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    Clinical Trial Results:
    A Postauthorization Safety Surveillance Study of Patients Switching to ReFacto AF From ReFacto or Other Factor VIII Products in Usual Care Settings

    Summary
    EudraCT number
    2008-007997-39
    Trial protocol
    DE   BE   ES   SE   AT   FI   DK   FR   IT   PT   NL   GB   CZ   GR   HU  
    Global end of trial date
    28 Mar 2013

    Results information
    Results version number
    v1(current)
    This version publication date
    30 May 2016
    First version publication date
    30 Jul 2015
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    3082B2-4432-WW
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT00884390
    WHO universal trial number (UTN)
    -
    Other trial identifiers
    Alias: B1831004
    Sponsors
    Sponsor organisation name
    Pfizer Inc.
    Sponsor organisation address
    235 E 42nd Street, New York, United States, NY 10017
    Public contact
    Pfizer ClinicalTrials.gov Call Center, Pfizer, Inc., 001 800-718-1021, ClinicalTrials.gov_Inquiries@pfizer.com
    Scientific contact
    Pfizer ClinicalTrials.gov Call Center, Pfizer, Inc., 001 800-718-1021, ClinicalTrials.gov_Inquiries@pfizer.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    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
    19 Aug 2013
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    28 Mar 2013
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The primary objective of the study was to evaluate the safety of ReFacto AF. The secondary objective was to evaluate the efficacy of ReFacto AF.
    Protection of trial subjects
    The study was in compliance with the ethical principles derived from the Declaration of Helsinki and in compliance with all International Conference on Harmonization (ICH) Good Clinical Practice (GCP) Guidelines. All the local regulatory requirements pertinent to safety of trial subjects were followed.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    07 May 2009
    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
    Romania: 10
    Country: Number of subjects enrolled
    Netherlands: 6
    Country: Number of subjects enrolled
    Spain: 62
    Country: Number of subjects enrolled
    Sweden: 10
    Country: Number of subjects enrolled
    United Kingdom: 12
    Country: Number of subjects enrolled
    Austria: 3
    Country: Number of subjects enrolled
    Belgium: 8
    Country: Number of subjects enrolled
    Denmark: 4
    Country: Number of subjects enrolled
    Finland: 8
    Country: Number of subjects enrolled
    France: 16
    Country: Number of subjects enrolled
    Germany: 35
    Country: Number of subjects enrolled
    Greece: 3
    Country: Number of subjects enrolled
    Hungary: 20
    Country: Number of subjects enrolled
    Italy: 11
    Worldwide total number of subjects
    208
    EEA total number of subjects
    208
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    42
    Adults (18-64 years)
    166
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    Two hundred and eight (208) subjects were enrolled into the study (146 subjects into the ReFacto Switch group [Cohort 1: subjects who switched from ReFacto to ReFacto Albumin Free [AF]] and 62 subjects into the Other Switch group [Cohort 2: subjects who switched from other Factor VIII (FVIII) products other than ReFacto to ReFacto AF]).

    Pre-assignment
    Screening details
    Study started on 07 May 2009 and ended on 28 March 2013. Overall, 208 subjects were enrolled into the study across 14 countries.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    ReFacto Switch
    Arm description
    Subjects who switched from ReFacto to ReFacto AF.
    Arm type
    Experimental

    Investigational medicinal product name
    ReFacto AF
    Investigational medicinal product code
    PF-05208756
    Other name
    Moroctocog alfa (Albumin Free Cell Culture[AF-CC])
    Pharmaceutical forms
    Powder for solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects who switched from ReFacto to ReFacto AF.

    Arm title
    Other Switch
    Arm description
    Subjects who switched from other FVIII products other than ReFacto to ReFacto AF.
    Arm type
    Experimental

    Investigational medicinal product name
    ReFacto AF
    Investigational medicinal product code
    PF-05208756
    Other name
    Moroctocog alfa (AF-CC)
    Pharmaceutical forms
    Powder for solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects who switched from other FVIII products other than ReFacto to ReFacto AF.

