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    Clinical Trial Results:
    A Phase 3b Continuation study of the Safety and Efficacy of PEGylated Recombinant Factor VIII (PEG-rFVIII; BAX 855) in Prophylaxis of Bleeding in Previously Treated Patients with Severe Hemophilia A

    Summary
    EudraCT number
    2013-002236-24
    Trial protocol
    BE   LT   BG   SE   GB   CZ   AT   NL   DE   ES   PL  
    Global end of trial date
    02 Mar 2018

    Results information
    Results version number
    v1(current)
    This version publication date
    16 Sep 2018
    First version publication date
    16 Sep 2018
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    261302
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01945593
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Shire
    Sponsor organisation address
    300 Shire Way, Lexington, United States, MA 02421
    Public contact
    Study Director, Shire, ClinicalTransparency@shire.com
    Scientific contact
    Study Director, 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-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?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    02 Mar 2018
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    02 Mar 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The co-primary objectives of the study were to determine the safety of BAX 855 based on the incidence of FVIII inhibitory antibody development and to determine the efficacy of BAX 855 based on annualized bleed rate (ABR) as determined by the development of spontaneous bleeds (bleeds not associated with trauma).
    Protection of trial subjects
    This study was conducted in accordance with 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
    15 Oct 2013
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Australia: 4
    Country: Number of subjects enrolled
    Austria: 5
    Country: Number of subjects enrolled
    Bulgaria: 12
    Country: Number of subjects enrolled
    Switzerland: 3
    Country: Number of subjects enrolled
    Czech Republic: 6
    Country: Number of subjects enrolled
    Germany: 5
    Country: Number of subjects enrolled
    Spain: 13
    Country: Number of subjects enrolled
    United Kingdom: 17
    Country: Number of subjects enrolled
    Hong Kong: 2
    Country: Number of subjects enrolled
    Israel: 3
    Country: Number of subjects enrolled
    Japan: 9
    Country: Number of subjects enrolled
    Korea, Republic of: 14
    Country: Number of subjects enrolled
    Lithuania: 6
    Country: Number of subjects enrolled
    Malaysia: 24
    Country: Number of subjects enrolled
    Netherlands: 3
    Country: Number of subjects enrolled
    Poland: 5
    Country: Number of subjects enrolled
    Romania: 2
    Country: Number of subjects enrolled
    Russian Federation: 2
    Country: Number of subjects enrolled
    Sweden: 1
    Country: Number of subjects enrolled
    Turkey: 5
    Country: Number of subjects enrolled
    Taiwan: 3
    Country: Number of subjects enrolled
    Ukraine: 19
    Country: Number of subjects enrolled
    United States: 53
    Worldwide total number of subjects
    216
    EEA total number of subjects
    75
    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)
    3
    Children (2-11 years)
    62
    Adolescents (12-17 years)
    30
    Adults (18-64 years)
    121
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    The study was conducted at 86 centers in 23 countries between 15 October 2013 (first subject first visit) and 02 March 2018 (last subject last visit).

    Pre-assignment
    Screening details
    A total of 218 subjects were enrolled, of them 216 subjects received treatment.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Not applicable
    Blinding used
    Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    BAX 855: Age < 6 Years
    Arm description
    Subjects of age < 6 years received an infusion of 50 +/- 10 International Units/kilogram (IU/kg) of BAX 855 twice weekly; may be increased to 80 IU/kg or a pharmacokinetically tailored (PK-tailored) prophylactic dose (should not exceed 80 IU/kg and the FVIII peak levels were not to exceed 200%) twice weekly based on the subject's individual PK to maintain Factor VIII (FVIII) trough levels of greater than or equal to (>=) 3% until reached at least 100 exposure days (EDs).
    Arm type
    Experimental

    Investigational medicinal product name
    PEGylated rFVIII
    Investigational medicinal product code
    BAX 855
    Other name
    Pharmaceutical forms
    Powder and solvent for solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects received age-dependent intravenous infusion of BAX855 twice weekly until at least 100 EDs.

    Arm title
    BAX 855: Age >= 6 to <12 Years
    Arm description
    Subjects of age >= 6 to <12 years received an infusion of 50 +/- 10 IU/kg of BAX 855 twice weekly; may be increased to 80 IU/kg or a PK-tailored prophylactic dose (should not exceed 80 IU/kg and the FVIII peak levels were not to exceed 200%) twice weekly based on the subject's individual PK to maintain FVIII trough levels of >= 3% until reached at least 100 EDs.
    Arm type
    Experimental

    Investigational medicinal product name
    PEGylated rFVIII
    Investigational medicinal product code
    BAX 855
    Other name
    Pharmaceutical forms
    Powder and solvent for solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects received age-dependent intravenous infusion of BAX855 twice weekly until at least 100 EDs.

    Arm title
    BAX 855: Age >= 12 to <18 Years
    Arm description
    Subjects of age >= 12 to <18 years received an infusion of 45 +/- 5 IU/kg of BAX 855 twice weekly; may be increased to 80 IU/kg or a PK-tailored prophylactic dose (should not exceed 80 IU/kg and the FVIII peak levels were not to exceed 200%) twice weekly based on the subject's individual PK to maintain FVIII trough levels of >= 3% until reached at least 100 EDs.
    Arm type
    Experimental

    Investigational medicinal product name
    PEGylated rFVIII
    Investigational medicinal product code
    BAX 855
    Other name
    Pharmaceutical forms
    Powder and solvent for solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects received age-dependent intravenous infusion of BAX855 twice weekly until at least 100 EDs.

    Arm title
    BAX 855: Age >= 18 Years
    Arm description
    Subjects of age >= 18 years received an infusion of 45 +/- 5 IU/kg of BAX 855 twice weekly; may be increased to 80 IU/kg or a PK-tailored prophylactic dose (should not exceed 80 IU/kg and the FVIII peak levels were not to exceed 200%) twice weekly based on the subject's individual PK to maintain FVIII trough levels of >= 3% until reached at least 100 EDs.
    Arm type
    Experimental

    Investigational medicinal product name
    PEGylated rFVIII
    Investigational medicinal product code
    BAX 855
    Other name
    Pharmaceutical forms
    Powder and solvent for solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects received age-dependent intravenous infusion of BAX855 twice weekly until at least 100 EDs.

    Number of subjects in period 1
    BAX 855: Age < 6 Years BAX 855: Age >= 6 to <12 Years BAX 855: Age >= 12 to <18 Years BAX 855: Age >= 18 Years
    Started
    32
    33
    30
    121
    Completed
    31
    28
    27
    101
    Not completed
    1
    5
    3
    20
         Protocol deviation
    1
    1
    1
    3
         Physician decision
    -
    -
    1
    1
         Other
    -
    2
    -
    7
         Adverse event, serious fatal
    -
    -
    1
    -
         Adverse event, non-fatal
    -
    -
    -
    5
         Consent withdrawn by subject
    -
    2
    -
    4

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    BAX 855: Age < 6 Years
    Reporting group description
    Subjects of age < 6 years received an infusion of 50 +/- 10 International Units/kilogram (IU/kg) of BAX 855 twice weekly; may be increased to 80 IU/kg or a pharmacokinetically tailored (PK-tailored) prophylactic dose (should not exceed 80 IU/kg and the FVIII peak levels were not to exceed 200%) twice weekly based on the subject's individual PK to maintain Factor VIII (FVIII) trough levels of greater than or equal to (>=) 3% until reached at least 100 exposure days (EDs).

    Reporting group title
    BAX 855: Age >= 6 to <12 Years
    Reporting group description
    Subjects of age >= 6 to <12 years received an infusion of 50 +/- 10 IU/kg of BAX 855 twice weekly; may be increased to 80 IU/kg or a PK-tailored prophylactic dose (should not exceed 80 IU/kg and the FVIII peak levels were not to exceed 200%) twice weekly based on the subject's individual PK to maintain FVIII trough levels of >= 3% until reached at least 100 EDs.

