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    Clinical Trial Results:
    A-LONG: An Open-label, Multicenter Evaluation of the Safety, Pharmacokinetics, and Efficacy of Recombinant Factor VIII Fc Fusion Protein (rFVIIIFc) in the Prevention and Treatment of Bleeding in Previously Treated Subjects With Severe Hemophilia A

    Summary
    EudraCT number
    2010-020558-33
    Trial protocol
    SE   GB   FR   DE   BE   ES   AT   IT   PT  
    Global end of trial date
    06 Aug 2012

    Results information
    Results version number
    v1(current)
    This version publication date
    04 Feb 2016
    First version publication date
    20 Jun 2015
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    997HA301
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01181128
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Biogen
    Sponsor organisation address
    225 Binney Street , Cambridge, United States, 02142
    Public contact
    Biogen Study Medical Director, Biogen , Clinicaltrials@biogen.com
    Scientific contact
    Biogen Study Medical Director, Biogen , Clinicaltrials@biogen.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    EMEA-001114-PIP01-10
    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
    06 Aug 2012
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    06 Aug 2012
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objectives of this study are: to evaluate the safety and tolerability of rFVIIIFc administered as a prophylaxis (Arm 1), weekly (Arm 2), on-demand (Arm 3), and surgical treatment regimen; to evaluate the efficacy of the rFVIIIFc tailored prophylaxis regimen (Arm 1); to evaluate the efficacy of rFVIIIFc administered as an on-demand (Arm 3) and surgical treatment regimen. The secondary objectives of this study are: to characterize the pharmacokinetic (PK) profile of rFVIIIFc and compare the PK of rFVIIIFc with the currently marketed product, Advate®; to characterize the range of dose and schedules required to adequately prevent bleeding in a prophylaxis regimen, maintain hemostasis in a surgical setting, or to treat bleeding episodes in an on-demand, weekly treatment, or prophylaxis setting.
    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 form and were allowed to ask, and have answered, questions concerning all portions of the conduct of the study. Through the informed consent process each participant 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
    29 Nov 2010
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Australia: 8
    Country: Number of subjects enrolled
    Brazil: 3
    Country: Number of subjects enrolled
    Canada: 2
    Country: Number of subjects enrolled
    Hong Kong: 4
    Country: Number of subjects enrolled
    India: 15
    Country: Number of subjects enrolled
    Israel: 4
    Country: Number of subjects enrolled
    Japan: 14
    Country: Number of subjects enrolled
    New Zealand: 3
    Country: Number of subjects enrolled
    South Africa: 17
    Country: Number of subjects enrolled
    Switzerland: 1
    Country: Number of subjects enrolled
    United States: 54
    Country: Number of subjects enrolled
    Spain: 2
    Country: Number of subjects enrolled
    Sweden: 1
    Country: Number of subjects enrolled
    United Kingdom: 20
    Country: Number of subjects enrolled
    Austria: 5
    Country: Number of subjects enrolled
    Belgium: 1
    Country: Number of subjects enrolled
    France: 2
    Country: Number of subjects enrolled
    Germany: 4
    Country: Number of subjects enrolled
    Italy: 5
    Worldwide total number of subjects
    165
    EEA total number of subjects
    40
    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)
    13
    Adults (18-64 years)
    151
    From 65 to 84 years
    1
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    -

    Pre-assignment
    Screening details
    The screening period to determine subject eligibility was to last for up to 8 weeks and included at least a 96-hour washout from Factor VIII (FVIII) prior to initial study dosing. A 72-hour washout was allowed for adolescent subjects (i.e., 12 to 17 years old).

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Arm 1: Individualized (Tailored) Prophylaxis
    Arm description
    On rFVIIIFc Day 0, all subjects underwent PK analysis with 50 IU/kg rFVIIIFc to estimate their PK parameters and guide the appropriate dose or interval of dosing. A subset of subjects (Sequential PK subgroup) also had PK analyses performed with a single dose of 50 IU/kg Advate (Advate Day 0) within 8 weeks prior to rFVIIIFc Day 0. A >= 96 hour washout was performed before the PK dose of Advate or rFVIIIFc was administered. Repeat PK profiling with a single dose of 50 IU/kg rFVIIIFc was conducted at Week 14 or after 12 to 24 weeks of prophylaxis with rFVIIIFc. After PK assessments, all subjects started twice weekly treatment with 25 IU/kg of rFVIIIFc via intravenous (IV) injection on Day 1 and 50 IU/kg on Day 4, followed by individualized dose and interval modification within the range of 25 to 65 IU/kg every 3 to 5 days, as determined by rFVIIIFc PK analysis, to maintain a trough level of 1% to 3% (or higher, as clinically indicated) FVIII activity.
    Arm type
    Experimental

    Investigational medicinal product name
    recombinant Factor VIII Fc
    Investigational medicinal product code
    rFVIIIFc
    Other name
    BIIB031, ELOCTATE, rFVIIIFc, antihemophilic factor (recombinant) Fc fusion protein, recombinant coagulation factor VIII Fc fusion protein, efmoroctocog alfa
    Pharmaceutical forms
    Powder and solvent for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Study site staff members were instructed to refer to the Directions for Handling and Administration located in the Investigator Site File and/or the Pharmacy Manual for specific instructions on the handling, preparation, administration, and disposal of the study treatment.

    Investigational medicinal product name
    Advate®
    Investigational medicinal product code
    Other name
    octocog alfa, Antihemophilic Factor [Recombinant] Plasma/Albumin Free Method
    Pharmaceutical forms
    Powder and solvent for solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Study site staff members were instructed to refer to the Directions for Handling and Administration located in the Investigator Site File and/or the Pharmacy Manual for specific instructions on the handling, preparation, administration, and disposal of the study treatment.

    Arm title
    Arm 2: Weekly Prophylaxis
    Arm description
    65 IU/kg of rFVIIIFc via IV injection every 7 days
    Arm type
    Experimental

    Investigational medicinal product name
    recombinant Factor VIII Fc
    Investigational medicinal product code
    rFVIIIFc
    Other name
    BIIB031, ELOCTATE, rFVIIIFc, antihemophilic factor (recombinant) Fc fusion protein, recombinant coagulation factor VIII Fc fusion protein, efmoroctocog alfa
    Pharmaceutical forms
    Powder and solvent for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Study site staff members were instructed to refer to the Directions for Handling and Administration located in the Investigator Site File and/or the Pharmacy Manual for specific instructions on the handling, preparation, administration, and disposal of the study treatment.

    Arm title
    Arm 3: Episodic (On-Demand) Dosing
    Arm description
    10 to 50 IU/kg rFVIIIFc via IV injection, as required to treat a bleeding episode
    Arm type
    Experimental

    Investigational medicinal product name
    recombinant Factor VIII Fc
    Investigational medicinal product code
    rFVIIIFc
    Other name
    BIIB031, ELOCTATE, rFVIIIFc, antihemophilic factor (recombinant) Fc fusion protein, recombinant coagulation factor VIII Fc fusion protein, efmoroctocog alfa
    Pharmaceutical forms
    Powder and solvent for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Study site staff members were instructed to refer to the Directions for Handling and Administration located in the Investigator Site File and/or the Pharmacy Manual for specific instructions on the handling, preparation, administration, and disposal of the study treatment.

    Number of subjects in period 1
    Arm 1: Individualized (Tailored) Prophylaxis Arm 2: Weekly Prophylaxis Arm 3: Episodic (On-Demand) Dosing
    Started
    118
    24
    23
    Pharmacokinetic (PK) Subgroup
    30 [1]
    0 [2]
    0 [3]
    Perioperative Management Subgroup
    8 [4]
    1 [5]
    0 [6]
    Completed
    112
    19
    22
    Not completed
    6
    5
    1
         Physician decision
    2
    -
    -
         Not specified
    1
    1
    1
         Adverse event, serious fatal
    1
    -
    -
         Adverse event, non-fatal
    -
    2
    -
         Consent withdrawn by subject
    2
    2
    -
    Notes
    [1] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: Milestones are provided to account for PK Subgroup and Perioperative Management Subgroup populations.
    [2] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: Milestones are provided to account for PK Subgroup and Perioperative Management Subgroup populations.
    [3] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: Milestones are provided to account for PK Subgroup and Perioperative Management Subgroup populations.
    [4] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: Milestones are provided to account for PK Subgroup and Perioperative Management Subgroup populations.
    [5] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: Milestones are provided to account for PK Subgroup and Perioperative Management Subgroup populations.
    [6] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: Milestones are provided to account for PK Subgroup and Perioperative Management Subgroup populations.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Arm 1: Individualized (Tailored) Prophylaxis
    Reporting group description
    On rFVIIIFc Day 0, all subjects underwent PK analysis with 50 IU/kg rFVIIIFc to estimate their PK parameters and guide the appropriate dose or interval of dosing. A subset of subjects (Sequential PK subgroup) also had PK analyses performed with a single dose of 50 IU/kg Advate (Advate Day 0) within 8 weeks prior to rFVIIIFc Day 0. A >= 96 hour washout was performed before the PK dose of Advate or rFVIIIFc was administered. Repeat PK profiling with a single dose of 50 IU/kg rFVIIIFc was conducted at Week 14 or after 12 to 24 weeks of prophylaxis with rFVIIIFc. After PK assessments, all subjects started twice weekly treatment with 25 IU/kg of rFVIIIFc via intravenous (IV) injection on Day 1 and 50 IU/kg on Day 4, followed by individualized dose and interval modification within the range of 25 to 65 IU/kg every 3 to 5 days, as determined by rFVIIIFc PK analysis, to maintain a trough level of 1% to 3% (or higher, as clinically indicated) FVIII activity.

    Reporting group title
    Arm 2: Weekly Prophylaxis
    Reporting group description
    65 IU/kg of rFVIIIFc via IV injection every 7 days

    Reporting group title
    Arm 3: Episodic (On-Demand) Dosing
    Reporting group description
    10 to 50 IU/kg rFVIIIFc via IV injection, as required to treat a bleeding episode

    Reporting group values
    Arm 1: Individualized (Tailored) Prophylaxis Arm 2: Weekly Prophylaxis Arm 3: Episodic (On-Demand) Dosing Total
    Number of subjects
    118 24 23 165
    Age categorical
    Units: Subjects
        Adolescents (12-17 years)
    11 0 2 13
        Adults (18-64 years)
    106 24 21 151
        From 65-84 years
    1 0 0 1
    Age continuous
    Units: years
        median (full range (min-max))
    29 (12 to 65) 31.5 (18 to 59) 34 (13 to 62) -
    Gender categorical
    Units: Subjects
        Female
    0 0 0 0
        Male
    118 24 23 165

    End points

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    End points reporting groups
    Reporting group title
    Arm 1: Individualized (Tailored) Prophylaxis
    Reporting group description
    On rFVIIIFc Day 0, all subjects underwent PK analysis with 50 IU/kg rFVIIIFc to estimate their PK parameters and guide the appropriate dose or interval of dosing. A subset of subjects (Sequential PK subgroup) also had PK analyses performed with a single dose of 50 IU/kg Advate (Advate Day 0) within 8 weeks prior to rFVIIIFc Day 0. A >= 96 hour washout was performed before the PK dose of Advate or rFVIIIFc was administered. Repeat PK profiling with a single dose of 50 IU/kg rFVIIIFc was conducted at Week 14 or after 12 to 24 weeks of prophylaxis with rFVIIIFc. After PK assessments, all subjects started twice weekly treatment with 25 IU/kg of rFVIIIFc via intravenous (IV) injection on Day 1 and 50 IU/kg on Day 4, followed by individualized dose and interval modification within the range of 25 to 65 IU/kg every 3 to 5 days, as determined by rFVIIIFc PK analysis, to maintain a trough level of 1% to 3% (or higher, as clinically indicated) FVIII activity.

    Reporting group title
    Arm 2: Weekly Prophylaxis
    Reporting group description
    65 IU/kg of rFVIIIFc via IV injection every 7 days

    Reporting group title
    Arm 3: Episodic (On-Demand) Dosing
    Reporting group description
    10 to 50 IU/kg rFVIIIFc via IV injection, as required to treat a bleeding episode

    Subject analysis set title
    Arm 1: Individualized (Tailored) Prophylaxis, Advate
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    Subjects in the Individualized (Tailored) Prophylaxis arm who received at least 1 dose of Advate.

