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    Clinical Trial Results:
    A Randomized, Open-Label, Crossover Study to Evaluate the Pharmacokinetics of 2 Vial Strengths of Recombinant Factor VIII Fc Fusion Protein (rFVIIIFc; BIIB031) in Previously Treated Subjects With Severe Hemophilia A

    Summary
    EudraCT number
    2013-003013-18
    Trial protocol
    GB  
    Global end of trial date
    20 May 2015

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

    Trial information

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    Trial identification
    Sponsor protocol code
    997HA307
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02083965
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Biogen
    Sponsor organisation address
    225 Binney Street, Cambridge, Massachusetts, United States, 02142
    Public contact
    Medical Director, Biogen, clinicaltrials@biogen.com
    Scientific contact
    Medical Director, Biogen, clinicaltrials@biogen.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
    20 May 2015
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    20 May 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of the study was to characterize the pharmacokinetics (PK) of rFVIIIFc administered at vial strengths of 1000 and 3000 IU in subjects with severe hemophilia A. The secondary objective of the study was to evaluate the safety of rFVIIIFc beyond the PK assessment for up to 6 months for a continued treatment period.
    Protection of trial subjects
    Written informed consent was obtained from each subject prior to evaluations being performed for eligibility. Subjects were given adequate time to review the information in the informed consent and were allowed to ask, and have answered, questions concerning all portions of the conduct of the study. Through the informed consent process each subject was made aware of the purpose of the study, the procedures, the benefits and risks of the study, the discomforts and the precautions taken. Any side effects or other health issues occurring during the study were followed up by the study doctor. Subjects were able to stop taking part in the study at any time without giving any reason.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    24 Mar 2014
    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
    United Kingdom: 9
    Country: Number of subjects enrolled
    Australia: 5
    Country: Number of subjects enrolled
    United States: 5
    Worldwide total number of subjects
    19
    EEA total number of subjects
    9
    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)
    10
    Adults (18-64 years)
    9
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    -

    Pre-assignment
    Screening details
    During screening, subjects continued on their prior FVIII treatment/regimen and treated any bleeding episodes accordingly. After eligibility was confirmed at a screening visit, subjects underwent a 4-day washout period before receiving rFVIIIFc. Subjects may have repeated the washout period only once if bleeding occurred during the washout period.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    rFVIIIFc 1000/3000
    Arm description
    Following the minimum 4-day washout, subjects received a single injection 50 IU/kg at a strength of 1000 IU/vial of rFVIIIFc (on Injection 1 Day 1) with 96 hours of PK assessments followed by a minimum of a 5-day washout prior to a second single injection of rFVIIIFc 50 IU/kg at a strength of 3000 IU/vial (on Injection 2 Day 1) with 96 hours of PK assessments. After completing the PK assessment, all subjects began 1 of 3 continued treatment regimens for up to 6 months: 1. A prophylaxis regimen at a starting dose of 50 IU/kg of rFVIIIFc given every 3 to 5 days; further dose and interval adjustments were based on the Investigator’s discretion as needed to prevent or treat bleeding 2. A prophylaxis regimen of 65 IU/kg administered every 7 days was considered for appropriate subjects who were selected based on the opinion of the Investigator 3. An episodic (on-demand) treatment with rFVIIIFc at 20 to 50 IU/kg, depending on the severity of the bleeding episode.
    Arm type
    Experimental

    Investigational medicinal product name
    recombinant Factor VIII-Fc
    Investigational medicinal product code
    rFVIIIFc
    Other name
    BIIB031, Eloctate, Elocta, antihemophilic factor (recombinant) Fc fusion protein, recombinant coagulation factor VIII Fc fusion protein, efmoroctocog alfa
    Pharmaceutical forms
    Powder and solvent for solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    During the PK assessment, rFVIIIFc injections were prepared and administered in the clinic by study personnel. During continued treatment, rFVIIIFc injections were prepared and administered at home. At home and in the clinic, rFVIIIFc was to be delivered by IV injection over 5 minutes.

    Arm title
    rFVIIIFc 3000/1000
    Arm description
    Following the minimum 4-day washout, subjects received a single injection 50 IU/kg at a strength of 3000 IU/vial of rFVIIIFc (on Injection 1 Day 1) with 96 hours of PK assessments followed by a minimum of a 5-day washout prior to a second single injection of rFVIIIFc 50 IU/kg at a strength of 1000 IU/vial (on Injection 2 Day 1) with 96 hours of PK assessments. After completing the PK assessment, all subjects began 1 of 3 continued treatment regimens for up to 6 months: 1. A prophylaxis regimen at a starting dose of 50 IU/kg of rFVIIIFc given every 3 to 5 days; further dose and interval adjustments were based on the Investigator’s discretion as needed to prevent or treat bleeding 2. A prophylaxis regimen of 65 IU/kg administered every 7 days was considered for appropriate subjects who were selected based on the opinion of the Investigator 3. An episodic (on-demand) treatment with rFVIIIFc at 20 to 50 IU/kg, depending on the severity of the bleeding episode.
    Arm type
    Experimental