    Number of subjects in period 1
    ReFacto Switch Other Switch
    Started
    146
    62
    Completed
    123
    54
    Not completed
    23
    8
         Physician decision
    2
    1
         Protocol Violation
    4
    1
         Discontinuation of Study by Sponsor
    2
    2
         Consent withdrawn by subject
    4
    1
         Adverse Event
    -
    1
         Lost to follow-up
    -
    1
         Not Specified
    11
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    ReFacto Switch
    Reporting group description
    Subjects who switched from ReFacto to ReFacto AF.

    Reporting group title
    Other Switch
    Reporting group description
    Subjects who switched from other FVIII products other than ReFacto to ReFacto AF.

    Reporting group values
    ReFacto Switch Other Switch Total
    Number of subjects
    146 62 208
    Age categorical
    Units: Subjects
        12-17 years
    33 9 42
        18-65 years
    113 53 166
    Gender categorical
    Units: Subjects
        Female
    0 0 0
        Male
    146 62 208

    End points

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    End points reporting groups
    Reporting group title
    ReFacto Switch
    Reporting group description
    Subjects who switched from ReFacto to ReFacto AF.

    Reporting group title
    Other Switch
    Reporting group description
    Subjects who switched from other FVIII products other than ReFacto to ReFacto AF.

    Subject analysis set title
    Annualized Bleed Rate
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    Annualized Bleed Rate (ABR) by regimen at baseline is summarized for all subjects for on-demand regimen, preventive regimen and prophylaxis regimen, respectively.

    Subject analysis set title
    First Infusion Per Bleed
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    Includes the first infusion for an associated bleeding episode.

    Subject analysis set title
    All Subjects With Bleeds
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    Includes any infusion with an associated bleeding episode, regardless of the reason for treatment indicated on the case report form.

    Subject analysis set title
    Subjects Who Received at Least One Prophylactic Infusion
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    Subjects who had at least one prophylaxis dose, and at least one bleed.

    Subject analysis set title
    All Subjects
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    All enrolled subjects following a prophylaxis regimen at baseline.

    Subject analysis set title
    Subjects Following a Non-prophylaxis Regimen at Baseline
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    All enrolled subjects following an on-demand or preventive regimen at baseline.

    Subject analysis set title
    Subjects Following a Prophylaxis Regimen at Baseline
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    All enrolled subjects following a prophylaxis regimen at baseline.

    Subject analysis set title
    All Subjects With at Least One Bleed
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    All enrolled subjects with at least one bleed.

    Subject analysis set title
    All Subjects With at Least One Prophylaxis Infusion
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    All enrolled subjects with at least one prophylaxis infusion.

    Primary: Number of Subjects With Clinically Significant Factor VIII Inhibitor Development

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    End point title
    Number of Subjects With Clinically Significant Factor VIII Inhibitor Development [1]
    End point description
    Number of subjects with clinically significant FVIII inhibitor development after switching from ReFacto to moroctocog alfa (AF-CC). Clinically significant inhibitors are defined as a central laboratory confirmed positive inhibitor (greater than or equal to [≥] 0.6 Bethesda unit [BU] using the Nijmegen modification of the Bethesda assay present at 2 consecutive blood draws within a 6-week interval) and within 28 days before the initial or within 28 days following the second positive FVIII inhibitor sample collection one of the following: the need for the subject to administer alternative hemostatic products in order to achieve sufficient efficacy, or ≥2 adverse event reports of decreased drug effect (or other adverse event indicating a decrease in the efficacy of the test article). All enrolled subjects who took at least 1 dose of ReFacto AF study drug were included in the safety and efficacy analyses.
    End point type
    Primary
    End point timeframe
    100 exposure days to study medication (approximately 2 years)
    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: Only descriptive data was planned to be reported for this endpoint.
    End point values
    ReFacto Switch Other Switch
    Number of subjects analysed
    146
    62
    Units: Number of subjects
        number (confidence interval 95%)
    0 (0 to 2.49)
    0 (0 to 5.78)
    No statistical analyses for this end point