    Reporting group title
    BAX 855: Age >= 12 to <18 Years
    Reporting group description
    Subjects of age >= 12 to <18 years received an infusion of 45 +/- 5 IU/kg of BAX 855 twice weekly; may be increased to 80 IU/kg or a PK-tailored prophylactic dose (should not exceed 80 IU/kg and the FVIII peak levels were not to exceed 200%) twice weekly based on the subject's individual PK to maintain FVIII trough levels of >= 3% until reached at least 100 EDs.

    Reporting group title
    BAX 855: Age >= 18 Years
    Reporting group description
    Subjects of age >= 18 years received an infusion of 45 +/- 5 IU/kg of BAX 855 twice weekly; may be increased to 80 IU/kg or a PK-tailored prophylactic dose (should not exceed 80 IU/kg and the FVIII peak levels were not to exceed 200%) twice weekly based on the subject's individual PK to maintain FVIII trough levels of >= 3% until reached at least 100 EDs.

    Reporting group values
    BAX 855: Age < 6 Years BAX 855: Age >= 6 to <12 Years BAX 855: Age >= 12 to <18 Years BAX 855: Age >= 18 Years Total
    Number of subjects
    32 33 30 121
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    3.6 ± 1.29 7.8 ± 1.70 14.2 ± 1.63 34.1 ± 11.47 -
    Gender categorical
    Units:
        Male
    32 32 30 121 215
        Female
    0 1 0 0 1

    End points

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    End points reporting groups
    Reporting group title
    BAX 855: Age < 6 Years
    Reporting group description
    Subjects of age < 6 years received an infusion of 50 +/- 10 International Units/kilogram (IU/kg) of BAX 855 twice weekly; may be increased to 80 IU/kg or a pharmacokinetically tailored (PK-tailored) prophylactic dose (should not exceed 80 IU/kg and the FVIII peak levels were not to exceed 200%) twice weekly based on the subject's individual PK to maintain Factor VIII (FVIII) trough levels of greater than or equal to (>=) 3% until reached at least 100 exposure days (EDs).

    Reporting group title
    BAX 855: Age >= 6 to <12 Years
    Reporting group description
    Subjects of age >= 6 to <12 years received an infusion of 50 +/- 10 IU/kg of BAX 855 twice weekly; may be increased to 80 IU/kg or a PK-tailored prophylactic dose (should not exceed 80 IU/kg and the FVIII peak levels were not to exceed 200%) twice weekly based on the subject's individual PK to maintain FVIII trough levels of >= 3% until reached at least 100 EDs.

    Reporting group title
    BAX 855: Age >= 12 to <18 Years
    Reporting group description
    Subjects of age >= 12 to <18 years received an infusion of 45 +/- 5 IU/kg of BAX 855 twice weekly; may be increased to 80 IU/kg or a PK-tailored prophylactic dose (should not exceed 80 IU/kg and the FVIII peak levels were not to exceed 200%) twice weekly based on the subject's individual PK to maintain FVIII trough levels of >= 3% until reached at least 100 EDs.

    Reporting group title
    BAX 855: Age >= 18 Years
    Reporting group description
    Subjects of age >= 18 years received an infusion of 45 +/- 5 IU/kg of BAX 855 twice weekly; may be increased to 80 IU/kg or a PK-tailored prophylactic dose (should not exceed 80 IU/kg and the FVIII peak levels were not to exceed 200%) twice weekly based on the subject's individual PK to maintain FVIII trough levels of >= 3% until reached at least 100 EDs.

    Subject analysis set title
    BAX 855: Overall
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Subjects received an infusion of 30-80 +/- 5 IU/kg of BAX 855 twice weekly; may be increased to 80 IU/kg or a PKtailored prophylactic dose (should not exceed 80 IU/kg and the FVIII peak levels were not to exceed 200%) twice weekly based on the subject's individual PK to maintain FVIII trough levels of >= 3% until reached at least 100 EDs.

    Primary: Number of Subjects With Inhibitory Antibodies to Factor VIII (FVIII)

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    End point title
    Number of Subjects With Inhibitory Antibodies to Factor VIII (FVIII) [1]
    End point description
    Inhibitory antibodies to Factor VIII was measured by the Nijmegen modification of the Bethesda assay. Inhibitors must be confirmed by 2 separate assessments within a 2 to 4 week period from the central laboratory. Safety analysis set (SAS) included all subjects with at least 1 BAX 855 infusion. The analysis included subjects that developed inhibitory antibodies to FVIII and subjects that did not develop inhibitory antibodies to FVIII and had 100 or more EDs to BAX 855 across all studies and a FVIII inhibitory test result after the 100th exposure day.
    End point type
    Primary
    End point timeframe
    Baseline through end of study assessed every 3 months (53 months)
    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: Descriptive statistics were done, no inferential statistical analyses were performed.
    End point values
    BAX 855: Age < 6 Years BAX 855: Age >= 6 to <12 Years BAX 855: Age >= 12 to <18 Years BAX 855: Age >= 18 Years
    Number of subjects analysed
    29
    31
    30
    114
    Units: Subjects
    0
    0
    0
    0
    No statistical analyses for this end point

    Primary: Annualized Bleed Rate (ABR) - Spontaneous Bleeds

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    End point title
    Annualized Bleed Rate (ABR) - Spontaneous Bleeds [2]
    End point description
    The ABR was assessed based upon each individual bleeding episode. A bleeding episode was defined as subjective (pain consistent with a joint bleed) or objective evidence of bleeding which may or may not require treatment with FVIII. Bleeding episodes occurring at the same anatomical location with the same etiology within 24 hours (+/- 2 hours) of onset of the first episode, bleeding occurring at multiple locations related to the same injury was counted as a single bleeding episode. The ABR of spontaneous bleeds was reported separately for twice weekly, PK-t R, each of the every 5 days and every 7 days treatment regimens at the time of bleed. Here, FDR refers to fixed-dose regimen, PK-t R to PK-tailored regimen and "n" indicates the number of subjects evaluable for this endpoint. Full analysis set (FAS) included all subjects with at least 1 BAX 855 infusion. 99999 indicates the data was not calculated due to less number of subjects.
    End point type
    Primary
    End point timeframe
    Baseline through end of study assessed every 3 months (53 months)
    Notes
    [2] - 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: Descriptive statistics were done, no inferential statistical analyses were performed.
    End point values
    BAX 855: Age < 6 Years BAX 855: Age >= 6 to <12 Years BAX 855: Age >= 12 to <18 Years BAX 855: Age >= 18 Years
    Number of subjects analysed
    32
    33
    30
    121
    Units: Annualized bleed rate
    number (confidence interval 95%)
        FDR: Every 5 Days (n=0,0,8,48)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    1.034 (0.498 to 2.147)
    1.184 (0.741 to 1.894)
        FDR: Every 7 Days (n=0,0,2,13)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    0.000 (0.000 to 0.000)
    2.215 (0.914 to 5.368)
        FDR: Twice Weekly (n=31,31,23,101)
    0.656 (0.394 to 1.094)
    0.762 (0.438 to 1.325)
    1.768 (1.093 to 2.859)
    1.259 (0.876 to 1.812)
        PK-t R (n=4,6,6,9)
    0.915 (0.221 to 3.792)
    0.874 (0.407 to 1.875)
    0.842 (0.122 to 5.821)
    1.006 (0.449 to 2.252)
    No statistical analyses for this end point

    Secondary: Total Annualized Bleed Rate (ABR)

