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    Clinical Trial Results:
    An Open-Label, Multicenter Evaluation of the Long-Term Safety and Efficacy of Recombinant Human Coagulation Factor VIII Fusion Protein (rFVIIIFc) in the Prevention and Treatment of Bleeding Episodes in Previously Treated Subjects With Hemophilia A

    Summary
    EudraCT number
    		 2011-003072-37
    Trial protocol
    		 SE   BE   GB   DE   AT   ES   IT   IE   PL   NL  
    Global end of trial date
    18 Oct 2017

    Results information
    Results version number
    		 v1(current)
    This version publication date
    03 May 2018
    First version publication date
    03 May 2018
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    8HA01EXT
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01454739
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Bioverativ Therapeutics Inc.
    Sponsor organisation address
    225 Second Avenue, Waltham, Massachusetts (MA), United States, 02451
    Public contact
    Not available, Bioverativ Therapeutics Inc., clinicaltrials@bioverativ.com
    Scientific contact
    Not available, Bioverativ Therapeutics Inc., 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 Oct 2017
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    18 Oct 2017
    Global end of trial reached?
    Yes
    Global end of trial date
    18 Oct 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The main objective of this study was to evaluate the long-term safety of Recombinant human Factor VIII (rFVIIIFc) in subjects with hemophilia A.
    Protection of trial subjects
    The conduct of this clinical study met all local legal and regulatory requirements. The study was conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki and the International Conference on Harmonization guideline E6: Good Clinical Practice. Safety evaluations included monitoring of adverse events (AEs) and serious adverse events (SAEs), physical examination, medical and surgical history (from previous study and updated), height, weight and Concomitant therapy and procedure recording and Laboratory Safety Assessments (hematology, blood chemistry and Nijmegen-modified Bethesda assay.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    15 Dec 2011
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Netherlands: 1
    Country: Number of subjects enrolled
    Poland: 3
    Country: Number of subjects enrolled
    Spain: 2
    Country: Number of subjects enrolled
    Sweden: 1
    Country: Number of subjects enrolled
    United Kingdom: 46
    Country: Number of subjects enrolled
    Austria: 3
    Country: Number of subjects enrolled
    Germany: 3
    Country: Number of subjects enrolled
    Ireland: 8
    Country: Number of subjects enrolled
    Italy: 5
    Country: Number of subjects enrolled
    Belgium: 1
    Country: Number of subjects enrolled
    France: 2
    Country: Number of subjects enrolled
    Australia: 21
    Country: Number of subjects enrolled
    Brazil: 3
    Country: Number of subjects enrolled
    Canada: 2
    Country: Number of subjects enrolled
    Hong Kong: 6
    Country: Number of subjects enrolled
    India: 14
    Country: Number of subjects enrolled
    Israel: 3
    Country: Number of subjects enrolled
    Japan: 13
    Country: Number of subjects enrolled
    New Zealand: 15
    Country: Number of subjects enrolled
    South Africa: 27
    Country: Number of subjects enrolled
    Switzerland: 1
    Country: Number of subjects enrolled
    United States: 60
    Worldwide total number of subjects
    240
    EEA total number of subjects
    75
    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)
    59
    Adolescents (12-17 years)
    24
    Adults (18-64 years)
    155
    From 65 to 84 years
    2
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 Subjects provided their written informed consent to participate in this study after the Investigator has verified that they are eligible per protocol defined criteria. For subjects, unable to provide written informed consent, parents or legal guardian(s) obtained the informed consent form.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 rFVIIIFc [Subjects from Study 8HA02PED]
    Arm description
    		 Tailored Prophylaxis(TP): 25 IU/kg-65 IU/kg rFVIIIFc every 3-5 days or 2 times/week at approximately 20 IU/kg to 65 IU/kg rFVIIIFc on Day 1 & 40 IU/kg-65 IU/kg rFVIIIFc on Day 4 as intravenous (IV) injection. Weekly: rFVIIIFc IV injection once weekly at approximately 65 IU/kg. Personalized P: If optimal prophylaxis dosing not achieved using TP/WP, Investigator personalized dosing to meet individual subjects’s needs (options: adding “prevention” dose prior to strenuous activity; targeting FVIII trough level of >3%, if bleeding history &/or activity level requires/dosing less frequently. Episodic (On demand): individual dose of rFVIIIFc IV based on clinical condition, type & severity of bleeding event & if indicated, FVIII levels (per investigator & Sponsor decision). The rate of administration determined by subject's comfort level. For subjects <12 years of age, weekly and episodic treatment regimens were only available once subjects were at least 12 years old.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Recombinant Factor VIII-Fc
    Investigational medicinal product code
    rFVIIIFc
    Other name
    BIIB031
    Pharmaceutical forms
    Powder for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects received rFVIIIFc as tailored, weekly, personalized prophylaxis or episodic (on-demand regimen). Subjects were allowed to change treatment regimens (for example, from prophylaxis to on-demand, or from on-demand to prophylaxis) per investigator decision.