    Secondary: Annualized Bleeding Rates (ABRs)

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    End point title
    Annualized Bleeding Rates (ABRs)
    End point description
    An ABR for each subject will be calculated as the number of bleeds requiring administration of FVIII replacement product (taken from the Infusion Log Diary case report form), divided by his total therapy duration (in days), then multiplied by 365.25. All enrolled subjects who took at least 1 dose of ReFacto AF study drug were included in the safety and efficacy analyses.
    End point type
    Secondary
    End point timeframe
    100 exposure days to study medication (approximately 2 years)
    End point values
    Annualized Bleed Rate
    Number of subjects analysed
    208
    Units: number of bleeds
    arithmetic mean (standard deviation)
        On-demand regimen (N=52)
    28.35 ± 18.781
        Preventive regimen (N=2)
    1.08 ± 1.528
        Primary or secondary prophylaxis regimen (N=154)
    8.43 ± 17.362
    No statistical analyses for this end point

    Secondary: Response Assessment of First On-demand Treatment of New Bleeds

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    End point title
    Response Assessment of First On-demand Treatment of New Bleeds
    End point description
    A 4-point scale of assessment of ‘on-demand’ treatment is defined as:Excellent: Definite pain relief and/or improvement in signs of bleeding starting within 8 hours after an infusion, with no additional infusion administered.Good: Definite pain relief and/or improvement in signs of bleeding starting within 8 hours after an infusion, with at least one additional infusion administered for complete resolution of the bleeding episode; or, Definite pain relief and/or improvement in signs of bleeding starting after 8 hours following the infusion, with no additional infusion administered.Moderate: Probable or slight improvement starting after 8 hours following the infusion, with at least one additional infusion administered for complete resolution of the bleeding episode.No Response: No improvement at all between infusions or during the 24-hour interval following an infusion, or condition worsens. All enrolled subjects who took at least 1 dose of ReFacto AF study drug.
    End point type
    Secondary
    End point timeframe
    100 exposure days to study medication (approximately 2 years)
    End point values
    First Infusion Per Bleed
    Number of subjects analysed
    156
    Units: number of observations
        Excellent
    1650
        Good
    1031
        Moderate
    191
        No response
    26
        Data not recorded
    343
        Total
    3241
    No statistical analyses for this end point

    Secondary: Number of ReFacto AF Infusions to Treat Each New Bleed

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    End point title
    Number of ReFacto AF Infusions to Treat Each New Bleed
    End point description
    The Infusion Log Diary case report form (CRF) was used to determine the number of test article infusions administered to treat a bleed. This was calculated by adding the initial (on-demand) infusion to any subsequent (on-demand) infusions for the same bleed (same bleed start date/time). The mean of infusions to produce an excellent, good, moderate and no response was reported. All enrolled subjects who took at least 1 dose of ReFacto AF study drug were included in the safety and efficacy analyses.
    End point type
    Secondary
    End point timeframe
    100 exposure days to study medication (approximately 2 years)
    End point values
    All Subjects With Bleeds
    Number of subjects analysed
    156
    Units: number of infusions
    arithmetic mean (standard deviation)
        Excellent
    1.1 ± 0.66
        Good
    1.4 ± 1.45
        Moderate
    2 ± 1.63
        No response
    2.5 ± 2.6
        Data not recorded
    1.3 ± 1.55
    No statistical analyses for this end point

    Secondary: Number of Bleeding Episodes Occurring Less Than Equal To (≤) 48 Hours After a Prophylaxis Infusion

