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    Clinical Trial Results:
    An Open-Label, Multicenter Evaluation of the Safety and Efficacy of Recombinant Coagulation Factor VIII Fc Fusion Protein (rFVIIIFc; BIIB031) in the Prevention and Treatment of Bleeding in Previously Untreated Patients With Severe Hemophilia A

    Summary
    EudraCT number
    		 2013-005512-10
    Trial protocol
    		 GB   IE   IT   ES   SE   DE   PL   FR   DK   NL  
    Global end of trial date
    23 Sep 2019

    Results information
    Results version number
    		 v1(current)
    This version publication date
    03 Apr 2020
    First version publication date
    03 Apr 2020
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    997HA306
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02234323
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 PUPs A: EFC16225
    Sponsors
    Sponsor organisation name
    Bioverativ, a Sanofi company
    Sponsor organisation address
    225 Second Avenue, Waltham, Massachusetts (MA), United States, 02451
    Public contact
    Trial Transparency Team, Bioverativ, a Sanofi company, clinicaltrials@bioverativ.com
    Scientific contact
    Trial Transparency Team, Bioverativ, a Sanofi company, clinicaltrials@bioverativ.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
    18 Nov 2019
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    23 Sep 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the safety of Recombinant Coagulation Factor VIII Fc Fusion Protein (rFVIIIFc) in previously untreated patients (PUPs) with severe hemophilia A.
    Protection of trial subjects
    The study was conducted by investigators experienced in the treatment of pediatric patients. The parent(s) or guardian(s) as well as the children were fully informed of all pertinent aspects of the clinical trial as well as the possibility to discontinue at any time. In addition to the consent form for the parent(s)/guardian(s), an assent form in child-appropriate language was provided and explained to the child. Repeated invasive procedures were minimized. The number of blood samples as well as the amount of blood drawn were adjusted according to age and weight. A topical anesthesia may have been used to minimize distress and discomfort.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    12 Jan 2015
    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
    Poland: 8
    Country: Number of subjects enrolled
    Spain: 2
    Country: Number of subjects enrolled
    Sweden: 2
    Country: Number of subjects enrolled
    United Kingdom: 15
    Country: Number of subjects enrolled
    France: 4
    Country: Number of subjects enrolled
    Germany: 6
    Country: Number of subjects enrolled
    Ireland: 6
    Country: Number of subjects enrolled
    Italy: 11
    Country: Number of subjects enrolled
    Australia: 7
    Country: Number of subjects enrolled
    Brazil: 14
    Country: Number of subjects enrolled
    Canada: 11
    Country: Number of subjects enrolled
    New Zealand: 1
    Country: Number of subjects enrolled
    United States: 21
    Worldwide total number of subjects
    108
    EEA total number of subjects
    54
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    6
    Infants and toddlers (28 days-23 months)
    93
    Children (2-11 years)
    9
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    0
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 The study was conducted at 44 active centers in 13 countries between 12-Jan-2015 to 23-Sep-2019.

    Pre-assignment
    Screening details
    		 110 subjects screened, 108 enrolled, 103 received drug.

    Period 1
    Period 1 title
    All Enrolled
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 Not Applicable
    Arm description
    		 -
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 1
    		Not Applicable
    Started
    108
    Completed
    103
    Not completed
    5
         Not Treated: Exceeded lab value limit
    1
         Not Treated: Consent withdrawn by subject
    2
         Not Treated: Completed study in database (DB)
    2
    Period 2
    Period 2 title
    All Treated
    Is this the baseline period?
    		 Yes [1]
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 Recombinant Coagulation Factor VIII Fc Fusion Protein
    Arm description
    		 Subjects were to receive rFVIIIFc as follows -PR (Prophylaxis regimen): rFVIIIFc 25-80 international units per kilogram (IU/kg), weekly until subject reached >= 50 exposure days (ED: 24-hour period in which >=1 injection/dose of rFVIIIFc was given), or study withdrawal/end of study. Adjustments to dose/dosing interval was done as needed by investigator; Treatment with an optional ER (Episodic regimen) can be initiated before PR at investigators discretion; ITI: rFVIIIFc 200 IU/kg, daily for subjects who, after exposure to rFVIIIFc, had positive high titre inhibitor (>=5.00 Bethesda Units per milliliter [BU/mL]) or positive low titre inhibitor (>=0.60 and <5.00 BU/mL) and had poorly controlled bleeding despite increased rFVIIIFc doses, or required bypassing agent to treat bleeding.
    Arm type
    		 Experimental

    Investigational medicinal product name
    rFVIIIFc
    Investigational medicinal product code
    Other name
    BIIB031
    Pharmaceutical forms
    Powder and solvent for solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects received rFVIIIFc as an intravenous (IV) injection for one or more of three treatment regimens: episodic, prophylactic and ITI.

