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    Clinical Trial Results:
    A Multicenter, Open-Label Study to Compare On-Demand Treatment With 2 Prophylaxis Regimens of Recombinant Coagulation Factor IX (BeneFIX) Reformulated Drug Product (rFIX-R) in Subjects With Severe Hemophilia B

    Summary
    EudraCT number
    		 2005-005246-40
    Trial protocol
    		 HU   BE   IT   DE   Outside EU/EEA  
    Global end of trial date
    12 Oct 2010

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

    Trial information

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    Trial identification
    Sponsor protocol code
    3090A1-400
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT00364182
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 alias: B1821002
    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
    29 Mar 2011
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    12 Oct 2010
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the efficacy and safety of BeneFIX infused as prophylaxis regimens, compared with BeneFIX administered in an on-demand regimen only.
    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 2007
    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
    Hungary: 3
    Country: Number of subjects enrolled
    Italy: 3
    Country: Number of subjects enrolled
    Canada: 2
    Country: Number of subjects enrolled
    Croatia: 3
    Country: Number of subjects enrolled
    Romania: 7
    Country: Number of subjects enrolled
    Russian Federation: 13
    Country: Number of subjects enrolled
    Serbia: 5
    Country: Number of subjects enrolled
    Spain: 3
    Country: Number of subjects enrolled
    United States: 11
    Worldwide total number of subjects
    50
    EEA total number of subjects
    19
    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)
    6
    Adolescents (12-17 years)
    4
    Adults (18-64 years)
    40
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 3 subjects who enrolled in the study were not randomized to either prophylaxis treatment regimen, but participated in the study during the first on demand treatment period.

    Period 1
    Period 1 title
    First Intervention
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Pre-Randomization
    Arm description
    		 Subjects were enrolled and received BeneFIX (recombinant coagulation factor IX) as intravenous (IV) bolus infusion in the first on-demand (OD1) period but were never randomized.
    Arm type
    		 Experimental

    Investigational medicinal product name
    BeneFIX
    Investigational medicinal product code
    Other name
    recombinant coagulation factor IX (rFIX), nonacog alfa
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous bolus use
    Dosage and administration details
    Subjects were enrolled and received BeneFIX (recombinant coagulation factor IX) as IV bolus infusion in the first on-demand (OD1) period but were never randomized.

    Arm title
    		 BeneFIX OD1, 100 IU/kg, OD2, 50 IU/kg: First Intervention
    Arm description
    		 BeneFIX (recombinant coagulation factor IX) on-demand for 16 weeks (OD1), followed by 100 international units per kilogram (IU/kg) once per week (QW) for 16 weeks prophylactically, followed by 8 weeks BeneFIX on-demand (OD2), followed by 50 IU/kg twice weekly (BW) for 16 weeks prophylactically. Subjects received BeneFIX OD1 during the first intervention period.
    Arm type
    		 Experimental

    Investigational medicinal product name
    BeneFIX
    Investigational medicinal product code
    Other name
    recombinant coagulation factor IX (rFIX), nonacog alfa
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous bolus use
    Dosage and administration details
    BeneFIX on-demand for 16 weeks (OD1) during the first intervention period.

    Arm title
    		 BeneFIX OD1, 50 IU/kg, OD2, 100 IU/kg; First Intervention
    Arm description
    		 BeneFIX (recombinant coagulation factor IX) on-demand for 16 weeks (OD1), followed by 50 IU/kg BW for 16 weeks prophylactically, followed by 8 weeks BeneFIX on-demand (OD2), followed by 100 IU/kg QW for 16 weeks prophylactically. Subjects received BeneFIX OD1 during the first intervention period.
    Arm type
    		 Experimental

    Investigational medicinal product name
    BeneFIX
    Investigational medicinal product code
    Other name
    recombinant coagulation factor IX (rFIX), nonacog alfa
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous bolus use
    Dosage and administration details
    BeneFIX on-demand for 16 weeks (OD1) during the first intervention period.