    Arm title
    		 rFVIIIFc [Subjects from Studies 997HA301/997HA307/997HA309]
    Arm description
    		 Tailored Prophylaxis (TP): 25 IU/kg-65 IU/kg rFVIIIFc every 3-5 days or 2 times/week at approximately 20 IU/kg to 65 IU/kg rFVIIIFc on Day 1 & 40 IU/kg-65 IU/kg rFVIIIFc on Day 4 as intravenous (IV) injection. Weekly: rFVIIIFc IV injection once weekly at approximately 65 IU/kg. Personalized P: If optimal prophylaxis dosing not achieved using TP/WP, Investigator personalized dosing to meet individual subjects’s needs (options: adding “prevention” dose prior to strenuous activity; targeting FVIII trough level of >3%, if bleeding history &/or activity level requires/dosing less frequently. Episodic (On demand): individual dose of rFVIIIFc IV based on clinical condition, type & severity of bleeding event & if indicated, FVIII levels (per investigator & Sponsor decision). The rate of administration determined by subject's comfort level.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Recombinant Factor VIII-Fc
    Investigational medicinal product code
    rFVIIIFc
    Other name
    BIIB031
    Pharmaceutical forms
    Powder for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects received rFVIIIFc as tailored, weekly, personalized prophylaxis or episodic (on-demand regimen). Subjects were allowed to change treatment regimens (for example, from prophylaxis to on-demand, or from on-demand to prophylaxis) per investigator decision.

    Number of subjects in period 1
    		rFVIIIFc [Subjects from Study 8HA02PED] rFVIIIFc [Subjects from Studies 997HA301/997HA307/997HA309]
    Started
    61
    179
    Completed
    54
    158
    Not completed
    7
    21
         Consent withdrawn by subject
    2
    6
         Physician decision
    -
    5
         Adverse Event
    -
    1
         Protocol violation
    2
    3
         Other
    3
    5
         Lost to follow-up
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    rFVIIIFc [Subjects from Study 8HA02PED]
    Reporting group description
    		 Tailored Prophylaxis(TP): 25 IU/kg-65 IU/kg rFVIIIFc every 3-5 days or 2 times/week at approximately 20 IU/kg to 65 IU/kg rFVIIIFc on Day 1 & 40 IU/kg-65 IU/kg rFVIIIFc on Day 4 as intravenous (IV) injection. Weekly: rFVIIIFc IV injection once weekly at approximately 65 IU/kg. Personalized P: If optimal prophylaxis dosing not achieved using TP/WP, Investigator personalized dosing to meet individual subjects’s needs (options: adding “prevention” dose prior to strenuous activity; targeting FVIII trough level of >3%, if bleeding history &/or activity level requires/dosing less frequently. Episodic (On demand): individual dose of rFVIIIFc IV based on clinical condition, type & severity of bleeding event & if indicated, FVIII levels (per investigator & Sponsor decision). The rate of administration determined by subject's comfort level. For subjects <12 years of age, weekly and episodic treatment regimens were only available once subjects were at least 12 years old.

    Reporting group title
    rFVIIIFc [Subjects from Studies 997HA301/997HA307/997HA309]
    Reporting group description
    		 Tailored Prophylaxis (TP): 25 IU/kg-65 IU/kg rFVIIIFc every 3-5 days or 2 times/week at approximately 20 IU/kg to 65 IU/kg rFVIIIFc on Day 1 & 40 IU/kg-65 IU/kg rFVIIIFc on Day 4 as intravenous (IV) injection. Weekly: rFVIIIFc IV injection once weekly at approximately 65 IU/kg. Personalized P: If optimal prophylaxis dosing not achieved using TP/WP, Investigator personalized dosing to meet individual subjects’s needs (options: adding “prevention” dose prior to strenuous activity; targeting FVIII trough level of >3%, if bleeding history &/or activity level requires/dosing less frequently. Episodic (On demand): individual dose of rFVIIIFc IV based on clinical condition, type & severity of bleeding event & if indicated, FVIII levels (per investigator & Sponsor decision). The rate of administration determined by subject's comfort level.