    Investigational medicinal product name
    recombinant Factor VIII-Fc
    Investigational medicinal product code
    rFVIIIFc
    Other name
    BIIB031, Eloctate, Elocta, antihemophilic factor (recombinant) Fc fusion protein, recombinant coagulation factor VIII Fc fusion protein, efmoroctocog alfa
    Pharmaceutical forms
    Powder and solvent for solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    During the PK assessment, rFVIIIFc injections were prepared and administered in the clinic by study personnel. During continued treatment, rFVIIIFc injections were prepared and administered at home. At home and in the clinic, rFVIIIFc was to be delivered by IV injection over 5 minutes.

    Number of subjects in period 1
    rFVIIIFc 1000/3000 rFVIIIFc 3000/1000
    Started
    10
    9
    Completed
    9
    8
    Not completed
    1
    1
         Withdrawal by subject
    -
    1
         Not specified
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    rFVIIIFc 1000/3000
    Reporting group description
    Following the minimum 4-day washout, subjects received a single injection 50 IU/kg at a strength of 1000 IU/vial of rFVIIIFc (on Injection 1 Day 1) with 96 hours of PK assessments followed by a minimum of a 5-day washout prior to a second single injection of rFVIIIFc 50 IU/kg at a strength of 3000 IU/vial (on Injection 2 Day 1) with 96 hours of PK assessments. After completing the PK assessment, all subjects began 1 of 3 continued treatment regimens for up to 6 months: 1. A prophylaxis regimen at a starting dose of 50 IU/kg of rFVIIIFc given every 3 to 5 days; further dose and interval adjustments were based on the Investigator’s discretion as needed to prevent or treat bleeding 2. A prophylaxis regimen of 65 IU/kg administered every 7 days was considered for appropriate subjects who were selected based on the opinion of the Investigator 3. An episodic (on-demand) treatment with rFVIIIFc at 20 to 50 IU/kg, depending on the severity of the bleeding episode.

    Reporting group title
    rFVIIIFc 3000/1000
    Reporting group description
    Following the minimum 4-day washout, subjects received a single injection 50 IU/kg at a strength of 3000 IU/vial of rFVIIIFc (on Injection 1 Day 1) with 96 hours of PK assessments followed by a minimum of a 5-day washout prior to a second single injection of rFVIIIFc 50 IU/kg at a strength of 1000 IU/vial (on Injection 2 Day 1) with 96 hours of PK assessments. After completing the PK assessment, all subjects began 1 of 3 continued treatment regimens for up to 6 months: 1. A prophylaxis regimen at a starting dose of 50 IU/kg of rFVIIIFc given every 3 to 5 days; further dose and interval adjustments were based on the Investigator’s discretion as needed to prevent or treat bleeding 2. A prophylaxis regimen of 65 IU/kg administered every 7 days was considered for appropriate subjects who were selected based on the opinion of the Investigator 3. An episodic (on-demand) treatment with rFVIIIFc at 20 to 50 IU/kg, depending on the severity of the bleeding episode.

    Reporting group values
    rFVIIIFc 1000/3000 rFVIIIFc 3000/1000 Total
    Number of subjects
    10 9 19
    Age categorical
    Units: Subjects
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    23 ± 12.45 30.9 ± 19.76 -
    Gender, Male/Female
    Units: participants
        Female
    0 0 0
        Male
    10 9 19

    End points

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    End points reporting groups
    Reporting group title
    rFVIIIFc 1000/3000
    Reporting group description
    Following the minimum 4-day washout, subjects received a single injection 50 IU/kg at a strength of 1000 IU/vial of rFVIIIFc (on Injection 1 Day 1) with 96 hours of PK assessments followed by a minimum of a 5-day washout prior to a second single injection of rFVIIIFc 50 IU/kg at a strength of 3000 IU/vial (on Injection 2 Day 1) with 96 hours of PK assessments. After completing the PK assessment, all subjects began 1 of 3 continued treatment regimens for up to 6 months: 1. A prophylaxis regimen at a starting dose of 50 IU/kg of rFVIIIFc given every 3 to 5 days; further dose and interval adjustments were based on the Investigator’s discretion as needed to prevent or treat bleeding 2. A prophylaxis regimen of 65 IU/kg administered every 7 days was considered for appropriate subjects who were selected based on the opinion of the Investigator 3. An episodic (on-demand) treatment with rFVIIIFc at 20 to 50 IU/kg, depending on the severity of the bleeding episode.