    Number of subjects in period 1
    		Pre-Randomization BeneFIX OD1, 100 IU/kg, OD2, 50 IU/kg: First Intervention BeneFIX OD1, 50 IU/kg, OD2, 100 IU/kg; First Intervention
    Started
    3
    22
    25
    Completed
    0
    22
    25
    Not completed
    3
    0
    0
         Consent withdrawn by subject
    2
    -
    -
         Secondary prophylaxis
    1
    -
    -
    Period 2
    Period 2 title
    Second Intervention
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 BeneFIX OD1, 100 IU/kg, OD2, 50 IU/kg: Second Intervention
    Arm description
    		 BeneFIX (recombinant coagulation factor IX) on-demand for 16 weeks (OD1), followed by 100 IU/kg QW for 16 weeks prophylactically, followed by 8 weeks BeneFIX on-demand (OD2), followed by 50 IU/kg BW for 16 weeks prophylactically. Subjects received BeneFIX (100 IU/kg) during the second intervention period.
    Arm type
    		 Experimental

    Investigational medicinal product name
    BeneFIX
    Investigational medicinal product code
    Other name
    recombinant coagulation factor IX (rFIX), nonacog alfa
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous bolus use
    Dosage and administration details
    BeneFIX 100 IU/kg QW for 16 weeks prophylactically during the second intervention period.

    Arm title
    		 BeneFIX OD1, 50 IU/kg, OD2, 100 IU/kg: Second Intervention
    Arm description
    		 BeneFIX (recombinant coagulation factor IX) on-demand for 16 weeks (OD1), followed by 50 IU/kg BW for 16 weeks prophylactically, followed by 8 weeks BeneFIX on-demand (OD2), followed by 100 IU/kg QW for 16 weeks prophylactically. Subjects received BeneFIX (50 IU/kg) during the second intervention period.
    Arm type
    		 Experimental

    Investigational medicinal product name
    BeneFIX
    Investigational medicinal product code
    Other name
    recombinant coagulation factor IX (rFIX), nonacog alfa
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous bolus use
    Dosage and administration details
    BeneFIX 50 IU/kg BW for 16 weeks prophylactically during the second intervention period.

    Number of subjects in period 2
    		BeneFIX OD1, 100 IU/kg, OD2, 50 IU/kg: Second Intervention BeneFIX OD1, 50 IU/kg, OD2, 100 IU/kg: Second Intervention
    Started
    22
    25
    Randomized
    22
    25
    Completed
    20
    23
    Not completed
    2
    2
         Adverse Event
    -
    1
         Non-compliance
    1
    1
         Protocol Violation
    1
    -
    Period 3
    Period 3 title
    Third Intervention
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 BeneFIX OD1, 100 IU/kg, OD2, 50 IU/kg: Third Intervention
    Arm description
    		 BeneFIX (recombinant coagulation factor IX) on-demand for 16 weeks (OD1), followed by 100 IU/kg QW for 16 weeks prophylactically, followed by 8 weeks BeneFIX on-demand (OD2), followed by 50 IU/kg BW for 16 weeks prophylactically. Subjects received BeneFIX OD2 during the third intervention period.
    Arm type
    		 Experimental

    Investigational medicinal product name
    BeneFIX
    Investigational medicinal product code
    Other name
    recombinant coagulation factor IX (rFIX), nonacog alfa
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous bolus use
    Dosage and administration details
    BeneFIX on-demand for 8 weeks (OD2) during the third intervention period.

    Arm title
    		 BeneFIX OD1, 50 IU/kg, OD2, 100 IU/kg: Third Intervention
    Arm description
    		 BeneFIX (recombinant coagulation factor IX) on-demand for 16 weeks (OD1), followed by 50 IU/kg BW for 16 weeks prophylactically, followed by 8 weeks BeneFIX on-demand (OD2), followed by 100 IU/kg QW for 16 weeks prophylactically. Subjects received BeneFIX OD2 during the third intervention period.
    Arm type
    		 Experimental

    Investigational medicinal product name
    BeneFIX
    Investigational medicinal product code
    Other name
    recombinant coagulation factor IX (rFIX), nonacog alfa
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous bolus use
    Dosage and administration details
    BeneFIX on-demand for 8 weeks (OD2) during the third intervention period.

