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    Clinical Trial Results:
    An open label study of the safety and efficacy of Refacto AF in previously untreated patients in usual care settings.

    Summary
    EudraCT number
    		 2008-008436-93
    Trial protocol
    		 DE   FR   AT   ES   IT   SE   NL   GR  
    Global end of trial date
    24 Nov 2016

    Results information
    Results version number
    		 v1(current)
    This version publication date
    09 Jun 2017
    First version publication date
    09 Jun 2017
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    B1831006
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Pfizer, Inc.
    Sponsor organisation address
    235 Est 42nd Street, New York, United States, 10017
    Public contact
    Pfizer ClinicalTrials.gov Call Center, Pfizer, Inc., +1 800-718-1021, ClinicalTrials.gov_Inquiries@pfizer.com
    Scientific contact
    Pfizer ClinicalTrials.gov Call Center, Pfizer, Inc., +1 800-718-1021, ClinicalTrials.gov_Inquiries@pfizer.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    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
    24 Nov 2016
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    24 Nov 2016
    Global end of trial reached?
    Yes
    Global end of trial date
    24 Nov 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the safety of ReFacto albumin free (AF) in previously untreated male participants less than 6 years of age.
    Protection of trial subjects
    This study was conducted in compliance with the ethical principles originating in or derived from the Declaration of Helsinki and in compliance with all International Conference on Harmonization (ICH) Good Clinical Practice (GCP) Guidelines. In addition, all local regulatory requirements were followed, in particular, those affording greater protection to the safety of trial participants.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    10 Feb 2010
    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
    France: 1
    Country: Number of subjects enrolled
    Germany: 7
    Country: Number of subjects enrolled
    Italy: 1
    Country: Number of subjects enrolled
    Netherlands: 1
    Country: Number of subjects enrolled
    Spain: 3
    Country: Number of subjects enrolled
    Turkey: 9
    Country: Number of subjects enrolled
    Ukraine: 1
    Worldwide total number of subjects
    23
    EEA total number of subjects
    13
    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)
    21
    Children (2-11 years)
    2
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    0
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 A total of 23 participants were enrolled in this non-randomized open-label study. Participants received ReFacto AF at a dose & frequency prescribed by each participant’s treating physician as per local standard of care & in accordance with summary of product characteristics (SmPC). Participants were expected to be in the study for about 26 months.

    Pre-assignment
    Screening details
    		 The study was conducted at 11 centers across various countries. All participants were male less than 6 years of age with severe hemophilia A (FVIII activity in plasma [FVIII:C]<1%) who had not received any prior factor products or blood products for their hemophilia A were enrolled in this study.

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

    Arms
    Arm title
    		 Overall participants
    Arm description
    		 This group consisted of all participants enrolled in the study who had received at least one dose of ReFacto AF.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Moroctocog alfa (AF CC)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder and solvent for solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Participants received ReFacto AF at a dose and frequency prescribed by each participant’s treating physician as per local standard of care and in accordance with the SmPC.

    Number of subjects in period 1
    		Overall participants
    Started
    23
    Completed
    20
    Not completed
    3
         Adverse event, non-fatal
    2
         Parent/Legal Guardian Request
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Overall participants
    Reporting group description
    		 This group consisted of all participants enrolled in the study who had received at least one dose of ReFacto AF.

    Reporting group values
    		 Overall participants Total
    Number of subjects
    		 23 23
    Age categorical
    Units: Subjects
        In utero
    		 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0
        Newborns (0-27 days)
    		 0 0
        Infants and toddlers (28 days < 1 year)
    		 17 17
        Children (1 year to < 6 years)
    		 6 6
        Adolescents (12-17 years)
    		 0 0
        Adults (18-64 years)
    		 0 0
        From 65-84 years
    		 0 0
        85 years and over
    		 0 0
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    		 1 ± 1.09 -
    Gender, Male/Female
    Units: Subjects
        Female
    		 0 0
        Male
    		 23 23
    Subject analysis sets

    Subject analysis set title
    Observed clinically significant inhibitor rate
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Observed inhibitor recorded in participants. NOTE: Total number of participants with clinically significant FVIII inhibitor = 5.

