned to the prophylactic arm or the on-demand treatment regimen

    Subject analysis set title
    Pharmacokinetic Full Analysis Set
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Comprised all subjects in Arm A who consented to PK evaluation, who were treated with at least 1 ADVATE and 1 BAX 855 PK dose, and who were evaluable for PK for the ADVATE and initial BAX 855 PK infusions (PK-1 and PK-2). Subjects were PK evaluable if they had at least 3 post-infusion FVIII measurements above the limit of quantification (LoQ) before the first FVIII measurement below the LoQ.

    Subject analysis set title
    Safety Analysis Set
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    Comprised all subjects treated with at least 1 BAX 855 dose.

    Subject analysis sets values
    Full Analysis Set Pharmacokinetic Full Analysis Set Safety Analysis Set
    Number of subjects
    138
    26
    137
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    113
    18
    112
        Adolescents (12-17 years)
    25
    8
    25
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    30 ± 12.34
    25.6 ± 12.03
    30 ± 12.38
    Gender categorical
    Units:
        Female
    0
    0
    0
        Male
    138
    26
    137

    End points

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    End points reporting groups
    Reporting group title
    Arm A: Prophylactic treatment
    Reporting group description
    Prophylactic treatment with BAX 855 at a dose of 45 ± 5 IU/kg twice weekly

    Reporting group title
    Arm B: On-demand treatment
    Reporting group description
    On-demand therapy with BAX 855 at a dose of 10 to 60 IU/kg dose

    Subject analysis set title
    Full Analysis Set
    Subject analysis set type
    Full analysis
    Subject analysis set description
    Comprised all subjects who were assigned to the prophylactic arm or the on-demand treatment regimen

    Subject analysis set title
    Pharmacokinetic Full Analysis Set
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Comprised all subjects in Arm A who consented to PK evaluation, who were treated with at least 1 ADVATE and 1 BAX 855 PK dose, and who were evaluable for PK for the ADVATE and initial BAX 855 PK infusions (PK-1 and PK-2). Subjects were PK evaluable if they had at least 3 post-infusion FVIII measurements above the limit of quantification (LoQ) before the first FVIII measurement below the LoQ.

    Subject analysis set title
    Safety Analysis Set
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    Comprised all subjects treated with at least 1 BAX 855 dose.

    Primary: Annualized Bleeding Episode Rates (ABRs)

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    End point title
    Annualized Bleeding Episode Rates (ABRs)
    End point description
    Comparisons between prophylactic and on-demand treatment were based on ABR estimates from a negative binomial regression model, taking into account the treatment regimen, target joints and age at screening, and duration of the observation period for efficacy.
    End point type
    Primary
    End point timeframe
    At least 50 exposure days or 6 months (±2 weeks), whichever occurs last, for the prophylaxis arm and 6 months (± 2 weeks) for the on-demand arm.
    End point values
    Arm A: Prophylactic treatment Arm B: On-demand treatment
    Number of subjects analysed
    120
    17
    Units: ABR
        least squares mean (confidence interval 95%)
    4.3 (3.4 to 5.5)
    43.4 (25.2 to 74.8)
    Statistical analysis title
    Ratio Annualized Bleeding Rate Prophyl./On-demand
    Statistical analysis description
    Ratio Annualized Bleeding Rate (ABR) Prophylaxis/On-demand: Prophylaxis treatment will be considered to be successful if the upper limit of the 95% CI for the ratio between treatment regimen does not exceed 0.5 (corresponding to a 50% reduction of the mean ABR compared to the on-demand treatment). H01: μ1 ≥0.5*μ2 Ha1: μ1<0.5*μ2 where μ1 and μ2 are the mean ABRs in on prophylaxis and on-demand, respectively
    Comparison groups
    Arm A: Prophylactic treatment v Arm B: On-demand treatment
    Number of subjects included in analysis
    137
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    Regression, Negative binomial
    Parameter type
    Ratio of means
    Point estimate
    0.1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.06
         upper limit
    0.19