    Number of subjects in period 3
    		BeneFIX OD1, 100 IU/kg, OD2, 50 IU/kg: Third Intervention BeneFIX OD1, 50 IU/kg, OD2, 100 IU/kg: Third Intervention
    Started
    20
    23
    Completed
    19
    22
    Not completed
    1
    1
         Non-compliance
    1
    -
         Lost to follow-up
    -
    1
    Period 4
    Period 4 title
    Fourth Intervention
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 BeneFIX OD1, 100 IU/kg, OD2, 50 IU/kg: Fourth Intervention
    Arm description
    		 BeneFIX (recombinant coagulation factor IX) on-demand for 16 weeks (OD1), followed by 100 IU/kg QW for 16 weeks prophylactically, followed by 8 weeks BeneFIX on-demand (OD2), followed by 50 IU/kg BW for 16 weeks prophylactically. Subjects received BeneFIX (50 IU/kg) during the fourth intervention period.
    Arm type
    		 Experimental

    Investigational medicinal product name
    BeneFIX
    Investigational medicinal product code
    Other name
    recombinant coagulation factor IX (rFIX), nonacog alfa
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous bolus use
    Dosage and administration details
    BeneFIX 50 IU/kg BW for 16 weeks prophylactically during the fourth intervention period.

    Arm title
    		 BeneFIX OD1, 50 IU/kg, OD2, 100 IU/kg: Fourth intervention
    Arm description
    		 BeneFIX (recombinant coagulation factor IX) on-demand for 16 weeks (OD1), followed by 50 IU/kg BW for 16 weeks prophylactically, followed by 8 weeks BeneFIX on-demand (OD2), followed by 100 IU/kg QW for 16 weeks prophylactically. Subjects received BeneFIX (100 IU/kg) during the fourth intervention period.
    Arm type
    		 Experimental

    Investigational medicinal product name
    BeneFIX
    Investigational medicinal product code
    Other name
    recombinant coagulation factor IX (rFIX), nonacog alfa
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous bolus use
    Dosage and administration details
    BeneFIX 100 IU/kg QW for 16 weeks prophylactically during the fourth intervention period.

    Number of subjects in period 4
    		BeneFIX OD1, 100 IU/kg, OD2, 50 IU/kg: Fourth Intervention BeneFIX OD1, 50 IU/kg, OD2, 100 IU/kg: Fourth intervention
    Started
    19
    22
    Completed
    19
    22

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Pre-Randomization
    Reporting group description
    		 Subjects were enrolled and received BeneFIX (recombinant coagulation factor IX) as intravenous (IV) bolus infusion in the first on-demand (OD1) period but were never randomized.

    Reporting group title
    BeneFIX OD1, 100 IU/kg, OD2, 50 IU/kg: First Intervention
    Reporting group description
    		 BeneFIX (recombinant coagulation factor IX) on-demand for 16 weeks (OD1), followed by 100 international units per kilogram (IU/kg) once per week (QW) for 16 weeks prophylactically, followed by 8 weeks BeneFIX on-demand (OD2), followed by 50 IU/kg twice weekly (BW) for 16 weeks prophylactically. Subjects received BeneFIX OD1 during the first intervention period.

    Reporting group title
    BeneFIX OD1, 50 IU/kg, OD2, 100 IU/kg; First Intervention
    Reporting group description
    		 BeneFIX (recombinant coagulation factor IX) on-demand for 16 weeks (OD1), followed by 50 IU/kg BW for 16 weeks prophylactically, followed by 8 weeks BeneFIX on-demand (OD2), followed by 100 IU/kg QW for 16 weeks prophylactically. Subjects received BeneFIX OD1 during the first intervention period.