    Notes
    [1] - Period 1 is not the baseline period. It is expected that period 1 will be the baseline period.
    Justification: Baseline data was reported for safety analysis set which was less than all enrolled set. Period 2 shows the disposition of safety analysis set.
    Number of subjects in period 2 [2]
    		Recombinant Coagulation Factor VIII Fc Fusion Protein
    Started
    103
    Episodic Treatment Regimen
    81 [3]
    Prophylactic Treatment Regimen
    89
    Immune Tolerance Induction (ITI)
    15 [4]
    Completed
    85
    Not completed
    18
         Physician decision
    5
         Death
    1
         Unspecified
    7
         Exceeded lab value limit
    2
         Lack of efficacy
    3
    Notes
    [2] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: Baseline data was reported for safety analysis set which was less than all enrolled set. Period 2 shows the disposition of safety analysis set.
    [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: Subjects could be treated in more than one regimen and were counted in all categories wherever applicable.
    [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: Subjects could be treated in more than one regimen and were counted in all categories wherever applicable.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    All Treated
    Reporting group description
    		 The Safety Analysis Set was defined as all subjects who received at least 1 dose of rFVIIIFc.

    Reporting group values
    		 All Treated Total
    Number of subjects
    		 103 103
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        median (full range (min-max))
    		 0.58 (0.02 to 4.00) -
    Gender categorical
    Units: Subjects
        Female
    		 0 0
        Male
    		 103 103
    Race
    Units: Subjects
        White
    		 79 79
        Black or African-American
    		 2 2
        Asian
    		 5 5
        American Indian or Alaska Native
    		 0 0
        Native Hawaiian or other Pacific Islander
    		 2 2
        Not reported due to confidentiality regulations
    		 4 4
        Other
    		 11 11

    End points

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    End points reporting groups
    Reporting group title
    Not Applicable
    Reporting group description
    		 -
    Reporting group title
    Recombinant Coagulation Factor VIII Fc Fusion Protein
    Reporting group description
    		 Subjects were to receive rFVIIIFc as follows -PR (Prophylaxis regimen): rFVIIIFc 25-80 international units per kilogram (IU/kg), weekly until subject reached >= 50 exposure days (ED: 24-hour period in which >=1 injection/dose of rFVIIIFc was given), or study withdrawal/end of study. Adjustments to dose/dosing interval was done as needed by investigator; Treatment with an optional ER (Episodic regimen) can be initiated before PR at investigators discretion; ITI: rFVIIIFc 200 IU/kg, daily for subjects who, after exposure to rFVIIIFc, had positive high titre inhibitor (>=5.00 Bethesda Units per milliliter [BU/mL]) or positive low titre inhibitor (>=0.60 and <5.00 BU/mL) and had poorly controlled bleeding despite increased rFVIIIFc doses, or required bypassing agent to treat bleeding.

    Primary: Percentage of Subjects With Confirmed Inhibitor Development as Measured by the Nijmegen-Modified Bethesda Assay