    Secondary: Rate of success for BAX 855 treatment of bleeding episodes

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    End point title
    Rate of success for BAX 855 treatment of bleeding episodes
    End point description
    Success in the control of bleeding was defined as a rating of excellent or good using the Efficacy Rating Scale for Treatment of Bleeding Episodes measured 24 hours after initiation of treatment for the bleeding episode. 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 is required for the control of bleeding. Administration of further infusions to maintain hemostasis would 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 a single infusion. Required more than 1 infusion for complete resolution. NONE: No improvement or condition worsens.
    End point type
    Secondary
    End point timeframe
    All bleeding episodes treated with BAX 855 in subjects on on-demand and prophylaxis treatment regimens. At least 50 exposure days or 6 months (±2 weeks), whichever occurs last, for the prophylaxis arm and 6 months (± 2 weeks) for the on-demand arm.
    End point values
    Full Analysis Set
    Number of subjects analysed
    81
    Units: Proportion of excellent/good bleeds
        number (confidence interval 95%)
    0.96 (0.91 to 0.98)
    No statistical analyses for this end point

    Secondary: Total weight-adjusted consumption of BAX 855

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    End point title
    Total weight-adjusted consumption of BAX 855
    End point description
    End point type
    Secondary
    End point timeframe
    At least 50 exposure days or 6 months (±2 weeks), whichever occurs last, for the prophylaxis arm and 6 months (± 2 weeks) for the on-demand arm.
    End point values
    Full Analysis Set
    Number of subjects analysed
    Units: IU/kg
    arithmetic mean (standard deviation)
        Per Prophylactic Infusion
    44.51 ± 4.556
        Per PK Infusion
    45.48 ± 2.592
        Per Treatment of Bleeding Episode
    37.44 ± 28.105
        Per Bleeding Episode for Maintenance of Hemostasis
    39.29 ± 34.206
    No statistical analyses for this end point

    Secondary: Number of Subjects with Positive Inhibitory Antibodies to FVIII, Binding Antibodies to FVIII, BAX 855, PEG and Anti-CHO Antibodies at Study Completion/Termination

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    End point title
    Number of Subjects with Positive Inhibitory Antibodies to FVIII, Binding Antibodies to FVIII, BAX 855, PEG and Anti-CHO Antibodies at Study Completion/Termination
    End point description
    Note for Inhibitory Antibodies to FVIII: Subjects = 112 for Arm A; 14 for Arm B; 126 for Safety Analysis Set.
    End point type
    Secondary
    End point timeframe
    From first exposure to BAX 855 until the end of the study [at least 50 exposure days or 6 months (±2 weeks), whichever occurs last, for the prophylaxis arm and 6 months (± 2 weeks) for the on-demand arm].
    End point values
    Arm A: Prophylactic treatment Arm B: On-demand treatment Safety Analysis Set
    Number of subjects analysed
    117
    15
    132
    Units: Number of subjects
    number (not applicable)
        Inhibitory Antibodies to FVIII
    0
    0
    0
        IgG: Binding Antibodies FVIII
    0
    0
    0
        IgM: Binding Antibodies FVIII
    0
    0
    0
        IgG: Binding Antibodies PEG
    0
    0
    0
        IgM: Binding Antibodies PEG
    0
    0
    0
        IgG: Binding Antibodies PEG-FVIII
    0
    1
    1
        IgM: Binding Antibodies PEG-FVIII
    0
    0
    0
        CHO-Protein Ab
    0
    0
    0
    No statistical analyses for this end point

    Secondary: Safety - Occurrence of adverse events (AEs) following BAX 855 administration

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    End point title
    Safety - Occurrence of adverse events (AEs) following BAX 855 administration
    End point description
    Abbreviations: serious adverse event - SAE; non-serious adverse event - nSAE
    End point type
    Secondary
    End point timeframe
    From first exposure to BAX 855 until the end of the study [at least 50 exposure days or 6 months (±2 weeks), whichever occurs last, for the prophylaxis arm and 6 months (± 2 weeks) for the on-demand arm].
    End point values
    Safety Analysis Set
    Number of subjects analysed
    137
    Units: Percentage of subjects with AEs
    number (not applicable)
        SAE-Moderate-Unrelated
    0.7
        SAE-Severe-Unrelated
    2.9
        nSAE-Mild-Unrelated
    40.1
        nSAE-Mild-Related
    3.6
        nSAE-Moderate-Unrelated
    19
        nSAE-Moderate-Related
    1.5
        nSAE-Unknown Severity-Unrelated
    0.7
        nSAE-Severe-Unrelated
    1.5
    No statistical analyses for this end point