    Reporting group values
    		 Pre-Randomization BeneFIX OD1, 100 IU/kg, OD2, 50 IU/kg: First Intervention BeneFIX OD1, 50 IU/kg, OD2, 100 IU/kg; First Intervention Total
    Number of subjects
    		 3 22 25 50
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 19.3 ± 4.5 31.7 ± 13.4 25.1 ± 14.4 -
    Gender categorical
    Units: Subjects
        Female
    		 0 0 0 0
        Male
    		 3 22 25 50

    End points

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    End points reporting groups
    Reporting group title
    Pre-Randomization
    Reporting group description
    		 Subjects were enrolled and received BeneFIX (recombinant coagulation factor IX) as intravenous (IV) bolus infusion in the first on-demand (OD1) period but were never randomized.

    Reporting group title
    BeneFIX OD1, 100 IU/kg, OD2, 50 IU/kg: First Intervention
    Reporting group description
    		 BeneFIX (recombinant coagulation factor IX) on-demand for 16 weeks (OD1), followed by 100 international units per kilogram (IU/kg) once per week (QW) for 16 weeks prophylactically, followed by 8 weeks BeneFIX on-demand (OD2), followed by 50 IU/kg twice weekly (BW) for 16 weeks prophylactically. Subjects received BeneFIX OD1 during the first intervention period.

    Reporting group title
    BeneFIX OD1, 50 IU/kg, OD2, 100 IU/kg; First Intervention
    Reporting group description
    		 BeneFIX (recombinant coagulation factor IX) on-demand for 16 weeks (OD1), followed by 50 IU/kg BW for 16 weeks prophylactically, followed by 8 weeks BeneFIX on-demand (OD2), followed by 100 IU/kg QW for 16 weeks prophylactically. Subjects received BeneFIX OD1 during the first intervention period.
    Reporting group title
    BeneFIX OD1, 100 IU/kg, OD2, 50 IU/kg: Second Intervention
    Reporting group description
    		 BeneFIX (recombinant coagulation factor IX) on-demand for 16 weeks (OD1), followed by 100 IU/kg QW for 16 weeks prophylactically, followed by 8 weeks BeneFIX on-demand (OD2), followed by 50 IU/kg BW for 16 weeks prophylactically. Subjects received BeneFIX (100 IU/kg) during the second intervention period.

    Reporting group title
    BeneFIX OD1, 50 IU/kg, OD2, 100 IU/kg: Second Intervention
    Reporting group description
    		 BeneFIX (recombinant coagulation factor IX) on-demand for 16 weeks (OD1), followed by 50 IU/kg BW for 16 weeks prophylactically, followed by 8 weeks BeneFIX on-demand (OD2), followed by 100 IU/kg QW for 16 weeks prophylactically. Subjects received BeneFIX (50 IU/kg) during the second intervention period.
    Reporting group title
    BeneFIX OD1, 100 IU/kg, OD2, 50 IU/kg: Third Intervention
    Reporting group description
    		 BeneFIX (recombinant coagulation factor IX) on-demand for 16 weeks (OD1), followed by 100 IU/kg QW for 16 weeks prophylactically, followed by 8 weeks BeneFIX on-demand (OD2), followed by 50 IU/kg BW for 16 weeks prophylactically. Subjects received BeneFIX OD2 during the third intervention period.

    Reporting group title
    BeneFIX OD1, 50 IU/kg, OD2, 100 IU/kg: Third Intervention
    Reporting group description
    		 BeneFIX (recombinant coagulation factor IX) on-demand for 16 weeks (OD1), followed by 50 IU/kg BW for 16 weeks prophylactically, followed by 8 weeks BeneFIX on-demand (OD2), followed by 100 IU/kg QW for 16 weeks prophylactically. Subjects received BeneFIX OD2 during the third intervention period.
    Reporting group title
    BeneFIX OD1, 100 IU/kg, OD2, 50 IU/kg: Fourth Intervention
    Reporting group description
    		 BeneFIX (recombinant coagulation factor IX) on-demand for 16 weeks (OD1), followed by 100 IU/kg QW for 16 weeks prophylactically, followed by 8 weeks BeneFIX on-demand (OD2), followed by 50 IU/kg BW for 16 weeks prophylactically. Subjects received BeneFIX (50 IU/kg) during the fourth intervention period.