    Reporting group title
    rFVIIIFc 3000/1000
    Reporting group description
    Following the minimum 4-day washout, subjects received a single injection 50 IU/kg at a strength of 3000 IU/vial of rFVIIIFc (on Injection 1 Day 1) with 96 hours of PK assessments followed by a minimum of a 5-day washout prior to a second single injection of rFVIIIFc 50 IU/kg at a strength of 1000 IU/vial (on Injection 2 Day 1) with 96 hours of PK assessments. After completing the PK assessment, all subjects began 1 of 3 continued treatment regimens for up to 6 months: 1. A prophylaxis regimen at a starting dose of 50 IU/kg of rFVIIIFc given every 3 to 5 days; further dose and interval adjustments were based on the Investigator’s discretion as needed to prevent or treat bleeding 2. A prophylaxis regimen of 65 IU/kg administered every 7 days was considered for appropriate subjects who were selected based on the opinion of the Investigator 3. An episodic (on-demand) treatment with rFVIIIFc at 20 to 50 IU/kg, depending on the severity of the bleeding episode.

    Subject analysis set title
    Pharmacokinetic Analysis Set: rFVIIIFc 1000 IU
    Subject analysis set type
    Per protocol
    Subject analysis set description
    The Pharmacokinetic Analysis Set is defined as all eligible subjects who received at least one dose of rFVIIIFc and had sufficient PK data points to calculate at least one of the PK parameters of interest from either the aPTT clotting assay or the two-stage chromogenic clotting assay.

    Subject analysis set title
    Pharmacokinetic Analysis Set: rFVIIIFc 3000 IU
    Subject analysis set type
    Per protocol
    Subject analysis set description
    The Pharmacokinetic Analysis Set is defined as all eligible subjects who received at least one dose of rFVIIIFc and had sufficient PK data points to calculate at least one of the PK parameters of interest from either the aPTT clotting assay or the two-stage chromogenic clotting assay.

    Subject analysis set title
    Safety Analysis Set
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    The Safety Analysis Set included subjects who received at least 1 dose of rFVIIIFc.

    Primary: Area Under the Concentration-time Curve From Time Zero to Infinity (AUCinf) as Measured by Activated Partial Thromboplastin Time (aPTT) Clotting Assay

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    End point title
    Area Under the Concentration-time Curve From Time Zero to Infinity (AUCinf) as Measured by Activated Partial Thromboplastin Time (aPTT) Clotting Assay [1]
    End point description
    Area under the plasma concentration versus time curve (AUC) from time zero (pre-dose) to extrapolated infinite time (0 - ∞).
    End point type
    Primary
    End point timeframe
    Up to 96 hours (±60 minutes) after each of 2 injections
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Descriptive statistics are presented, per protocol.
    End point values
    Pharmacokinetic Analysis Set: rFVIIIFc 1000 IU Pharmacokinetic Analysis Set: rFVIIIFc 3000 IU
    Number of subjects analysed
    17 [2]
    18
    Units: IU*h/dL
        geometric mean (confidence interval 95%)
    2888.9 (2440 to 3420.5)
    2646.3 (2149.8 to 3257.5)
    Notes
    [2] - subjects with sufficient PK data
    No statistical analyses for this end point

    Primary: Incremental Recovery (IR, K value) as Estimated From the FVIII Activity Data Measured by aPTT Clotting Assay

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    End point title
    Incremental Recovery (IR, K value) as Estimated From the FVIII Activity Data Measured by aPTT Clotting Assay [3]
    End point description
    The rise in FVIII activity in IU/dL per unit dose administered in IU/kg (IR, K value), as estimated from the FVIII activity data.
    End point type
    Primary
    End point timeframe
    Up to 96 hours (±60 minutes) after each of 2 injections
    Notes
    [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Descriptive statistics are presented, per protocol.
    End point values
    Pharmacokinetic Analysis Set: rFVIIIFc 1000 IU Pharmacokinetic Analysis Set: rFVIIIFc 3000 IU
    Number of subjects analysed
    18
    18
    Units: IU/dL
        geometric mean (confidence interval 95%)
    2.33 (2.182 to 2.487)
    2.412 (2.169 to 2.682)
    No statistical analyses for this end point

    Secondary: Maximum Activity (Cmax) as Measured by the aPTT Clotting Assay

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    End point title
    Maximum Activity (Cmax) as Measured by the aPTT Clotting Assay
    End point description
    Maximum measured concentration of rFVIIIFc.
    End point type
    Secondary
    End point timeframe
    Up to 96 hours (±60 minutes) after each of 2 injections
    End point values
    Pharmacokinetic Analysis Set: rFVIIIFc 1000 IU Pharmacokinetic Analysis Set: rFVIIIFc 3000 IU
    Number of subjects analysed
    18
    18
    Units: IU/dL
        geometric mean (confidence interval 95%)
    122.2 (113.77 to 131.25)
    129.08 (114.62 to 145.37)
    No statistical analyses for this end point