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    End point title
    Total Annualized Bleed Rate (ABR)
    End point description
    The ABR was assessed based upon each individual bleeding episode. A bleeding episode was defined as subjective (pain consistent with a joint bleed) or objective evidence of bleeding which may or may not require treatment with FVIII. Bleeding episodes occurring at the same anatomical location with the same etiology within 24 hours (+/- 2 hours) of onset of the first episode, bleeding occurring at multiple locations related to the same injury was counted as a single bleeding episode. Bleeding occurring at multiple locations related to the same injury (e.g., knee and ankle bleed following a fall) was counted as a single bleeding episode. Total annualized bleed rate (spontaneous and traumatic bleeding episodes) was reported. FAS included all subjects with at least 1 BAX 855 infusion.
    End point type
    Secondary
    End point timeframe
    Baseline through end of study assessed every 3 months (53 months)
    End point values
    BAX 855: Age < 6 Years BAX 855: Age >= 6 to <12 Years BAX 855: Age >= 12 to <18 Years BAX 855: Age >= 18 Years
    Number of subjects analysed
    32
    33
    30
    121
    Units: Annualized bleed rate
        arithmetic mean (standard deviation)
    2.311 ± 3.510
    2.380 ± 2.371
    3.163 ± 2.673
    2.404 ± 3.295
    No statistical analyses for this end point

    Secondary: Overall Hemostatic Efficacy Rating of BAX 855 for Treatment of Breakthrough Bleeding Episodes

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    End point title
    Overall Hemostatic Efficacy Rating of BAX 855 for Treatment of Breakthrough Bleeding Episodes
    End point description
    The subject or caregiver rated the severity (minor, moderate, or major) of the bleeding episode and rated the overall treatment response at 24 (+/- 2) hours after the initiation of treatment using a 4-point efficacy rating scale as Excellent: Full relief of pain and cessation of objective signs of bleeding after a single infusion and no additional infusion is required for the control of bleeding; Good: Definite pain relief and/or improvement in signs of bleeding after a single infusion and possibly requires more than 1 infusion for complete resolution; Fair: Slight relief of pain and slight improvement in signs of bleeding after a single infusion and required more than 1 infusion for complete resolution and None: No improvement or condition worsens. FAS included all subjects with at least 1 BAX 855 infusion.
    End point type
    Secondary
    End point timeframe
    Baseline through end of study assessed every 3 months (53 months)
    End point values
    BAX 855: Age < 6 Years BAX 855: Age >= 6 to <12 Years BAX 855: Age >= 12 to <18 Years BAX 855: Age >= 18 Years
    Number of subjects analysed
    24
    22
    28
    91
    Units: Treated bleeds
        Excellent
    37
    74
    104
    223
        Good
    26
    43
    76
    223
        Fair
    3
    2
    8
    35
        None
    0
    0
    1
    3
        Not Reported
    6
    7
    13
    26
    No statistical analyses for this end point

    Secondary: BAX 855 Infusions Needed to Treat Bleeding Episodes

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    End point title
    BAX 855 Infusions Needed to Treat Bleeding Episodes
    End point description
    The BAX 855 infusions to treat each bleeding episode was determined by the subject, the subject’s caregiver, and/or investigator, and was based upon the subject’s response to treatment. A bleeding episode was defined as subjective (pain consistent with a joint bleed) or objective evidence of bleeding which may or may not require treatment with FVIII. Bleeding episodes occurring at the same anatomical location with the same etiology within 24 hours (+/- 2 hours) of onset of the first episode, bleeding occurring at multiple locations related to the same injury was counted as a single bleeding episode. FAS included all subjects with at least 1 BAX 855 infusion.
    End point type
    Secondary
    End point timeframe
    Baseline through end of study assessed every 3 months (53 months)
    End point values
    BAX 855: Age < 6 Years BAX 855: Age >= 6 to <12 Years BAX 855: Age >= 12 to <18 Years BAX 855: Age >= 18 Years
    Number of subjects analysed
    32
    33
    30
    121
    Units: Infusions
        arithmetic mean (standard deviation)
    1.4 ± 1.46
    1.4 ± 0.88
    1.4 ± 1.68
    1.4 ± 1.12
    No statistical analyses for this end point

    Secondary: Total Time Intervals Between Bleeding Episodes

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    End point title
    Total Time Intervals Between Bleeding Episodes
    End point description
    The time interval between bleeding episodes was calculated based upon the date and time reported for each bleeding episode. A bleeding episode was defined as subjective (pain consistent with a joint bleed) or objective evidence of bleeding which may or may not require treatment with FVIII. Bleeding episodes occurring at the same anatomical location with the same etiology within 24 hours (+/- 2 hours) of onset of the first episode, bleeding occurring at multiple locations related to the same injury was counted as a single bleeding episode. FAS with evaluable subjects for this endpoint were analyzed.
    End point type
    Secondary
    End point timeframe
    Baseline through end of study assessed every 3 months (53 months)
    End point values
    BAX 855: Age < 6 Years BAX 855: Age >= 6 to <12 Years BAX 855: Age >= 12 to <18 Years BAX 855: Age >= 18 Years
    Number of subjects analysed
    17
    21
    25
    80
    Units: Months
        median (full range (min-max))
    5.460 (0.756 to 14.867)
    4.158 (1.405 to 10.760)
    5.232 (1.228 to 14.571)
    5.818 (0.617 to 22.686)
    No statistical analyses for this end point

    Secondary: Average Dose of BAX 855 per Prophylactic Infusion

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    End point title
    Average Dose of BAX 855 per Prophylactic Infusion
    End point description
    The average dose of BAX 855 per prophylactic infusion was reported. SAS included all subjects with at least 1 BAX 855 infusion.
    End point type
    Secondary
    End point timeframe
    Baseline through end of study assessed every 3 months (53 months)
    End point values
    BAX 855: Age < 6 Years BAX 855: Age >= 6 to <12 Years BAX 855: Age >= 12 to <18 Years BAX 855: Age >= 18 Years
    Number of subjects analysed
    32
    33
    30
    121
    Units: International units per kilogram (IU/kg)
        arithmetic mean (standard deviation)
    53.303 ± 7.569
    54.109 ± 8.224
    53.940 ± 10.588
    49.462 ± 8.447
    No statistical analyses for this end point

    Secondary: Number of Subjects With Adverse Events (AEs) and Serious Adverse Events (SAEs)

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    End point title
    Number of Subjects With Adverse Events (AEs) and Serious Adverse Events (SAEs)
    End point description
    An AE was any unfavorable and unintended sign (eg, an abnormal laboratory finding), symptom (eg, rash, pain, discomfort, fever, dizziness, etc.), disease (eg, peritonitis, bacteremia, etc.), or outcome of death temporally associated with the use of an investigational product (IP), whether or not considered causally related to the IP. A serious adverse event (SAE) was defined as an untoward medical occurrence that at any dose met one or more of the following criteria: outcome was fatal/resulted in death; was life-threatening; required inpatient hospitalization or resulted in prolongation of an existing hospitalization; resulted in persistent or significant disability/incapacity; was a congenital anomaly/birth defect; was a medically important event. SAS included all subjects with at least 1 BAX 855 infusion.
    End point type
    Secondary
    End point timeframe
    Baseline through end of study assessed every 3 months (53 months)
    End point values
    BAX 855: Age < 6 Years BAX 855: Age >= 6 to <12 Years BAX 855: Age >= 12 to <18 Years BAX 855: Age >= 18 Years
    Number of subjects analysed
    32
    33
    30
    121
    Units: Subjects
        AE
    26
    29
    21
    98
        SAE
    5
    2
    4
    22
    No statistical analyses for this end point