    Reporting group title
    BeneFIX OD1, 50 IU/kg, OD2, 100 IU/kg: Fourth intervention
    Reporting group description
    		 BeneFIX (recombinant coagulation factor IX) on-demand for 16 weeks (OD1), followed by 50 IU/kg BW for 16 weeks prophylactically, followed by 8 weeks BeneFIX on-demand (OD2), followed by 100 IU/kg QW for 16 weeks prophylactically. Subjects received BeneFIX (100 IU/kg) during the fourth intervention period.

    Subject analysis set title
    BeneFIX OD1
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    BeneFIX on-demand IV bolus infusion for 16 weeks (first intervention).

    Subject analysis set title
    BeneFIX 100 IU/kg
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    BeneFIX 100 IU/kg IV bolus infusion QW for 16 weeks.

    Subject analysis set title
    BeneFIX 50 IU/kg
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    BeneFIX 50 IU/kg IV bolus infusion BW for 16 weeks.

    Subject analysis set title
    BeneFIX OD2
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    BeneFIX on-demand IV bolus infusion for 8 weeks (third intervention).

    Primary: Annualized Number of Bleeding Episodes

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    End point title
    		 Annualized Number of Bleeding Episodes
    End point description
    Annualized bleed rate (ABR) or number of bleeds per year derived for each subject for each treatment regimen by using the following formula: ABR = number of bleeds / (days on treatment regimen / 365.25). Intention-to-treat (ITT) population: all enrolled subjects.
    End point type
    Primary
    End point timeframe
    Baseline up to Week 56.
    End point values
    		 BeneFIX OD1 BeneFIX 100 IU/kg BeneFIX 50 IU/kg
    Number of subjects analysed
    50
    44
    44
    Units: episodes
        least squares mean (confidence interval 95%)
    35.1 (28.8 to 41.4)
    4.6 (2.1 to 7.2)
    2.6 (-0.1 to 5.3)
    Statistical analysis title
    		 ABR: BeneFIX OD1 vs. BeneFIX 100 IU/kg
    Statistical analysis description
    As this was a cross over study, same subjects were to receive all the formulations. Total number of subjects in the analysis were 44. Point estimate was calculated by subtracting BeneFIX OD1 from BeneFIX 100 IU/kg. For 95 percent (%) CI, upper limit value was subtracted from lower limit value.
    Comparison groups
    BeneFIX OD1 v BeneFIX 100 IU/kg
    Number of subjects included in analysis
    94
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [1]
    Method
    		 ANOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -30.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -36.5
         upper limit
    		 -24.5
    Notes
    [1] - P-values based on a model including terms for treatment regimen, treatment sequence, and the interaction of these terms with repeated measures on subjects.
    Statistical analysis title
    		 ABR: BeneFIX OD1 vs. BeneFIX 50 IU/kg
    Statistical analysis description
    As this was a cross over study, same subjects were to receive all the formulations. Total number of subjects in the analysis were 43. Point estimate was calculated by subtracting BeneFIX OD1 from BeneFIX 50 IU/kg. For 95 percent (%) CI, upper limit value was subtracted from lower limit value.
    Comparison groups
    BeneFIX OD1 v BeneFIX 50 IU/kg
    Number of subjects included in analysis
    94
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [2]
    Method
    		 ANOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -32.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -38.5
         upper limit
    		 -26.6
    Notes
    [2] - P-values based on a model including terms for treatment regimen, treatment sequence, and the interaction of these terms with repeated measures on subjects.
    Statistical analysis title
    		 ABR: BeneFIX 100 IU/kg vs. BeneFIX 50 IU/kg
    Statistical analysis description
    As this was a cross over study, same subjects were to receive all the formulations. Total number of subjects in the analysis were 41. Point estimate was calculated by subtracting BeneFIX 50 IU/kg from BeneFIX 100 IU/kg. For 95 % CI, upper limit value was subtracted from lower limit value.
    Comparison groups
    BeneFIX 100 IU/kg v BeneFIX 50 IU/kg
    Number of subjects included in analysis
    88
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.2167 [3]
    Method
    		 ANOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.2
         upper limit
    		 5.2
    Notes
    [3] - P-values based on a model including terms for treatment regimen, treatment sequence, and the interaction of these terms with repeated measures on subjects.