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    End point title
    		 Percentage of Subjects With Confirmed Inhibitor Development as Measured by the Nijmegen-Modified Bethesda Assay [1]
    End point description
    A positive inhibitor result occurs when a subject has a value >=0.6 Bethesda Units (BU)/mL by central laboratory testing using Nijmegen-modified Bethesda assay, that is confirmed on re-testing of a separate sample collected >=2 weeks after the initial sample. Exposure day (ED) is a 24-hour period in which subject received >=1 dose of rFVIIIFc injections. Positive inhibitor incidence rate=Number of subjects with an inhibitor/Number of subjects reaching >=10 EDs and had >=1 inhibitor test performed at or beyond this milestone or who have an inhibitor. Any subject who develops an inhibitor following the initial rFVIIIFc administration will be included in the numerator and denominator. Analysis performed on subjects in safety analysis set (all subjects who received >=1 dose of study treatment) meeting above criteria.
    End point type
    Primary
    End point timeframe
    Up to 3 years
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Analysis was descriptive in nature, no inferential analysis was provided.
    End point values
    		 Recombinant Coagulation Factor VIII Fc Fusion Protein
    Number of subjects analysed
    90
    Units: percentage of subjects
        number (confidence interval 95%)
    31.11 (21.77 to 41.74)
    No statistical analyses for this end point

    Secondary: Annualized Number of Bleeding Episodes (Spontaneous and Traumatic) per Subject (Annualized Bleeding Rate [ABR])

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    End point title
    		 Annualized Number of Bleeding Episodes (Spontaneous and Traumatic) per Subject (Annualized Bleeding Rate [ABR])
    End point description
    ABR is annualized number of bleeding episodes during efficacy period (EP) per subject annualized to a 1-year interval of time. Bleeding episodes were classified as spontaneous if parent/caregiver/subject records bleeding event when there is no known contributing factor such as definite trauma or antecedent “strenuous” activity and as traumatic when there is known reason for bleed. ABR=(Number of bleeding episodes during EP/total number of days during EP)*365.25. EP is sum of all intervals of time during which subjects were treated with rFVIIIFc per treatment regimens of study excluding surgical/rehabilitation periods and large injection intervals (greater than [>]28 days). Subjects were included in summary of more than 1 treatment regimen if their regimen changed during study. Analysis performed on Full Analysis Set (FAS) subjects within the EP. FAS included all enrolled subjects with >=1 dose of study treatment. n= number of FAS subjects analysed in each treatment regimen.
    End point type
    Secondary
    End point timeframe
    Up to 3 years
    End point values
    		 Recombinant Coagulation Factor VIII Fc Fusion Protein
    Number of subjects analysed
    101
    Units: episodes per subject per year
    median (full range (min-max))
        Episodic Treatment (n= 81)
    2.24 (0.0 to 39.8)
        Prophylaxis Treatment (n= 89)
    1.49 (0.0 to 18.7)
        ITI Treatment (n= 15)
    0.00 (0.0 to 6.6)
    No statistical analyses for this end point

    Secondary: Annualized Number of Spontaneous Joint Bleeding Episodes

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    End point title
    		 Annualized Number of Spontaneous Joint Bleeding Episodes
    End point description
    Bleeding episodes were classified as spontaneous if parent/caregiver/subject records a bleeding event when there is no known contributing factor such as a definite trauma or antecedent “strenuous” activity. Annualized spontaneous joint bleeding episodes=(Total number of spontaneous joint bleeding episodes during EP divided by total number of days during EP)*365.25. EP reflects sum of all intervals of time during which subjects were treated with rFVIIIFc per treatment regimen excluding major and minor surgical/rehabilitation periods and large injection intervals (> 28 days). Bleeding episodes were summarized by treatment regimen. Subjects were included in summary of more than 1 treatment regimen if their regimen changed during study. Analysis performed on FAS subjects within the EP. Here, ‘n’ signifies number of FAS subjects who were analysed in each treatment regimen.
    End point type
    Secondary
    End point timeframe
    Up to 3 years
    End point values
    		 Recombinant Coagulation Factor VIII Fc Fusion Protein
    Number of subjects analysed
    101
    Units: episodes per subject per year
    median (inter-quartile range (Q1-Q3))
        Episodic Treatment (n= 81)
    0.00 (0.0 to 0.0)
        Prophylaxis Treatment (n= 89)
    0.00 (0.0 to 0.0)
        ITI Treatment (n= 15)
    0.00 (0.0 to 0.0)
    No statistical analyses for this end point

    Secondary: Number of rFVIIIFc Injections with Excellent or Good, Moderate or None Treatment Response Assessed Using a 4-Point Scale