    Secondary: Terminal half-life (One-stage Clotting)

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    End point title
    Terminal half-life (One-stage Clotting)
    End point description
    Terminal half-life of BAX 855 following initial and repeat administration after at least 50 exposure days, and as compared to ADVATE. Terminal half-life calculated as log_e2/λ where λ is the terminal elimination rate constant calculate by WinNonlin NCA (Model 201, curve stripping as described in the User’s Guide, page 263). Subjects: 26 subjects for PK1 and PK2; 22 subjects for PK3
    End point type
    Secondary
    End point timeframe
    Pharmacokinetic (PK) evaluation: Within 30 minutes prior to start of infusion; and post-infusion at 10, 30 minutes, and 1, 3, 6, 9, 24, 32, 48, 56, 72 (PK2 and PK3 only), and 96 hours (PK2 and PK3 only).
    End point values
    Pharmacokinetic Full Analysis Set
    Number of subjects analysed
    26
    Units: hours
    arithmetic mean (standard deviation)
        PK 1 ADVATE
    10.4 ± 2.244
        PK2 BAX855
    14.3 ± 3.838
        PK3 BAX855
    16.02 ± 4.922
    No statistical analyses for this end point

    Secondary: Mean Residence Time (One-stage Clotting)

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    End point title
    Mean Residence Time (One-stage Clotting)
    End point description
    Mean Residence Time (One-stage Clotting) of BAX 855 following initial and repeat administration after at least 50 exposure days, and as compared to ADVATE. The mean residence time (MRT) was calculated as total area under the moment curve divided by the total area under the curve starting from the begin of infusion (or the end of infusion if start time is not available). Subjects: 26 subjects for PK1 and PK2; 22 subjects for PK3
    End point type
    Secondary
    End point timeframe
    Pharmacokinetic (PK) evaluation: Within 30 minutes prior to start of infusion; and post-infusion at 10, 30 minutes, and 1, 3, 6, 9, 24, 32, 48, 56, 72 (PK2 and PK3 only), and 96 hours (PK2 and PK3 only).
    End point values
    Pharmacokinetic Full Analysis Set
    Number of subjects analysed
    26
    Units: hours
    arithmetic mean (standard deviation)
        PK1 ADVATE
    12.86 ± 3.044
        PK2 BAX 855
    19.56 ± 5.315
        PK3 BAX 855
    20.65 ± 4.821
    No statistical analyses for this end point

    Secondary: Total body clearance (One-stage Clotting)

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    End point title
    Total body clearance (One-stage Clotting)
    End point description
    Total body clearance (One-stage Clotting) of BAX 855 following initial and repeat administration after at least 50 EDs, and as compared to ADVATE. Clearance in dL/(kg*hours) was calculated as the dose in IU/kg divided by the total area under the curve starting from the begin of infusion (or the end of infusion if start time is not available). Subjects: 26 subjects for PK1 and PK2; 22 subjects for PK3.
    End point type
    Secondary
    End point timeframe
    Pharmacokinetic (PK) evaluation: Within 30 minutes prior to start of infusion; and post-infusion at 10, 30 minutes, and 1, 3, 6, 9, 24, 32, 48, 56, 72 (PK2 and PK3 only), and 96 hours (PK2 and PK3 only).
    End point values
    Pharmacokinetic Full Analysis Set
    Number of subjects analysed
    26
    Units: dL/(kg*hours)
    arithmetic mean (standard deviation)
        PK1 ADVATE
    0.04551 ± 0.021725
        PK2 BAX 855
    0.0276 ± 0.020288
        PK3 BAX 855
    0.02474 ± 0.008225
    No statistical analyses for this end point