    Subject analysis set title
    Annualized bleed rate (ABR)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    The ABR recorded in participants receiving treatment with ReFacto AF.

    Subject analysis set title
    First intravenous (IV) infusion per bleed
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    First IV infusions of ReFacto AF received by the participants. NOTE: One participant who had an infusion with a response of ‘Good’ on 17 Apr 2012 was not included in the bleed count for this analysis, as the infusion reason was not recorded as ‘on-demand’ treatment.

    Subject analysis set title
    Follow-up IV infusions
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Follow-up IV infusions of ReFacto AF received by the participants.

    Subject analysis set title
    All IV infusions
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    A sum of all IV infusions of ReFacto AF received by the participants.

    Subject analysis set title
    One IV infusion
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Number of bleeds requiring 1 IV infusion to resolve

    Subject analysis set title
    Two IV infusions
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Number of bleeds requiring 2 IV infusions to resolve

    Subject analysis set title
    Three IV infusions
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Number of bleeds requiring 3 IV infusions to resolve

    Subject analysis set title
    Four IV infusions
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Number of bleeds requiring 4 IV infusions to resolve

    Subject analysis set title
    Greater than 4 IV infusions
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Number of bleeds requiring > 4 IV infusions to resolve

    Subject analysis set title
    Total number of bleeds
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Total number of bleeds reported in the study.

    Subject analysis set title
    Number of bleeds within 48 hours of a prophylaxis dose
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Total number of bleeds reported within 48 hours of a prophylaxis dose. NOTE: A total of 22 participants who had received at least one prophylaxis dose were analyzed. Nine participants experienced a total of 12 bleeds.

    Subject analysis set title
    Reason for IV Infusion = On Demand
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    The average IV infusion dose and total factor consumption recorded in participants in on demand setting.

    Subject analysis set title
    Reason for IV infusion = Preventive
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    The average IV infusion dose and total factor consumption recorded in participants in on preventive setting

    Subject analysis set title
    Reason for IV infusion=Prophylaxis
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    The average IV infusion dose and total factor consumption recorded in participants in prophylaxis setting.

    Subject analysis set title
    Reason for IV infusion=Not Specified
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    The average IV infusion dose and total factor consumption recorded in participants in unspecified setting.

    Subject analysis set title
    Total: All Reasons for IV infusion
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    The average IV infusion dose and total factor consumption recorded for all participants in the study.

    Subject analysis set title
    Number of participants who required dose escalation
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Number of participants who require dose escalation of their prescribed prophylaxis regimen during their participation in this study.

    Subject analysis set title
    LETE in the Prophylaxis Setting
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Number of bleeds recorded in participants. NOTE: This was prophylaxis Setting LETEs with no confounding factors

    Subject analysis set title
    Number of Potential LETEs in Low Recovery Setting
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Number of bleeds recorded in participants. NOTE: 1) A potential LETE: Recovery lower-than-expected recovery of FVIII in the opinion of the investigator following infusion of ReFacto AF in the absence of confounding factors.

    Subject analysis set title
    LETE in the On-Demand Setting
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Number of bleeds recorded in participants. NOTE: Based on the response to treatment of a bleeding episode.