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    End point title
    		 Number of rFVIIIFc Injections with Excellent or Good, Moderate or None Treatment Response Assessed Using a 4-Point Scale
    End point description
    Using e-diary, each subject’s parent/caregiver rated treatment response to any bleeding episode (BE) at approximately (approx.) 8-12 hours(hr) from time of injection and prior to additional doses of rFVIIIFc given for same BE, using 4-point scale: 1=Excellent: abrupt pain relief and/or improvement in signs of bleeding within approx. 8hr after initial injection; 2=Good: definite pain relief and/or improvement in signs of bleeding within approx. 8hr after injection, but possibly requiring more than 1 injection after 24–48 hr for complete resolution; 3=Moderate: Probable/slight beneficial effect within 8 hr after initial injection and requires more than 1 injection and 4=None: No improvement or condition worsens within approx. 8 hr after initial injection. Subjects included in more than 1 treatment regimen if their regimen changed during study. Analysis performed on FAS subjects within the EP and based on all injections. n= number of injections reported for each treatment regimen.
    End point type
    Secondary
    End point timeframe
    Up to 3 years
    End point values
    		 Recombinant Coagulation Factor VIII Fc Fusion Protein
    Number of subjects analysed
    101
    Units: responses to injections
    number (not applicable)
        Episodic Regimen: Excellent or Good (n=238)
    102
        Episodic Regimen: Moderate (n=238)
    16
        Episodic Regimen: None (n=238)
    2
        Episodic Regimen: Response not provided (n=238)
    118
        Prophylaxis regimen: Excellent or Good (n=293)
    163
        Prophylaxis regimen: Moderate (n=293)
    27
        Prophylaxis regimen: None (n=293)
    14
        Prophylaxis regimen: Response not provided (n=293)
    89
        ITI regimen: Excellent or Good (n=48)
    20
        ITI regimen: Moderate (n=48)
    14
        ITI regimen: None (n=48)
    3
        ITI regimen: Response not provided (n=48)
    11
    No statistical analyses for this end point

    Secondary: Total Number of Exposure Days (EDs)

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    End point title
    		 Total Number of Exposure Days (EDs)
    End point description
    An ED was defined as a 24-hour period in which a subject received one or more doses of rFVIIIFc injections, with the time of the first injection of rFVIIIFc defined as the start of the ED. Subjects who did not have a particular injection type are counted as having zero injections for that type. Analysis performed on safety analysis set.
    End point type
    Secondary
    End point timeframe
    Up to 3 years
    End point values
    		 Recombinant Coagulation Factor VIII Fc Fusion Protein
    Number of subjects analysed
    103
    Units: days
        median (full range (min-max))
    100.0 (0 to 649)
    No statistical analyses for this end point

    Secondary: Total Annualized rFVIIIFc Consumption per Subject for the Prevention and Treatment of Bleeding Episodes

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    End point title
    		 Total Annualized rFVIIIFc Consumption per Subject for the Prevention and Treatment of Bleeding Episodes
    End point description
    Total annualized rFVIIIFc consumption (in IU/kg) was calculated for each subject as: Annualized consumption = (Total IU/kg of rFVIIIFc during EP divided by total number of days during EP)*365.25. EP reflects the sum of all intervals of time during which subjects are treated with rFVIIIFc according to the treatment regimens of the study excluding surgical/rehabilitation periods and large injection intervals (>28 days). Subjects were included in summary of more than 1 treatment regimen if their regimen changed during study. Analysis performed on FAS subjects within the EP. Here, ‘n’ signifies number of FAS subjects who were analysed in each treatment regimen.
    End point type
    Secondary
    End point timeframe
    Up to 3 years
    End point values
    		 Recombinant Coagulation Factor VIII Fc Fusion Protein
    Number of subjects analysed
    101
    Units: IU per kilogram per subject per year
    median (full range (min-max))
        Episodic Treatment (n= 81)
    197.6 (0 to 3177)
        Prophylaxis Treatment (n= 89)
    5384.4 (0 to 40126)
        ITI Treatment (n= 15)
    67310.0 (33323 to 78871)
    No statistical analyses for this end point

    Secondary: Number of Injections of rFVIIIFc Required to Resolve a Bleeding Episode