    Subject analysis set title
    Arm 1: Individualized (Tailored) Prophylaxis, rFVIIIFc Only
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    Subjects in the Individualized (Tailored) Prophylaxis arm who received at least 1 dose of rFVIIIFc.

    Subject analysis set title
    Any Arm: Perioperative Management (Surgery) Subgroup
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Subjects from any arm who underwent major surgery. The surgical period and dosing were dependent on the type of surgery the subject underwent.

    Subject analysis set title
    Arm 1: Individualized Prophylaxis: Sequential PK Subgroup
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    On rFVIIIFc Day 0, all subjects underwent pharmacokinetic (PK) analysis with 50 IU/kg rFVIIIFc to estimate their PK parameters and guide the appropriate dose or interval of dosing. A subset of subjects (Sequential PK subgroup) also had PK analyses performed with a single dose of 50 IU/kg Advate (Advate Day 0) within 8 weeks prior to rFVIIIFc Day 0. A >= 96 hour washout was performed before the PK dose of Advate or rFVIIIFc was administered. Repeat PK profiling with a single dose of 50 IU/kg rFVIIIFc was conducted at Week 14 or after 12 to 24 weeks of prophylaxis with rFVIIIFc. Analysis set includes subjects who had evaluable one- or two-stagePK profiles for both Advate and baseline rFVIIIFc.

    Subject analysis set title
    Arm 1: Individualized Prophylaxis, Prestudy Prophylaxis
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    On rFVIIIFc Day 0, all subjects underwent pharmacokinetic (PK) analysis with 50 IU/kg rFVIIIFc to estimate their PK parameters and guide the appropriate dose or interval of dosing. A subset of subjects (Sequential PK subgroup) also had PK analyses performed with a single dose of 50 IU/kg Advate (Advate Day 0) within 8 weeks prior to rFVIIIFc Day 0. A >= 96 hour washout was performed before the PK dose of Advate or rFVIIIFc was administered. Repeat PK profiling with a single dose of 50 IU/kg rFVIIIFc was conducted at Week 14 or after 12 to 24 weeks of prophylaxis with rFVIIIFc. After PK assessments, all subjects started twice weekly treatment with 25 IU/kg of rFVIIIFc via intravenous (IV) injection on Day 1 and 50 IU/kg on Day 4, followed by individualized dose and interval modification within the range of 25 to 65 IU/kg every 3 to 5 days, as determined by rFVIIIFc PK analysis, to maintain a trough level of 1% to 3% (or higher, as clinically indicated) FVIII activity.

    Subject analysis set title
    Arm 1: Individualized Prophylaxis, Prestudy On-demand
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    On rFVIIIFc Day 0, all subjects underwent pharmacokinetic (PK) analysis with 50 IU/kg rFVIIIFc to estimate their PK parameters and guide the appropriate dose or interval of dosing. A subset of subjects (Sequential PK subgroup) also had PK analyses performed with a single dose of 50 IU/kg Advate (Advate Day 0) within 8 weeks prior to rFVIIIFc Day 0. A >= 96 hour washout was performed before the PK dose of Advate or rFVIIIFc was administered. Repeat PK profiling with a single dose of 50 IU/kg rFVIIIFc was conducted at Week 14 or after 12 to 24 weeks of prophylaxis with rFVIIIFc. After PK assessments, all subjects started twice weekly treatment with 25 IU/kg of rFVIIIFc via intravenous (IV) injection on Day 1 and 50 IU/kg on Day 4, followed by individualized dose and interval modification within the range of 25 to 65 IU/kg every 3 to 5 days, as determined by rFVIIIFc PK analysis, to maintain a trough level of 1% to 3% (or higher, as clinically indicated) FVIII activity.

    Subject analysis set title
    All Arms: Total
    Subject analysis set type
    Full analysis
    Subject analysis set description
    All subjects from the Individualized (Tailored) Prophylaxis, Weekly Prophylaxis, and Episodic (On-Demand) Dosing arms.

    Primary: Incidence Rate of FVIII Inhibitor Development

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    End point title
    Incidence Rate of FVIII Inhibitor Development [1]
    End point description
    An inhibitor test result ≥0.6 Bethesda units (BU)/mL, identified and confirmed by re-testing of a second sample obtained within 2 to 4 weeks, was considered positive. Both tests were to be performed using the Nijmegen-modified Bethesda Assay by the central laboratory. The incidence rates along with the 95% confidence interval (CI) were summarized for all titers for subjects with 50 or more exposure days (EDs) to rFVIIIFc and a valid inhibitor test after the 50th exposure. In addition, the incidence rates for all subjects regardless of their EDs to rFVIIIFc were also summarized. The 95% CI was calculated using Clopper-Pearson exact method. Safety Analysis Set: subjects who received at least 1 dose of Advate or at least 1 dose of rFVIIIFc.
    End point type
    Primary
    End point timeframe
    up to 52 weeks ± 2 weeks
    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: Per protocol, descriptive statistics were collected for this endpoint.
    End point values
    Arm 1: Individualized (Tailored) Prophylaxis Arm 2: Weekly Prophylaxis Arm 3: Episodic (On-Demand) Dosing All Arms: Total
    Number of subjects analysed
    118 [2]
    24 [3]
    23 [4]
    165 [5]
    Units: percentage of subjects
    number (confidence interval 95%)
        Subjects with>=50 EDs; n=107, 1, 2, 110
    0 (0 to 3.4)
    0 (0 to 97.5)
    0 (0 to 84.2)
    0 (0 to 3.3)
        All subjects; n=117, 24, 23, 164
    0 (0 to 3.1)
    0 (0 to 14.2)
    0 (0 to 14.8)
    0 (0 to 2.2)
    Notes
    [2] - Safety Analysis Set; n=subjects with given number of exposure days and a valid inhibitor test.
    [3] - Safety Analysis Set; n=subjects with given number of exposure days and a valid inhibitor test.
    [4] - Safety Analysis Set; n=subjects with given number of exposure days and a valid inhibitor test.
    [5] - Safety Analysis Set; n=subjects with given number of exposure days and a valid inhibitor test.
    No statistical analyses for this end point

    Primary: Number of Subjects With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs)

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    End point title
    Number of Subjects With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs) [6] [7]
    End point description
    AE=any untoward medical occurrence that did not necessarily have a causal relationship with treatment. TEAE=AE present prior to receiving the first injection of Advate or rFVIIIFc that subsequently worsened in severity or not present prior to receiving the first injection but subsequently appeared before the last visit on study. Serious AE (SAE)=AE resulting in death, immediate risk of death, inpatient hospitalization or prolongation of existing hospitalization, persistent or significant disability/incapacity, or a congenital anomaly/birth defect, or any other medically important event. For Arm 1, AEs emergent between the first on-study Advate dose and 1st rFVIIIFc dose are reported as treatment-emergent to Advate (first column); AEs emergent after the first rFVIIIFc injection are reported as treatment-emergent to rFVIIIFc (2nd column). Safety Analysis Set: subjects who received at least 1 dose of Advate or at least 1 dose of rFVIIIFc.
    End point type
    Primary
    End point timeframe
    up to 52 weeks + 30 days ± 1 week
    Notes
    [6] - 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: Per protocol, descriptive statistics were collected for this endpoint.
    [7] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: For Arm 1, AEs emergent between the first on-study Advate dose and the first rFVIIIFc dose are reported as treatment-emergent to Advate; AEs emergent after the first rFVIIIFc injection are reported as treatment-emergent to rFVIIIFc (2 separate columns).
    End point values
    Arm 2: Weekly Prophylaxis Arm 3: Episodic (On-Demand) Dosing Arm 1: Individualized (Tailored) Prophylaxis, Advate Arm 1: Individualized (Tailored) Prophylaxis, rFVIIIFc Only Any Arm: Perioperative Management (Surgery) Subgroup
    Number of subjects analysed
    24
    23
    30
    117
    9
    Units: subjects
        >=1 TEAE
    18
    10
    3
    80
    4
        >=1 Related TEAE
    3
    2
    0
    5
    0
        >=1 TESAE
    2
    0
    0
    10
    2
        >=1 Related TESAE
    0
    0
    0
    0
    0
    No statistical analyses for this end point

    Primary: Number of Subjects With Potentially Clinically Significant Abnormal Laboratory Values From Baseline

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    End point title
    Number of Subjects With Potentially Clinically Significant Abnormal Laboratory Values From Baseline [8]
    End point description
    Clinical laboratory evaluations included hematology and blood chemistry. Table does not include laboratory tests evaluated during the surgical/rehabilitation period. ULN=upper limit of normal. Safety Analysis Set: subjects who received at least 1 dose of Advate or at least 1 dose of rFVIIIFc.
    End point type
    Primary
    End point timeframe
    up to 52 weeks ± 2 weeks
    Notes
    [8] - 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: Per protocol, descriptive statistics were collected for this endpoint.
    End point values
    Arm 1: Individualized (Tailored) Prophylaxis Arm 2: Weekly Prophylaxis Arm 3: Episodic (On-Demand) Dosing
    Number of subjects analysed
    118 [9]
    24 [10]
    23 [11]
    Units: subjects
        Leukocytes <3.0*10^9/L; n=117, 24, 23
    2
    0
    2
        Leukocytes >=16*10^9/L; n=117, 24, 23
    1
    0
    0
        Lymphocytes <0.8*10^9/L; n=104, 22, 21
    3
    1
    1
        Lymphocytes >12*10^9/L; n=104, 22, 21
    0
    0
    0
        Neutrophils <1.5*10^9/L; n=104, 22, 21
    4
    0
    1
        Neutrophils >13.5*10^9/L; n=104, 22, 21
    1
    0
    0
        Monocytes >2.5*10^9/L; n=104, 22, 21
    0
    0
    0
        Eosinophils >1.6*10^9/L; n=104, 22, 21
    0
    0
    0
        Basophils >1.6*10^9/L; n=104, 22, 21
    0
    0
    0
        Erythrocytes <=3.5*10^12/L; n=117, 24, 23
    1
    0
    0
        Erythrocytes >=6.4*10^12/L; n=117, 24, 23
    1
    0
    1
        Hemoglobin <=115 g/L; n=117, 24, 23
    3
    0
    1
        Hemoglobin >=190 g/L; n=117, 24, 23
    0
    0
    0
        Hematocrit <=37%; n=117, 24, 23
    5
    2
    1
        Hematocrit >=60%; n=117, 24, 23
    0
    0
    0
        Platelets <=75*10^9/L; n=117, 24, 23
    0
    0
    0
        Platelets >=700*10^9/L; n=117, 24, 23
    0
    0
    0
        Alanine Aminotransferase >=3*ULN; n=117, 24, 23
    4
    0
    0
        Aspartate Aminotransferase >=3*ULN; n=117, 24, 23
    4
    1
    0
        Alkaline Phosphatase >=3*ULN; n=117, 24, 23
    0
    0
    0
        Total Bilirubin >=34.2 μmol/L; n=117, 24, 23
    3
    0
    2
        Blood Urea Nitrogen >=10.7 mmol/L; n=117, 24, 23
    1
    1
    0
        Creatinine >=176.8 μmol/L; n=117, 24, 23
    0
    0
    0
        Sodium <=126 mmol/L; n=117, 24, 23
    0
    0
    0
        Sodium >=156 mmol/L; n=117, 24, 23
    1
    0
    0
        Potassium <=3 mmol/L; n=117, 24, 23
    0
    0
    0
        Potassium >=6 mmol/L; n=117, 24, 23
    0
    0
    0
        Chloride <=90 mmol/L; n=117, 24, 23
    1
    0
    0
        Chloride >=118 mmol/L; n=117, 24, 23
    0
    0
    0
        Phosphate <=0.55 mmol/L n=117, 24, 23
    1
    0
    0
        Phosphate >=1.71 mmol/L; n=117, 24, 23
    0
    0
    0
        Glucose <=2.22 mmol/L; n=117, 24, 23
    0
    0
    0
        Glucose >=9.71 mmol/L; n=117, 24, 23
    2
    1
    0
        Total Protein <=45 g/L; n=117, 24, 23
    0
    0
    0
        Total Protein >=100 g/L; n=117, 24, 23
    0
    0
    0
    Notes
    [9] - n=the number of subjects with at least one postbaseline value.
    [10] - n=the number of subjects with at least one postbaseline value.
    [11] - n=the number of subjects with at least one postbaseline value.
    No statistical analyses for this end point