    Secondary: Amount of Sleep Measured by Sleep Diary After Hemarthrosis

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    End point title
    		 Amount of Sleep Measured by Sleep Diary After Hemarthrosis
    End point description
    For each bleeding event, a diary was filled out that night and the subsequent night. Questions included: How long do you think you slept last night? Reported as average duration of sleep during study. ITT population.
    End point type
    Secondary
    End point timeframe
    24 and 48 hours post-bleed
    End point values
    		 BeneFIX OD1 BeneFIX 100 IU/kg BeneFIX 50 IU/kg BeneFIX OD2
    Number of subjects analysed
    50
    44
    44
    43
    Units: hours
    arithmetic mean (standard deviation)
        24 hours post-bleed
    7.5 ± 2
    7.3 ± 1.8
    7.1 ± 1.6
    7.4 ± 1.9
        48 hours post-bleed
    7.9 ± 1.7
    7.8 ± 1.6
    7.5 ± 1.4
    8 ± 1.7
    Attachments
    		 Statistical Analysis for Amount of Sleep
    No statistical analyses for this end point

    Secondary: Quality of Sleep Measured by Sleep Diary After Hemarthrosis

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    End point title
    		 Quality of Sleep Measured by Sleep Diary After Hemarthrosis
    End point description
    For each bleeding event, a diary was filled out that night and the subsequent night. Questions included: How would you describe the quality of your sleep last night? 1=Very Good, 2=Good, 3=Fair, 4=Poor, 5=Very Poor. Reported as quality of sleep during study.
    End point type
    Secondary
    End point timeframe
    24 and 48 hours post-bleed
    End point values
    		 BeneFIX OD1 BeneFIX 100 IU/kg BeneFIX 50 IU/kg BeneFIX OD2
    Number of subjects analysed
    50
    44
    44
    43
    Units: Units on a scale
    arithmetic mean (standard deviation)
        24 hours post-bleed
    2.4 ± 0.9
    2.5 ± 0.9
    2.3 ± 0.9
    2.4 ± 0.9
        48 hours post-bleed
    2.1 ± 0.7
    2.1 ± 0.8
    2.1 ± 0.7
    2.1 ± 0.9
    Attachments
    		 Statistical Analysis for Quality of Sleep
    No statistical analyses for this end point

    Secondary: Acute Pain After Hemarthrosis

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    End point title
    		 Acute Pain After Hemarthrosis
    End point description
    For each bleeding event, a diary was filled out that night and the subsequent night and included a Brief Pain Inventory (BPI): self-reported scale that measured severity of pain experienced over the past 24 hours. Questions included How much pain right now? 0 (no pain) to 10 (pain as severe as you can imagine). ITT population.
    End point type
    Secondary
    End point timeframe
    24 and 48 hours post-bleed
    End point values
    		 BeneFIX OD1 BeneFIX 100 IU/kg BeneFIX 50 IU/kg BeneFIX OD2
    Number of subjects analysed
    50
    44
    44
    43
    Units: units on a scale
    arithmetic mean (standard deviation)
        24 hours post-bleed
    2.8 ± 2.1
    2.8 ± 2
    3.1 ± 2.2
    3 ± 2.1
        48 hours post-bleed
    2.3 ± 1.6
    1.8 ± 1.2
    2.7 ± 1.5
    4.1 ± 2.4
    No statistical analyses for this end point