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    End point title
    Number of Bleeding Episodes Occurring Less Than Equal To (≤) 48 Hours After a Prophylaxis Infusion
    End point description
    First, the bleed start time from the Infusion Log Diary CRF was used to determine the number of breakthrough bleeds that occurred ≤48 hours after an infusion marked as “Prophylaxis” (which had no associated bleed). If there was more than 1 bleed location (i.e. ankle and joint) with identical bleed start date and time, it was treated as 1 bleed occurrence. If a response was given, or if a bleed time was given, but “On Demand” was not listed as “treatment type”, it was still counted as an on-demand bleed for analyses/summaries. Bleeding episodes were not categorized as spontaneous (atraumatic) or traumatic. All enrolled subjects who took at least 1 dose of ReFacto AF study drug were included in the safety and efficacy analyses.
    End point type
    Secondary
    End point timeframe
    100 exposure days to study medication (approximately 2 years)
    End point values
    Subjects Who Received at Least One Prophylactic Infusion
    Number of subjects analysed
    108
    Units: bleeds
    96
    No statistical analyses for this end point

    Secondary: Number of Subjects With Breakthrough Bleeds

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    End point title
    Number of Subjects With Breakthrough Bleeds
    End point description
    The number of subjects with any breakthrough bleed were reported. All enrolled Subjects who took at least 1 dose of ReFacto AF study drug were included in the safety and efficacy analyses.
    End point type
    Secondary
    End point timeframe
    100 exposure days to study medication (approximately 2 years)
    End point values
    Subjects Who Received at Least One Prophylactic Infusion
    Number of subjects analysed
    108
    Units: subjects
    33
    No statistical analyses for this end point

    Secondary: Total Factor Consumption (TFC) Following a Non-prophylaxis Regimen at Baseline for All Subjects

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    End point title
    Total Factor Consumption (TFC) Following a Non-prophylaxis Regimen at Baseline for All Subjects
    End point description
    The total amount (in International Units [IU]) infused for each test article infusion recorded in the Infusion Log Diary CRF was summed to calculate the TFC for each subject. All enrolled subjects who took at least 1 dose of ReFacto AF study drug were included in the safety and efficacy analyses.
    End point type
    Secondary
    End point timeframe
    100 exposure days to study medication (approximately 2 years)
    End point values
    All Subjects
    Number of subjects analysed
    54
    Units: IU
    arithmetic mean (standard deviation)
        On demand (n=50)
    115451.5 ± 67186.92
        Preventive (n=43)
    35156.8 ± 40690.91
        Prophylaxis (n=19)
    73001.9 ± 66969.64
        Not specified (n=54)
    39268.3 ± 65013.77
        Total (n=54)
    199848.9 ± 79308.82
    No statistical analyses for this end point

    Secondary: TFC Following a Prophylaxis Regimen at Baseline for All Subjects

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    End point title
    TFC Following a Prophylaxis Regimen at Baseline for All Subjects
    End point description
    The total amount (in IU) infused for each test article infusion recorded in the Infusion Log Diary CRF was summed to calculate the TFC for each subject. All enrolled subjects who took at least 1 dose of ReFacto AF study drug were included in the safety and efficacy analyses.
    End point type
    Secondary
    End point timeframe
    100 exposure days to study medication (approximately 2 years)
    End point values
    Subjects Following a Prophylaxis Regimen at Baseline
    Number of subjects analysed
    154
    Units: IU
    arithmetic mean (standard deviation)
        On demand (n=98)
    26063.4 ± 32876.96
        Preventive (n=65)
    22498.8 ± 29987.52
        Prophylaxis (n=143)
    165124.6 ± 88373.55
        Not specified (n=154)
    43812.8 ± 67588.23
        Total (n=154)
    223224.8 ± 86493.58
    No statistical analyses for this end point