    Secondary: Change From Baseline in Body Temperature

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    End point title
    Change From Baseline in Body Temperature
    End point description
    Change in body temperature at pre-infusion and post-infusion was reported. In the below table, FDR refers to fixed dose regimen, PK-tR refers to PK tailored regimen at the time of sampling and "n" indicates the number of subjects evaluable for this endpoint. SAS included all subjects with at least 1 BAX 855 infusion.
    End point type
    Secondary
    End point timeframe
    Baseline, end of study (53 months)
    End point values
    BAX 855: Overall
    Number of subjects analysed
    216
    Units: Degree celsius
    arithmetic mean (standard deviation)
        FDR: Pre-Infusion (n=186)
    -0.03 ± 0.380
        FDR: Post-Infusion (n=148)
    -0.01 ± 0.388
        PK-tR: Pre-Infusion (n=23)
    0.03 ± 0.468
        PK-tR: Post-Infusion (n=21)
    0.06 ± 0.447
    No statistical analyses for this end point

    Secondary: Change From Baseline in Pulse Rate

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    End point title
    Change From Baseline in Pulse Rate
    End point description
    Change in pulse rate at pre-infusion and post-infusion was reported. In the below table, FDR refers to fixed dose regimen, PK-tR refers to PK tailored regimen at the time of sampling and "n" indicates the number of subjects evaluable for this endpoint. SAS included all subjects with at least 1 BAX 855 infusion.
    End point type
    Secondary
    End point timeframe
    Baseline, end of study (53 months)
    End point values
    BAX 855: Overall
    Number of subjects analysed
    214
    Units: Beats per minute (beats/min)
    arithmetic mean (standard deviation)
        FDR: Pre-Infusion (n=186)
    -1.5 ± 12.69
        FDR: Post-Infusion (n=149)
    -1.0 ± 12.59
        PK-tR: Pre-Infusion (n=23)
    1.7 ± 9.83
        PK-tR: Post-Infusion (n=21)
    -4.0 ± 11.66
    No statistical analyses for this end point

    Secondary: Change From Baseline in Respiratory Rate

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    End point title
    Change From Baseline in Respiratory Rate
    End point description
    Change in respiratory rate at pre-infusion and post-infusion was reported. In the below table, FDR refers to fixed dose regimen, PK-tR refers to PK tailored regimen at the time of sampling and "n" indicates the number of subjects evaluable for this endpoint. SAS included all subjects with at least 1 BAX 855 infusion.
    End point type
    Secondary
    End point timeframe
    Baseline, end of study (53 months)
    End point values
    BAX 855: Overall
    Number of subjects analysed
    214
    Units: Breaths per minute (breaths/min)
    arithmetic mean (standard deviation)
        FDR: Pre-Infusion (n=185)
    -0.2 ± 3.26
        FDR: Post-Infusion (n=149)
    -0.6 ± 3.18
        PK-tR: Pre-Infusion (n=23)
    0.0 ± 5.17
        PK-tR: Post-Infusion (n=21)
    -0.3 ± 4.62
    No statistical analyses for this end point

    Secondary: Change From Baseline in Blood Pressure

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    End point title
    Change From Baseline in Blood Pressure
    End point description
    Change in systolic and diastolic blood pressure at pre-infusion and post-infusion were reported. In the below table, FDR refers to fixed dose regimen, PK-tR refers to PK tailored regimen at the time of sampling, SBP refers to systolic blood pressure, DBP refers to diastolic blood pressure and "n" indicates the number of subjects evaluable for this endpoint. SAS with evaluable subjects for this endpoint were analyzed.
    End point type
    Secondary
    End point timeframe
    Baseline, end of study (53 months)
    End point values
    BAX 855: Overall
    Number of subjects analysed
    214
    Units: Millimeter of mercury (mmHg)
    arithmetic mean (standard deviation)
        FDR: SBP: Pre-Infusion (n=186)
    2.7 ± 12.13
        FDR: SBP: Post-Infusion (n=146)
    0.2 ± 11.64
        PK-tR: SBP: Pre-Infusion (n=23)
    1.4 ± 11.36
        PK-tR: SBP: Post-Infusion (n=21)
    2.1 ± 11.57
        FDR: DBP: Pre-Infusion (n=186)
    1.7 ± 9.00
        FDR: DBP: Post-Infusion (n=146)
    1.2 ± 9.05
        PK-tR: DBP: Pre-Infusion (n=23)
    1.6 ± 8.53
        PK-tR: DBP: Post-Infusion (n=21)
    -1.7 ± 7.08
    No statistical analyses for this end point

    Secondary: Number of Subjects with Shifts in Clinical Chemistry Laboratory Assessments

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    End point title
    Number of Subjects with Shifts in Clinical Chemistry Laboratory Assessments
    End point description
    The number of subjects with clinically significant shifts from "normal" and "abnormal not clinically significant (abnormal NCS)" at baseline to "abnormal clinically significant (CS)" at completion were reported. In the below table, FDR refers to fixed dose regimen at the time of sampling, AlA refers to alanine aminotransferase, AP refers to alkaline phosphatase, AsA refers to aspartate aminotransferase and "n" indicates the number of subjects evaluable for this endpoint. SAS included all subjects with at least 1 BAX 855 infusion.
    End point type
    Secondary
    End point timeframe
    Baseline through end of study assessed every 3 months (53 months)
    End point values
    BAX 855: Overall
    Number of subjects analysed
    216
    Units: Subjects
        FDR: AlA- Normal to CS (n=214)
    2
        FDR: AlA- Abnormal NCS to CS (n=214)
    1
        FDR: AP- Normal to CS (n=214)
    3
        FDR: AP- Abnormal NCS to CS (n=214)
    0
        FDR: AsA- Normal to CS (n=214)
    1
        FDR: AsA- Abnormal NCS to CS (n=214)
    1
        FDR: Bilirubin- Normal to CS (n=214)
    0
        FDR: Bilirubin- Abnormal NCS to CS (n=214)
    1
        FDR: Glucose- Normal to CS (n=214)
    1
        FDR: Glucose- Abnormal NCS to CS (n=214)
    0
    No statistical analyses for this end point

    Secondary: Number of Subjects with Shifts in Hematology Laboratory Assessments

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    End point title
    Number of Subjects with Shifts in Hematology Laboratory Assessments
    End point description
    The number of subjects with clinically significant shifts from "normal" and "abnormal not clinically significant (abnormal NCS)" at baseline to "abnormal clinically significant (CS)" at completion were reported. In the below table, FDR refers to fixed dose regimen, PK-tR refers to PK tailored regimen at the time of sampling, Leu refers to leukocytes, MCV refers to mean corpuscular volume, Lym/Leu refers to lymphocytes/leukocytes and "n" indicates the number of subjects evaluable for this endpoint. SAS included all subjects with at least 1 BAX 855 infusion.
    End point type
    Secondary
    End point timeframe
    Baseline through end of study assessed every 3 months (53 months)
    End point values
    BAX 855: Overall
    Number of subjects analysed
    216
    Units: Subjects
        FDR: Eosinophils/Leu- Normal to CS (n=214)
    1
        FDR:Eosinophils/Leu- Abnormal NCS to CS (n=214)
    0
        FDR: Erythrocytes MCV- Normal to CS (n=214)
    1
        FDR: Erythrocytes MCV- Abnormal NCS to CS (n=214)
    1
        FDR: Erythrocytes- Normal to CS (n=214)
    0
        FDR: Erythrocytes- Abnormal NCS to CS (n=214)
    1
        FDR: Hematocrit- Normal to CS (n=214)
    1
        FDR: Hematocrit- Abnormal NCS to CS (n=214)
    2
        FDR: Hemoglobin- Normal to CS (n=214)
    1
        FDR: Hemoglobin- Abnormal NCS to CS (n=214)
    1
        FDR: Leukocytes- Normal to CS (n=214)
    1
        FDR: Leukocytes- Abnormal NCS to CS (n=214)
    0
        FDR: Lym/Leu- Normal to CS (n=214)
    1
        FDR: Lym/Leu- Abnormal NCS to CS (n=214)
    0
        FDR: Platelets- Normal to CS (n=214)
    1
        FDR: Platelets- Abnormal NCS to CS (n=214)
    0
        PK-t R: Hematocrit- Normal to CS (n=25)
    1
        PK-t R: Hematocrit- Abnormal NCS to CS (n=25)
    0
        PK-t R: Hemoglobin- Normal to CS (n=25)
    1
        PK-t R: Hemoglobin- Abnormal NCS to CS (n=25)
    0
    No statistical analyses for this end point