    Secondary: Health-Related Productivity Questionnaire (HRPQ) Score: Hours Lost From Work or School at 24 Hours Post-bleed

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    End point title
    		 Health-Related Productivity Questionnaire (HRPQ) Score: Hours Lost From Work or School at 24 Hours Post-bleed
    End point description
    HRPQ: self-reported scale that measured for each bleed event, hours lost from work, school and housework because of hemophilia and its treatments. Mean and standard deviations calculated from measured values. ITT population.
    End point type
    Secondary
    End point timeframe
    24 hours post-bleed
    End point values
    		 BeneFIX OD1 BeneFIX 100 IU/kg BeneFIX 50 IU/kg BeneFIX OD2
    Number of subjects analysed
    50
    44
    44
    43
    Units: hours
    arithmetic mean (standard deviation)
        Work missed
    0.4 ± 1.6
    1.2 ± 2.6
    0.6 ± 1.9
    0.6 ± 1.3
        Housework couldn't do
    0.7 ± 2.4
    0.3 ± 0.8
    0.4 ± 0.7
    0.2 ± 0.5
        Classwork couldn't do
    0.8 ± 1.7
    0.7 ± 2.2
    0.4 ± 1.1
    0 ± 0
    No statistical analyses for this end point

    Secondary: HRPQ Score: Hours Lost From Work or School at 48 Hours Post-bleed

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    End point title
    		 HRPQ Score: Hours Lost From Work or School at 48 Hours Post-bleed
    End point description
    HRPQ: self-reported scale that measured for each bleed event, hours lost from work, school and housework because of hemophilia and its treatments. Mean and standard deviations calculated from measured values. ITT Population.
    End point type
    Secondary
    End point timeframe
    48 hours post-bleed.
    End point values
    		 BeneFIX OD1 BeneFIX 100 IU/kg BeneFIX 50 IU/kg BeneFIX OD2
    Number of subjects analysed
    50
    44
    44
    43
    Units: hours
    arithmetic mean (standard deviation)
        Work missed
    0.2 ± 1
    0.7 ± 2.1
    0.1 ± 0.4
    0.2 ± 0.5
        Housework couldn't do
    0.5 ± 1.4
    0.3 ± 0.7
    0 ± 0.2
    0 ± 0
        Classwork couldn't do
    0.4 ± 1.2
    0.7 ± 2.4
    0 ± 0
    1.7 ± 2.6
    No statistical analyses for this end point

    Secondary: 36-Item Short-Form Health Survey (SF-36): Physical Functioning Domain

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    End point title
    		 36-Item Short-Form Health Survey (SF-36): Physical Functioning Domain
    End point description
    SF-36: standardized survey evaluating 8 aspects of functional health and well being: physical and social functioning, physical and emotional role limitations, bodily pain, general health, vitality, and mental health. The physical functioning domain score was an average of the individual physical functioning question scores across all time points, which was scaled 0-100 (100=highest level of functioning). ITT; N=number of subjects with evaluable data.
    End point type
    Secondary
    End point timeframe
    Weeks 16, 32, and 56
    End point values
    		 BeneFIX OD1 BeneFIX 100 IU/kg BeneFIX 50 IU/kg
    Number of subjects analysed
    40 [4]
    35 [5]
    34 [6]
    Units: units on a scale
        arithmetic mean (standard deviation)
    64 ± 26
    66 ± 25
    63 ± 28
    Notes
    [4] - Number of subjects with evaluable data.
    [5] - Number of subjects with evaluable data.
    [6] - Number of subjects with evaluable data.
    Statistical analysis title
    		 SF-36: BeneFIX OD1 vs. BeneFIX 100 IU/kg
    Statistical analysis description
    As this was a cross over study, same subjects were to receive all the formulations. Total number of subjects in the analysis were 50.
    Comparison groups
    BeneFIX OD1 v BeneFIX 100 IU/kg
    Number of subjects included in analysis
    75
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.544
    Method
    		 ANOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    -2.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -9.2
         upper limit
    		 4.9
    Statistical analysis title
    		 SF-36: BeneFIX OD1 vs. BeneFIX 50 IU/kg
    Statistical analysis description
    As this was a cross over study, same subjects were to receive all the formulations. Total number of subjects in the analysis were 50.
    Comparison groups
    BeneFIX OD1 v BeneFIX 50 IU/kg
    Number of subjects included in analysis
    74
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.592
    Method
    		 ANOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    -1.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -7.5
         upper limit
    		 4.3
    Statistical analysis title
    		 SF-36: BeneFIX 100 IU/kg vs. BeneFIX 50 IU/kg
    Statistical analysis description
    As this was a cross over study, same subjects were to receive all the formulations. Total number of subjects in the analysis were 50.
    Comparison groups
    BeneFIX 100 IU/kg v BeneFIX 50 IU/kg
    Number of subjects included in analysis
    69
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.131
    Method
    		 ANOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    3.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.1
         upper limit
    		 8.4