    Primary: Number of Subjects With Clinically Relevant Abnormalities in Vital Signs or Relevant Changes From Baseline in Vital Signs

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    End point title
    Number of Subjects With Clinically Relevant Abnormalities in Vital Signs or Relevant Changes From Baseline in Vital Signs [12]
    End point description
    Number of subjects with clinically relevant abnormalities or relevant changes from baseline in temperature, pulse (beats per minute [bpm]), systolic blood pressure (SBP), and diastolic blood pressure (DBP) are presented. Baseline (BL) is defined as the last non-missing evaluable assessment taken prior and closest to the first rFVIIIFc dose. ↑signifies increase and ↓ signifies decrease. Safety Analysis Set: subjects who received at least 1 dose of Advate or at least 1 dose of rFVIIIFc and had a baseline assessment and at least 1 postbaseline assessment for temperature or at least 1 postbaseline assessment for pulse, SBP, and DBP.
    End point type
    Primary
    End point timeframe
    up to 52 weeks ± 2 weeks
    Notes
    [12] - 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: Per protocol, descriptive statistics were collected for this endpoint.
    End point values
    Arm 1: Individualized (Tailored) Prophylaxis Arm 2: Weekly Prophylaxis Arm 3: Episodic (On-Demand) Dosing
    Number of subjects analysed
    113
    24
    23
    Units: subjects
        Temperature: >38°C and ≥1°C ↑ from BL
    1
    0
    0
        Pulse: >120 bpm or >20 bpm ↑ from BL
    11
    2
    0
        Pulse: <50 bpm or >20 bpm ↓ from BL
    11
    2
    1
        SBP: >180 mm Hg or >40 mm Hg ↑ from BL
    0
    1
    0
        SBP: <90 mm Hg or >30 mm Hg ↓ from BL
    5
    1
    1
        DBP: >105 mm Hg or >30 mm Hg ↑ from BL
    1
    0
    0
        DBP: <50 mm Hg or >20 mm Hg ↓ from BL
    5
    0
    1
    No statistical analyses for this end point

    Primary: Annualized Bleeding Rate

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    End point title
    Annualized Bleeding Rate [13]
    End point description
    Annualized bleeding episodes = (number of bleeding episodes during the efficacy period / number of days during the efficacy period)*365.25. The efficacy period in Arms 1 and 2 began with the first prophylactic dose of rFVIIIFc and ended with the last dose (regardless of reason for dosing). The efficacy period in Arm 3 began at the time of last PK rFVIIIFc sampling timepoint and ended at the date of the last study visit. Periods of PK evaluations and surgery/rehabilitation are not included in the efficacy period. A bleeding episode started from the first sign of a bleed, and ended 72 hours after the last treatment for the bleeding, within which any symptoms of bleeding at the same location, or injections less than or equal to 72 hours apart, were considered the same bleeding episode. Full Analysis Set: subjects who received at least 1 dose of rFVIIIFc with an efficacy assessment.
    End point type
    Primary
    End point timeframe
    up to 52 weeks ± 2 weeks (efficacy period as defined in description)
    Notes
    [13] - 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: See "Comparison of Annualized Bleeding Rates: Arm 1 Versus Arm 3" endpoint for statistical analysis.
    End point values
    Arm 1: Individualized (Tailored) Prophylaxis Arm 2: Weekly Prophylaxis Arm 3: Episodic (On-Demand) Dosing
    Number of subjects analysed
    117
    23
    23
    Units: episodes per subject per year
        median (inter-quartile range (Q1-Q3))
    1.6 (0 to 4.69)
    3.59 (1.86 to 8.36)
    33.57 (21.14 to 48.69)
    No statistical analyses for this end point

    Primary: Comparison of Annualized Bleeding Rates: Arm 1 Versus Arm 3

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    End point title
    Comparison of Annualized Bleeding Rates: Arm 1 Versus Arm 3 [14]
    End point description
    Estimated using the negative binomial model with treatment arm as covariate, based on whole study duration for all subjects. Annualized bleeding episodes = (number of bleeding episodes / number of days in the respective period)*365.25.The efficacy period in Arm 1 began with the first prophylactic dose of rFVIIIFc and ended with the last dose (regardless of reason for dosing). The efficacy period in Arm 3 began at the time of last PK rFVIIIFc sampling timepoint and ended at the date of the last study visit. Periods of PK evaluations and surgery/rehabilitation are not included in the efficacy period. A bleeding episode started from the first sign of a bleed, and ended 72 hours after the last treatment for the bleeding, within which any symptoms of bleeding at the same location, or injections less than or equal to 72 hours apart, were considered part of the same bleeding episode. Full Analysis Set: subjects who received at least 1 dose of rFVIIIFc with an efficacy assessment.
    End point type
    Primary
    End point timeframe
    up to 52 weeks ± 2 weeks (efficacy period as defined in description)
    Notes
    [14] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Per protocol, Arm 1 versus Arm 3 only was analyzed as a primary endpoint. Arm 2 versus Arm 3 only was analyzed as a secondary endpoint. Both are included in this record.
    End point values
    Arm 1: Individualized (Tailored) Prophylaxis Arm 3: Episodic (On-Demand) Dosing
    Number of subjects analysed
    117
    23
    Units: episodes per subject per year
        number (confidence interval 95%)
    2.91 (2.3 to 3.68)
    37.25 (24.03 to 57.74)
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    The null hypothesis for the primary endpoint is no difference between the individualized (tailored) prophylaxis regimen and the on-demand regimen. The sample size of this study was mainly based on clinical rather than statistical considerations. However it was projected to have > 90% power at the 2-sided 0.05 level of significance to detect a 60% reduction in annualized bleeding episodes, based upon this hypothesis test.
    Comparison groups
    Arm 1: Individualized (Tailored) Prophylaxis v Arm 3: Episodic (On-Demand) Dosing
    Number of subjects included in analysis
    140
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.001
    Method
    negative binomial model
    Parameter type
    Bleeding Rate Ratio
    Point estimate
    0.08
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.05
         upper limit
    0.13

    Primary: Area Under the Curve (AUC) Per Dose (One-stage Clotting Assay)

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    End point title
    Area Under the Curve (AUC) Per Dose (One-stage Clotting Assay) [15]
    End point description
    Dose normalized area under the drug concentration-time curve. Sampling for Advate PK profiling was conducted, following at least 96 hours of washout, at these timepoints: preinjection and at either 30 (±3) minutes or 10 (±3) minutes, 1 hour (±15 minutes), 6 (±1) hours, 24 (±2) hours (Day 1), 48 (±2) hours (Day 2), and 72 (±2) hours (Day 3) from the start of the injection. Sampling for rFVIIIFc PK profiling was conducted at Day 0 (directly following at least 96 hours washout from Advate PK profiling or within 4 weeks of the Advate dose or other rFVIII product) and repeated 12 to 24 weeks later at the following timepoints: preinjection and at 30 (±3) minutes (or 10 (±3) minutes), 1 hour (±15 minutes), 6 (±1) hours, 24 (±2) hours (Day 1), 72 (±2) hours (Day 3), 96 (±2) hours (Day 4), and 120 (±2) hours (Day 5) from the start of the injection.
    End point type
    Primary
    End point timeframe
    See endpoint description for complete time frame.
    Notes
    [15] - 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: Statistical analysis for this endpoint cannot be entered due EudraCT system restrictions for within-group comparison.
    End point values
    Arm 1: Individualized Prophylaxis: Sequential PK Subgroup
    Number of subjects analysed
    28 [16]
    Units: IU*h/dL per IU/kg
    geometric mean (confidence interval 95%)
        rFVIIIFc Baseline
    51.24 (44.97 to 58.38)
        Advate
    32.88 (29.31 to 36.88)
    Notes
    [16] - Subjects who had evaluable one-stage PK profiles for both Advate and baseline rFVIIIFc.
    No statistical analyses for this end point

    Primary: Elimination Half Life (t1/2; One-stage Clotting Assay)

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    End point title
    Elimination Half Life (t1/2; One-stage Clotting Assay) [17]
    End point description
    Time required for the activity of the drug to reach half of its original value. Sampling for Advate PK profiling was conducted, following at least 96 hours of washout, at these timepoints: preinjection and at either 30 (±3) minutes or 10 (±3) minutes, 1 hour (±15 minutes), 6 (±1) hours, 24 (±2) hours (Day 1), 48 (±2) hours (Day 2), and 72 (±2) hours (Day 3) from the start of the injection. Sampling for rFVIIIFc PK profiling was conducted at Day 0 (directly following at least 96 hours washout from Advate PK profiling or within 4 weeks of the Advate dose or other rFVIII product) and repeated 12 to 24 weeks later at the following timepoints: preinjection and at 30 (±3) minutes (or 10 (±3) minutes), 1 hour (±15 minutes), 6 (±1) hours, 24 (±2) hours (Day 1), 72 (±2) hours (Day 3), 96 (±2) hours (Day 4), and 120 (±2) hours (Day 5) from the start of the injection.
    End point type
    Primary
    End point timeframe
    See endpoint description for complete time frame.
    Notes
    [17] - 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: Statistical analysis for this endpoint cannot be entered due EudraCT system restrictions for within-group comparison.
    End point values
    Arm 1: Individualized Prophylaxis: Sequential PK Subgroup
    Number of subjects analysed
    28 [18]
    Units: hours
    geometric mean (confidence interval 95%)
        rFVIIIFc Baseline
    18.97 (17.03 to 21.12)
        Advate
    12.43 (11.14 to 13.86)
    Notes
    [18] - Subjects who had evaluable one-stage PK profiles for both Advate and baseline rFVIIIFc.
    No statistical analyses for this end point

    Primary: Clearance (CL; One-stage Clotting Assay)

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    End point title
    Clearance (CL; One-stage Clotting Assay) [19]
    End point description
    Rate at which the body removes the drug, measured as the volume of the plasma cleared of drug per unit time per unit weight. Sampling for Advate PK profiling was conducted, following at least 96 hours of washout, at these timepoints: preinjection and at either 30 (±3) minutes or 10 (±3) minutes, 1 hour (±15 minutes), 6 (±1) hours, 24 (±2) hours (Day 1), 48 (±2) hours (Day 2), and 72 (±2) hours (Day 3) from the start of the injection. Sampling for rFVIIIFc PK profiling was conducted at Day 0 (directly following at least 96 hours washout from Advate PK profiling or within 4 weeks of the Advate dose or other rFVIII product) and repeated 12 to 24 weeks later at the following timepoints: preinjection and at 30 (±3) minutes (or 10 (±3) minutes), 1 hour (±15 minutes), 6 (±1) hours, 24 (±2) hours (Day 1), 72 (±2) hours (Day 3), 96 (±2) hours (Day 4), and 120 (±2) hours (Day 5) from the start of the injection.
    End point type
    Primary
    End point timeframe
    See endpoint description for complete time frame.
    Notes
    [19] - 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: Statistical analysis for this endpoint cannot be entered due EudraCT system restrictions for within-group comparison.
    End point values
    Arm 1: Individualized Prophylaxis: Sequential PK Subgroup
    Number of subjects analysed
    28 [20]
    Units: mL/h/kg
    geometric mean (confidence interval 95%)
        rFVIIIFc Baseline
    1.952 (1.713 to 2.224)
        Advate
    3.041 (2.711 to 3.412)
    Notes
    [20] - Subjects who had evaluable one-stage PK profiles for both Advate and baseline rFVIIIFc.
    No statistical analyses for this end point

    Primary: Mean Residence Time (MRT; One-stage Clotting Assay)