    Secondary: Half-life (t½) as Measured by aPTT Clotting Assay

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    End point title
    Half-life (t½) as Measured by aPTT Clotting Assay
    End point description
    Time required for the concentration of the drug to reach half of its original value.
    End point type
    Secondary
    End point timeframe
    Up to 96 hours (±60 minutes) after each of 2 injections
    End point values
    Pharmacokinetic Analysis Set: rFVIIIFc 1000 IU Pharmacokinetic Analysis Set: rFVIIIFc 3000 IU
    Number of subjects analysed
    17 [4]
    18
    Units: hours
        geometric mean (confidence interval 95%)
    18.28 (16.1 to 20.75)
    17.49 (15.22 to 20.1)
    Notes
    [4] - subjects with sufficient PK data
    No statistical analyses for this end point

    Secondary: Clearance (CL) as Measured by the aPTT Clotting Assay

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    End point title
    Clearance (CL) as Measured by the aPTT Clotting Assay
    End point description
    The measure of the efficiency of the body to remove the drug and the unit is the volume of the plasma or blood cleared of drug per unit time.
    End point type
    Secondary
    End point timeframe
    Up to 96 hours (±60 minutes) after each of 2 injections
    End point values
    Pharmacokinetic Analysis Set: rFVIIIFc 1000 IU Pharmacokinetic Analysis Set: rFVIIIFc 3000 IU
    Number of subjects analysed
    17 [5]
    18
    Units: mL/h/kg
        geometric mean (confidence interval 95%)
    1.807 (1.534 to 2.128)
    2.016 (1.642 to 2.476)
    Notes
    [5] - subjects with sufficient PK data
    No statistical analyses for this end point

    Secondary: Volume of Distribution at Steady State (Vss) as Measured by the aPTT Clotting Assay

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    End point title
    Volume of Distribution at Steady State (Vss) as Measured by the aPTT Clotting Assay
    End point description
    The apparent volume of distribution at steady state. (Volume of distribution is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired blood concentration of a drug.)
    End point type
    Secondary
    End point timeframe
    Up to 96 hours (±60 minutes) after each of 2 injections
    End point values
    Pharmacokinetic Analysis Set: rFVIIIFc 1000 IU Pharmacokinetic Analysis Set: rFVIIIFc 3000 IU
    Number of subjects analysed
    17 [6]
    18
    Units: mL/kg
        geometric mean (confidence interval 95%)
    47 (43.87 to 50.35)
    48.65 (44.83 to 52.79)
    Notes
    [6] - subjects with sufficient PK data
    No statistical analyses for this end point

    Secondary: Mean Residence Time (MRT) as Measured by the aPTT Clotting Assay

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    End point title
    Mean Residence Time (MRT) as Measured by the aPTT Clotting Assay
    End point description
    The average time at which the number of absorbed molecules reside in the body, after single-dose administration.
    End point type
    Secondary
    End point timeframe
    Up to 96 hours (±60 minutes) after each of 2 injections
    End point values
    Pharmacokinetic Analysis Set: rFVIIIFc 1000 IU Pharmacokinetic Analysis Set: rFVIIIFc 3000 IU
    Number of subjects analysed
    17 [7]
    18
    Units: hours
        geometric mean (confidence interval 95%)
    26.01 (22.49 to 30.08)
    24.13 (20.46 to 28.46)
    Notes
    [7] - subjects with sufficient PK data
    No statistical analyses for this end point

    Secondary: Time of Cmax (Tmax) as Measured by aPTT Clotting Assay

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    End point title
    Time of Cmax (Tmax) as Measured by aPTT Clotting Assay
    End point description
    Time at which maximum activity (Cmax) is observed.
    End point type
    Secondary
    End point timeframe
    Up to 96 hours (±60 minutes) after each of 2 injections
    End point values
    Pharmacokinetic Analysis Set: rFVIIIFc 1000 IU Pharmacokinetic Analysis Set: rFVIIIFc 3000 IU
    Number of subjects analysed
    18
    18
    Units: hours
        geometric mean (confidence interval 95%)
    0.66 (0.55 to 0.79)
    0.58 (0.51 to 0.67)
    No statistical analyses for this end point

    Secondary: Area Under the Curve to the Last Measurable Time Point (AUClast) as Measured by aPTT Clotting Assay

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    End point title
    Area Under the Curve to the Last Measurable Time Point (AUClast) as Measured by aPTT Clotting Assay
    End point description
    Area under the plasma concentration time-curve from zero to the last measured concentration.
    End point type
    Secondary
    End point timeframe
    Up to 96 hours (±60 minutes) after each of 2 injections
    End point values
    Pharmacokinetic Analysis Set: rFVIIIFc 1000 IU Pharmacokinetic Analysis Set: rFVIIIFc 3000 IU
    Number of subjects analysed
    17 [8]
    18
    Units: IU*h/dL
        geometric mean (confidence interval 95%)
    2792.5 (2378.5 to 3278.6)
    2562.2 (2100.8 to 3125)
    Notes
    [8] - subjects with sufficient PK data
    No statistical analyses for this end point

    Secondary: Terminal Exponential Rate Constant (Lambda Z) as Measured by aPTT Clotting Assay