    Secondary: Number of Subjects with Shifts in Lipid Panel Assessments

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    End point title
    Number of Subjects with Shifts in Lipid Panel Assessments
    End point description
    The number of subjects with clinically significant shifts from "normal" and "abnormal not clinically significant (abnormal NCS)" at baseline to "abnormal clinically significant (CS)" at completion were reported. In the below table, HDL refers to high density lipoprotein, LDL refers to low density lipoprotein, VLDL refers to very low density lipoprotein and "n" indicates the number of subjects evaluable for this endpoint. SAS included all subjects with at least 1 BAX 855 infusion.
    End point type
    Secondary
    End point timeframe
    Baseline through end of study assessed every 3 months (53 months)
    End point values
    BAX 855: Overall
    Number of subjects analysed
    216
    Units: Subjects
        FDR: Cholesterol- Normal to CS (n=214)
    2
        FDR: Cholesterol- Abnormal NCS to CS (n=214)
    0
        FDR: HDL Cholesterol- Normal to CS (n=214)
    1
        FDR: HDL Cholesterol- Abnormal NCS to CS (n=214)
    0
        FDR: LDL Cholesterol- Normal to CS (n=214)
    2
        FDR: LDL Cholesterol- Abnormal NCS to CS (n=214)
    0
        FDR: Triglycerides- Normal to CS (n=214)
    2
        FDR: Triglycerides- Abnormal NCS to CS (n=214)
    1
        FDR: VLDL Cholesterol- Normal to CS (n=214)
    2
        FDR: VLDL Cholesterol- Abnormal NCS to CS (n=214)
    0
        PK-tR: VLDL Cholesterol- Normal to CS (n=25)
    2
        PK-tR: VLDL Cholesterol- Abnormal NCS to CS (n=25)
    0
    No statistical analyses for this end point

    Secondary: Number of Subjects With Binding antibodies

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    End point title
    Number of Subjects With Binding antibodies
    End point description
    Binding antibodies (IgG and IgM) against FVIII, polyethylene glycol (PEG) and PEGylated FVIII (PEG-FVIII) were analyzed using enzyme-linked immunosorbent assay (ELISA). SAS included all subjects with at least 1 BAX 855 infusion.
    End point type
    Secondary
    End point timeframe
    Baseline through end of study assessed every 3 months (53 months)
    End point values
    BAX 855: Age < 6 Years BAX 855: Age >= 6 to <12 Years BAX 855: Age >= 12 to <18 Years BAX 855: Age >= 18 Years
    Number of subjects analysed
    32
    33
    30
    121
    Units: Subjects
        IgG to FVIII
    0
    2
    1
    2
        IgM to FVIII
    0
    0
    0
    0
        IgG to PEG-FVIII
    2
    2
    0
    4
        IgM to PEG-FVIII
    0
    0
    0
    0
        IgG to PEG
    0
    0
    0
    0
        IgM to PEG
    0
    0
    0
    0
    No statistical analyses for this end point

    Secondary: Number of Subjects With Anti-Chinese Hamster Ovary (CHO) Antibodies

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    End point title
    Number of Subjects With Anti-Chinese Hamster Ovary (CHO) Antibodies
    End point description
    Testing for binding of anti-CHO protein antibodies was performed on citrate-anti-coagulated plasma using an ELISA employing polyclonal antihuman IgG antibodies. SAS included all subjects with at least 1 BAX 855 infusion.
    End point type
    Secondary
    End point timeframe
    Baseline through end of study assessed every 3 months (53 months)
    End point values
    BAX 855: Age < 6 Years BAX 855: Age >= 6 to <12 Years BAX 855: Age >= 12 to <18 Years BAX 855: Age >= 18 Years
    Number of subjects analysed
    32
    33
    30
    121
    Units: Subjects
    0
    0
    0
    0
    No statistical analyses for this end point

    Secondary: Change From Baseline in Bleed Severity

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    End point title
    Change From Baseline in Bleed Severity [3]
    End point description
    Hemophilia symptom (haemo-SYM) questionnaire has two subscales: pain and bleed. It was used to asses the bleed severity for subjects >=18 years of age as: severity of spontaneous bleeding in my joints (unrelated to injury or activity), spontaneous bleeding in my muscles (unrelated to injury or activity), prolonged bleeding after injury in spite of treatment, intense pain because of bleeding event, joint pain due to active bleed and bleeding during personal hygiene routine, blood in my urine, nose bleeds and assigned a score of 0=Absent, 1=very mild, 2=mild, 3=moderate, 4=severe and 5=very severe. The score was determined as (mean score/5)*100 where mean score is the mean of the available results in the particular subscale. Higher scores on the Haemo-SYM indicate more severe symptoms. Therefore, negative change scores indicate that symptoms have improved. Here, "n" indicates the number of subjects evaluable for this endpoint. FAS included all subjects with at least 1 BAX 855 infusion.
    End point type
    Secondary
    End point timeframe
    Baseline, end of study (53 months)
    Notes
    [3] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Haemo-SYM questionnaire was used to measure bleed severity in subjects >=18 years of age.
    End point values
    BAX 855: Age >= 18 Years
    Number of subjects analysed
    108
    Units: Score on a scale
    arithmetic mean (standard deviation)
        Fixed dose regimen (n=72)
    -7.824 ± 18.514
        PK-tailored regimen (n=9)
    -16.667 ± 14.337
    No statistical analyses for this end point

    Secondary: Change From Baseline in Pain Severity

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    End point title
    Change From Baseline in Pain Severity [4]
    End point description
    Hemophilia symptom (haemo-SYM) questionnaire has two subscales: pain and bleed. It was used to asses the pain severity for subjects >=18 years of age as: pain because of swelling in my joints, climbing stairs, upon waking in the morning, active arthritis; constant pain, in my muscles, that needs medication; joint sensitivity to weather conditions; reduced range of joint movement, joint deformity, sleep disturbance because of pain or bleeds, blood in my urine, nose bleeds and assigned a score of 0=Absent, 1=very mild, 2=mild, 3=moderate, 4=severe and 5=very severe. The score was determined as (mean score/5)*100 where mean score is the mean of the available results in the particular subscale. Higher scores on the Haemo-SYM indicate more severe symptoms. Therefore, negative change scores indicate that symptoms have improved. Here, "n" indicates the number of subjects evaluable for this endpoint. FAS included all subjects with at least 1 BAX 855 infusion.
    End point type
    Secondary
    End point timeframe
    Baseline, end of study (53 months)
    Notes
    [4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Haemo-SYM questionnaire was used to measure pain severity in subjects >=18 years of age.
    End point values
    BAX 855: Age >= 18 Years
    Number of subjects analysed
    108
    Units: Score on a scale
    arithmetic mean (standard deviation)
        Fixed dose regimen (n=72)
    -1.341 ± 11.531
        PK-tailored regimen (n=9)
    -8.889 ± 20.659
    No statistical analyses for this end point

    Secondary: Change From Baseline in Patient Reported Outcomes: Health-related Quality of Life (HRQoL): Short Form-36 (SF-36)