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    End point title
    Mean Residence Time (MRT; One-stage Clotting Assay) [21]
    End point description
    The average time that a drug molecule is present in the systemic circulation. Sampling for Advate PK profiling was conducted, following at least 96 hours of washout, at these timepoints: preinjection and at either 30 (±3) minutes or 10 (±3) minutes, 1 hour (±15 minutes), 6 (±1) hours, 24 (±2) hours (Day 1), 48 (±2) hours (Day 2), and 72 (±2) hours (Day 3) from the start of the injection. Sampling for rFVIIIFc PK profiling was conducted at Day 0 (directly following at least 96 hours washout from Advate PK profiling or within 4 weeks of the Advate dose or other rFVIII product) and repeated 12 to 24 weeks later at the following timepoints: preinjection and at 30 (±3) minutes (or 10 (±3) minutes), 1 hour (±15 minutes), 6 (±1) hours, 24 (±2) hours (Day 1), 72 (±2) hours (Day 3), 96 (±2) hours (Day 4), and 120 (±2) hours (Day 5) from the start of the injection.
    End point type
    Primary
    End point timeframe
    See endpoint description for complete time frame.
    Notes
    [21] - 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: Statistical analysis for this endpoint cannot be entered due EudraCT system restrictions for within-group comparison.
    End point values
    Arm 1: Individualized Prophylaxis: Sequential PK Subgroup
    Number of subjects analysed
    28 [22]
    Units: hours
    geometric mean (confidence interval 95%)
        rFVIIIFc Baseline
    25.15 (22.65 to 27.91)
        Advate
    16.84 (15.22 to 18.63)
    Notes
    [22] - Subjects who had evaluable one-stage PK profiles for both Advate and baseline rFVIIIFc.
    No statistical analyses for this end point

    Primary: Incremental Recovery (One-stage Clotting Assay)

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    End point title
    Incremental Recovery (One-stage Clotting Assay) [23]
    End point description
    The rise in FVIII activity in IU/dL per unit dose administered in IU/kg. Sampling for Advate PK profiling was conducted, following at least 96 hours of washout, at these timepoints: preinjection and at either 30 (±3) minutes or 10 (±3) minutes, 1 hour (±15 minutes), 6 (±1) hours, 24 (±2) hours (Day 1), 48 (±2) hours (Day 2), and 72 (±2) hours (Day 3) from the start of the injection. Sampling for rFVIIIFc PK profiling was conducted at Day 0 (directly following at least 96 hours washout from Advate PK profiling or within 4 weeks of the Advate dose or other rFVIII product) and repeated 12 to 24 weeks later at the following timepoints: preinjection and at 30 (±3) minutes (or 10 (±3) minutes), 1 hour (±15 minutes), 6 (±1) hours, 24 (±2) hours (Day 1), 72 (±2) hours (Day 3), 96 (±2) hours (Day 4), and 120 (±2) hours (Day 5) from the start of the injection.
    End point type
    Primary
    End point timeframe
    See endpoint description for complete time frame.
    Notes
    [23] - 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: Statistical analysis for this endpoint cannot be entered due EudraCT system restrictions for within-group comparison.
    End point values
    Arm 1: Individualized Prophylaxis: Sequential PK Subgroup
    Number of subjects analysed
    28 [24]
    Units: IU/dL per IU/kg
    geometric mean (confidence interval 95%)
        rFVIIIFc Baseline
    2.2395 (2.1116 to 2.3753)
        Advate
    2.3516 (2.211 to 2.501)
    Notes
    [24] - Subjects who had evaluable one-stage PK profiles for both Advate and baseline rFVIIIFc.
    No statistical analyses for this end point

    Secondary: Comparison of Annualized Bleeding Rates: Arm 2 Versus Arm 3

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    End point title
    Comparison of Annualized Bleeding Rates: Arm 2 Versus Arm 3 [25]
    End point description
    Estimated using the negative binomial model with treatment arm as covariate, based on whole study duration for all subjects. Annualized bleeding episodes = (number of bleeding episodes / number of days in the respective period)*365.25.The efficacy period in Arm 2 began with the first prophylactic dose of rFVIIIFc and ended with the last dose (regardless of reason for dosing). The efficacy period in Arm 3 began at the time of last PK rFVIIIFc sampling timepoint and ended at the date of the last study visit. Periods of PK evaluations and surgery/rehabilitation are not included in the efficacy period. A bleeding episode started from the first sign of a bleed, and ended 72 hours after the last treatment for the bleeding, within which any symptoms of bleeding at the same location, or injections less than or equal to 72 hours apart, were considered the same bleeding episode. Full Analysis Set: subjects who received at least 1 dose of rFVIIIFc with an efficacy assessment.
    End point type
    Secondary
    End point timeframe
    up to 52 weeks ± 2 weeks (efficacy period as defined in description)
    Notes
    [25] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Per protocol, Arm 1 versus Arm 3 only was analyzed as a primary endpoint. Arm 2 versus Arm 3 only was analyzed as a secondary endpoint. Both are included in this record.
    End point values
    Arm 2: Weekly Prophylaxis Arm 3: Episodic (On-Demand) Dosing
    Number of subjects analysed
    23
    23
    Units: episodes per subject per year
        number (confidence interval 95%)
    8.92 (5.48 to 14.51)
    37.25 (24.03 to 57.74)
    Statistical analysis title
    Statistical Analysis 1
    Comparison groups
    Arm 2: Weekly Prophylaxis v Arm 3: Episodic (On-Demand) Dosing
    Number of subjects included in analysis
    46
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.001
    Method
    negative binomial model
    Parameter type
    Bleeding Rate Ratio
    Point estimate
    0.24
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.12
         upper limit
    0.46

    Secondary: Annualized rFVIIIFc Consumption Per Subject

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    End point title
    Annualized rFVIIIFc Consumption Per Subject
    End point description
    Consumption is calculated for the efficacy period. The efficacy period in Arms 1 and 2 began with the first prophylactic dose of rFVIIIFc and ended with the last dose (regardless of reason for dosing). The efficacy period in Arm 3 began at the time of last PK rFVIIIFc sampling timepoint and ended at the date of the last study visit. Periods of PK evaluations and surgery/rehabilitation are not included in the efficacy period. Overall units (IU/kg) of annualized rFVIIIFc consumption = [Total rFVIIIFc IU/kg received during the efficacy period / number of days in efficacy period] x 365.25. Full Analysis Set: subjects who received at least 1 dose of rFVIIIFc. 'Overall' n=subjects in the Full Analysis Set with evaluable data in the efficacy period; 'Last 3 Months on Study' n=subjects in the Full Analysis Set with evaluable data and >=6 months on study.
    End point type
    Secondary
    End point timeframe
    up to 52 weeks ± 2 weeks (efficacy period as defined in description)
    End point values
    Arm 1: Individualized (Tailored) Prophylaxis Arm 2: Weekly Prophylaxis Arm 3: Episodic (On-Demand) Dosing
    Number of subjects analysed
    117
    24
    23
    Units: IU/kg rFVIIIFc per subject per year
    arithmetic mean (standard deviation)
        Overall; n=117, 23, 23
    4631.98 ± 1041.608
    4003.69 ± 652.573
    1304.36 ± 874.361
        Last 3 months on study; n=112, 16, 18
    4868.35 ± 1365.108
    3882.89 ± 583.344
    1225.8 ± 848.656
    No statistical analyses for this end point

    Secondary: Subject Assessment of Response to Injections to Treat a Bleeding Episode

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    End point title
    Subject Assessment of Response to Injections to Treat a Bleeding Episode
    End point description
    Subject's assessment of the response to the first rFVIIIFc injection for each bleeding episode. Percentages were based on the number of bleeding episodes for which a response was provided for the first injection, using the following 4-point scale: excellent; good; moderate; no response. Full Analysis Set: subjects who received at least 1 dose of rFVIIIFc and had at least 1 evaluable bleeding episode; based on the number of injections with an evaluation.
    End point type
    Secondary
    End point timeframe
    up to 52 weeks ± 2 weeks
    End point values
    Arm 1: Individualized (Tailored) Prophylaxis Arm 2: Weekly Prophylaxis Arm 3: Episodic (On-Demand) Dosing
    Number of subjects analysed
    63 [26]
    19 [27]
    23 [28]
    Units: percentage of responses
    number (not applicable)
        Excellent or Good
    79.7
    64
    80.2
        Excellent
    33.7
    18
    30.8
        Good
    46
    46.1
    49.3
        Moderate
    18.8
    34.8
    19.6
        No Response
    1.5
    1.1
    0.2
    Notes
    [26] - Number of bleeding episodes analyzed=202
    [27] - Number of bleeding episodes analyzed=89
    [28] - Number of bleeding episodes analyzed=454
    No statistical analyses for this end point

    Secondary: Investigator's Assessment of Subjects' Bleeding Response to rFVIIIFc Injection

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    End point title
    Investigator's Assessment of Subjects' Bleeding Response to rFVIIIFc Injection
    End point description
    The investigator was given the opportunity to record an assessment of a subject’s response to treatment, if the subject was treated in the hospital for a major bleed, using the following 4-point scale: excellent; good; moderate; no response.
    End point type
    Secondary
    End point timeframe
    up to 52 weeks ± 2 weeks
    End point values
    Arm 1: Individualized (Tailored) Prophylaxis Arm 2: Weekly Prophylaxis Arm 3: Episodic (On-Demand) Dosing
    Number of subjects analysed
    0 [29]
    0 [30]
    0 [31]
    Units: percentage of responses
        number (not applicable)
    Notes
    [29] - This supplemental assessment was not summarized because of insufficient data.
    [30] - This supplemental assessment was not summarized because of insufficient data.
    [31] - This supplemental assessment was not summarized because of insufficient data.
    No statistical analyses for this end point

    Secondary: Annualized Bleeding Rate by Location of Bleed (Joint, Muscle, Internal, Skin/Mucosa)

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    End point title
    Annualized Bleeding Rate by Location of Bleed (Joint, Muscle, Internal, Skin/Mucosa)
    End point description
    Annualized bleeding episodes = (Number of bleeding episodes at the specified location / number of days in efficacy period) x 365.25. The efficacy period in Arms 1 and 2 began with the first prophylactic dose of rFVIIIFc and ended with the last dose (regardless of reason for dosing). The efficacy period in Arm 3 began at the time of last PK rFVIIIFc sampling timepoint and ended at the date of the last study visit. Periods of PK evaluations and surgery/rehabilitation were not included in the efficacy period. A bleeding episode started from the first sign of a bleed, and ended 72 hours after the last treatment for the bleeding, within which any symptoms of bleeding at the same location, or injections less than or equal to 72 hours apart, were considered the same bleeding episode. Any bleeding at a different location was a separate bleeding episode regardless of time from the last injection. Full Analysis Set: subjects who received at least 1 dose of rFVIIIFc with evaluable data.
    End point type
    Secondary
    End point timeframe
    up to 52 weeks ± 2 weeks (efficacy period as defined in description)
    End point values
    Arm 1: Individualized (Tailored) Prophylaxis Arm 2: Weekly Prophylaxis Arm 3: Episodic (On-Demand) Dosing
    Number of subjects analysed
    117
    23
    23
    Units: episodes per subject per year
    median (inter-quartile range (Q1-Q3))
        Joint
    0 (0 to 3.11)
    1.93 (0 to 7.62)
    22.76 (15.07 to 39.02)
        Muscle
    0 (0 to 0)
    0 (0 to 2.01)
    5.57 (1.86 to 10.05)
        Internal
    0 (0 to 0)
    0 (0 to 0)
    0 (0 to 0)
        Soft Tissue
    0 (0 to 0)
    0 (0 to 0)
    0 (0 to 1.86)
        Skin/Mucosa
    0 (0 to 0)
    0 (0 to 0)
    0 (0 to 0)
    No statistical analyses for this end point

    Secondary: Annualized Joint Bleeding Rate (Spontaneous and Traumatic)