    Secondary: Incremental recovery (One-stage Clotting)

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    End point title
    Incremental recovery (One-stage Clotting)
    End point description
    Incremental recovery (One-stage Clotting) of BAX 855 following initial and repeat administration after at least 50 EDs, and as compared to ADVATE. Subjects: 26 subjects for PK1 and PK2; 22 subjects for PK3
    End point type
    Secondary
    End point timeframe
    Pharmacokinetic (PK) evaluation: Within 30 minutes prior to start of infusion; and post-infusion at 10, 30 minutes, and 1, 3, 6, 9, 24, 32, 48, 56, 72 (PK2 and PK3 only), and 96 hours (PK2 and PK3 only).
    End point values
    Pharmacokinetic Full Analysis Set
    Number of subjects analysed
    26
    Units: (IU/dL)/(IU/kg)
    arithmetic mean (standard deviation)
        PK1 ADVATE
    2.372 ± 0.5357
        PK2 BAX 855
    2.493 ± 0.6944
        PK3 BAX 855
    2.297 ± 0.6377
    No statistical analyses for this end point

    Secondary: Patient Reporting Outcome Short Form (SF)-36

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    End point title
    Patient Reporting Outcome Short Form (SF)-36
    End point description
    Change from Baseline to Completion of Study for SF-36 Questionnaire is provided. Scores for individual SF-36 categories range from 0 to 100 with higher scores representing better health. Given that higher scores indicate better health-related quality of life (HRQoL) and that the change scores were calculated as the value at study completion minus the value at baseline, a negative change score indicates a worsening of HRQoL. Subjects for Treatment Arm A (prophylactic treatment): 97 subjects for physical functioning, role-physical, bodily pain, social functioning, role emotional; 96 for general health, vitality, mental health, physical component score, mental component score.
    End point type
    Secondary
    End point timeframe
    From screening to end of study visit [at least 50 exposure days or 6 months (±2 weeks), whichever occurs last, for the prophylaxis arm and 6 months (± 2 weeks) for the on-demand arm].
    End point values
    Arm A: Prophylactic treatment Arm B: On-demand treatment
    Number of subjects analysed
    97
    12
    Units: point change
    arithmetic mean (standard deviation)
        Physical Functioning
    0.49 ± 5.27
    -2.46 ± 4.29
        Role-physical
    1.31 ± 7.36
    -3.67 ± 9.01
        Bodily Pain
    2.08 ± 8.19
    0.6 ± 4.44
        General Health
    0.4 ± 6.43
    -0.28 ± 9.04
        Vitality
    -0.38 ± 7.43
    0.26 ± 9.36
        Social Functioning
    0.9 ± 7.54
    -3.18 ± 6.35
        Role Emotional
    -0.2 ± 8.46
    0.65 ± 7.92
        Mental Health
    0.09 ± 7.26
    -3.29 ± 7.95
        Physical Component Score
    1.36 ± 5.76
    -1.58 ± 4.97
        Mental Component Score
    -0.37 ± 7.38
    -1.14 ± 5.03
    No statistical analyses for this end point

    Secondary: Patient Reporting Outcome Haemo-SYM Questionnaire

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    End point title
    Patient Reporting Outcome Haemo-SYM Questionnaire
    End point description
    Change from Baseline to Completion of Study for Haemo-SYM Questionnaire. The 17-item HAEMO-SYM has two subscales: pain and bleeds. Given that higher scores indicate more severe symptoms on the Haemo-SYM and that the change scores were calculated as the value at study completion minus the value at baseline, a negative change score indicates an improvement (reduction in symptoms). Conversely, a positive change score indicates worsening symptoms.
    End point type
    Secondary
    End point timeframe
    From screening to end of study visit [at least 50 exposure days or 6 months (±2 weeks), whichever occurs last, for the prophylaxis arm and 6 months (± 2 weeks) for the on-demand arm].
    End point values
    Arm A: Prophylactic treatment Arm B: On-demand treatment
    Number of subjects analysed
    82
    11
    Units: Point change
    arithmetic mean (standard deviation)
        Bleed Severity Total Score
    -4.17 ± 17.05
    -4.24 ± 15.71
        Paint Severity Total Score
    -1.22 ± 12.5
    -0.17 ± 11.88
        Total Score
    -2.7 ± 13.42
    -2.2 ± 10.92
    No statistical analyses for this end point