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    End point title
    		 Number of Injections of rFVIIIFc Required to Resolve a Bleeding Episode
    End point description
    Number of Injections of rFVIIIFc required to resolve a bleeding episode during EP were reported. EP reflects the sum of all intervals of time during which subjects were treated with rFVIIIFc according to the treatment regimens of the study excluding surgical/rehabilitation periods and large injection intervals (>28 days). All injections given from the initial sign of a bleed, until the last date/time within the bleed window were counted. Subjects were included in summary of more than 1 treatment regimen if their regimen changed during study. Analysis performed on FAS subjects within the EP. Here, ‘n’ signifies number of FAS subjects who were analysed in each treatment regimen.
    End point type
    Secondary
    End point timeframe
    Up to 3 years
    End point values
    		 Recombinant Coagulation Factor VIII Fc Fusion Protein
    Number of subjects analysed
    101
    Units: injections
    median (full range (min-max))
        Episodic Treatment (n= 81)
    1.0 (1 to 13)
        Prophylaxis Treatment (n= 89)
    1.0 (1 to 7)
        ITI Treatment (n= 15)
    1.0 (1 to 22)
    No statistical analyses for this end point

    Secondary: Average Dose per Injection of rFVIIIFc Required to Resolve a Bleeding Episode

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    End point title
    		 Average Dose per Injection of rFVIIIFc Required to Resolve a Bleeding Episode
    End point description
    The average dose of rFVIIIFc per injection per bleeding episode was calculated as the average of all doses (IU/kg) administered to treat the bleeding episode during efficacy period (EP). EP begins with the first treatment regimen dose of rFVIIIFc and ends with the last dose (regardless of the reason for dosing). Surgery/rehabilitation periods are not included in the EP. Subjects were included in summary of more than 1 treatment regimen if their regimen changed during study. Analysis performed on FAS subjects within the EP. Here, ‘n’ signifies number of FAS subjects who were analysed in each treatment regimen.
    End point type
    Secondary
    End point timeframe
    Up to 3 years
    End point values
    		 Recombinant Coagulation Factor VIII Fc Fusion Protein
    Number of subjects analysed
    101
    Units: IU/kg
    median (full range (min-max))
        Episodic Treatment (n= 81)
    45.45 (19.2 to 106.0)
        Prophylaxis Treatment (n= 89)
    48.08 (17.9 to 144.0)
        ITI Treatment (n= 15)
    189.44 (76.9 to 250.0)
    No statistical analyses for this end point

    Secondary: Change From Baseline in rFVIIIFc Incremental Recovery

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    End point title
    		 Change From Baseline in rFVIIIFc Incremental Recovery
    End point description
    Blood samples were taken at trough (predose) and Cmax for assessment of incremental recovery, measured by the one-stage clotting assay. IR (International Units per deciliter [IU/dL] per IU/kg) = (Cmax for FVIII activity – Pre-dose FVIII activity) (IU/dL)/ Actual dose (IU/kg), where Cmax (maximum concentration) is 30-minute FVIII activity post-dose and FVIII activity less than (<)0.5 IU/dL was set to 0 IU/dL for calculation of IR. Analysis performed on FAS subjects within the EP. Here ‘n’ signifies number of FAS subjects with available data for each visit.
    End point type
    Secondary
    End point timeframe
    Baseline, Weeks 12, 24, 36, 48, 60, 72, 84, 96, 108 and 120
    End point values
    		 Recombinant Coagulation Factor VIII Fc Fusion Protein
    Number of subjects analysed
    101
    Units: IU/dL per IU/kg
    median (inter-quartile range (Q1-Q3))
        Change at Week 12 (n= 35)
    -0.5 (-1.26 to -0.26)
        Change at Week 24 (n= 34)
    -0.7 (-1.50 to 0.05)
        Change at Week 36 (n= 39)
    -0.4 (-1.06 to 0.27)
        Change at Week 48 (n= 37)
    -0.5 (-1.09 to -0.05)
        Change at Week 60 (n= 25)
    -0.4 (-1.06 to 0.04)
        Change at Week 72 (n= 21)
    -0.8 (-1.10 to -0.24)
        Change at Week 84 (n= 15)
    -0.6 (-1.55 to 0.01)
        Change at Week 96 (n= 7)
    -0.6 (-1.21 to -0.34)
        Change at Week 108 (n= 2)
    -1.5 (-2.68 to -0.31)
        Change at Week 120 (n= 1)
    -0.6 (-0.6 to -0.6)
    No statistical analyses for this end point