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    End point title
    Annualized Joint Bleeding Rate (Spontaneous and Traumatic)
    End point description
    Annualized bleeding episodes = (Number of bleeding episodes of the specified type / number of days in efficacy period) x 365.25. The efficacy period in Arms 1 and 2 began with the first prophylactic dose of rFVIIIFc and ended with the last dose (regardless of reason for dosing). The efficacy period in Arm 3 began at the time of last PK rFVIIIFc sampling timepoint and ended at the date of the last study visit. Periods of PK evaluations and surgery/rehabilitation were not included in the efficacy period. A bleeding episode started from the first sign of a bleed, and ended 72 hours after the last treatment for the bleeding, within which any symptoms of bleeding at the same location, or injections less than or equal to 72 hours apart, were considered the same bleeding episode. Full Analysis Set: subjects who received at least 1 dose of rFVIIIFc with evaluable data.
    End point type
    Secondary
    End point timeframe
    up to 52 weeks ± 2 weeks (efficacy period as defined in description)
    End point values
    Arm 1: Individualized (Tailored) Prophylaxis Arm 2: Weekly Prophylaxis Arm 3: Episodic (On-Demand) Dosing
    Number of subjects analysed
    117
    23
    23
    Units: bleeding episodes per subject per year
    median (inter-quartile range (Q1-Q3))
        Spontaneous
    0 (0 to 1.73)
    0 (0 to 3.81)
    18.59 (7.59 to 29.59)
        Traumatic
    0 (0 to 1.16)
    0 (0 to 2.01)
    3.93 (0 to 8.56)
        Unknown
    0 (0 to 0)
    0 (0 to 0)
    0 (0 to 0)
    No statistical analyses for this end point

    Secondary: Number of Days From Last Treatment Injection to a New Bleeding Episode

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    End point title
    Number of Days From Last Treatment Injection to a New Bleeding Episode
    End point description
    Number of days from the last injection to treat a bleeding episode to a new bleeding episode, analyzed for per evaluable bleeding episode and per subject. For “per subject” values, number of days from last injection to treat a bleed to a new bleeding episode is averaged across all evaluable bleeding episodes for each subject first, and then descriptive statistics were calculated across subjects. A follow-up injection administered >72 hours after the most recent injection given to treat a bleed was considered a new bleed at the same location and was classified as type=Unknown (not evaluable). Please see the endpoint "Annualized Bleeding Rate" for a definition of the efficacy period. Full Analysis Set: subjects who received at least 1 dose of rFVIIIFc and had at least 1 evaluable bleeding episode. The first bleed for each subject could not be included in this analysis since there was no previous bleed from which to measure time.
    End point type
    Secondary
    End point timeframe
    up to 52 weeks ± 2 weeks (efficacy period as defined in description).
    End point values
    Arm 1: Individualized (Tailored) Prophylaxis Arm 2: Weekly Prophylaxis Arm 3: Episodic (On-Demand) Dosing
    Number of subjects analysed
    48 [32]
    12 [33]
    23 [34]
    Units: days
    median (inter-quartile range (Q1-Q3))
        Per bleeding episode
    19.83 (8.58 to 55.46)
    8 (5.35 to 15.38)
    6.55 (4.46 to 10.27)
        Per subject
    42.9 (20.25 to 65.93)
    40.71 (11.75 to 52.39)
    10.12 (7.42 to 16.37)
    Notes
    [32] - Number of evaluable bleeding episodes analyzed=149
    [33] - Number of evaluable bleeding episodes analyzed=76
    [34] - Number of evaluable bleeding episodes analyzed=430
    No statistical analyses for this end point

    Secondary: Number of Injections Required for Resolution of a Bleeding Episode

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    End point title
    Number of Injections Required for Resolution of a Bleeding Episode
    End point description
    A bleeding episode started from the first sign of a bleed, and ended 72 hours after the last treatment for the bleeding, within which any symptoms of bleeding at the same location, or injections less than or equal to 72 hours apart, were considered the same bleeding episode. All injections given from the initial sign of a bleed until the last date/time within the bleed window are counted. The resolution of a bleed is defined as no sign of bleeding following injection for the bleed. The efficacy period in Arms 1 and 2 began with the first prophylactic dose of rFVIIIFc and ended with the last dose (regardless of reason for dosing). The efficacy period in Arm 3 began at the time of last PK rFVIIIFc sampling timepoint and ended at the date of the last study visit. Periods of PK evaluations and surgery/rehabilitation are not included in the efficacy period. Full Analysis Set: subjects who received at least 1 dose of rFVIIIFc and had at least 1 bleeding episode.
    End point type
    Secondary
    End point timeframe
    up to 52 weeks ± 2 weeks (efficacy period as defined in description)
    End point values
    Arm 1: Individualized (Tailored) Prophylaxis Arm 2: Weekly Prophylaxis Arm 3: Episodic (On-Demand) Dosing
    Number of subjects analysed
    64 [35]
    19 [36]
    23 [37]
    Units: injections
    median (inter-quartile range (Q1-Q3))
        Per bleeding episode
    1 (1 to 1)
    1 (1 to 1)
    1 (1 to 1)
        Per subject
    1 (1 to 1.33)
    1 (1 to 1.43)
    1.03 (1 to 1.17)
    Notes
    [35] - Number of bleeding episodes analyzed=209
    [36] - Number of bleeding episodes analyzed=92
    [37] - Number of bleeding episodes analyzed=456
    No statistical analyses for this end point

    Secondary: Number of Injections Required for Resolution of a Bleeding Episode by Location of Bleed

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    End point title
    Number of Injections Required for Resolution of a Bleeding Episode by Location of Bleed
    End point description
    Please see previous Endpoint for a definition of the efficacy period. A bleeding episode started from the first sign of a bleed, and ended 72 hours after the last treatment for the bleeding, within which any symptoms of bleeding at the same location, or injections less than or equal to 72 hours apart, were considered the same bleeding episode. All injections given from the initial sign of a bleed until the last date/time within the bleed window were counted. The resolution of a bleed was defined as no sign of bleeding following injection for the bleed. Bleeding episodes that presented in multiple locations are included as a single event in the overall summary for the number of injections to resolve that bleeding episode but are included in summaries for each location. Full Analysis Set: subjects who received at least 1 dose of rFVIIIFc and had evaluable efficacy assessments; n=total number of bleeds at given location.
    End point type
    Secondary
    End point timeframe
    up to 52 weeks ± 2 weeks (efficacy period as defined in description)
    End point values
    Arm 1: Individualized (Tailored) Prophylaxis Arm 2: Weekly Prophylaxis Arm 3: Episodic (On-Demand) Dosing
    Number of subjects analysed
    64
    19
    23
    Units: injections
    median (inter-quartile range (Q1-Q3))
        Joint; n=151, 67, 366
    1 (1 to 1)
    1 (1 to 1)
    1 (1 to 1)
        Muscle; n=35, 23, 82
    1 (1 to 1)
    1 (1 to 1)
    1 (1 to 1)
        Soft Tissue; n=24, 5, 25
    1 (1 to 1)
    1 (1 to 2)
    1 (1 to 1)
        Internal; n=3, 2, 6
    1 (1 to 1)
    1 (1 to 1)
    1 (1 to 1)
        Skin/Mucosa; n=11, 6, 8
    1 (1 to 1)
    1 (1 to 1)
    1 (1 to 1)
    No statistical analyses for this end point

    Secondary: Total Dose Per Injection Required for Resolution of a Bleeding Episode by Location of Bleed

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    End point title
    Total Dose Per Injection Required for Resolution of a Bleeding Episode by Location of Bleed
    End point description
    For each bleeding episode at one location, the total dose is the sum of the doses (IU/kg) administered across all injections given to treat that bleeding episode. Please see the above Endpoint for a definition of the efficacy period. A bleeding episode started from the first sign of a bleed, and ended 72 hours after the last treatment for the bleeding, within which any symptoms of bleeding at the same location, or injections less than or equal to 72 hours apart, were considered part of the same bleeding episode. Bleeding episodes that presented in multiple locations are included as a single event in the overall summary for dose administered to resolve that bleeding episode but are included in the individual summaries for each location. Full Analysis Set: subjects who received at least 1 dose of rFVIIIFc and had complete information on the dose administered to treat a bleeding episode; n=total number of bleeding episodes at this location.
    End point type
    Secondary
    End point timeframe
    up to 52 weeks ± 2 weeks (efficacy period as defined in description)
    End point values
    Arm 1: Individualized (Tailored) Prophylaxis Arm 2: Weekly Prophylaxis Arm 3: Episodic (On-Demand) Dosing
    Number of subjects analysed
    63
    19
    23
    Units: IU/kg
    median (inter-quartile range (Q1-Q3))
        Joint; n=151, 67, 366
    29.69 (24.1 to 53.44)
    28.23 (20.16 to 40.32)
    27.35 (22.73 to 39.22)
        Muscle; n=35, 23, 82
    40.98 (26.79 to 53.1)
    32.12 (26.98 to 32.47)
    27.78 (23.47 to 31.01)
        Soft Tissue; n=23, 5, 25
    30.6 (24.51 to 53.13)
    51.88 (20.16 to 54.88)
    27.78 (23.44 to 31.45)
        Internal; n=3, 2, 6
    32.63 (23.39 to 51.72)
    58.4 (48.08 to 68.73)
    32.54 (30 to 49.18)
        Skin/Mucosa; n=11, 6, 8
    33.9 (28.23 to 53.19)
    28.34 (21.65 to 44.35)
    21.37 (19.95 to 25.16)
    No statistical analyses for this end point

    Secondary: Volume at Steady State (Vss; One-stage Clotting Assay)

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    End point title
    Volume at Steady State (Vss; One-stage Clotting Assay)
    End point description
    Volume of distribution at steady state. Sampling for Advate PK profiling was conducted, following at least 96 hours of washout, at these timepoints: preinjection and at either 30 (±3) minutes or 10 (±3) minutes, 1 hour (±15 minutes), 6 (±1) hours, 24 (±2) hours (Day 1), 48 (±2) hours (Day 2), and 72 (±2) hours (Day 3) from the start of the injection. Sampling for rFVIIIFc PK profiling was conducted at Day 0 (directly following at least 96 hours washout from Advate PK profiling or within 4 weeks of the Advate dose or other rFVIII product) and repeated 12 to 24 weeks later at the following timepoints: preinjection and at 30 (±3) minutes (or 10 (±3) minutes), 1 hour (±15 minutes), 6 (±1) hours, 24 (±2) hours (Day 1), 72 (±2) hours (Day 3), 96 (±2) hours (Day 4), and 120 (±2) hours (Day 5) from the start of the injection.
    End point type
    Secondary
    End point timeframe
    See endpoint description for complete time frame.
    End point values
    Arm 1: Individualized Prophylaxis: Sequential PK Subgroup
    Number of subjects analysed
    28 [38]
    Units: mL/kg
    geometric mean (confidence interval 95%)
        rFVIIIFc Baseline
    49.1 (46.6 to 51.7)
        Advate
    51.2 (47.2 to 55.5)
    Notes
    [38] - Subjects who had evaluable one-stage PK profiles for both Advate and baseline rFVIIIFc.
    No statistical analyses for this end point

    Secondary: Volume at Steady State (Vss; Two-stage Chromogenic Assay)

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    End point title
    Volume at Steady State (Vss; Two-stage Chromogenic Assay)
    End point description
    Volume of distribution at steady state. Sampling for Advate PK profiling was conducted, following at least 96 hours of washout, at these timepoints: preinjection and at either 30 (±3) minutes or 10 (±3) minutes, 1 hour (±15 minutes), 6 (±1) hours, 24 (±2) hours (Day 1), 48 (±2) hours (Day 2), and 72 (±2) hours (Day 3) from the start of the injection. Sampling for rFVIIIFc PK profiling was conducted at Day 0 (directly following at least 96 hours washout from Advate PK profiling or within 4 weeks of the Advate dose or other rFVIII product) and repeated 12 to 24 weeks later at the following timepoints: preinjection and at 30 (±3) minutes (or 10 (±3) minutes), 1 hour (±15 minutes), 6 (±1) hours, 24 (±2) hours (Day 1), 72 (±2) hours (Day 3), 96 (±2) hours (Day 4), and 120 (±2) hours (Day 5) from the start of the injection.
    End point type
    Secondary
    End point timeframe
    See endpoint description for complete time frame.
    End point values
    Arm 1: Individualized Prophylaxis: Sequential PK Subgroup
    Number of subjects analysed
    27 [39]
    Units: mL/kg
    geometric mean (confidence interval 95%)
        rFVIIIFc Baseline
    52.6 (47.4 to 58.3)
        Advate
    56.8 (51.5 to 62.7)
    Notes
    [39] - Subjects who had evaluable two-stage PK profiles for both Advate and baseline rFVIIIFc.
    No statistical analyses for this end point