    Secondary: Average Infusion Dose

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    End point title
    Average Infusion Dose
    End point description
    The average infusion dose for each subject was calculated as his total factor consumption (in IU) divided by the number of infusions administered. Summary statistics were reported for both of these variables separately for those subjects classified at baseline as following an on-demand regimen, and for those on a primary or secondary prophylaxis regimen. All enrolled subjects who took at least 1 dose of ReFacto AF study drug were included in the safety and efficacy analyses.
    End point type
    Secondary
    End point timeframe
    100 exposure days to study medication (approximately 2 years)
    End point values
    Subjects Following a Non-prophylaxis Regimen at Baseline Subjects Following a Prophylaxis Regimen at Baseline
    Number of subjects analysed
    54
    154
    Units: IU
        arithmetic mean (standard deviation)
    2326.8 ± 691.31
    2290.3 ± 701.36
    No statistical analyses for this end point

    Secondary: Incidence of Less-Than-Expected-Therapeutic Effect (LETE) in the On-demand Setting

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    End point title
    Incidence of Less-Than-Expected-Therapeutic Effect (LETE) in the On-demand Setting
    End point description
    The calculation of incidence of on-demand LETE used the number of bleeds identified as, or with a result of, LETE as the numerator (from the On Demand LETE CRF), and the denominator was the number of bleeding episodes treated in an on-demand setting. This denominator could include new bleeding episodes in prophylaxis subjects breakthrough bleeds), and if subsequent on-demand doses for such a bleed met the on-demand LETE criteria, then an on-demand LETE was reported. All enrolled subjects who took at least 1 dose of ReFacto AF study drug were included in the safety and efficacy analyses.
    End point type
    Secondary
    End point timeframe
    100 exposure days to study medication (approximately 2 years)
    End point values
    All Subjects With at Least One Bleed
    Number of subjects analysed
    208
    Units: percentage of bleeds LETE
        number (confidence interval 95%)
    0.06 (0.01 to 0.22)
    No statistical analyses for this end point

    Secondary: Incidence of Less-than-expected-therapeutic Effect (LETE) in the Prophylaxis Setting

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    End point title
    Incidence of Less-than-expected-therapeutic Effect (LETE) in the Prophylaxis Setting
    End point description
    The calculation of incidence of prophylaxis LETE used the number of bleeds identified as, or with a result of, LETE as the numerator (from the Prophylactic LETE CRF), and the denominator was the number of routine prophylaxis infusions. Each infusion was classified in the infusion log (“Prophylaxis/ On Demand/ Preventive”), and subjects were instructed to select “On Demand” if the infusion was to treat a bleed, even if the subject typically followed a prophylaxis regimen. Only the infusions classified as “Prophylaxis” were counted in this denominator.
    End point type
    Secondary
    End point timeframe
    100 exposure days to study medication (approximately 2 years)
    End point values
    All Subjects With at Least One Prophylaxis Infusion
    Number of subjects analysed
    208
    Units: percentage of bleeding episodes
        number (confidence interval 95%)
    0.19 (0.12 to 0.28)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Duration of participation in study (Baseline up to 28 days after last dose of investigational product)
    Adverse event reporting additional description
    The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    15.0
    Reporting groups
    Reporting group title
    All Subjects
    Reporting group description
    The primary safety analysis was performed on all subjects who received at least 1 dose of ReFacto AF.