    Secondary: Number of Subjects with Response to Immune Tolerance Induction (ITI)

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    End point title
    		 Number of Subjects with Response to Immune Tolerance Induction (ITI)
    End point description
    Complete Success was defined as meeting all of the following criteria: Negative inhibitor titres in 2 consecutive determinations at least 4 weeks apart; IR >=66% of baseline in 2 consecutive determinations at least 4 weeks apart; Half life >=6 hours. Partial Success was defined as meeting the first criteria for Complete Success and one of the other 2 after 33 months of ITI. Analysis performed on ITI analysis set which was defined as all subjects who consented to and initiated the ITI sub-study.
    End point type
    Secondary
    End point timeframe
    Up to 3 years
    End point values
    		 Recombinant Coagulation Factor VIII Fc Fusion Protein
    Number of subjects analysed
    15
    Units: subjects
        Complete Success
    5
        Partial Success
    2
        Early Withdrawal
    3
        ITI Ongoing at end of Study
    5
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    All Adverse Events (AEs) were collected from signature of the informed consent form up to end of the study (up to 3 years) regardless of seriousness or relationship to investigational product.
    Adverse event reporting additional description
    Reported AE are treatment-emergent AE i.e. AE that was present prior to receiving first injection of rFVIIIFc and subsequently worsened in severity, or was not present prior to receiving first injection but subsequently appeared before last visit/follow-up call, whichever came later. Analysis performed on safety analysis set.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    22.0
    Reporting groups
    Reporting group title
    Recombinant Coagulation Factor VIII Fc Fusion Protein
    Reporting group description
    		 Subjects were to receive rFVIIIFc as follows -PR (Prophylaxis regimen): rFVIIIFc 25-80 international units per kilogram (IU/kg), weekly until subject reached >= 50 exposure days (ED: 24-hour period in which >=1 injection/dose of rFVIIIFc was given), or study withdrawal/end of study. Adjustments to dose/dosing interval was done as needed by investigator; Treatment with an optional ER (Episodic regimen) can be initiated before PR at investigators discretion; ITI: rFVIIIFc 200 IU/kg, daily for subjects who, after exposure to rFVIIIFc, had positive high titre inhibitor (>=5.00 Bethesda Units per milliliter [BU/mL]) or positive low titre inhibitor (>=0.60 and <5.00 BU/mL) and had poorly controlled bleeding despite increased rFVIIIFc doses, or required bypassing agent to treat bleeding.