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Baseline up to 15 days after last administration dose of BeneFIX
    Adverse event reporting additional description
    The same event may appear as both an AE and an SAE. However, what is presented are distinct events. An event may be categorized as serious in 1 subject and as nonserious in another subject, or 1 subject may have experienced both a serious and nonserious event during the study.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    18
    Reporting groups
    Reporting group title
    BeneFIX OD1
    Reporting group description
    		 BeneFIX in an on-demand IV bolus infusion for 16 weeks (first intervention).

    Reporting group title
    BeneFIX 100 IU/kg
    Reporting group description
    		 BeneFIX 100 IU/kg IV bolus infusion QW for 16 weeks.

    Reporting group title
    BeneFIX 50 IU/kg
    Reporting group description
    		 BeneFIX 50 IU/kg IV bolus infusion BW for 16 weeks.

    Reporting group title
    BeneFIX OD2
    Reporting group description
    		 BeneFIX on-demand IV bolus infusion for 8 weeks (third intervention).

    Serious adverse events
    		 BeneFIX OD1 BeneFIX 100 IU/kg BeneFIX 50 IU/kg BeneFIX OD2
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 50 (2.00%)
    2 / 44 (4.55%)
    2 / 44 (4.55%)
    0 / 43 (0.00%)
         number of deaths (all causes)
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    Injury, poisoning and procedural complications
    Ulna fracture
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 44 (0.00%)
    0 / 44 (0.00%)
    0 / 43 (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
    Reproductive system and breast disorders
    Testicular pain
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 44 (0.00%)
    1 / 44 (2.27%)
    0 / 43 (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
    Pneumothorax
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 44 (2.27%)
    0 / 44 (0.00%)
    0 / 43 (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
    Renal and urinary disorders
    Calculus urinary
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 44 (2.27%)
    0 / 44 (0.00%)
    0 / 43 (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
    Renal colic
         subjects affected / exposed
    0 / 50 (0.00%)
    1 / 44 (2.27%)
    0 / 44 (0.00%)
    0 / 43 (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
    Arthropathy
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 44 (0.00%)
    1 / 44 (2.27%)
    0 / 43 (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
    Back pain
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 44 (0.00%)
    1 / 44 (2.27%)
    0 / 43 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         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
    		 BeneFIX OD1 BeneFIX 100 IU/kg BeneFIX 50 IU/kg BeneFIX OD2
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    8 / 50 (16.00%)
    8 / 44 (18.18%)
    4 / 44 (9.09%)
    4 / 43 (9.30%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    3 / 50 (6.00%)
    6 / 44 (13.64%)
    2 / 44 (4.55%)
    2 / 43 (4.65%)
         occurrences all number
    3
    7
    2
    2
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    5 / 50 (10.00%)
    4 / 44 (9.09%)
    2 / 44 (4.55%)
    2 / 43 (4.65%)
         occurrences all number
    13
    21
    2
    6

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    Although the protocol-defined endpoint was days lost from work or school after hemarthrosis, data was collected and reported in hours.
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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