    Serious adverse events
    All Subjects
    Total subjects affected by serious adverse events
         subjects affected / exposed
    20 / 208 (9.62%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Vascular disorders
    Hypertension
         subjects affected / exposed
    1 / 208 (0.48%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Injury, poisoning and procedural complications
    Alcohol poisoning
         subjects affected / exposed
    1 / 208 (0.48%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Tooth fracture
         subjects affected / exposed
    1 / 208 (0.48%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Investigations
    Anti factor VIII antibody positive
         subjects affected / exposed
    1 / 208 (0.48%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Epistaxis
         subjects affected / exposed
    1 / 208 (0.48%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Oropharyngeal pain
         subjects affected / exposed
    1 / 208 (0.48%)
         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
    5 / 208 (2.40%)
         occurrences causally related to treatment / all
    4 / 5
         deaths causally related to treatment / all
    0 / 0
    Nervous system disorders
    Headache
         subjects affected / exposed
    1 / 208 (0.48%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Syncope
         subjects affected / exposed
    1 / 208 (0.48%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Eye disorders
    Photophobia
         subjects affected / exposed
    1 / 208 (0.48%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Visual impairment
         subjects affected / exposed
    1 / 208 (0.48%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    General disorders and administration site conditions
    Chills
         subjects affected / exposed
    1 / 208 (0.48%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pain
         subjects affected / exposed
    1 / 208 (0.48%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorders
    Acute abdomen
         subjects affected / exposed
    1 / 208 (0.48%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Dyspepsia
         subjects affected / exposed
    1 / 208 (0.48%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Haematemesis
         subjects affected / exposed
    1 / 208 (0.48%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Intestinal haematoma
         subjects affected / exposed
    1 / 208 (0.48%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    1 / 208 (0.48%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Mallory-Weiss syndrome
         subjects affected / exposed
    1 / 208 (0.48%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Skin and subcutaneous tissue disorders
    Hyperhidrosis
         subjects affected / exposed
    1 / 208 (0.48%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Musculoskeletal and connective tissue disorders
    Muscle haemorrhage
         subjects affected / exposed
    1 / 208 (0.48%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Musculoskeletal stiffness
         subjects affected / exposed
    1 / 208 (0.48%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Pain in extremity
         subjects affected / exposed
    1 / 208 (0.48%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Acute tonsillitis
         subjects affected / exposed
    1 / 208 (0.48%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Post procedural infection
         subjects affected / exposed
    1 / 208 (0.48%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Septic arthritis streptococcal
         subjects affected / exposed
    1 / 208 (0.48%)
         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
    All Subjects
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    90 / 208 (43.27%)
    Injury, poisoning and procedural complications
    Limb injury
         subjects affected / exposed
    15 / 208 (7.21%)
         occurrences all number
    25
    Nervous system disorders
    Headache
         subjects affected / exposed
    21 / 208 (10.10%)
         occurrences all number
    47
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    26 / 208 (12.50%)
         occurrences all number
    69
    Haemarthrosis
         subjects affected / exposed
    24 / 208 (11.54%)
         occurrences all number
    86
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    32 / 208 (15.38%)
         occurrences all number
    44
    Influenza
         subjects affected / exposed
    13 / 208 (6.25%)
         occurrences all number
    18

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    28 May 2009
    1) Modification of definition of “clinically significant FVIII inhibitor” to remove any association of this definition with LETEs. 2) Deleted definition of “lack of effect” to disassociate this term with “LETE”, so as to allow sites to report lack of effect as an AE. This was independent of occurrences of LETE. 3) Added an exclusion that subjects who have had previous exposure to ReFacto AF were not permitted to participate in this study.
    30 Aug 2010
    1) Modified the time specified for the interim analysis. Previously, it was “An interim analysis will be conducted when approximately 50% of the subjects have achieved 50 EDs” and now it is “An interim analysis will be conducted before 2 years of enrollment, when data is available for 50% of the subjects who have achieved 50 EDs”.
    24 Mar 2011
    1) The efficacy endpoint, number of spontaneous/breakthrough bleeds within 48 hours of a preventive or prophylaxis dose of ReFacto AF, ABR was modified to indicate that all bleeds reported within 48 hours of a prophylaxis dose would be included.

    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.
    The study was terminated early by agreement with the EMA (European Medicines Agency) before full recruitment was attained, but this is not considered to affect the overall results and the ability of the study to address its objectives.
    The status of studies in GB is no longer updated from 1.1.2021
    For the UK, as from 1.1.2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI
    EU Clinical Trials Register Service Desk: https://servicedesk.ema.europa.eu
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