    Serious adverse events
    		 Recombinant Coagulation Factor VIII Fc Fusion Protein
    Total subjects affected by serious adverse events
         subjects affected / exposed
    60 / 103 (58.25%)
         number of deaths (all causes)
    1
         number of deaths resulting from adverse events
    0
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    1 / 103 (0.97%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Haematoma
         subjects affected / exposed
    3 / 103 (2.91%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Poor venous access
         subjects affected / exposed
    3 / 103 (2.91%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Subgaleal haematoma
         subjects affected / exposed
    1 / 103 (0.97%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Surgical and medical procedures
    Arteriovenous fistula operation
         subjects affected / exposed
    1 / 103 (0.97%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Central venous catheter removal
         subjects affected / exposed
    1 / 103 (0.97%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Central venous catheterisation
         subjects affected / exposed
    26 / 103 (25.24%)
         occurrences causally related to treatment / all
    0 / 30
         deaths causally related to treatment / all
    0 / 0
    Ventriculo-peritoneal shunt
         subjects affected / exposed
    1 / 103 (0.97%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    General disorders and administration site conditions
    Device related thrombosis
         subjects affected / exposed
    1 / 103 (0.97%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Pyrexia
         subjects affected / exposed
    4 / 103 (3.88%)
         occurrences causally related to treatment / all
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    1 / 103 (0.97%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Psychiatric disorders
    Mental status changes
         subjects affected / exposed
    1 / 103 (0.97%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Product issues
    Device issue
         subjects affected / exposed
    1 / 103 (0.97%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Injury, poisoning and procedural complications
    Concussion
         subjects affected / exposed
    1 / 103 (0.97%)
         occurrences causally related to treatment / all
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    Contusion
         subjects affected / exposed
    1 / 103 (0.97%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Craniocerebral injury
         subjects affected / exposed
    2 / 103 (1.94%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Facial bones fracture
         subjects affected / exposed
    1 / 103 (0.97%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Fall
         subjects affected / exposed
    11 / 103 (10.68%)
         occurrences causally related to treatment / all
    0 / 19
         deaths causally related to treatment / all
    0 / 0
    Head injury
         subjects affected / exposed
    8 / 103 (7.77%)
         occurrences causally related to treatment / all
    0 / 13
         deaths causally related to treatment / all
    0 / 0
    Palate injury
         subjects affected / exposed
    1 / 103 (0.97%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Post procedural haemorrhage
         subjects affected / exposed
    1 / 103 (0.97%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Skin laceration
         subjects affected / exposed
    1 / 103 (0.97%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Traumatic haematoma
         subjects affected / exposed
    1 / 103 (0.97%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Vascular access site haematoma
         subjects affected / exposed
    1 / 103 (0.97%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cardiac disorders
    Supraventricular tachycardia
         subjects affected / exposed
    1 / 103 (0.97%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Nervous system disorders
    Febrile convulsion
         subjects affected / exposed
    2 / 103 (1.94%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Haemorrhage intracranial
         subjects affected / exposed
    2 / 103 (1.94%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    Intraventricular haemorrhage
         subjects affected / exposed
    1 / 103 (0.97%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Blood and lymphatic system disorders
    Factor viii inhibition
         subjects affected / exposed
    28 / 103 (27.18%)
         occurrences causally related to treatment / all
    28 / 29
         deaths causally related to treatment / all
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    1 / 103 (0.97%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Spontaneous haematoma
         subjects affected / exposed
    1 / 103 (0.97%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorders
    Tongue haemorrhage
         subjects affected / exposed
    1 / 103 (0.97%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Musculoskeletal and connective tissue disorders
    Haemarthrosis
         subjects affected / exposed
    2 / 103 (1.94%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Haematoma muscle
         subjects affected / exposed
    1 / 103 (0.97%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Soft tissue haemorrhage
         subjects affected / exposed
    1 / 103 (0.97%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Bacterial sepsis
         subjects affected / exposed
    1 / 103 (0.97%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastroenteritis norovirus
         subjects affected / exposed
    1 / 103 (0.97%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Haematoma infection
         subjects affected / exposed
    1 / 103 (0.97%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Meningitis aseptic
         subjects affected / exposed
    1 / 103 (0.97%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Parainfluenzae virus infection
         subjects affected / exposed
    2 / 103 (1.94%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Pneumonia
         subjects affected / exposed
    2 / 103 (1.94%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Rotavirus infection
         subjects affected / exposed
    1 / 103 (0.97%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Staphylococcal bacteraemia
         subjects affected / exposed
    1 / 103 (0.97%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Staphylococcal infection
         subjects affected / exposed
    2 / 103 (1.94%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Staphylococcal skin infection
         subjects affected / exposed
    1 / 103 (0.97%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Vascular device infection
         subjects affected / exposed
    2 / 103 (1.94%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Viral infection
         subjects affected / exposed
    2 / 103 (1.94%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Viral upper respiratory tract infection
         subjects affected / exposed
    2 / 103 (1.94%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Recombinant Coagulation Factor VIII Fc Fusion Protein
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    85 / 103 (82.52%)
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    9 / 103 (8.74%)
         occurrences all number
    16
    Fall
         subjects affected / exposed
    52 / 103 (50.49%)
         occurrences all number
    146
    Head injury
         subjects affected / exposed
    28 / 103 (27.18%)
         occurrences all number
    63
    Limb injury
         subjects affected / exposed
    8 / 103 (7.77%)
         occurrences all number
    9
    Lip injury
         subjects affected / exposed
    6 / 103 (5.83%)
         occurrences all number
    6
    Mouth injury
         subjects affected / exposed
    9 / 103 (8.74%)
         occurrences all number
    10
    Skin abrasion
         subjects affected / exposed
    7 / 103 (6.80%)
         occurrences all number
    19
    Skin laceration
         subjects affected / exposed
    9 / 103 (8.74%)
         occurrences all number
    13
    Vaccination complication
         subjects affected / exposed
    6 / 103 (5.83%)
         occurrences all number
    6
    Blood and lymphatic system disorders
    Iron deficiency anaemia
         subjects affected / exposed
    10 / 103 (9.71%)
         occurrences all number
    10
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    31 / 103 (30.10%)
         occurrences all number
    47
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    9 / 103 (8.74%)
         occurrences all number
    9
    Diarrhoea
         subjects affected / exposed
    18 / 103 (17.48%)
         occurrences all number
    23
    Teething
         subjects affected / exposed
    12 / 103 (11.65%)
         occurrences all number
    23
    Vomiting
         subjects affected / exposed
    19 / 103 (18.45%)
         occurrences all number
    20
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    13 / 103 (12.62%)
         occurrences all number
    20
    Rhinorrhoea
         subjects affected / exposed
    9 / 103 (8.74%)
         occurrences all number
    9
    Skin and subcutaneous tissue disorders
    Eczema
         subjects affected / exposed
    6 / 103 (5.83%)
         occurrences all number
    9
    Rash
         subjects affected / exposed
    10 / 103 (9.71%)
         occurrences all number
    12
    Infections and infestations
    Conjunctivitis
         subjects affected / exposed
    8 / 103 (7.77%)
         occurrences all number
    8
    Ear infection
         subjects affected / exposed
    19 / 103 (18.45%)
         occurrences all number
    28
    Gastroenteritis
         subjects affected / exposed
    7 / 103 (6.80%)
         occurrences all number
    7
    Hand-foot-and-mouth disease
         subjects affected / exposed
    6 / 103 (5.83%)
         occurrences all number
    6
    Influenza
         subjects affected / exposed
    10 / 103 (9.71%)
         occurrences all number
    14
    Nasopharyngitis
         subjects affected / exposed
    31 / 103 (30.10%)
         occurrences all number
    54
    Otitis media
         subjects affected / exposed
    10 / 103 (9.71%)
         occurrences all number
    11
    Rhinitis
         subjects affected / exposed
    7 / 103 (6.80%)
         occurrences all number
    11
    Upper respiratory tract infection
         subjects affected / exposed
    28 / 103 (27.18%)
         occurrences all number
    41
    Varicella
         subjects affected / exposed
    6 / 103 (5.83%)
         occurrences all number
    6
    Viral infection
         subjects affected / exposed
    17 / 103 (16.50%)
         occurrences all number
    32
    Viral upper respiratory tract infection
         subjects affected / exposed
    11 / 103 (10.68%)
         occurrences all number
    27