    Subject analysis sets values
    		 Observed clinically significant inhibitor rate Annualized bleed rate (ABR) First intravenous (IV) infusion per bleed Follow-up IV infusions All IV infusions One IV infusion Two IV infusions Three IV infusions Four IV infusions Greater than 4 IV infusions Total number of bleeds Number of bleeds within 48 hours of a prophylaxis dose Reason for IV Infusion = On Demand Reason for IV infusion = Preventive Reason for IV infusion=Prophylaxis Reason for IV infusion=Not Specified Total: All Reasons for IV infusion Number of participants who required dose escalation LETE in the Prophylaxis Setting Number of Potential LETEs in Low Recovery Setting LETE in the On-Demand Setting
    Number of subjects
    23
    23
    23
    23
    23
    23
    23
    23
    23
    23
    23
    22
    21
    7
    22
    4
    23
    22
    22
    23
    23
    Age categorical
    Units: Subjects
        In utero
        Preterm newborn infants (gestational age < 37 wks)
        Newborns (0-27 days)
        Infants and toddlers (28 days < 1 year)
        Children (1 year to < 6 years)
        Adolescents (12-17 years)
        Adults (18-64 years)
        From 65-84 years
        85 years and over
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    0 ± 0
    0 ± 0
    0 ± 0
    0 ± 0
    0 ± 0
    0 ± 0
    0 ± 0
    0 ± 0
    0 ± 0
    0 ± 0
    0 ± 0
    0 ± 0
    0 ± 0
    0 ± 0
    0 ± 0
    0 ± 0
    0 ± 0
    0 ± 0
    0 ± 0
    0 ± 0
    0 ± 0
    Gender, Male/Female
    Units: Subjects
        Female
        Male

    End points

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    End points reporting groups
    Reporting group title
    Overall participants
    Reporting group description
    		 This group consisted of all participants enrolled in the study who had received at least one dose of ReFacto AF.

    Subject analysis set title
    Observed clinically significant inhibitor rate
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Observed inhibitor recorded in participants. NOTE: Total number of participants with clinically significant FVIII inhibitor = 5.

    Subject analysis set title
    Annualized bleed rate (ABR)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    The ABR recorded in participants receiving treatment with ReFacto AF.

    Subject analysis set title
    First intravenous (IV) infusion per bleed
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    First IV infusions of ReFacto AF received by the participants. NOTE: One participant who had an infusion with a response of ‘Good’ on 17 Apr 2012 was not included in the bleed count for this analysis, as the infusion reason was not recorded as ‘on-demand’ treatment.

    Subject analysis set title
    Follow-up IV infusions
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Follow-up IV infusions of ReFacto AF received by the participants.

    Subject analysis set title
    All IV infusions
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    A sum of all IV infusions of ReFacto AF received by the participants.

    Subject analysis set title
    One IV infusion
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Number of bleeds requiring 1 IV infusion to resolve

    Subject analysis set title
    Two IV infusions
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Number of bleeds requiring 2 IV infusions to resolve

    Subject analysis set title
    Three IV infusions
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Number of bleeds requiring 3 IV infusions to resolve

    Subject analysis set title
    Four IV infusions
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Number of bleeds requiring 4 IV infusions to resolve

    Subject analysis set title
    Greater than 4 IV infusions
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Number of bleeds requiring > 4 IV infusions to resolve

    Subject analysis set title
    Total number of bleeds
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Total number of bleeds reported in the study.

    Subject analysis set title
    Number of bleeds within 48 hours of a prophylaxis dose
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Total number of bleeds reported within 48 hours of a prophylaxis dose. NOTE: A total of 22 participants who had received at least one prophylaxis dose were analyzed. Nine participants experienced a total of 12 bleeds.

    Subject analysis set title
    Reason for IV Infusion = On Demand
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    The average IV infusion dose and total factor consumption recorded in participants in on demand setting.

    Subject analysis set title
    Reason for IV infusion = Preventive
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    The average IV infusion dose and total factor consumption recorded in participants in on preventive setting

    Subject analysis set title
    Reason for IV infusion=Prophylaxis
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    The average IV infusion dose and total factor consumption recorded in participants in prophylaxis setting.

    Subject analysis set title
    Reason for IV infusion=Not Specified
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    The average IV infusion dose and total factor consumption recorded in participants in unspecified setting.

    Subject analysis set title
    Total: All Reasons for IV infusion
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    The average IV infusion dose and total factor consumption recorded for all participants in the study.

    Subject analysis set title
    Number of participants who required dose escalation
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Number of participants who require dose escalation of their prescribed prophylaxis regimen during their participation in this study.