    Reporting group values
    		 rFVIIIFc [Subjects from Study 8HA02PED] rFVIIIFc [Subjects from Studies 997HA301/997HA307/997HA309] Total
    Number of subjects
    		 61 179 240
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 59 0 59
        Adolescents (12-17 years)
    		 2 22 24
        Adults (18-64 years)
    		 0 155 155
        From 65-84 years
    		 0 2 2
        85 years and over
    		 0 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 6.7 ( 2.74 ) 33.5 ( 13.48 ) -
    Gender categorical
    Units: Subjects
        Female
    		 0 0 0
        Male
    		 61 179 240

    End points

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    End points reporting groups
    Reporting group title
    rFVIIIFc [Subjects from Study 8HA02PED]
    Reporting group description
    		 Tailored Prophylaxis(TP): 25 IU/kg-65 IU/kg rFVIIIFc every 3-5 days or 2 times/week at approximately 20 IU/kg to 65 IU/kg rFVIIIFc on Day 1 & 40 IU/kg-65 IU/kg rFVIIIFc on Day 4 as intravenous (IV) injection. Weekly: rFVIIIFc IV injection once weekly at approximately 65 IU/kg. Personalized P: If optimal prophylaxis dosing not achieved using TP/WP, Investigator personalized dosing to meet individual subjects’s needs (options: adding “prevention” dose prior to strenuous activity; targeting FVIII trough level of >3%, if bleeding history &/or activity level requires/dosing less frequently. Episodic (On demand): individual dose of rFVIIIFc IV based on clinical condition, type & severity of bleeding event & if indicated, FVIII levels (per investigator & Sponsor decision). The rate of administration determined by subject's comfort level. For subjects <12 years of age, weekly and episodic treatment regimens were only available once subjects were at least 12 years old.

    Reporting group title
    rFVIIIFc [Subjects from Studies 997HA301/997HA307/997HA309]
    Reporting group description
    		 Tailored Prophylaxis (TP): 25 IU/kg-65 IU/kg rFVIIIFc every 3-5 days or 2 times/week at approximately 20 IU/kg to 65 IU/kg rFVIIIFc on Day 1 & 40 IU/kg-65 IU/kg rFVIIIFc on Day 4 as intravenous (IV) injection. Weekly: rFVIIIFc IV injection once weekly at approximately 65 IU/kg. Personalized P: If optimal prophylaxis dosing not achieved using TP/WP, Investigator personalized dosing to meet individual subjects’s needs (options: adding “prevention” dose prior to strenuous activity; targeting FVIII trough level of >3%, if bleeding history &/or activity level requires/dosing less frequently. Episodic (On demand): individual dose of rFVIIIFc IV based on clinical condition, type & severity of bleeding event & if indicated, FVIII levels (per investigator & Sponsor decision). The rate of administration determined by subject's comfort level.

    Subject analysis set title
    rFVIIIFc [8HA02PED (<6 years old age cohort)]
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Subjects enrolled from the study 8HA02PED with <6 years old age.

    Subject analysis set title
    rFVIIIFc [8HA02PED (6 - <12 years old age cohort)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Subjects enrolled from the study 8HA02PED with 6 - <12 years old age.

    Subject analysis set title
    rFVIIIFc [Subjects from Study 997HA301/997HA307/997HA309]
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Subjects were included from studies 997HA301/997HA307/997HA309.

    Primary: Number of Subjects with any Positive Inhibitor Development

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    End point title
    		 Number of Subjects with any Positive 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. Safety Analysis Set included subjects who received at least 1 dose of rFVIIIFc in study 8HA01EXT.
    End point type
    Primary
    End point timeframe
    Approximately 5 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: Descriptive statistics were done, no inferential statistical analyses were performed.
    End point values
    		 rFVIIIFc [Subjects from Study 8HA02PED] rFVIIIFc [Subjects from Studies 997HA301/997HA307/997HA309]
    Number of subjects analysed
    61
    179
    Units: subjects with any positive inhibitor
    0
    0
    No statistical analyses for this end point