    Secondary: Time to 1% and 3% FVIII Activity (One-stage Clotting Assay)

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    End point title
    Time to 1% and 3% FVIII Activity (One-stage Clotting Assay)
    End point description
    Estimated time after dose (in days) when FVIII activity has declined to approximately 1 or 3 IU/dL (1% or 3%) above baseline, respectively. Sampling for Advate PK profiling was conducted, following at least 96 hours of washout, at these timepoints: preinjection and at either 30 (±3) minutes or 10 (±3) minutes, 1 hour (±15 minutes), 6 (±1) hours, 24 (±2) hours (Day 1), 48 (±2) hours (Day 2), and 72 (±2) hours (Day 3) from the start of the injection. Sampling for rFVIIIFc PK profiling was conducted at Day 0 (directly following at least 96 hours washout from Advate PK profiling or within 4 weeks of the Advate dose or other rFVIII product) and repeated 12 to 24 weeks later at the following timepoints: preinjection and at 30 (±3) minutes (or 10 (±3) minutes), 1 hour (±15 minutes), 6 (±1) hours, 24 (±2) hours (Day 1), 72 (±2) hours (Day 3), 96 (±2) hours (Day 4), and 120 (±2) hours (Day 5) from the start of the injection.
    End point type
    Secondary
    End point timeframe
    See endpoint description for complete time frame.
    End point values
    Arm 1: Individualized Prophylaxis: Sequential PK Subgroup
    Number of subjects analysed
    28 [40]
    Units: days
    geometric mean (confidence interval 95%)
        Advate: Time 1%
    3.298 (2.985 to 3.645)
        Advate: Time 3%
    2.478 (2.242 to 2.738)
        rFVIIIFc Baseline: Time 1%
    4.918 (4.434 to 5.455)
        rFVIIIFc Baseline: Time 3%
    3.707 (3.325 to 4.133)
    Notes
    [40] - Subjects who had evaluable one-stage PK profiles for both Advate and baseline rFVIIIFc.
    No statistical analyses for this end point

    Secondary: Time to 1% and 3% FVIII Activity (Two-stage Chromogenic Assay)

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    End point title
    Time to 1% and 3% FVIII Activity (Two-stage Chromogenic Assay)
    End point description
    Estimated time after dose (in days) when FVIII activity has declined to approximately 1 or 3 IU/dL (1% or 3%) above baseline, respectively. Sampling for Advate PK profiling was conducted, following at least 96 hours of washout, at these timepoints: preinjection and at either 30 (±3) minutes or 10 (±3) minutes, 1 hour (±15 minutes), 6 (±1) hours, 24 (±2) hours (Day 1), 48 (±2) hours (Day 2), and 72 (±2) hours (Day 3) from the start of the injection. Sampling for rFVIIIFc PK profiling was conducted at Day 0 (directly following at least 96 hours washout from Advate PK profiling or within 4 weeks of the Advate dose or other rFVIII product) and repeated 12 to 24 weeks later at the following timepoints: preinjection and at 30 (±3) minutes (or 10 (±3) minutes), 1 hour (±15 minutes), 6 (±1) hours, 24 (±2) hours (Day 1), 72 (±2) hours (Day 3), 96 (±2) hours (Day 4), and 120 (±2) hours (Day 5) from the start of the injection.
    End point type
    Secondary
    End point timeframe
    See endpoint description for complete time frame.
    End point values
    Arm 1: Individualized Prophylaxis: Sequential PK Subgroup
    Number of subjects analysed
    27 [41]
    Units: days
    geometric mean (confidence interval 95%)
        Advate: Time 1%
    3.22 (2.97 to 3.491)
        Advate: Time 3%
    2.306 (2.12 to 2.509)
        rFVIIIFc Baseline: Time 1%
    5.01 (4.525 to 5.548)
        rFVIIIFc Baseline: Time 3%
    3.612 (3.25 to 4.015)
    Notes
    [41] - Subjects who had evaluable two-stage PK profiles for both Advate and baseline rFVIIIFc.
    No statistical analyses for this end point

    Secondary: Time at Maximum Activity (Tmax; One-stage Clotting Assay)

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    End point title
    Time at Maximum Activity (Tmax; One-stage Clotting Assay)
    End point description
    Time at which maximum activity (Cmax) is observed. Sampling for Advate PK profiling was conducted, following at least 96 hours of washout, at these timepoints: preinjection and at either 30 (±3) minutes or 10 (±3) minutes, 1 hour (±15 minutes), 6 (±1) hours, 24 (±2) hours (Day 1), 48 (±2) hours (Day 2), and 72 (±2) hours (Day 3) from the start of the injection. Sampling for rFVIIIFc PK profiling was conducted at Day 0 (directly following at least 96 hours washout from Advate PK profiling or within 4 weeks of the Advate dose or other rFVIII product) and repeated 12 to 24 weeks later at the following timepoints: preinjection and at 30 (±3) minutes (or 10 (±3) minutes), 1 hour (±15 minutes), 6 (±1) hours, 24 (±2) hours (Day 1), 72 (±2) hours (Day 3), 96 (±2) hours (Day 4), and 120 (±2) hours (Day 5) from the start of the injection.
    End point type
    Secondary
    End point timeframe
    See endpoint description for complete time frame.
    End point values
    Arm 1: Individualized Prophylaxis: Sequential PK Subgroup
    Number of subjects analysed
    28 [42]
    Units: hours
    geometric mean (confidence interval 95%)
        rFVIIIFc Baseline
    0.49 (0.37 to 0.63)
        Advate
    0.48 (0.33 to 0.68)
    Notes
    [42] - Subjects who had evaluable one-stage PK profiles for both Advate and baseline rFVIIIFc.
    No statistical analyses for this end point

    Secondary: Time at Maximum Activity (Tmax; Two-stage Chromogenic Assay)

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    End point title
    Time at Maximum Activity (Tmax; Two-stage Chromogenic Assay)
    End point description
    Time at which the maximum activity (Cmax) is observed. Sampling for Advate PK profiling was conducted, following at least 96 hours of washout, at these timepoints: preinjection and at either 30 (±3) minutes or 10 (±3) minutes, 1 hour (±15 minutes), 6 (±1) hours, 24 (±2) hours (Day 1), 48 (±2) hours (Day 2), and 72 (±2) hours (Day 3) from the start of the injection. Sampling for rFVIIIFc PK profiling was conducted at Day 0 (directly following at least 96 hours washout from Advate PK profiling or within 4 weeks of the Advate dose or other rFVIII product) and repeated 12 to 24 weeks later at the following timepoints: preinjection and at 30 (±3) minutes (or 10 (±3) minutes), 1 hour (±15 minutes), 6 (±1) hours, 24 (±2) hours (Day 1), 72 (±2) hours (Day 3), 96 (±2) hours (Day 4), and 120 (±2) hours (Day 5) from the start of the injection.
    End point type
    Secondary
    End point timeframe
    See endpoint description for complete time frame.
    End point values
    Arm 1: Individualized Prophylaxis: Sequential PK Subgroup
    Number of subjects analysed
    27 [43]
    Units: hours
    geometric mean (confidence interval 95%)
        rFVIIIFc Baseline
    0.55 (0.41 to 0.75)
        Advate
    0.46 (0.35 to 0.61)
    Notes
    [43] - Subjects who had evaluable two-stage PK profiles for both Advate and baseline rFVIIIFc.
    No statistical analyses for this end point

    Secondary: Area Under the Curve (AUC) Per Dose (Two-stage Chromogenic Assay)

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    End point title
    Area Under the Curve (AUC) Per Dose (Two-stage Chromogenic Assay)
    End point description
    Dose normalized area under the drug concentration-time curve. Sampling for Advate PK profiling was conducted, following at least 96 hours of washout, at these timepoints: preinjection and at either 30 (±3) minutes or 10 (±3) minutes, 1 hour (±15 minutes), 6 (±1) hours, 24 (±2) hours (Day 1), 48 (±2) hours (Day 2), and 72 (±2) hours (Day 3) from the start of the injection. Sampling for rFVIIIFc PK profiling was conducted at Day 0 (directly following at least 96 hours washout from Advate PK profiling or within 4 weeks of the Advate dose or other rFVIII product) and repeated 12 to 24 weeks later at the following timepoints: preinjection and at 30 (±3) minutes (or 10 (±3) minutes), 1 hour (±15 minutes), 6 (±1) hours, 24 (±2) hours (Day 1), 72 (±2) hours (Day 3), 96 (±2) hours (Day 4), and 120 (±2) hours (Day 5) from the start of the injection.
    End point type
    Secondary
    End point timeframe
    See endpoint description for complete time frame.
    End point values
    Arm 1: Individualized Prophylaxis: Sequential PK Subgroup
    Number of subjects analysed
    27 [44]
    Units: IU*h/dL per IU/kg
    geometric mean (confidence interval 95%)
        rFVIIIFc Baseline
    47.45 (41.55 to 54.18)
        Advate
    28.05 (24.85 to 31.65)
    Notes
    [44] - Subjects who had evaluable two-stage PK profiles for both Advate and baseline rFVIIIFc.
    No statistical analyses for this end point

    Secondary: Elimination Half Life (t1/2; Two-stage Chromogenic Assay)

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    End point title
    Elimination Half Life (t1/2; Two-stage Chromogenic Assay)
    End point description
    Time required for the activity of the drug to reach half of its original value. Sampling for Advate PK profiling was conducted, following at least 96 hours of washout, at these timepoints: preinjection and at either 30 (±3) minutes or 10 (±3) minutes, 1 hour (±15 minutes), 6 (±1) hours, 24 (±2) hours (Day 1), 48 (±2) hours (Day 2), and 72 (±2) hours (Day 3) from the start of the injection. Sampling for rFVIIIFc PK profiling was conducted at Day 0 (directly following at least 96 hours washout from Advate PK profiling or within 4 weeks of the Advate dose or other rFVIII product) and repeated 12 to 24 weeks later at the following timepoints: preinjection and at 30 (±3) minutes (or 10 (±3) minutes), 1 hour (±15 minutes), 6 (±1) hours, 24 (±2) hours (Day 1), 72 (±2) hours (Day 3), 96 (±2) hours (Day 4), and 120 (±2) hours (Day 5) from the start of the injection.
    End point type
    Secondary
    End point timeframe
    See endpoint description for complete time frame.
    End point values
    Arm 1: Individualized Prophylaxis: Sequential PK Subgroup
    Number of subjects analysed
    27 [45]
    Units: hours
    geometric mean (confidence interval 95%)
        rFVIIIFc Baseline
    20.89 (18.23 to 23.93)
        Advate
    13.67 (12.31 to 15.18)
    Notes
    [45] - Subjects who had evaluable two-stage PK profiles for both Advate and baseline rFVIIIFc.
    No statistical analyses for this end point

    Secondary: Clearance (CL; Two-stage Chromogenic Assay)