    Secondary: Average number of BAX855 infusions needed for the treatment of bleeding episodes

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    End point title
    Average number of BAX855 infusions needed for the treatment of bleeding episodes
    End point description
    End point type
    Secondary
    End point timeframe
    From first exposure to BAX 855 until the end of the study [at least 50 exposure days or 6 months (±2 weeks), whichever occurs last, for the prophylaxis arm and 6 months (± 2 weeks) for the on-demand arm].
    End point values
    Arm A: Prophylactic treatment Arm B: On-demand treatment
    Number of subjects analysed
    65
    17
    Units: Average number of infusions
        arithmetic mean (standard deviation)
    1.37 ± 0.8
    1.21 ± 0.35
    No statistical analyses for this end point

    Secondary: Time intervals between bleeding episodes

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    End point title
    Time intervals between bleeding episodes
    End point description
    Interval between Bleeds in months was calculated as: Observation period for efficacy (in days)/(number of bleeds)*(12/365.2425)
    End point type
    Secondary
    End point timeframe
    From first exposure to BAX 855 until the end of the study [at least 50 exposure days or 6 months (±2 weeks), whichever occurs last, for the prophylaxis arm and 6 months (± 2 weeks) for the on-demand arm].
    End point values
    Arm A: Prophylactic treatment Arm B: On-demand treatment
    Number of subjects analysed
    120
    17
    Units: Number of subjects
        No bleed
    45
    0
        Interval: > 6 months
    5
    0
        Interval: 6 months
    20
    0
        Interval: 5 months
    3
    0
        Interval: 4 months
    0
    0
        Interval: 3 months
    11
    0
        Interval: 2 months
    16
    0
        Interval: <= 1 month
    20
    17
    No statistical analyses for this end point

    Secondary: Area under the concentration versus time curve from 0 to infinity (One-stage Clotting)

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    End point title
    Area under the concentration versus time curve from 0 to infinity (One-stage Clotting)
    End point description
    Area under the concentration versus time curve from 0 to infinity of BAX 855 following initial and repeat administration after at least 50 EDs, and as compared to ADVATE. Calculated by WinNonlin NCA (Model 201, calculation method: Linear Trapezoidal Linear/Log Interpolation). Subjects: 26 subjects for PK1 and PK2; 22 subjects for PK3
    End point type
    Secondary
    End point timeframe
    Pharmacokinetic (PK) evaluation: Within 30 minutes prior to start of infusion; and post-infusion at 10, 30 minutes, and 1, 3, 6, 9, 24, 32, 48, 56, 72 (PK2 and PK3 only), and 96 hours (PK2 and PK3 only).
    End point values
    Pharmacokinetic Full Analysis Set
    Number of subjects analysed
    26
    Units: IU*hours/dL
    arithmetic mean (standard deviation)
        PK1 ADVATE
    1168 ± 425.4
        PK2 BAX855
    2073.3 ± 778.41
        PK3 BAX855
    2008.7 ± 631.53
    No statistical analyses for this end point

    Secondary: Apparent Volume of Distribution at Steady State (One-stage Clotting)

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    End point title
    Apparent Volume of Distribution at Steady State (One-stage Clotting)
    End point description
    Apparent Volume of Distribution at Steady State of BAX 855 following initial and repeat administration after at least 50 EDs, and as compared to ADVATE. Calculated as Clearance * Mean Residence Time. Subjects: 26 subjects for PK1 and PK2; 22 subjects for PK3
    End point type
    Secondary
    End point timeframe
    Pharmacokinetic (PK) evaluation: Within 30 minutes prior to start of infusion; and post-infusion at 10, 30 minutes, and 1, 3, 6, 9, 24, 32, 48, 56, 72 (PK2 and PK3 only), and 96 hours (PK2 and PK3 only).
    End point values
    Pharmacokinetic Full Analysis Set
    Number of subjects analysed
    26
    Units: dL/kg
    arithmetic mean (standard deviation)
        PK1 ADVATE
    0.5487 ± 0.20213
        PK2 BAX855
    0.4715 ± 0.14602
        PK3 BAX855
    0.497 ± 0.15756
    No statistical analyses for this end point