    Secondary: Annualized Bleeding Rate

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    End point title
    		 Annualized Bleeding Rate
    End point description
    Bleeding episodes should be classified as spontaneous if a subject records a bleeding event when there is no known contributing factor such as definite trauma or antecedent strenuous activity. Bleeding episodes should be classified as traumatic if a subject records a bleeding event when there is a known or believed reason for the bleed. Full Analysis Set (FAS) included all subjects who received at least 1 dose of rFVIIIFc. Here, "n" indicates number of subject analyzed in specified treatment regimen. "99999" indicates that the data was not analyzed for the arm in the specified category. Annualized bleeding episodes=(Number of bleeding episodes during the efficacy period/number of days during efficacy period)*365.25. The efficacy period reflects the sum of all intervals of time during which subjects were treated with rFVIIIFc according to the treatment regimens of the study excluding major and minor surgical/rehabilitation periods and large injection intervals.
    End point type
    Secondary
    End point timeframe
    Approximately 5 years
    End point values
    		 rFVIIIFc [8HA02PED (<6 years old age cohort)] rFVIIIFc [8HA02PED (6 - <12 years old age cohort) rFVIIIFc [Subjects from Study 997HA301/997HA307/997HA309]
    Number of subjects analysed
    30
    31
    179
    Units: episodes per subject per year
    median (inter-quartile range (Q1-Q3))
        Tailored Prophylaxis (n= 29, 30, 131)
    1.18 (0.60 to 2.37)
    1.59 (0.55 to 3.55)
    0.64 (0.00 to 2.84)
        Weekly Prophylaxis (n= 0, 0, 34)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    1.90 (0.27 to 4.85)
        Personalized Prophylaxis (n= 2, 1, 23)
    3.72 (3.35 to 4.09)
    1.01 (1.01 to 1.01)
    4.11 (0.64 to 8.78)
        Episodic (n= 0, 0, 13)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    19.10 (15.12 to 30.46)
    No statistical analyses for this end point

    Secondary: Annualized Spontaneous Joint Bleeding Episodes

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    End point title
    		 Annualized Spontaneous Joint Bleeding Episodes
    End point description
    Bleeding episodes should be classified as spontaneous if a subject records a bleeding event when there is no known contributing factor such as definite trauma or antecedent strenuous activity. In addition of type of bleeding episode (e.g., spontaneous, traumatic), the location of the bleed (joint, internal, skin/mucosa, or muscle) were also collected. FAS included all subjects who received at least 1 dose of rFVIIIFc. Annualized spontaneous joint bleeding episodes = (Number of spontaneous joint bleeding episodes during the efficacy period / number of days during efficacy period) *365.25. Here, "n" indicates number of subject analyzed in specified treatment regimen. "99999" indicates that the data was not analyzed for the arm in the specified category.
    End point type
    Secondary
    End point timeframe
    Approximately 5 years
    End point values
    		 rFVIIIFc [8HA02PED (<6 years old age cohort)] rFVIIIFc [8HA02PED (6 - <12 years old age cohort) rFVIIIFc [Subjects from Study 997HA301/997HA307/997HA309]
    Number of subjects analysed
    30
    31
    179
    Units: episodes per subject per year
    median (inter-quartile range (Q1-Q3))
        Tailored Prophylaxis (n= 29, 30, 131)
    0.00 (0.00 to 0.55)
    0.00 (0.00 to 0.55)
    0.00 (0.00 to 0.63)
        Weekly Prophylaxis (n= 0, 0, 34)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    0.58 (0.00 to 1.90)
        Personalized Prophylaxis (n= 2, 1, 23)
    2.20 (1.34 to 3.07)
    0.00 (0.00 to 0.00)
    0.91 (0.00 to 2.84)
        Episodic (n= 0, 0, 13)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    9.22 (4.35 to 15.70)
    No statistical analyses for this end point

    Secondary: Total Number of Days of Exposure

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    End point title
    		 Total Number of Days of Exposure
    End point description
    An exposure day is a 24-hour period in which one or more rFVIIIFc injections are given. The total number of days of exposure to rFVIIIFc were summarized. Safety Analysis Set included subjects who received at least 1 dose of rFVIIIFc in study 8HA01EXT. Here, "n" indicates number of subject analyzed in specified treatment regimen. "99999" indicates that the data was not analyzed for the arm in the specified category.
    End point type
    Secondary
    End point timeframe
    Approximately 5 years
    End point values
    		 rFVIIIFc [Subjects from Study 8HA02PED] rFVIIIFc [Subjects from Studies 997HA301/997HA307/997HA309]
    Number of subjects analysed
    61
    179
    Units: days
    median (full range (min-max))
        Tailored Prophylaxis (n= 59, 131)
    332.00 (18.0 to 467.0)
    257.00 (4.0 to 660.0)
        Weekly Prophylaxis (n= 0, 34)
    99999 (99999 to 99999)
    203.50 (5.0 to 318.0)
        Personalized Prophylaxis (n= 3, 23)
    107.00 (102.0 to 152.0)
    223.00 (14.0 to 535.0)
        Episodic (n= 0, 13)
    99999 (99999 to 99999)
    27.00 (0.0 to 88.0)
    No statistical analyses for this end point