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    End point title
    Terminal Exponential Rate Constant (Lambda Z) as Measured by aPTT Clotting Assay
    End point description
    First order rate constant associated with the terminal portion of the curve (lambda z) .
    End point type
    Secondary
    End point timeframe
    Up to 96 hours (±60 minutes) after each of 2 injections
    End point values
    Pharmacokinetic Analysis Set: rFVIIIFc 1000 IU Pharmacokinetic Analysis Set: rFVIIIFc 3000 IU
    Number of subjects analysed
    17 [9]
    18
    Units: 1/h
        geometric mean (confidence interval 95%)
    0.03792 (0.0334 to 0.04304)
    0.03963 (0.03449 to 0.04554)
    Notes
    [9] - subjects with sufficient PK data
    No statistical analyses for this end point

    Secondary: Percentage of AUCinf From the Last Data Point to Infinity (AUCext) as Measured by aPTT Clotting Assay

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    End point title
    Percentage of AUCinf From the Last Data Point to Infinity (AUCext) as Measured by aPTT Clotting Assay
    End point description
    Percentage of AUCinf extrapolated from the last data point to infinity.
    End point type
    Secondary
    End point timeframe
    Up to 96 hours (±60 minutes) after each of 2 injections
    End point values
    Pharmacokinetic Analysis Set: rFVIIIFc 1000 IU Pharmacokinetic Analysis Set: rFVIIIFc 3000 IU
    Number of subjects analysed
    17 [10]
    18
    Units: percentage of AUCinf
        geometric mean (confidence interval 95%)
    2.561 (1.703 to 3.852)
    2.279 (1.505 to 3.45)
    Notes
    [10] - subjects with sufficient PK data
    No statistical analyses for this end point

    Secondary: Dose Normalized Area Under the Curve (DNAUC) as Measured by aPTT Clotting Assay

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    End point title
    Dose Normalized Area Under the Curve (DNAUC) as Measured by aPTT Clotting Assay
    End point description
    Dose normalized area under the FVIII activity-time curve.
    End point type
    Secondary
    End point timeframe
    Up to 96 hours (±60 minutes) after each of 2 injections
    End point values
    Pharmacokinetic Analysis Set: rFVIIIFc 1000 IU Pharmacokinetic Analysis Set: rFVIIIFc 3000 IU
    Number of subjects analysed
    17 [11]
    18
    Units: IU*h/dL per IU/kg
        geometric mean (confidence interval 95%)
    55.35 (47 to 65.18)
    49.6 (40.4 to 60.9)
    Notes
    [11] - subjects with sufficient PK data
    No statistical analyses for this end point

    Secondary: Terminal Exponential Volume of Distribution (Vz) as Measured by aPTT Clotting Assay

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    End point title
    Terminal Exponential Volume of Distribution (Vz) as Measured by aPTT Clotting Assay
    End point description
    The theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug.
    End point type
    Secondary
    End point timeframe
    Up to 96 hours (±60 minutes) after each of 2 injections
    End point values
    Pharmacokinetic Analysis Set: rFVIIIFc 1000 IU Pharmacokinetic Analysis Set: rFVIIIFc 3000 IU
    Number of subjects analysed
    17 [12]
    18
    Units: mL/kg
        geometric mean (confidence interval 95%)
    47.65 (43.73 to 51.93)
    50.87 (45.56 to 56.8)
    Notes
    [12] - subjects with sufficient PK data
    No statistical analyses for this end point

    Secondary: AUCinf as Estimated From the FVIII Activity Data as Measured by Two-Stage Chromogenic Clotting Assay

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    End point title
    AUCinf as Estimated From the FVIII Activity Data as Measured by Two-Stage Chromogenic Clotting Assay
    End point description
    Area under the plasma concentration versus time curve (AUC) from time zero (pre-dose) to extrapolated infinite time (0 - ∞).
    End point type
    Secondary
    End point timeframe
    Up to 96 hours (±60 minutes) after each of 2 injections
    End point values
    Pharmacokinetic Analysis Set: rFVIIIFc 1000 IU Pharmacokinetic Analysis Set: rFVIIIFc 3000 IU
    Number of subjects analysed
    15 [13]
    16 [14]
    Units: IU*h/dL
        geometric mean (confidence interval 95%)
    2649 (2230.2 to 3146.5)
    2628 (2206.2 to 3130.5)
    Notes
    [13] - subjects with sufficient PK data
    [14] - subjects with sufficient PK data
    No statistical analyses for this end point