    Subject analysis set title
    LETE in the Prophylaxis Setting
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Number of bleeds recorded in participants. NOTE: This was prophylaxis Setting LETEs with no confounding factors

    Subject analysis set title
    Number of Potential LETEs in Low Recovery Setting
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Number of bleeds recorded in participants. NOTE: 1) A potential LETE: Recovery lower-than-expected recovery of FVIII in the opinion of the investigator following infusion of ReFacto AF in the absence of confounding factors.

    Subject analysis set title
    LETE in the On-Demand Setting
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Number of bleeds recorded in participants. NOTE: Based on the response to treatment of a bleeding episode.

    Primary: Proportion of participants who develop clinically significant FVIII inhibitors during the course of the study.

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    End point title
    		 Proportion of participants who develop clinically significant FVIII inhibitors during the course of the study. [1]
    End point description
    To evaluate the proportion of participants who developed clinically significant FVIII inhibitors (those persistent over a defined period with clinically impactful effects (ie breakthrough bleed, low recovery, etc)) during the course of the study.
    End point type
    Primary
    End point timeframe
    At protocol defined time-points during approximately 2 years study period
    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: No statistical analyses have been specified for this primary end point. No inferential statistical analysis was done.
    End point values
    		 Observed clinically significant inhibitor rate
    Number of subjects analysed
    23
    Units: Percentage
        number (confidence interval 95%)
    21.74 (7.46 to 43.7)
    No statistical analyses for this end point

    Secondary: Annualized bleeding rates (ABR).

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    End point title
    		 Annualized bleeding rates (ABR).
    End point description
    Annualized bleeding rate was calculated as the number of bleeds divided by the treatment interval duration (enrollment visit to final visit) and then multiplied by 365.25. If there was more than 1 bleed location (ie, ankle and joint) with identical bleed start date and time, it was treated as 1 bleed occurrence. NOTE: The ABR listed is regardless of regimen (regimen was not collected).
    End point type
    Secondary
    End point timeframe
    At protocol defined time-points during approximately 2 years study period
    End point values
    		 Annualized bleed rate (ABR)
    Number of subjects analysed
    23
    Units: Number
        arithmetic mean (standard deviation)
    5.88 ± 8.082
    No statistical analyses for this end point

    Secondary: Response to the first on-demand treatment with Refacto AF for all new bleeds.

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    End point title
    		 Response to the first on-demand treatment with Refacto AF for all new bleeds.
    End point description
    The 4-point response scale of assessment (excellent, good, moderate and no response) was completed each time a participant experienced a new bleed requiring an ‘on-demand’ infusion. All participant assessments were provided by the parent/legal representative or investigator.
    End point type
    Secondary
    End point timeframe
    At protocol defined time-points during approximately 2 years study period
    End point values
    		 First intravenous (IV) infusion per bleed Follow-up IV infusions All IV infusions
    Number of subjects analysed
    23
    23
    23
    Units: Number
        Excellent
    51
    7
    58
        Good
    48
    19
    67
        Moderate
    28
    12
    40
        No response
    3
    5
    8
        Data Not Recorded
    19
    1
    20
        Total
    149
    44
    193
    No statistical analyses for this end point

    Secondary: Response to First Infusion with ReFacto AF

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    End point title
    		 Response to First Infusion with ReFacto AF
    End point description
    To assess the response of each bleed to first ‘on-demand’ infusion and also to assess number of infusions required to treat each bleed ie.1, 2, 3, 4, or more than 4 infusions. Result: A total of 21 participants had 150 bleeding episodes. After the first infusion, the majority (132/150 [88.0%]) of bleeds resolved.
    End point type
    Secondary
    End point timeframe
    At protocol defined time-points during approximately 2 years study period
    End point values
    		 One IV infusion Two IV infusions Three IV infusions Four IV infusions Greater than 4 IV infusions Total number of bleeds
    Number of subjects analysed
    23
    23
    23
    23
    23
    23
    Units: Number
        Excellent (15 participants)
    48
    3
    0
    0
    0
    51
        Good (14 participants)
    43
    5
    0
    0
    1
    49
        Moderate (6 participants)
    22
    4
    0
    0
    2
    28
        No response (2 participants)
    2
    0
    0
    0
    1
    3
        Data Not Recorded (7 participants)
    17
    1
    1
    0
    0
    19
        Total (Any) (21 participants)
    132
    13
    1
    0
    4
    150
    No statistical analyses for this end point

    Secondary: The number of bleeds within 48 hours of a prophylaxis dose of ReFacto AF.