    Secondary: Annualized rFVIIIFc Consumption as Total Dose per Kilogram (kg) per Subject per Year

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    End point title
    		 Annualized rFVIIIFc Consumption as Total Dose per Kilogram (kg) per Subject per Year
    End point description
    Annualized consumption = (total IU/kg of study treatment received during the efficacy period / total number of days during the efficacy period) multiplied by 365.25. FAS included all subjects who received at least 1 dose of rFVIIIFc. Here, "n" indicates number of subject analyzed in specified treatment regimen. "99999" indicates that the data was not analyzed for the arm in the specified category.
    End point type
    Secondary
    End point timeframe
    Approximately 5 years
    End point values
    		 rFVIIIFc [8HA02PED (<6 years old age cohort)] rFVIIIFc [8HA02PED (6 - <12 years old age cohort) rFVIIIFc [Subjects from Study 997HA301/997HA307/997HA309]
    Number of subjects analysed
    30
    31
    179
    Units: dose per kilogram per subject per year
    median (inter-quartile range (Q1-Q3))
        Tailored Prophylaxis (n= 29, 30, 131)
    5417.9 (4683.4 to 6303.9)
    4989.7 (4293.8 to 5842.4)
    4359.8 (3993.8 to 5630.3)
        Weekly Prophylaxis (n= 0, 0, 34)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    3505.2 (3267.9 to 3639.0)
        Personalized Prophylaxis (n= 2, 1, 23)
    5457.1 (4435.0 to 6479.1)
    4572.3 (4572.3 to 4572.3)
    3926.7 (3261.8 to 6194.8)
        Episodic (n= 0, 0, 13)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    801.7 (286.2 to 1057.7)
    No statistical analyses for this end point

    Secondary: Physician’s Global Assessment of Response to Treatment Using a 4-point Scale

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    End point title
    		 Physician’s Global Assessment of Response to Treatment Using a 4-point Scale
    End point description
    Subjects were assessed for response to their rFVIIIFc regimen using the following 4-point scale: Excellent: bleeding episodes responded to less than or equal to (<=) the usual number of injections or <= the usual dose of rFVIIIFc, or the rate of breakthrough bleeding during prophylaxis was <= that usually observed; Effective: most bleeding episodes responded to the same number of injections and dose, but some required more injections or higher doses, or there was a minor increase in the rate of breakthrough; Partially Effective: bleeding episodes most often required more injections and/or higher doses than expected, or adequate breakthrough bleeding prevention during prophylaxis required more frequent injections and/or higher doses and Ineffective: routine failure to control hemostasis or hemostatic control require additional agents. FAS included all subjects who received at least 1 dose of rFVIIIFc. The results were reported based on the efficacy period for overall treatment regimen.
    End point type
    Secondary
    End point timeframe
    Approximately 5 years
    End point values
    		 rFVIIIFc [Subjects from Study 8HA02PED] rFVIIIFc [Subjects from Studies 997HA301/997HA307/997HA309]
    Number of subjects analysed
    61
    179
    Units: percentage of visits
    number (not applicable)
        Excellent
    94.2
    84.7
        Effective
    5.6
    14.9
        Partially Effective
    0.2
    0.4
        Ineffective
    0
    0
    No statistical analyses for this end point

    Secondary: Percentage of Subjects with Excellent or Good Response to Treatment Using a 4-Point Scale