    Secondary: IR, K Value as Measured by Two-Stage Chromogenic Clotting Assay

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    End point title
    IR, K Value as Measured by Two-Stage Chromogenic Clotting Assay
    End point description
    The rise in FVIII activity in IU/dL per unit dose administered in IU/kg (IR, K value), as estimated from the FVIII activity data.
    End point type
    Secondary
    End point timeframe
    Up to 96 hours (±60 minutes) after each of 2 injections
    End point values
    Pharmacokinetic Analysis Set: rFVIIIFc 1000 IU Pharmacokinetic Analysis Set: rFVIIIFc 3000 IU
    Number of subjects analysed
    17 [15]
    18
    Units: IU/dL per IU/kg
        geometric mean (confidence interval 95%)
    2.535 (2.245 to 2.862)
    2.287 (2.01 to 2.601)
    Notes
    [15] - subjects with sufficient PK data
    No statistical analyses for this end point

    Secondary: Cmax as Measured by Two-Stage Chromogenic Clotting Assay

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    End point title
    Cmax as Measured by Two-Stage Chromogenic Clotting Assay
    End point description
    Maximum measured concentration of rFVIIIFc.
    End point type
    Secondary
    End point timeframe
    Up to 96 hours (±60 minutes) after each of 2 injections
    End point values
    Pharmacokinetic Analysis Set: rFVIIIFc 1000 IU Pharmacokinetic Analysis Set: rFVIIIFc 3000 IU
    Number of subjects analysed
    17 [16]
    18
    Units: IU/dL
        geometric mean (confidence interval 95%)
    132.61 (116.85 to 150.5)
    122.29 (106.8 to 140.03)
    Notes
    [16] - subjects with sufficient PK data
    No statistical analyses for this end point

    Secondary: t½ as Measured by Two-Stage Chromogenic Clotting Assay

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    End point title
    t½ as Measured by Two-Stage Chromogenic Clotting Assay
    End point description
    Time required for the concentration of the drug to reach half of its original value.
    End point type
    Secondary
    End point timeframe
    Up to 96 hours (±60 minutes) after each of 2 injections
    End point values
    Pharmacokinetic Analysis Set: rFVIIIFc 1000 IU Pharmacokinetic Analysis Set: rFVIIIFc 3000 IU
    Number of subjects analysed
    15 [17]
    16 [18]
    Units: hours
        geometric mean (confidence interval 95%)
    18.58 (16.35 to 21.12)
    19.1 (16.44 to 22.19)
    Notes
    [17] - subjects with sufficient PK data
    [18] - subjects with sufficient PK data
    No statistical analyses for this end point

    Secondary: CL as Measured by Two-Stage Chromogenic Clotting Assay

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    End point title
    CL as Measured by Two-Stage Chromogenic Clotting Assay
    End point description
    The measure of the efficiency of the body to remove the drug and the unit is the volume of the plasma or blood cleared of drug per unit time.
    End point type
    Secondary
    End point timeframe
    Up to 96 hours (±60 minutes) after each of 2 injections
    End point values
    Pharmacokinetic Analysis Set: rFVIIIFc 1000 IU Pharmacokinetic Analysis Set: rFVIIIFc 3000 IU
    Number of subjects analysed
    15 [19]
    16 [20]
    Units: mL/h/kg
        geometric mean (confidence interval 95%)
    1.962 (1.665 to 2.311)
    2.006 (1.72 to 2.339)
    Notes
    [19] - subjects with sufficient PK data
    [20] - subjects with sufficient PK data
    No statistical analyses for this end point

    Secondary: Vss as Measured by Two-Stage Chromogenic Clotting Assay

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    End point title
    Vss as Measured by Two-Stage Chromogenic Clotting Assay
    End point description
    The apparent volume of distribution at steady state. (Volume of distribution is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired blood concentration of a drug.)
    End point type
    Secondary
    End point timeframe
    Up to 96 hours (±60 minutes) after each of 2 injections
    End point values
    Pharmacokinetic Analysis Set: rFVIIIFc 1000 IU Pharmacokinetic Analysis Set: rFVIIIFc 3000 IU
    Number of subjects analysed
    15 [21]
    16 [22]
    Units: mL/kg
        geometric mean (confidence interval 95%)
    47.41 (43.01 to 52.26)
    51.27 (44.65 to 58.88)
    Notes
    [21] - subjects with sufficient PK data
    [22] - subjects with sufficient PK data
    No statistical analyses for this end point

    Secondary: MRT as Measured by Two-Stage Chromogenic Clotting Assay

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    End point title
    MRT as Measured by Two-Stage Chromogenic Clotting Assay
    End point description
    The average time at which the number of absorbed molecules reside in the body, after single-dose administration.
    End point type
    Secondary
    End point timeframe
    Up to 96 hours (±60 minutes) after each of 2 injections
    End point values
    Pharmacokinetic Analysis Set: rFVIIIFc 1000 IU Pharmacokinetic Analysis Set: rFVIIIFc 3000 IU
    Number of subjects analysed
    15 [23]
    16 [24]
    Units: hours
        geometric mean (confidence interval 95%)
    24.17 (21.16 to 27.6)
    25.56 (22.15 to 29.5)
    Notes
    [23] - subjects with sufficient PK data
    [24] - subjects with sufficient PK data
    No statistical analyses for this end point