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    End point title
    Clearance (CL; Two-stage Chromogenic Assay)
    End point description
    Rate at which the body removes the drug, measured as the volume of the plasma cleared of drug per unit time per unit weight. Sampling for Advate PK profiling was conducted, following at least 96 hours of washout, at these timepoints: preinjection and at either 30 (±3) minutes or 10 (±3) minutes, 1 hour (±15 minutes), 6 (±1) hours, 24 (±2) hours (Day 1), 48 (±2) hours (Day 2), and 72 (±2) hours (Day 3) from the start of the injection. Sampling for rFVIIIFc PK profiling was conducted at Day 0 (directly following at least 96 hours washout from Advate PK profiling or within 4 weeks of the Advate dose or other rFVIII product) and repeated 12 to 24 weeks later at the following timepoints: preinjection and at 30 (±3) minutes (or 10 (±3) minutes), 1 hour (±15 minutes), 6 (±1) hours, 24 (±2) hours (Day 1), 72 (±2) hours (Day 3), 96 (±2) hours (Day 4), and 120 (±2) hours (Day 5) from the start of the injection.
    End point type
    Secondary
    End point timeframe
    See endpoint description for complete time frame.
    End point values
    Arm 1: Individualized Prophylaxis: Sequential PK Subgroup
    Number of subjects analysed
    27 [46]
    Units: mL/h/kg
    geometric mean (confidence interval 95%)
        rFVIIIFc Baseline
    2.108 (1.846 to 2.407)
        Advate
    3.566 (3.159 to 4.024)
    Notes
    [46] - Subjects who had evaluable two-stage PK profiles for both Advate and baseline rFVIIIFc.
    No statistical analyses for this end point

    Secondary: Mean Residence Time (MRT; Two-stage Chromogenic Assay)

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    End point title
    Mean Residence Time (MRT; Two-stage Chromogenic Assay)
    End point description
    The average time that a drug molecule is present in the systemic circulation. Sampling for Advate PK profiling was conducted, following at least 96 hours of washout, at these timepoints: preinjection and at either 30 (±3) minutes or 10 (±3) minutes, 1 hour (±15 minutes), 6 (±1) hours, 24 (±2) hours (Day 1), 48 (±2) hours (Day 2), and 72 (±2) hours (Day 3) from the start of the injection. Sampling for rFVIIIFc PK profiling was conducted at Day 0 (directly following at least 96 hours washout from Advate PK profiling or within 4 weeks of the Advate dose or other rFVIII product) and repeated 12 to 24 weeks later at the following timepoints: preinjection and at 30 (±3) minutes (or 10 (±3) minutes), 1 hour (±15 minutes), 6 (±1) hours, 24 (±2) hours (Day 1), 72 (±2) hours (Day 3), 96 (±2) hours (Day 4), and 120 (±2) hours (Day 5) from the start of the injection.
    End point type
    Secondary
    End point timeframe
    See endpoint description for complete time frame.
    End point values
    Arm 1: Individualized Prophylaxis: Sequential PK Subgroup
    Number of subjects analysed
    27 [47]
    Units: hours
    geometric mean (confidence interval 95%)
        rFVIIIFc Baseline
    24.96 (22.41 to 27.8)
        Advate
    15.94 (14.7 to 17.27)
    Notes
    [47] - Subjects who had evaluable two-stage PK profiles for both Advate and baseline rFVIIIFc.
    No statistical analyses for this end point

    Secondary: Incremental Recovery (Two-stage Chromogenic Assay)

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    End point title
    Incremental Recovery (Two-stage Chromogenic Assay)
    End point description
    The rise in FVIII activity in IU/dL per unit dose administered in IU/kg. Sampling for Advate PK profiling was conducted, following at least 96 hours of washout, at these timepoints: preinjection and at either 30 (±3) minutes or 10 (±3) minutes, 1 hour (±15 minutes), 6 (±1) hours, 24 (±2) hours (Day 1), 48 (±2) hours (Day 2), and 72 (±2) hours (Day 3) from the start of the injection. Sampling for rFVIIIFc PK profiling was conducted at Day 0 (directly following at least 96 hours washout from Advate PK profiling or within 4 weeks of the Advate dose or other rFVIII product) and repeated 12 to 24 weeks later at the following timepoints: preinjection and at 30 (±3) minutes (or 10 (±3) minutes), 1 hour (±15 minutes), 6 (±1) hours, 24 (±2) hours (Day 1), 72 (±2) hours (Day 3), 96 (±2) hours (Day 4), and 120 (±2) hours (Day 5) from the start of the injection.
    End point type
    Secondary
    End point timeframe
    See endpoint description for complete time frame.
    End point values
    Arm 1: Individualized Prophylaxis: Sequential PK Subgroup
    Number of subjects analysed
    27 [48]
    Units: IU/dL per IU/kg
    geometric mean (confidence interval 95%)
        rFVIIIFc Baseline
    2.4912 (2.2762 to 2.7265)
        Advate
    2.5589 (2.3247 to 2.8168)
    Notes
    [48] - Subjects who had evaluable two-stage PK profiles for both Advate and baseline rFVIIIFc.
    No statistical analyses for this end point

    Secondary: Hemophilia-Specific Quality of Life Index for Adults (Haem-A-QoL) Questionnaire: Change From Baseline to Week 14

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    End point title
    Hemophilia-Specific Quality of Life Index for Adults (Haem-A-QoL) Questionnaire: Change From Baseline to Week 14 [49]
    End point description
    The Haem-A-QoL consists of items pertaining to 10 domains specific to living with hemophilia and was administered to adult subjects (17 years and older). The 10 domains are: physical health, feeling, view of yourself, sports/leisure, school/work, dealing with hemophilia, and treatment (time frame for all 7 domains, during the last month) and future, family planning, and outlook for the future (time frame for all 3 domains, recently). Lower scores represent better QoL; therefore, a negative change from baseline represents improvement during the course of the study. Scores on a scale range between 0 and 100. Subjects in Arm 1 were stratified by their prestudy regimen (either prophylaxis or on demand). Full Analysis Set: subjects over 17 years of age who received at least 1 dose of rFVIIIFc and had an assessment; n=subjects who had specified assessment at given timepoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 14
    Notes
    [49] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: For this endpoint, the Individualized Prophylaxis arm (Arm 1) is broken down by the subject's prestudy treatment regimen (either Prestudy Prophylaxis or Prestudy On-demand). Both are presented here.
    End point values
    Arm 2: Weekly Prophylaxis Arm 3: Episodic (On-Demand) Dosing Arm 1: Individualized Prophylaxis, Prestudy Prophylaxis Arm 1: Individualized Prophylaxis, Prestudy On-demand
    Number of subjects analysed
    15
    17
    69
    22
    Units: units on a scale
    median (full range (min-max))
        Total Score; n=57, 17, 14, 14
    -4.73 (-30.5 to 3.2)
    -2.09 (-25.1 to 5.4)
    -2.18 (-25 to 20.9)
    -1.48 (-28.6 to 5.1)
        Physical Health; n=68, 22, 15, 17
    -10 (-40 to 10)
    0 (-55 to 40)
    -5 (-70 to 75)
    -12.5 (-42.5 to 45)
        Feeling; n=68, 22, 15, 17
    -6.25 (-50 to 6.3)
    -6.25 (-37.5 to 6.3)
    0 (-43.8 to 43.8)
    -6.25 (-37.5 to 12.5)
        View of Yourself; n=68, 22, 15, 17
    0 (-30 to 15)
    -5 (-40 to 20)
    0 (-70 to 25)
    5 (-30 to 25)
        Sports and Leisure; n=48, 12, 12, 8
    -10 (-30 to 0)
    -2.5 (-30 to 15)
    0 (-55 to 40)
    -2.5 (-25 to 18.8)
        Work and School; n=53, 17,13, 14
    0 (-31.3 to 39.6)
    0 (-58.3 to 12.5)
    -6.25 (-56.3 to 25)
    -6.25 (-37.5 to 25)
        Dealing with Hemophilia; n=65, 22, 15, 17
    0 (-25 to 41.7)
    0 (-50 to 100)
    0 (-33.3 to 50)
    0 (-25 to 16.7)
        Treatment; n=68, 21, 15, 16
    -3.13 (-31.3 to 18.8)
    0 (-21.9 to 18.8)
    -3.13 (-37.1 to 21.9)
    -3.13 (-43.8 to 31.3)
        Future; n=66, 21, 15, 17
    -5 (-35 to 15)
    -5 (-55 to 25)
    2.5 (-35 to 25)
    0 (-30 to 55)
        Family Planning; n=38, 10, 8, 7
    0 (-50 to 8.3)
    -2.08 (-31.3 to 0)
    0 (-31.3 to 18.8)
    0 (-18.8 to 31.3)
        Partnership and Sexuality; n=62, 20, 15, 17
    0 (-41.7 to 0)
    0 (-100 to 25)
    0 (-25 to 41.7)
    0 (-25 to 58.3)
    No statistical analyses for this end point

    Secondary: Hemophilia-Specific Quality of Life Index for Adults (Haem-A-QoL) Questionnaire: Change From Baseline to Week 28

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    End point title
    Hemophilia-Specific Quality of Life Index for Adults (Haem-A-QoL) Questionnaire: Change From Baseline to Week 28 [50]
    End point description
    The Haem-A-QoL consists of items pertaining to 10 domains specific to living with hemophilia and was administered to adult subjects (17 years and older). The 10 domains are: physical health, feeling, view of yourself, sports/leisure, school/work, dealing with hemophilia, and treatment (time frame for all 7 domains, during the last month) and future, family planning, and outlook for the future (time frame for all 3 domains, recently). Lower scores represent better QoL; therefore, a negative change from baseline represents improvement during the course of the study. Scores on a scale range between 0 and 100. Subjects in Arm 1 were stratified by their prestudy regimen (either prophylaxis or on demand). Full Analysis Set: subjects over 17 years of age who received at least 1 dose of rFVIIIFc and had an assessment; n=subjects who had specified assessment at given timepoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 28
    Notes
    [50] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: For this endpoint, the Individualized Prophylaxis arm (Arm 1) is broken down by the subject's prestudy treatment regimen (either Prestudy Prophylaxis or Prestudy On-demand). Both are presented here.
    End point values
    Arm 2: Weekly Prophylaxis Arm 3: Episodic (On-Demand) Dosing Arm 1: Individualized Prophylaxis, Prestudy Prophylaxis Arm 1: Individualized Prophylaxis, Prestudy On-demand
    Number of subjects analysed
    3
    7
    42
    17
    Units: units on a scale
    median (full range (min-max))
        Total Score; n=34, 12, 3, 5
    -5.81 (-9.8 to 5.4)
    -0.56 (-11.2 to 3.4)
    -1.03 (-26.7 to 11.5)
    -4.31 (-35.6 to 13.9)
        Physical Health; n=40, 17, 3, 7
    -5 (-45 to -5)
    0 (-15 to 20)
    0 (-31.3 to 60)
    -25 (-65 to 25)
        Feeling; n=40, 17, 3, 7
    -6.25 (-18.8 to 6.3)
    0 (-12.5 to 18.8)
    -3.13 (-50 to 25)
    -6.25 (-50 to 18.8)
        View of Yourself; n=42, 17, 3, 7
    0 (-5 to 5)
    0 (-5 to 15)
    0 (-40 to 35)
    0 (-40 to 20)
        Sports and Leisure; n=29, 10, 2, 5
    -10 (-25 to 5)
    5 (-8.8 to 5)
    0 (-68.8 to 45)
    -5 (-50 to 5)
        Work and School; n=34, 15, 2, 6
    -9.38 (-18.8 to 0)
    -3.13 (-25 to 6.3)
    0 (-50 to 37.5)
    -6.25 (-56.3 to 25)
        Dealing with Hemophilia; n=40, 17, 3, 7
    0 (-16.7 to 25)
    0 (-16.7 to 8.3)
    0 (-33.3 to 33.3)
    0 (-25 to 58.3)
        Treatment; n=42, 14, 3, 7
    6.25 (-12.5 to 28.1)
    0 (-18.8 to 6.3)
    0 (-28.1 to 18.8)
    -4.69 (-43.8 to 12.5)
        Future; n=40, 17, 3, 6
    -5 (-20 to -5)
    7.5 (-15 to 10)
    0 (-45 to 35)
    -5 (-45 to 60)
        Family Planning; n=19, 10, 2, 2
    0 (0 to 0)
    9.38 (0 to 18.8)
    0 (-25 to 16.7)
    0 (-18.8 to 33.3)
        Partnership and Sexuality; n=37, 14, 3, 7
    0 (-8.3 to 0)
    0 (-25 to 8.3)
    0 (-25 to 66.7)
    0 (-25 to 91.7)
    No statistical analyses for this end point

    Secondary: Hemophilia-Specific Quality of Life Index for Children (Haemo-QoL) Questionnaire: Change From Baseline to Week 14 and Week 28 in Haemo-QoL III Total Score