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    End point title
    Change From Baseline in Patient Reported Outcomes: Health-related Quality of Life (HRQoL): Short Form-36 (SF-36) [5]
    End point description
    HRQoL in subjects aged >=14 years was measured using the SF-36 questionnaire. The questionnaire was divided into 8 domains and scored as: physical functioning (1=yes, limited a lot to 3=no, not limited at all), role-physical (1=all of the time to 5=none of the time), bodily pain (1=very severe to 6=none), general health (1=poor to 5=excellent), vitality (1=none of the time to 5=all of the time), social functioning (1=all of the time: to 5=none of the time), role emotional (1=all of the time to 5=none of the time) and mental health (1=all of the time to 5=none of the time). The score for each domain is then to be transformed to a 0-100 range as [(actual raw score-lowest possible raw score)/possible raw score range]*100. Positive change scores indicate improved HRQoL. Here "n" indicates the number of subjects evaluable for this endpoint. FAS included all subjects with at least 1 BAX 855 infusion.
    End point type
    Secondary
    End point timeframe
    Baseline, end of study (53 months)
    Notes
    [5] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: SF-36 questionnaire was used to measure HRQoL in subjects aged >=14 years.
    End point values
    BAX 855: Age >= 12 to <18 Years BAX 855: Age >= 18 Years
    Number of subjects analysed
    18
    108
    Units: Score on a scale
    arithmetic mean (standard deviation)
        FDR: Physical functioning (n=9,74)
    3.778 ± 4.604
    -0.150 ± 3.019
        PK-t R: Physical functioning (n=4,9)
    1.250 ± 1.500
    -0.778 ± 4.816
        FDR: Role-physical (n=9,74)
    1.4 ± 4.39
    0.3 ± 3.85
        PK-t R: Role-physical (n=4,9)
    1.8 ± 2.63
    1.0 ± 3.00
        FDR: Bodily pain (n=9,74)
    1.69 ± 2.639
    0.76 ± 2.011
        PK-t R: Bodily pain (n=4,9)
    0.95 ± 2.119
    -0.01 ± 3.493
        FDR: General health (n=9,73)
    2.80 ± 3.599
    0.39 ± 3.795
        PK-t R: General health (n=4,9)
    3.15 ± 3.419
    1.02 ± 4.196
        FDR: Vitality (n=9,73)
    0.3 ± 3.46
    -0.01 ± 2.34
        PK-t R: Vitality (n=4,9)
    1.0 ± 4.55
    1.0 ± 3.54
        FDR: Social functioning (n=9,74)
    0.6 ± 1.67
    -0.03 ± 1.37
        PK-t R: Social functioning (n=4,9)
    1.0 ± 1.15
    -1.7 ± 2.06
        FDR: Role emotional (n=9,74)
    -0.6 ± 2.13
    -0.4 ± 2.46
        PK-t R: Role emotional (n=4,9)
    0.3 ± 0.50
    -1.3 ± 2.69
        FDR: Mental health (n=9,73)
    -0.7 ± 2.06
    -0.4 ± 3.18
        PK-t R: Mental health (n=4,9)
    0.0 ± 1.41
    -0.6 ± 2.92
        FDR: Physical component score (n=9,73)
    9.381 ± 12.588
    1.764 ± 6.843
        PK-t R: Physical component score (n=4,9)
    5.631 ± 6.997
    2.258 ± 9.817
        FDR: Mental component score (n=9,73)
    -3.854 ± 6.839
    -1.570 ± 9.102
        PK-t R: Mental component score (n=4,9)
    0.980 ± 7.125
    -4.677 ± 9.195
    No statistical analyses for this end point

    Secondary: Change From Baseline in Patient Reported Outcomes: Health-related Quality of Life (HRQoL): Pediatrics Quality of Life (PedsQL) Questionnaire

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    End point title
    Change From Baseline in Patient Reported Outcomes: Health-related Quality of Life (HRQoL): Pediatrics Quality of Life (PedsQL) Questionnaire [6]
    End point description
    HRQoL in subjects aged <14 years was measured using the PedsQL. It capture data for the following domains: physical functioning, emotional functioning, social functioning, school functioning, psychosocial functioning, physical health and a total score. Each question of the PedsQL was scored as Never: 100, almost never: 75, sometimes: 50, often: 25, almost always: 0. The mean of the individual question scores was calculated. Lower scores on the PedsQL indicating worse HRQoL. Here, FDR refers to fixed dose regimen, PK-t R refers to PK-tailored regimen and "n" indicates the number of subjects evaluable for this endpoint. FAS included all subjects with at least 1 BAX 855 infusion.
    End point type
    Secondary
    End point timeframe
    Baseline, end of study (53 months)
    Notes
    [6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: PedsQL questionnaire was used to measure HRQoL in subjects aged <14 years.
    End point values
    BAX 855: Age < 6 Years BAX 855: Age >= 6 to <12 Years BAX 855: Age >= 12 to <18 Years
    Number of subjects analysed
    28
    33
    8
    Units: Score on a scale
    arithmetic mean (standard deviation)
        FDR: Physical functioning (n=21,20,3)
    -1.190 ± 18.181
    2.344 ± 17.876
    3.125 ± 15.625
        PK-t R: Physical functioning (n=3,4,2)
    -7.292 ± 15.415
    4.688 ± 8.268
    7.813 ± 6.629
        FDR: Emotional functioning (n=21,20,3)
    -1.0 ± 17.00
    -1.0 ± 17.29
    8.3 ± 20.21
        PK-t R: Emotional functioning (n=3,4,2)
    -11.7 ± 10.41
    5.0 ± 7.07
    10.0 ± 14.14
        FDR: Social functioning (n=21,20,3)
    -0.2 ± 14.70
    -0.5 ± 18.06
    8.3 ± 15.28
        PK-t R: Social functioning (n=3,4,2)
    -18.3 ± 23.63
    2.5 ± 12.58
    5.0 ± 7.07
        FDR: School functioning (n=16,20,3)
    5.625 ± 20.966
    1.750 ± 26.768
    15.000 ± 13.229
        PK-t R: School functioning (n=2,4,2)
    -12.500 ± 29.463
    -7.500 ± 12.583
    -12.500 ± 17.678
        FDR: Psychosocial functioning (n=21,20,3)
    0.568 ± 14.728
    0.083 ± 16.226
    10.556 ± 15.486
        PK-t R: Psychosocial functioning (n=3,4,2)
    -14.231 ± 14.881
    0.000 ± 8.714
    0.833 ± 3.536
        FDR: Total score (n=21,20,3)
    -0.113 ± 14.629
    0.870 ± 15.362
    7.971 ± 15.230
        PK-t R: Total score (n=3,4,2)
    -11.310 ± 15.023
    1.630 ± 7.183
    3.261 ± 0.000
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From start of study drug administration up to 36 months
    Assessment type
    Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    20.1
    Reporting groups
    Reporting group title
    BAX 855: Age < 6 Years
    Reporting group description
    Subjects of age less than 6 years received an infusion of 50 +/ - 10 International Units (IU)/ kilogram (kg) of BAX 855 or a pharmacokinetically tailored (PK-tailored) prophylactic dose based on the participant's individual PK to maintain FVIII trough levels of greater than or equal to 3% twice weekly until they had reached at least 100 exposure days (EDs).

    Reporting group title
    BAX 855: Age >= 6 to <12 Years
    Reporting group description
    Subjects of age greater than or equal to 6 to less than 12 years received an infusion of 50 +/ - 10 IU/ kg of BAX 855 or a PK-tailored prophylactic dose based on the participant's individual PK to maintain FVIII trough levels of greater than or equal to 3% twice weekly until they had reached at least 100 exposure days (EDs).

    Reporting group title
    BAX 855: Age >= 12 to <18 Years
    Reporting group description
    Subjects of age greater than or equal to 12 to less than 18 years received an infusion of 45 +/ - 5 IU/ kg of BAX 855 or a PK-tailored prophylactic dose based on the participant's individual PK to maintain FVIII trough levels of greater than or equal to 3% twice weekly until they had reached at least 100 exposure days (EDs).

    Reporting group title
    BAX 855: Age >= 18 Years
    Reporting group description
    Subjects of age greater than or equal to 18 years received an infusion of 45 +/ - 5 IU/ kg of BAX 855 or a PK-tailored prophylactic dose based on the participant's individual PK to maintain FVIII trough levels of greater than or equal to 3% twice weekly until they had reached at least 100 exposure days (EDs).