    Secondary: Tmax as Measured by Two-Stage Chromogenic Clotting Assay

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    End point title
    Tmax as Measured by Two-Stage Chromogenic Clotting Assay
    End point description
    Time at which maximum activity (Cmax) is observed.
    End point type
    Secondary
    End point timeframe
    Up to 96 hours (±60 minutes) after each of 2 injections
    End point values
    Pharmacokinetic Analysis Set: rFVIIIFc 1000 IU Pharmacokinetic Analysis Set: rFVIIIFc 3000 IU
    Number of subjects analysed
    17 [25]
    18
    Units: hours
        geometric mean (confidence interval 95%)
    0.61 (0.51 to 0.71)
    0.61 (0.52 to 0.72)
    Notes
    [25] - subjects with sufficient PK data
    No statistical analyses for this end point

    Secondary: AUClast as Measured by Two-Stage Chromogenic Clotting Assay

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    End point title
    AUClast as Measured by Two-Stage Chromogenic Clotting Assay
    End point description
    Area under the plasma concentration time-curve from zero to the last measured concentration.
    End point type
    Secondary
    End point timeframe
    Up to 96 hours (±60 minutes) after each of 2 injections
    End point values
    Pharmacokinetic Analysis Set: rFVIIIFc 1000 IU Pharmacokinetic Analysis Set: rFVIIIFc 3000 IU
    Number of subjects analysed
    15 [26]
    16 [27]
    Units: IU*h/dL
        geometric mean (confidence interval 95%)
    2555.4 (2166.7 to 3013.9)
    2520.5 (2124.4 to 2990.5)
    Notes
    [26] - subjects with sufficient PK data
    [27] - subjects with sufficient PK data
    No statistical analyses for this end point

    Secondary: Lambda Z as Measured by Two-Stage Chromogenic Clotting Assay

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    End point title
    Lambda Z as Measured by Two-Stage Chromogenic Clotting Assay
    End point description
    First order rate constant associated with the terminal portion of the curve (lambda z).
    End point type
    Secondary
    End point timeframe
    Up to 96 hours (±60 minutes) after each of 2 injections
    End point values
    Pharmacokinetic Analysis Set: rFVIIIFc 1000 IU Pharmacokinetic Analysis Set: rFVIIIFc 3000 IU
    Number of subjects analysed
    15 [28]
    16 [29]
    Units: 1/h
        geometric mean (confidence interval 95%)
    0.0373 (0.03282 to 0.04239)
    0.03629 (0.03124 to 0.04216)
    Notes
    [28] - subjects with sufficient PK data
    [29] - subjects with sufficient PK data
    No statistical analyses for this end point

    Secondary: AUCext as Measured by Two-Stage Chromogenic Clotting Assay

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    End point title
    AUCext as Measured by Two-Stage Chromogenic Clotting Assay
    End point description
    Percentage of AUCinf extrapolated from the last data point to infinity.
    End point type
    Secondary
    End point timeframe
    Up to 96 hours (±60 minutes) after each of 2 injections
    End point values
    Pharmacokinetic Analysis Set: rFVIIIFc 1000 IU Pharmacokinetic Analysis Set: rFVIIIFc 3000 IU
    Number of subjects analysed
    15 [30]
    16 [31]
    Units: percentage of AUCinf
        geometric mean (confidence interval 95%)
    2.923 (2.106 to 4.057)
    2.965 (1.89 to 4.65)
    Notes
    [30] - subjects with sufficient PK data
    [31] - subjects with sufficient PK data
    No statistical analyses for this end point

    Secondary: DNAUC as Measured by Two-Stage Chromogenic Clotting Assay

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    End point title
    DNAUC as Measured by Two-Stage Chromogenic Clotting Assay
    End point description
    Dose normalized area under the FVIII activity-time curve.
    End point type
    Secondary
    End point timeframe
    Up to 96 hours (±60 minutes) after each of 2 injections
    End point values
    Pharmacokinetic Analysis Set: rFVIIIFc 1000 IU Pharmacokinetic Analysis Set: rFVIIIFc 3000 IU
    Number of subjects analysed
    15 [32]
    16 [33]
    Units: IU*h/dL per IU/kg
        geometric mean (confidence interval 95%)
    50.97 (43.27 to 60.05)
    49.85 (42.75 to 58.13)
    Notes
    [32] - subjects with sufficient PK data
    [33] - subjects with sufficient PK data
    No statistical analyses for this end point

    Secondary: Vz as Measured by Two-Stage Chromogenic Clotting Assay

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    End point title
    Vz as Measured by Two-Stage Chromogenic Clotting Assay
    End point description
    The theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug.
    End point type
    Secondary
    End point timeframe
    Up to 96 hours (±60 minutes) after each of 2 injections
    End point values
    Pharmacokinetic Analysis Set: rFVIIIFc 1000 IU Pharmacokinetic Analysis Set: rFVIIIFc 3000 IU
    Number of subjects analysed
    15 [34]
    16 [35]
    Units: mL/kg
        geometric mean (confidence interval 95%)
    52.59 (47.31 to 58.47)
    55.28 (47.12 to 64.84)
    Notes
    [34] - subjects with sufficient PK data
    [35] - subjects with sufficient PK data
    No statistical analyses for this end point