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    06 Apr 2015
    The primary reason for this amendment was to change the cut-off age for the study from <18 years old to <6 years old to align with other studies focusing on previously untreated pediatric subjects.
    22 Jul 2016
    The primary reason for this amendment was to add provisions requested by regulatory authorities including revision of definitions of ITI therapy outcomes; addition of a tapering regimen and a monitoring period after ITI; replacement of the exclusion criterion related to hypersensitivity to IV immunoglobulin (IVIG) administration, with an exclusion criterion related to hypersensitivity to FVIIIFc administration; addition of data collection for concomitant medications administered to breastfeeding mothers of subjects; justification of collection of race and ethnicity data.
    22 Sep 2016
    The primary reason for this amendment was to correct outdated information regarding the enrollment criteria that was inadvertently left in the protocol. These changes included: the collection of AEs was removed from the screening period and subjects awaiting ITI were asked to follow the Prophylaxis Regimen rather than the Episodic Regimen.
    24 Feb 2017
    The primary reason for this amendment was to incorporate a change in responsibility and obligations of the study sponsor (according to Directive 2001/20/EC as well as International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) Guideline on Good Clinical Practice (GCP) E6[RI]). Bioverativ Therapeutics Inc took over the responsibility and obligations of the study sponsor from Biogen Idec Research Limited (UK) or Biogen MA Inc (US) or Biogen Australia Pty Ltd (Australia).
    12 Feb 2018
    The primary reason for this amendment was to redefine the EOS criteria for the study in light of the new draft version of the updated EMA guideline on the clinical investigation of recombinant and human plasma-derived factor VIII products.

    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
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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