    Serious adverse events
    BAX 855: Age < 6 Years BAX 855: Age >= 6 to <12 Years BAX 855: Age >= 12 to <18 Years BAX 855: Age >= 18 Years
    Total subjects affected by serious adverse events
         subjects affected / exposed
    5 / 32 (15.63%)
    2 / 33 (6.06%)
    4 / 30 (13.33%)
    22 / 121 (18.18%)
         number of deaths (all causes)
    0
    0
    1
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    Vascular disorders
    Haematoma
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 33 (0.00%)
    1 / 30 (3.33%)
    2 / 121 (1.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Metastases to lung
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 33 (0.00%)
    0 / 30 (0.00%)
    1 / 121 (0.83%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal cancer metastatic
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 33 (0.00%)
    0 / 30 (0.00%)
    1 / 121 (0.83%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    1 / 32 (3.13%)
    1 / 33 (3.03%)
    0 / 30 (0.00%)
    0 / 121 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Facial bones fracture
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 33 (0.00%)
    0 / 30 (0.00%)
    1 / 121 (0.83%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Fall
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 33 (3.03%)
    0 / 30 (0.00%)
    0 / 121 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Femoral neck fracture
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 33 (0.00%)
    0 / 30 (0.00%)
    1 / 121 (0.83%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Head injury
         subjects affected / exposed
    1 / 32 (3.13%)
    0 / 33 (0.00%)
    0 / 30 (0.00%)
    1 / 121 (0.83%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nasal injury
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 33 (3.03%)
    0 / 30 (0.00%)
    0 / 121 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Scapula fracture
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 33 (0.00%)
    0 / 30 (0.00%)
    1 / 121 (0.83%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Splenic rupture
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 33 (0.00%)
    1 / 30 (3.33%)
    0 / 121 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Traumatic fracture
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 33 (0.00%)
    0 / 30 (0.00%)
    1 / 121 (0.83%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Wound haemorrhage
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 33 (0.00%)
    0 / 30 (0.00%)
    1 / 121 (0.83%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Wrist fracture
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 33 (0.00%)
    0 / 30 (0.00%)
    1 / 121 (0.83%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Transaminases increased
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 33 (0.00%)
    0 / 30 (0.00%)
    1 / 121 (0.83%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 33 (0.00%)
    0 / 30 (0.00%)
    1 / 121 (0.83%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Splenic haematoma
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 33 (0.00%)
    1 / 30 (3.33%)
    0 / 121 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 33 (0.00%)
    0 / 30 (0.00%)
    1 / 121 (0.83%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Epistaxis
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 33 (3.03%)
    0 / 30 (0.00%)
    0 / 121 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 33 (0.00%)
    0 / 30 (0.00%)
    1 / 121 (0.83%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebral haemorrhage
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 33 (0.00%)
    1 / 30 (3.33%)
    0 / 121 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Gastrointestinal disorders
    Ileus
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 33 (0.00%)
    0 / 30 (0.00%)
    1 / 121 (0.83%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 33 (0.00%)
    0 / 30 (0.00%)
    2 / 121 (1.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 33 (0.00%)
    0 / 30 (0.00%)
    1 / 121 (0.83%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Ureterolithiasis
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 33 (0.00%)
    0 / 30 (0.00%)
    1 / 121 (0.83%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 33 (3.03%)
    0 / 30 (0.00%)
    0 / 121 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Haemarthrosis
         subjects affected / exposed
    2 / 32 (6.25%)
    0 / 33 (0.00%)
    0 / 30 (0.00%)
    0 / 121 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Muscle haemorrhage
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 33 (0.00%)
    1 / 30 (3.33%)
    0 / 121 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Abscess oral
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 33 (0.00%)
    0 / 30 (0.00%)
    1 / 121 (0.83%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Appendicitis
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 33 (0.00%)
    0 / 30 (0.00%)
    1 / 121 (0.83%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bacteraemia
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 33 (0.00%)
    0 / 30 (0.00%)
    1 / 121 (0.83%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cystitis
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 33 (3.03%)
    0 / 30 (0.00%)
    0 / 121 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Device related infection
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 33 (0.00%)
    0 / 30 (0.00%)
    1 / 121 (0.83%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Device related sepsis
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 33 (0.00%)
    0 / 30 (0.00%)
    1 / 121 (0.83%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Incision site abscess
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 33 (0.00%)
    0 / 30 (0.00%)
    1 / 121 (0.83%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Laryngitis
         subjects affected / exposed
    1 / 32 (3.13%)
    0 / 33 (0.00%)
    0 / 30 (0.00%)
    0 / 121 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Plasmodium falciparum infection
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 33 (0.00%)
    0 / 30 (0.00%)
    1 / 121 (0.83%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 33 (0.00%)
    0 / 30 (0.00%)
    2 / 121 (1.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin infection
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 33 (0.00%)
    0 / 30 (0.00%)
    1 / 121 (0.83%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Streptococcal bacteraemia
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 33 (0.00%)
    0 / 30 (0.00%)
    1 / 121 (0.83%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tonsillitis
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 33 (3.03%)
    0 / 30 (0.00%)
    0 / 121 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 32 (3.13%)
    0 / 33 (0.00%)
    0 / 30 (0.00%)
    0 / 121 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 33 (0.00%)
    0 / 30 (0.00%)
    2 / 121 (1.65%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    BAX 855: Age < 6 Years BAX 855: Age >= 6 to <12 Years BAX 855: Age >= 12 to <18 Years BAX 855: Age >= 18 Years
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    20 / 32 (62.50%)
    26 / 33 (78.79%)
    16 / 30 (53.33%)
    66 / 121 (54.55%)
    Injury, poisoning and procedural complications
    Head injury
         subjects affected / exposed
    2 / 32 (6.25%)
    1 / 33 (3.03%)
    0 / 30 (0.00%)
    0 / 121 (0.00%)
         occurrences all number
    2
    1
    0
    0
    Joint injury
         subjects affected / exposed
    0 / 32 (0.00%)
    2 / 33 (6.06%)
    0 / 30 (0.00%)
    3 / 121 (2.48%)
         occurrences all number
    0
    2
    0
    3
    Laceration
         subjects affected / exposed
    1 / 32 (3.13%)
    1 / 33 (3.03%)
    2 / 30 (6.67%)
    2 / 121 (1.65%)
         occurrences all number
    2
    1
    2
    2
    Ligament sprain
         subjects affected / exposed
    1 / 32 (3.13%)
    0 / 33 (0.00%)
    3 / 30 (10.00%)
    3 / 121 (2.48%)
         occurrences all number
    1
    0
    3
    5
    Limb injury
         subjects affected / exposed
    0 / 32 (0.00%)
    2 / 33 (6.06%)
    3 / 30 (10.00%)
    1 / 121 (0.83%)
         occurrences all number
    0
    2
    3
    1
    Skin abrasion
         subjects affected / exposed
    1 / 32 (3.13%)
    2 / 33 (6.06%)
    0 / 30 (0.00%)
    1 / 121 (0.83%)
         occurrences all number
    2
    2
    0
    1
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    10 / 32 (31.25%)
    3 / 33 (9.09%)
    0 / 30 (0.00%)
    7 / 121 (5.79%)
         occurrences all number
    13
    4
    0
    8
    Nasal congestion
         subjects affected / exposed
    1 / 32 (3.13%)
    2 / 33 (6.06%)
    1 / 30 (3.33%)
    4 / 121 (3.31%)
         occurrences all number
    1
    2
    1
    6
    Oropharyngeal pain
         subjects affected / exposed
    1 / 32 (3.13%)
    2 / 33 (6.06%)
    1 / 30 (3.33%)
    4 / 121 (3.31%)
         occurrences all number
    1
    2
    1
    7
    Rhinorrhoea
         subjects affected / exposed
    4 / 32 (12.50%)
    2 / 33 (6.06%)
    0 / 30 (0.00%)
    1 / 121 (0.83%)
         occurrences all number
    5
    2
    0
    1
    Blood and lymphatic system disorders
    Iron deficiency anaemia
         subjects affected / exposed
    2 / 32 (6.25%)
    0 / 33 (0.00%)
    0 / 30 (0.00%)
    0 / 121 (0.00%)
         occurrences all number
    2
    0
    0
    0
    Nervous system disorders
    Headache
         subjects affected / exposed
    1 / 32 (3.13%)
    5 / 33 (15.15%)
    1 / 30 (3.33%)
    12 / 121 (9.92%)
         occurrences all number
    1
    5
    1
    23
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    8 / 32 (25.00%)
    3 / 33 (9.09%)
    0 / 30 (0.00%)
    5 / 121 (4.13%)
         occurrences all number
    12
    3
    0
    5
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    2 / 32 (6.25%)
    1 / 33 (3.03%)
    0 / 30 (0.00%)
    3 / 121 (2.48%)
         occurrences all number
    2
    1
    0
    3
    Diarrhoea
         subjects affected / exposed
    4 / 32 (12.50%)
    2 / 33 (6.06%)
    1 / 30 (3.33%)
    7 / 121 (5.79%)
         occurrences all number
    6
    2
    1
    8
    Loose tooth
         subjects affected / exposed
    0 / 32 (0.00%)
    2 / 33 (6.06%)
    0 / 30 (0.00%)
    0 / 121 (0.00%)
         occurrences all number
    0
    2
    0
    0
    Vomiting
         subjects affected / exposed
    4 / 32 (12.50%)
    2 / 33 (6.06%)
    1 / 30 (3.33%)
    1 / 121 (0.83%)
         occurrences all number
    4
    4
    2
    2
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    2 / 32 (6.25%)
    1 / 33 (3.03%)
    1 / 30 (3.33%)
    1 / 121 (0.83%)
         occurrences all number
    3
    1
    1
    1
    Urticaria
         subjects affected / exposed
    2 / 32 (6.25%)
    0 / 33 (0.00%)
    0 / 30 (0.00%)
    2 / 121 (1.65%)
         occurrences all number
    2
    0
    0
    2
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    1 / 32 (3.13%)
    2 / 33 (6.06%)
    2 / 30 (6.67%)
    14 / 121 (11.57%)
         occurrences all number
    2
    2
    2
    20
    Back pain
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 33 (0.00%)
    1 / 30 (3.33%)
    7 / 121 (5.79%)
         occurrences all number
    0
    0
    1
    7
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    2 / 32 (6.25%)
    1 / 33 (3.03%)
    0 / 30 (0.00%)
    1 / 121 (0.83%)
         occurrences all number
    3
    1
    0
    1
    Ear infection
         subjects affected / exposed
    5 / 32 (15.63%)
    0 / 33 (0.00%)
    1 / 30 (3.33%)
    0 / 121 (0.00%)
         occurrences all number
    10
    0
    2
    0
    Gastroenteritis
         subjects affected / exposed
    2 / 32 (6.25%)
    0 / 33 (0.00%)
    0 / 30 (0.00%)
    2 / 121 (1.65%)
         occurrences all number
    2
    0
    0
    2
    Gastroenteritis viral
         subjects affected / exposed
    2 / 32 (6.25%)
    0 / 33 (0.00%)
    0 / 30 (0.00%)
    1 / 121 (0.83%)
         occurrences all number
    2
    0
    0
    1
    Influenza
         subjects affected / exposed
    2 / 32 (6.25%)
    3 / 33 (9.09%)
    0 / 30 (0.00%)
    3 / 121 (2.48%)
         occurrences all number
    2
    3
    0
    3
    Nasopharyngitis
         subjects affected / exposed
    6 / 32 (18.75%)
    7 / 33 (21.21%)
    3 / 30 (10.00%)
    24 / 121 (19.83%)
         occurrences all number
    12
    12
    6
    38
    Pharyngitis
         subjects affected / exposed
    2 / 32 (6.25%)
    2 / 33 (6.06%)
    0 / 30 (0.00%)
    5 / 121 (4.13%)
         occurrences all number
    2
    2
    0
    9
    Pharyngitis streptococcal
         subjects affected / exposed
    1 / 32 (3.13%)
    3 / 33 (9.09%)
    1 / 30 (3.33%)
    1 / 121 (0.83%)
         occurrences all number
    1
    4
    1
    1
    Rhinitis
         subjects affected / exposed
    2 / 32 (6.25%)
    2 / 33 (6.06%)
    3 / 30 (10.00%)
    1 / 121 (0.83%)
         occurrences all number
    2
    2
    5
    2
    Sinusitis
         subjects affected / exposed
    2 / 32 (6.25%)
    0 / 33 (0.00%)
    0 / 30 (0.00%)
    4 / 121 (3.31%)
         occurrences all number
    2
    0
    0
    4
    Skin infection
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 33 (0.00%)
    2 / 30 (6.67%)
    0 / 121 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Upper respiratory tract infection
         subjects affected / exposed
    6 / 32 (18.75%)
    5 / 33 (15.15%)
    1 / 30 (3.33%)
    12 / 121 (9.92%)
         occurrences all number
    12
    10
    1
    13
    Viral infection
         subjects affected / exposed
    2 / 32 (6.25%)
    1 / 33 (3.03%)
    1 / 30 (3.33%)
    0 / 121 (0.00%)
         occurrences all number
    5
    1
    1
    0