    Secondary: Maximum plasma concentration (One-stage Clotting)

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    End point title
    Maximum plasma concentration (One-stage Clotting)
    End point description
    Maximum plasma concentration of BAX 855 following initial and repeat administration after at least 50 EDs, and as compared to ADVATE. Determined as the maximum concentration achieved post-infusion. Subjects: 26 subjects for PK1 and PK2; 22 subjects for PK3
    End point type
    Secondary
    End point timeframe
    Pharmacokinetic (PK) evaluation: Within 30 minutes prior to start of infusion; and post-infusion at 10, 30 minutes, and 1, 3, 6, 9, 24, 32, 48, 56, 72 (PK2 and PK3 only), and 96 hours (PK2 and PK3 only).
    End point values
    Pharmacokinetic Full Analysis Set
    Number of subjects analysed
    26
    Units: IU/dL
    arithmetic mean (standard deviation)
        PK1 ADVATE
    108.45 ± 26.25
        PK2 BAX855
    113.68 ± 30.259
        PK3 BAX855
    103.34 ± 29.311
    No statistical analyses for this end point

    Secondary: Time to maximum concentration in plasma (One-stage Clotting)

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    End point title
    Time to maximum concentration in plasma (One-stage Clotting)
    End point description
    Time to maximum concentration in plasma of BAX 855 following initial and repeat administration after at least 50 EDs, and as compared to ADVATE. Defined as the time to reach maximum plasma concentration. Subjects: 26 subjects for PK1 and PK2; 22 subjects for PK3
    End point type
    Secondary
    End point timeframe
    Pharmacokinetic (PK) evaluation: Within 30 minutes prior to start of infusion; and post-infusion at 10, 30 minutes, and 1, 3, 6, 9, 24, 32, 48, 56, 72 (PK2 and PK3 only), and 96 hours (PK2 and PK3 only).
    End point values
    Pharmacokinetic Full Analysis Set
    Number of subjects analysed
    26
    Units: hours
    arithmetic mean (standard deviation)
        PK1 ADVATE
    0.296 ± 0.1662
        PK2 BAX855
    0.397 ± 0.2632
        PK3 BAX855
    0.467 ± 0.6044
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From first exposure to BAX 855 until the end of the study [at least 50 exposure days or 6 months (±2 weeks), whichever occurs last, for the prophylaxis arm and 6 months (± 2 weeks) for the on-demand arm].
    Adverse event reporting additional description
    The population consisted of subjects who received at least one dose of BAX 855 during the study.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    17.0
    Reporting groups
    Reporting group title
    Safety Analysis Set
    Reporting group description
    Comprised all subjects treated with at least 1 BAX 855 dose.

    Serious adverse events
    Safety Analysis Set
    Total subjects affected by serious adverse events
         subjects affected / exposed
    5 / 137 (3.65%)
         number of deaths (all causes)
    1
         number of deaths resulting from adverse events
    Injury, poisoning and procedural complications
    Humerus fracture
         subjects affected / exposed
    1 / 137 (0.73%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Neuroendocrine carcinoma
         subjects affected / exposed
    1 / 137 (0.73%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Musculoskeletal and connective tissue disorders
    Osteoarthritis
         subjects affected / exposed
    1 / 137 (0.73%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Muscle haemorrhage
         subjects affected / exposed
    1 / 137 (0.73%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Herpes zoster infection neurological
         subjects affected / exposed
    1 / 137 (0.73%)
         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
    Safety Analysis Set
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    27 / 137 (19.71%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    7 / 137 (5.11%)
         occurrences all number
    13
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    14 / 137 (10.22%)
         occurrences all number
    16
    Upper respiratory tract infection
         subjects affected / exposed
    9 / 137 (6.57%)
         occurrences all number
    10

    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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