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    End point title
    Hemophilia-Specific Quality of Life Index for Children (Haemo-QoL) Questionnaire: Change From Baseline to Week 14 and Week 28 in Haemo-QoL III Total Score
    End point description
    The Haemo-QoL III, a quality of life assessment instrument for adolescents with hemophilia, was administered to subjects from 13 to 16 years old. This instrument assesses domains specific to living with hemophilia and consists of 12 domains: physical health, feeling, view of yourself, family, friends, others, sports and school, treatment, perceived support, dealing with hemophilia, future, and relationships. Total HAEMO-QoL score is the sum of all raw scores for all subscales for subjects for whom at least the minimum number of required questions have been answered. Total scores are presented as the Transformed Scale Score (TSS) from 0-100%, with lower scores indicating a better quality of life. A negative change indicates improvement. Full Analysis Set: subjects 13 to 16 years of age who received at least 1 dose of rFVIIIFc and had an assessment; n=subjects who had specified assessment at given timepoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 14, Week 28
    End point values
    Arm 1: Individualized (Tailored) Prophylaxis Arm 2: Weekly Prophylaxis Arm 3: Episodic (On-Demand) Dosing
    Number of subjects analysed
    8
    0 [51]
    2 [52]
    Units: units on a scale
    median (full range (min-max))
        Baseline; n=8, 0, 2
    11.2 (-6.2 to -1.3)
    ( to )
    26.3 (16.2 to 36.4)
        Change from Baseline at Week 14; n=8, 0, 1
    -3.25 (6.5 to 38.3)
    ( to )
    -5.01 (-5.01 to -5.01)
        Change from Baseline at Week 28; n=4, 0, 0
    -3.73 (-21.9 to 2.3)
    ( to )
    0 (0 to 0)
    Notes
    [51] - No subjects had an assessment for this reporting group.
    [52] - All values of '0' for Week 28 are actually 'NA', since there were no subjects analyzed.
    No statistical analyses for this end point

    Secondary: Investigators'/Surgeons' Assessment of Subjects' Response to rFVIIIFc for Major Surgery

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    End point title
    Investigators'/Surgeons' Assessment of Subjects' Response to rFVIIIFc for Major Surgery
    End point description
    Based on the first assessment of hemostasis by the surgeon/investigator 24 hours or later post-surgery. Scaled responses: Excellent = 1, Good = 2, Fair = 3, Poor/none = 4. Subjects in the Full Analysis Set who received at least 1 dose of rFVIIIFc and underwent major surgery.
    End point type
    Secondary
    End point timeframe
    up to 52 weeks
    End point values
    Any Arm: Perioperative Management (Surgery) Subgroup
    Number of subjects analysed
    9 [53]
    Units: responses
        Excellent or Good
    9
        Excellent
    8
        Good
    1
        Fair
    0
        Poor/None
    0
    Notes
    [53] - Number of major surgeries analyzed=9
    No statistical analyses for this end point

    Secondary: Number of Injections Required to Maintain Hemostasis During Major Surgery

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    End point title
    Number of Injections Required to Maintain Hemostasis During Major Surgery
    End point description
    The number of injections to maintain hemostasis during surgery includes all injections for surgery purposes, including from the loading dose to the end date/time of surgery. Subjects in the Full Analysis Set who received at least 1 dose of rFVIIIFc and underwent major surgery.
    End point type
    Secondary
    End point timeframe
    up to 52 weeks
    End point values
    Any Arm: Perioperative Management (Surgery) Subgroup
    Number of subjects analysed
    9 [54]
    Units: injections
        median (full range (min-max))
    1 (1 to 1)
    Notes
    [54] - Number of major surgeries analyzed=9
    No statistical analyses for this end point

    Secondary: Dose Per Injection and Total Dose Required to Maintain Hemostasis During Major Surgery

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    End point title
    Dose Per Injection and Total Dose Required to Maintain Hemostasis During Major Surgery
    End point description
    Mean dose per injection is the average dose for all injections (including loading dose) needed to maintain hemostasis during surgery. Total dose is the sum across all injections (including loading dose) needed to maintain hemostasis during surgery. Subjects in the Full Analysis Set who received at least 1 dose of rFVIIIFc and underwent major surgery.
    End point type
    Secondary
    End point timeframe
    up to 52 weeks ± 2 weeks
    End point values
    Any Arm: Perioperative Management (Surgery) Subgroup
    Number of subjects analysed
    9 [55]
    Units: IU/kg
    median (full range (min-max))
        Dose per Injection
    51.4 (50 to 77)
        Total Dose
    51.4 (50 to 77)
    Notes
    [55] - Number of major surgeries analyzed=9
    No statistical analyses for this end point

    Secondary: Estimated Total Blood Loss During Major Surgery

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    End point title
    Estimated Total Blood Loss During Major Surgery
    End point description
    Subjects in the Full Analysis Set who received at least 1 dose of rFVIIIFc, underwent major surgery, and had blood loss during surgery information available.
    End point type
    Secondary
    End point timeframe
    up to 52 weeks ± 2 weeks
    End point values
    Any Arm: Perioperative Management (Surgery) Subgroup
    Number of subjects analysed
    9 [56]
    Units: mL
        median (full range (min-max))
    15 (0 to 600)
    Notes
    [56] - Number of major surgeries analyzed=7
    No statistical analyses for this end point

    Secondary: Number of Transfusions Required Per Surgery

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    End point title
    Number of Transfusions Required Per Surgery
    End point description
    Number of blood component transfusions during a single surgery. Subjects in the Full Analysis Set who received at least 1 dose of rFVIIIFc and underwent major surgery.
    End point type
    Secondary
    End point timeframe
    up to 52 weeks ± 2 weeks
    End point values
    Any Arm: Perioperative Management (Surgery) Subgroup
    Number of subjects analysed
    9 [57]
    Units: surgeries
        0 transfusions
    8
        1 transfusion
    0
        2 transfusions
    1
        3 transfusions
    0
        > 3 transfusions
    0
    Notes
    [57] - Number of major surgeries analyzed=9
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    up to 52 weeks + 30 days ± 1 week
    Adverse event reporting additional description
    Based on subjects treated with rFVIIIFc in each arm. One subject in Individualized (Tailored) Prophylaxis arm received only Advate and was not included in the treatment-emergent AE table. Does not include SAEs emergent during surgical/rehabilitation period (see Endpoint 2 for a summary of treatment-emergent events for this subgroup).
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    15.0
    Reporting groups
    Reporting group title
    Arm 1: Individualized (Tailored) Prophylaxis, rFVIIIFc
    Reporting group description
    Initial twice weekly dosing with 25 IU/kg of rFVIIIFc via IV injection on Day 1 and 50 IU/kg on Day 4, followed by individualized dose and interval modification within the range of 25 to 65 IU/kg every 3 to 5 days to maintain a trough level of 1% to 3% (or higher, as clinically indicated) rFVIIIFc activity. Prior to rFVIIIFc treatment, on rFVIIIFc Day 0, all subjects underwent PK analysis with rFVIIIFc in order to estimate subject's PK parameters and guide the appropriate dose or interval of dosing. Repeat PK profiling with a single dose of 50 IU/kg rFVIIIFc was conducted at Week 14 or after 12 to 24 weeks of prophylaxis with rFVIIIFc. A subset of subjects (Sequential PK Subgroup) also had PK profiling performed with a single dose of 50 IU/kg Advate (Advate Day 0) within 8 weeks prior to rFVIIIFc Day 0. A >= 96 hour washout from Advate or any other FVIII product was performed before the first PK dose of rFVIIIFc was administered.

    Reporting group title
    Arm 2: Weekly Prophylaxis
    Reporting group description
    65 IU/kg of rFVIIIFc via IV injection every 7 days

    Reporting group title
    Arm 3: Episodic (On-Demand) Dosing
    Reporting group description
    Initial single dose of 50 IU/kg of rFVIIIFc via IV injection followed by 10 to 50 IU/kg rFVIIIFc, as required to treat a bleeding episode.

    Serious adverse events
    Arm 1: Individualized (Tailored) Prophylaxis, rFVIIIFc Arm 2: Weekly Prophylaxis Arm 3: Episodic (On-Demand) Dosing
    Total subjects affected by serious adverse events
         subjects affected / exposed
    10 / 117 (8.55%)
    2 / 24 (8.33%)
    0 / 23 (0.00%)
         number of deaths (all causes)
    1
    0
    0
         number of deaths resulting from adverse events
    Vascular disorders
    Hypertensive emergency
         subjects affected / exposed
    1 / 117 (0.85%)
    0 / 24 (0.00%)
    0 / 23 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Face injury
         subjects affected / exposed
    1 / 117 (0.85%)
    0 / 24 (0.00%)
    0 / 23 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Femur fracture
         subjects affected / exposed
    0 / 117 (0.00%)
    1 / 24 (4.17%)
    0 / 23 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Overdose
         subjects affected / exposed
    1 / 117 (0.85%)
    0 / 24 (0.00%)
    0 / 23 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Cardiac disorders
    Tachycardia
         subjects affected / exposed
    1 / 117 (0.85%)
    0 / 24 (0.00%)
    0 / 23 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Respiratory distress
         subjects affected / exposed
    1 / 117 (0.85%)
    0 / 24 (0.00%)
    0 / 23 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Restless legs syndrome
         subjects affected / exposed
    1 / 117 (0.85%)
    0 / 24 (0.00%)
    0 / 23 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    1 / 117 (0.85%)
    0 / 24 (0.00%)
    0 / 23 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Completed suicide
         subjects affected / exposed
    1 / 117 (0.85%)
    0 / 24 (0.00%)
    0 / 23 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Inguinal hernia
         subjects affected / exposed
    1 / 117 (0.85%)
    0 / 24 (0.00%)
    0 / 23 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tooth disorder
         subjects affected / exposed
    1 / 117 (0.85%)
    0 / 24 (0.00%)
    0 / 23 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Nephrolithiasis
         subjects affected / exposed
    0 / 117 (0.00%)
    1 / 24 (4.17%)
    0 / 23 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    1 / 117 (0.85%)
    0 / 24 (0.00%)
    0 / 23 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haemarthrosis
         subjects affected / exposed
    1 / 117 (0.85%)
    0 / 24 (0.00%)
    0 / 23 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lumbar spinal stenosis
         subjects affected / exposed
    1 / 117 (0.85%)
    0 / 24 (0.00%)
    0 / 23 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Myalgia
         subjects affected / exposed
    1 / 117 (0.85%)
    0 / 24 (0.00%)
    0 / 23 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Arm 1: Individualized (Tailored) Prophylaxis, rFVIIIFc Arm 2: Weekly Prophylaxis Arm 3: Episodic (On-Demand) Dosing
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    32 / 117 (27.35%)
    8 / 24 (33.33%)
    7 / 23 (30.43%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    5 / 117 (4.27%)
    6 / 24 (25.00%)
    2 / 23 (8.70%)
         occurrences all number
    6
    7
    2
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    10 / 117 (8.55%)
    2 / 24 (8.33%)
    1 / 23 (4.35%)
         occurrences all number
    11
    3
    1
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    16 / 117 (13.68%)
    1 / 24 (4.17%)
    3 / 23 (13.04%)
         occurrences all number
    24
    1
    3
    Upper respiratory tract infection
         subjects affected / exposed
    6 / 117 (5.13%)
    0 / 24 (0.00%)
    3 / 23 (13.04%)
         occurrences all number
    7
    0
    3

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    13 Jun 2011
    - The required washout period from any FVIII product before collecting blood samples for PK assessment was reduced from 96 hours to 72 hours for adolescent subjects. - The inclusion criteria defining the cut-off value in international normalized ratio (INR) was removed. - Exclusion Criterion #1 was amended to define a positive inhibitor value.
    02 Apr 2012
    - The end-of-study definition was further clarified. - The criteria for recommending a modification of dose or dosing interval for subjects in Arm 1 were clarified.

    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

    Online references

    http://www.ncbi.nlm.nih.gov/pubmed/25196897
    http://www.ncbi.nlm.nih.gov/pubmed/24227821
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