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    02 Oct 2013
    - The timing of the first Follow-up visit changed from 1 month (+/- 2 weeks) to 6 weeks (- 1 or + 2 weeks). - Additional information was added to the description of the IP to more completely describe the BAX 855 molecule, the purpose of the study, how the data with BAX 855 be assessed in this study and the dosing rationale in this study. - The minimal duration of the washout period was changed to 72 hours to align with the pivotal study (Study 2012-003599-38) and to avoid additional risk of bleeding episodes. - A section on Treatment for Surgery or Dental Procedures was added to provide clarity on how subjects would be transferred to and from the surgery study (Study NCT01913405), what factor would be used, what and where the clinical data would be recorded. - A requirement for a 72-hour washout period before immunogenicity tests was added to implement the laboratory requirements and to avoid false results. - The level of detectable FVIII inhibitory antibodies determined by the central laboratory was changed to 0.4 Bethesda Units (BU) because the central laboratory was validated for this value. - To ensure safety and to be able to provide safety review data upon completion of the pivotal study, a safety review was added as planned interim analyses.
    23 May 2014
    - Primary study completion date and duration of subject participation to reach 100 EDs were adapted. - Instead of the rate of success of BAX 855 in the treatment of breakthrough bleeding episodes, an overall hemostatic efficacy rating was used. - Additional guidance was provided on the treatment of bleeding episodes and maintenance of hemostasis. - It was clarified that only BAX 855 would be used for the control of bleeding episodes. - The more general term PROs was introduced instead of HRQoL. - PROs were to be assessed every 6 months during the study, in addition to baseline and end of study visits. - The dose and dosage frequency of BAX 855 were revised. - The reference to male previously treated patients (PTPs) was removed (i.e., females could now be included). - The age limit was changed to <= 75 years at screening of the previous BAX 855 study for transitioning subjects. - BAX 855 naive subjects <6 years old needed to have >=50 documented EDs to plasma-derived FVIII. - The cut-off for detectable FVIII inhibitory antibodies was increased to >=0.6 BU from >=0.4 BU in alignment with other BAX 855 studies and to avoid the risk of false positive results at this low level given the assay variability. - BAX 855-naive subjects <12 years of age were not to be enrolled until enrollment in the BAX 855 pediatric PTP study in children aged <12 years (Study 2014-000742-30) had been completed.

    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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