    Secondary: Percentage of Subjects Developing Confirmed Inhibitors as Measured by the Nijmegen-modified Bethesda Assay

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    End point title
    Percentage of Subjects Developing Confirmed Inhibitors as Measured by the Nijmegen-modified Bethesda Assay
    End point description
    An inhibitor test result ≥0.6 Bethesda units (BU)/mL, confirmed on 2 separate samples drawn 2 to 4 weeks apart, was considered positive. Both tests were to be performed by the central laboratory using the Nijmegen-modified Bethesda Assay. An exact 95% CI for the percentage of subjects with a confirmed inhibitor was calculated using the Clopper-Pearson exact method.
    End point type
    Secondary
    End point timeframe
    up to Month 6 (26 ± 2 weeks) or Early Withdrawal
    End point values
    Safety Analysis Set
    Number of subjects analysed
    19
    Units: percentage of subjects
        number (confidence interval 95%)
    0 (0 to 17.65)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From screening (for serious adverse events) or first dose of study drug (for adverse events) until end of study (up to approximately 6 months).
    Adverse event reporting additional description
    Adverse events presented are treatment-emergent (ie, those that occurred or worsened following the first injection of rFVIIIFc).
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    15.0
    Reporting groups
    Reporting group title
    Total active
    Reporting group description
    Following the minimum 4-day washout, subjects received their first injection of rFVIIIFc (on Injection 1 Day 1) rFVIIIFc 50 IU/kg at a strength of either 1000 IU/vial or 3000 IU/vial. The second injection of rFVIIIFc 50 IU/kg at a strength of either 1000 IU/vial or 3000 IU/vial was administered, in a crossover fashion, after a minimum of a 5-day washout (on Injection 2 Day 1). After completing the PK assessment, all subjects began 1 of 3 continued treatment regimens for up to 6 months: 1. A prophylaxis regimen at a starting dose of 50 IU/kg of rFVIIIFc given every 3 to 5 days; further dose and interval adjustments were based on the Investigator’s discretion as needed to prevent or treat bleeding 2. A prophylaxis regimen of 65 IU/kg administered every 7 days was considered for appropriate subjects who were selected based on the opinion of the Investigator 3. An episodic (on-demand) treatment with rFVIIIFc at 20 to 50 IU/kg, depending on the severity of the bleeding episode

    Serious adverse events
    Total active
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 19 (10.53%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    Congenital, familial and genetic disorders
    Hydrocele
         subjects affected / exposed
    1 / 19 (5.26%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthropathy
         subjects affected / exposed
    1 / 19 (5.26%)
         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
    Total active
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    12 / 19 (63.16%)
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    1 / 19 (5.26%)
         occurrences all number
    1
    Joint injury
         subjects affected / exposed
    1 / 19 (5.26%)
         occurrences all number
    1
    Fall
         subjects affected / exposed
    1 / 19 (5.26%)
         occurrences all number
    1
    Limb injury
         subjects affected / exposed
    2 / 19 (10.53%)
         occurrences all number
    2
    Nervous system disorders
    Headache
         subjects affected / exposed
    1 / 19 (5.26%)
         occurrences all number
    1
    Ear and labyrinth disorders
    Tympanic membrane perforation
         subjects affected / exposed
    1 / 19 (5.26%)
         occurrences all number
    1
    Gastrointestinal disorders
    Abdominal discomfort
         subjects affected / exposed
    1 / 19 (5.26%)
         occurrences all number
    1
    Skin and subcutaneous tissue disorders
    Acne
         subjects affected / exposed
    2 / 19 (10.53%)
         occurrences all number
    2
    Musculoskeletal and connective tissue disorders
    Musculoskeletal chest pain
         subjects affected / exposed
    1 / 19 (5.26%)
         occurrences all number
    1
    Metabolism and nutrition disorders
    Vitamin d deficiency
         subjects affected / exposed
    1 / 19 (5.26%)
         occurrences all number
    1
    Infections and infestations
    Influenza
         subjects affected / exposed
    1 / 19 (5.26%)
         occurrences all number
    1
    Nasopharyngitis
         subjects affected / exposed
    2 / 19 (10.53%)
         occurrences all number
    2
    Oral herpes
         subjects affected / exposed
    1 / 19 (5.26%)
         occurrences all number
    1
    Post procedural cellulitis
         subjects affected / exposed
    1 / 19 (5.26%)
         occurrences all number
    1
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 19 (5.26%)
         occurrences all number
    1

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? No

    Interruptions (globally)

    Were there any global interruptions to the trial? No

    Limitations and caveats

    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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