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    End point title
    		 Percentage of Subjects with Excellent or Good Response to Treatment Using a 4-Point Scale
    End point description
    Using eDiary, subject received rating for treatment response to any bleeding episode (BE) using 4-point scale-Excellent: Abrupt pain relief and/or improvement in signs of bleeding within approximately (approx.) 8 hours (h) after initial injection (inj.); Good: Definite pain relief and/or improvement in signs of bleeding within approx. 8h after an injection, but possibly requiring more than 1 injection after 24–48h for complete resolution; Moderate: Probable/slight beneficial effect within 8h after initial injection and requires more than 1 injection and None: No improvement, or condition worsens within approx. 8h after initial injection. This assessment was to be made approx. 8 to 12h from time the injection was given to treat BE and prior to any additional doses of rFVIIIFc given for same bleeding episode. FAS population included. "n"=number of subject analyzed in specified treatment regimen during efficacy period. "99999"=data was not analyzed for the arm in the specified category.
    End point type
    Secondary
    End point timeframe
    Approximately 5 years
    End point values
    		 rFVIIIFc [8HA02PED (<6 years old age cohort)] rFVIIIFc [8HA02PED (6 - <12 years old age cohort) rFVIIIFc [Subjects from Study 997HA301/997HA307/997HA309]
    Number of subjects analysed
    30
    31
    179
    Units: % of first inj. with evaluations for BE
    number (not applicable)
        Tailored Prophylaxis (n= 29, 30, 131)
    88.0
    90.6
    74.5
        Weekly Prophylaxis (n= 0, 0, 34)
    99999
    99999
    76.2
        Personalized Prophylaxis (n= 2, 1, 23)
    100.0
    100.0
    82.2
        Episodic (n= 0, 0, 13)
    99999
    99999
    91.8
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From signing of ICF through follow-up [7 (+7) days after the last dose of rFVIIIFc] or final visit/early termination visit (approximately 5 years)
    Adverse event reporting additional description
    The Safety Analysis Set consisted of subjects who received at least 1 dose of rFVIIIFc in study. AEs emergent during major surgical/rehabilitation periods are excluded.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    15.0
    Reporting groups
    Reporting group title
    rFVIIIFc [Subjects from Study 8HA02PED]
    Reporting group description
    		 Tailored Prophylaxis (TP): 25 IU/kg-65 IU/kg rFVIIIFc every 3-5 days or 2 times/week at approximately 20 IU/kg to 65 IU/kg rFVIIIFc on Day 1 & 40 IU/kg-65 IU/kg rFVIIIFc on Day 4 as intravenous (IV) injection. Weekly: rFVIIIFc IV injection once weekly at approximately 65 IU/kg. Personalized P: If optimal prophylaxis dosing not achieved using TP/WP, Investigator personalized dosing to meet individual subjects’s needs (options: adding “prevention” dose prior to strenuous activity; targeting FVIII trough level of >3%, if bleeding history &/or activity level requires/dosing less frequently. Episodic (On demand): individual dose of rFVIIIFc IV based on clinical condition, type & severity of bleeding event & if indicated, FVIII levels (per investigator & Sponsor decision). The rate of administration determined by subject's comfort level. For subjects <12 years of age, weekly and episodic treatment regimens were only available once subjects were at least 12 years old.

    Reporting group title
    rFVIIIFc [Subjects from studies 997HA301/ 997HA307/997HA309]
    Reporting group description
    		 Tailored Prophylaxis (TP): 25 IU/kg-65 IU/kg rFVIIIFc every 3-5 days or 2 times/week at approximately 20 IU/kg to 65 IU/kg rFVIIIFc on Day 1 & 40 IU/kg-65 IU/kg rFVIIIFc on Day 4 as intravenous (IV) injection. Weekly: rFVIIIFc IV injection once weekly at approximately 65 IU/kg. Personalized P: If optimal prophylaxis dosing not achieved using TP/WP, Investigator personalized dosing to meet individual subjects’s needs (options: adding “prevention” dose prior to strenuous activity; targeting FVIII trough level of >3%, if bleeding history &/or activity level requires/dosing less frequently. Episodic (On demand): individual dose of rFVIIIFc IV based on clinical condition, type & severity of bleeding event & if indicated, FVIII levels (per investigator & Sponsor decision). The rate of administration determined by subject's comfort level.