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    End point title
    		 The number of bleeds within 48 hours of a prophylaxis dose of ReFacto AF.
    End point description
    To assess the number of bleeds within 48 hours of a prophylaxis infusion of ReFacto AF. Nine participants experienced a total of 12 bleeds.
    End point type
    Secondary
    End point timeframe
    At protocol defined time-points during approximately 2 years study period
    End point values
    		 Number of bleeds within 48 hours of a prophylaxis dose
    Number of subjects analysed
    22
    Units: Number
        arithmetic mean (standard deviation)
    1.3 ± 1
    No statistical analyses for this end point

    Secondary: The average infusion dose and total factor consumption. Summary of Moroctocog ALFA (AF -CC) consumption.

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    End point title
    		 The average infusion dose and total factor consumption. Summary of Moroctocog ALFA (AF -CC) consumption.
    End point description
    The total factor consumption (by weight) for each participant was calculated by summing the total amount (IU) infused. The average infusion dose for each participant was calculated by dividing total factor consumption (in IU) by the number of infusions administered.
    End point type
    Secondary
    End point timeframe
    At protocol defined time-points during approximately 2 years study period
    End point values
    		 Reason for IV Infusion = On Demand Reason for IV infusion = Preventive Reason for IV infusion=Prophylaxis Reason for IV infusion=Not Specified Total: All Reasons for IV infusion
    Number of subjects analysed
    21
    7
    22
    4
    23
    Units: Number
    arithmetic mean (standard deviation)
        Total Units (IU) per Participant TFC)
    4186 ± 3038.4
    1857 ± 2357.5
    55543 ± 55535.5
    1634 ± 2523.8
    57799 ± 55125.8
        Dose (IU) per Infusion
    552 ± 296.7
    544 ± 285.6
    628 ± 389.6
    481 ± 401.5
    619 ± 386.5
        Total Unit by Weight (IU/kg) per Participant
    388 ± 297
    93 ± 56.8
    4766 ± 4933.5
    187 ± 256.5
    4966 ± 4891.4
        Total Unit (IU) per Participant Annualized TFC)
    0 ± 0
    0 ± 0
    0 ± 0
    0 ± 0
    72336 ± 123407.9
        IU/kg per Participant (Annualized TFC by Weight)
    0 ± 0
    0 ± 0
    0 ± 0
    0 ± 0
    6398 ± 11102.8
        Dose by Weight (IU/kg) per Infusion
    49 ± 26.1
    42 ± 16.9
    55 ± 34.4
    50 ± 41
    53 ± 33.5
        Number of Infusions per Participant
    9 ± 8
    5 ± 8.9
    80 ± 36.9
    2 ± 1.9
    86 ± 37.5
        Exposure Days per Participant
    8 ± 6.3
    3 ± 3.7
    76 ± 31.3
    2 ± 1.9
    81 ± 32.4
    No statistical analyses for this end point

    Secondary: The number of participants who require dose escalation of their prescribed prophylaxis regimen during their participation in this study.

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    End point title
    		 The number of participants who require dose escalation of their prescribed prophylaxis regimen during their participation in this study.
    End point description
    The number of participants who met the dose escalation criteria were prescribed a higher dose and/or were prescribed more frequent doses. When dose escalation was required, the specific dose and dosing schedule was at the investigator’s discretion.
    End point type
    Secondary
    End point timeframe
    At protocol defined time-points during approximately 2 years study period
    End point values
    		 Number of participants who required dose escalation
    Number of subjects analysed
    22
    Units: Number
    15
    No statistical analyses for this end point

    Secondary: The incidence of less-than-expected therapeutic effect (LETE) in the Prophylaxis Setting.