    Reporting group title
    Overall rFVIIIFc
    Reporting group description
    		 -

    Serious adverse events
    		 rFVIIIFc [Subjects from Study 8HA02PED] rFVIIIFc [Subjects from studies 997HA301/ 997HA307/997HA309] Overall rFVIIIFc
    Total subjects affected by serious adverse events
         subjects affected / exposed
    20 / 61 (32.79%)
    43 / 179 (24.02%)
    63 / 240 (26.25%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Hepatic Neoplasm Malignant
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 179 (0.56%)
    1 / 240 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metastases to peritoneum
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 179 (0.56%)
    1 / 240 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Bleeding varicose vein
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 179 (0.56%)
    1 / 240 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Superior vena cava syndrome
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 179 (0.00%)
    1 / 240 (0.42%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Superior vena cava stenosis
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 179 (0.00%)
    1 / 240 (0.42%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Surgical and medical procedures
    Bone graft
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 179 (0.56%)
    1 / 240 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Carpal tunnel decompression
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 179 (0.56%)
    1 / 240 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Central venous catheter removal
         subjects affected / exposed
    4 / 61 (6.56%)
    0 / 179 (0.00%)
    4 / 240 (1.67%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Central venous catheterisation
         subjects affected / exposed
    2 / 61 (3.28%)
    1 / 179 (0.56%)
    3 / 240 (1.25%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Circumcision
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 179 (0.00%)
    1 / 240 (0.42%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Joint arthroplasty
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 179 (0.56%)
    1 / 240 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Knee arthroplasty
         subjects affected / exposed
    0 / 61 (0.00%)
    2 / 179 (1.12%)
    2 / 240 (0.83%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Device breakage
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 179 (0.00%)
    1 / 240 (0.42%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Device dislocation
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 179 (0.56%)
    1 / 240 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infusion site mass
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 179 (0.56%)
    1 / 240 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 179 (0.00%)
    1 / 240 (0.42%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Epistaxis
         subjects affected / exposed
    1 / 61 (1.64%)
    1 / 179 (0.56%)
    2 / 240 (0.83%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nasal polyps
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 179 (0.56%)
    1 / 240 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Depression
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 179 (0.56%)
    1 / 240 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Body temperature increased
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 179 (0.00%)
    1 / 240 (0.42%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nuclear magnetic resonance imaging abnormal
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 179 (0.00%)
    1 / 240 (0.42%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Accident
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 179 (0.56%)
    1 / 240 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Fall
         subjects affected / exposed
    6 / 61 (9.84%)
    0 / 179 (0.00%)
    6 / 240 (2.50%)
         occurrences causally related to treatment / all
    0 / 7
    0 / 0
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Forearm fracture
         subjects affected / exposed
    2 / 61 (3.28%)
    0 / 179 (0.00%)
    2 / 240 (0.83%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Head injury
         subjects affected / exposed
    6 / 61 (9.84%)
    1 / 179 (0.56%)
    7 / 240 (2.92%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 1
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 179 (0.56%)
    1 / 240 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Joint dislocation
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 179 (0.56%)
    1 / 240 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Periprosthetic fracture
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 179 (0.56%)
    1 / 240 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Skull fracture
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 179 (0.00%)
    1 / 240 (0.42%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Toxicity to various agents
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 179 (0.56%)
    1 / 240 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Transplant failure
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 179 (0.56%)
    1 / 240 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Traumatic haematoma
         subjects affected / exposed
    0 / 61 (0.00%)
    2 / 179 (1.12%)
    2 / 240 (0.83%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Traumatic haemorrhage
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 179 (0.00%)
    1 / 240 (0.42%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 179 (0.56%)
    1 / 240 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Angina pectoris
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 179 (0.56%)
    1 / 240 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 179 (0.56%)
    1 / 240 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Cubital tunnel syndrome
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 179 (0.56%)
    1 / 240 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 179 (0.00%)
    1 / 240 (0.42%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hydrocephalus
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 179 (0.56%)
    1 / 240 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nerve compression
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 179 (0.56%)
    1 / 240 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain upper
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 179 (0.56%)
    1 / 240 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 179 (0.56%)
    1 / 240 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Food poisoning
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 179 (0.56%)
    1 / 240 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastritis haemorrhagic
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 179 (0.56%)
    1 / 240 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Rectal haemorrhage
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 179 (0.56%)
    1 / 240 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tooth impacted
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 179 (0.56%)