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    End point title
    		 The incidence of less-than-expected therapeutic effect (LETE) in the Prophylaxis Setting.
    End point description
    LETE on the prophylaxis setting occurred when there was a spontaneous bleed within 48 hours after a regularly scheduled prophylactic dose of ReFacto AF in the absence of confounding factors.
    End point type
    Secondary
    End point timeframe
    At protocol defined time-points during approximately 2 years study period
    End point values
    		 LETE in the Prophylaxis Setting
    Number of subjects analysed
    22
    Units: Percentage
        number (confidence interval 95%)
    0.11 (0.01 to 0.41)
    No statistical analyses for this end point

    Secondary: The incidence of less-than-expected therapeutic effect (LETE) in Low Recovery Setting.

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    End point title
    		 The incidence of less-than-expected therapeutic effect (LETE) in Low Recovery Setting.
    End point description
    To assess the occurrence of low recovery LETE in the absence of confounding factors. Investigators reported 10 instances of potential low recovery (LETE) in 6 participants, including one subject in whom there were 3 instances of potential LETE in the low recovery setting for which no confounders were reported.
    End point type
    Secondary
    End point timeframe
    At protocol defined time-points during approximately 2 years study period
    End point values
    		 Number of Potential LETEs in Low Recovery Setting
    Number of subjects analysed
    23
    Units: Number
        No. of participants: 1
    1
        No. of participants: 1 with no confounders
    3
        No. of participants: 2
    2
        No. of participants: 3
    4
        Total particpants
    10
    No statistical analyses for this end point

    Secondary: The incidence of less-than-expected therapeutic effect (LETE) in On-Demand Setting.

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    End point title
    		 The incidence of less-than-expected therapeutic effect (LETE) in On-Demand Setting.
    End point description
    LETE in the on-demand setting occurred when a participant recorded 2 successive “No Response” ratings after 2 successive ReFacto AF infusions for treatment of the same bleed in the absence of confounding factors.
    End point type
    Secondary
    End point timeframe
    At protocol defined time-points during approximately 2 years study period
    End point values
    		 LETE in the On-Demand Setting
    Number of subjects analysed
    23
    Units: Number
        number (confidence interval 95%)
    0 (0 to 2.43)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events (AEs) were recorded from the time the participants provides informed consent, through completion of the final contact (Follow-up Phone Call). All serious AEs and all treatment emergent AEs with the threshold of more than 5% were reported.
    Adverse event reporting additional description
    An AE is any untoward medical occurrence in a clinical investigation subject administered a product or medical device; the event need not necessarily have a causal relationship with the treatment or usage. Any AE that meets any of the seriousness criteria listed in the study protocol will be considered as an SAE.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    19.1
    Reporting groups
    Reporting group title
    Hemophilia related + Non-Hemophilia (All Causalities)
    Reporting group description
    		 Overall number of participants in the study.

    Serious adverse events
    		 Hemophilia related + Non-Hemophilia (All Causalities)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    11 / 23 (47.83%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    1 / 23 (4.35%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Fall
         subjects affected / exposed
    1 / 23 (4.35%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Road traffic accident
         subjects affected / exposed
    1 / 23 (4.35%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Tongue injury
         subjects affected / exposed
    1 / 23 (4.35%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Nervous system disorders
    Febrile convulsion
         subjects affected / exposed
    1 / 23 (4.35%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Blood and lymphatic system disorders
    Factor VIII inhibition
         subjects affected / exposed
    8 / 23 (34.78%)
         occurrences causally related to treatment / all
    8 / 8
         deaths causally related to treatment / all
    0 / 0
    Immune system disorders
    Milk allergy
         subjects affected / exposed
    1 / 23 (4.35%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorders
    Ileus
         subjects affected / exposed
    1 / 23 (4.35%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Intussusception
         subjects affected / exposed
    1 / 23 (4.35%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Appendicitis
         subjects affected / exposed
    1 / 23 (4.35%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Enterobacter sepsis
         subjects affected / exposed
    1 / 23 (4.35%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    1 / 23 (4.35%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Sepsis
         subjects affected / exposed
    1 / 23 (4.35%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 23 (4.35%)
         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
    		 Hemophilia related + Non-Hemophilia (All Causalities)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    20 / 23 (86.96%)
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    4 / 23 (17.39%)
         occurrences all number
    8
    Head injury
         subjects affected / exposed
    2 / 23 (8.70%)
         occurrences all number
    3
    Lip injury
         subjects affected / exposed
    2 / 23 (8.70%)
         occurrences all number
    2
    Procedural pain
         subjects affected / exposed
    2 / 23 (8.70%)
         occurrences all number
    2
    Vascular disorders
    Haematoma
         subjects affected / exposed
    4 / 23 (17.39%)
         occurrences all number
    5
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    10 / 23 (43.48%)
         occurrences all number
    13
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    5 / 23 (21.74%)
         occurrences all number
    5
    Ear and labyrinth disorders
    Ear pain
         subjects affected / exposed
    2 / 23 (8.70%)
         occurrences all number
    2
    Immune system disorders
    Hypersensitivity
         subjects affected / exposed
    2 / 23 (8.70%)
         occurrences all number
    2
    Gastrointestinal disorders
    Mouth haemorrhage
         subjects affected / exposed
    4 / 23 (17.39%)
         occurrences all number
    4
    Diarrhoea
         subjects affected / exposed
    3 / 23 (13.04%)
         occurrences all number
    3
    Vomiting
         subjects affected / exposed
    3 / 23 (13.04%)
         occurrences all number
    3
    Teething
         subjects affected / exposed
    2 / 23 (8.70%)
         occurrences all number
    3
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    4 / 23 (17.39%)
         occurrences all number
    7
    Skin and subcutaneous tissue disorders
    Eczema
         subjects affected / exposed
    2 / 23 (8.70%)
         occurrences all number
    2
    Rash
         subjects affected / exposed
    2 / 23 (8.70%)
         occurrences all number
    2
    Musculoskeletal and connective tissue disorders
    Haemarthrosis
         subjects affected / exposed
    3 / 23 (13.04%)
         occurrences all number
    5
    Infections and infestations
    Gastroenteritis
         subjects affected / exposed
    6 / 23 (26.09%)
         occurrences all number
    7
    Nasopharyngitis
         subjects affected / exposed
    6 / 23 (26.09%)
         occurrences all number
    14
    Bronchitis
         subjects affected / exposed
    3 / 23 (13.04%)
         occurrences all number
    5
    Upper respiratory tract infection
         subjects affected / exposed
    3 / 23 (13.04%)
         occurrences all number
    4
    Conjunctivitis
         subjects affected / exposed
    2 / 23 (8.70%)
         occurrences all number
    2
    Influenza
         subjects affected / exposed
    2 / 23 (8.70%)
         occurrences all number
    2
    Pharyngitis
         subjects affected / exposed
    2 / 23 (8.70%)
         occurrences all number
    3
    Rhinitis
         subjects affected / exposed
    2 / 23 (8.70%)
         occurrences all number
    2

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    05 May 2010
    Amendment 2: Implemented the following changes • Minor clarifications to existing wording, administrative changes, and corrections of typographical errors. • Globally implemented changes outlined in Amendment 1, with the exception of exclusion criterion for body weight <5.4 kilograms.
    22 Mar 2011
    Amendment 4: Implemented the following changes: • Minor clarifications to existing wording, administrative changes, and corrections of typographical errors. • Globally implemented changes outlined in Amendment 3.
    23 Oct 2012
    Amendment 6: Implemented the following changes: • Minor clarifications to existing wording, administrative changes, and corrections of typographical errors. • Globally implemented changes outlined in Amendment 5.

    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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