    1 / 240 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Varices oesophageal
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 179 (0.56%)
    1 / 240 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 179 (0.56%)
    1 / 240 (0.42%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Biliary colic
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 179 (0.56%)
    1 / 240 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cholangitis acute
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 179 (0.56%)
    1 / 240 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Haemorrhage subcutaneous
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 179 (0.56%)
    1 / 240 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urticaria
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 179 (0.00%)
    1 / 240 (0.42%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Calculus ureteric
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 179 (0.56%)
    1 / 240 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haematuria
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 179 (0.00%)
    1 / 240 (0.42%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nephrolithiasis
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 179 (0.56%)
    1 / 240 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal impairment
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 179 (0.56%)
    1 / 240 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthropathy
         subjects affected / exposed
    0 / 61 (0.00%)
    2 / 179 (1.12%)
    2 / 240 (0.83%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haemarthrosis
         subjects affected / exposed
    2 / 61 (3.28%)
    3 / 179 (1.68%)
    5 / 240 (2.08%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haemophilic arthropathy
         subjects affected / exposed
    0 / 61 (0.00%)
    11 / 179 (6.15%)
    11 / 240 (4.58%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 12
    0 / 12
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Intervertebral disc disorder
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 179 (0.56%)
    1 / 240 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Osteoarthritis
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 179 (0.56%)
    1 / 240 (0.42%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Spinal osteoarthritis
         subjects affected / exposed
    0 / 61 (0.00%)
    2 / 179 (1.12%)
    2 / 240 (0.83%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Synovitis
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 179 (0.56%)
    1 / 240 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Appendicitis
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 179 (0.56%)
    1 / 240 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 179 (0.00%)
    1 / 240 (0.42%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Chronic sinusitis
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 179 (0.56%)
    1 / 240 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Device related infection
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 179 (0.56%)
    1 / 240 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatitis C
         subjects affected / exposed
    0 / 61 (0.00%)
    2 / 179 (1.12%)
    2 / 240 (0.83%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infectious pleural effusion
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 179 (0.56%)
    1 / 240 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 179 (0.56%)
    1 / 240 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pericoronitis
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 179 (0.56%)
    1 / 240 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 61 (1.64%)
    1 / 179 (0.56%)
    2 / 240 (0.83%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sinusitis
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 179 (0.00%)
    1 / 240 (0.42%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Staphylococcal bacteraemia
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 179 (0.56%)
    1 / 240 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Staphylococcal infection
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 179 (0.00%)
    1 / 240 (0.42%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Streptococcal sepsis
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 179 (0.56%)
    1 / 240 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Subcutaneous abscess
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 179 (0.56%)
    1 / 240 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tooth abscess
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 179 (0.00%)
    1 / 240 (0.42%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 179 (0.00%)
    1 / 240 (0.42%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Viral infection
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 179 (0.00%)
    1 / 240 (0.42%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Viral upper respiratory tract infection
         subjects affected / exposed
    1 / 61 (1.64%)
    0 / 179 (0.00%)
    1 / 240 (0.42%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    0 / 61 (0.00%)
    1 / 179 (0.56%)
    1 / 240 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         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
    		 rFVIIIFc [Subjects from Study 8HA02PED] rFVIIIFc [Subjects from studies 997HA301/ 997HA307/997HA309] Overall rFVIIIFc
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    49 / 61 (80.33%)
    110 / 179 (61.45%)
    159 / 240 (66.25%)
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    11 / 61 (18.03%)
    14 / 179 (7.82%)
    25 / 240 (10.42%)
         occurrences all number
    22
    14
    36
    Laceration
         subjects affected / exposed
    1 / 61 (1.64%)
    15 / 179 (8.38%)
    16 / 240 (6.67%)
         occurrences all number
    1
    19
    20
    Limb injury
         subjects affected / exposed
    4 / 61 (6.56%)
    10 / 179 (5.59%)
    14 / 240 (5.83%)
         occurrences all number
    4
    10
    14
    Vascular disorders
    Hypertension
         subjects affected / exposed
    0 / 61 (0.00%)
    9 / 179 (5.03%)
    9 / 240 (3.75%)
         occurrences all number
    0
    9
    9
    Nervous system disorders
    Headache
         subjects affected / exposed
    10 / 61 (16.39%)
    15 / 179 (8.38%)
    25 / 240 (10.42%)
         occurrences all number
    19
    18
    37
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    6 / 61 (9.84%)
    5 / 179 (2.79%)
    11 / 240 (4.58%)
         occurrences all number
    8
    6
    14
    Immune system disorders
    Seasonal allergy
         subjects affected / exposed
    9 / 61 (14.75%)
    5 / 179 (2.79%)
    14 / 240 (5.83%)
         occurrences all number
    12
    5
    17
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    5 / 61 (8.20%)
    16 / 179 (8.94%)
    21 / 240 (8.75%)
         occurrences all number
    5
    17
    22
    Nausea
         subjects affected / exposed
    2 / 61 (3.28%)
    8 / 179 (4.47%)
    10 / 240 (4.17%)
         occurrences all number
    2
    8
    10
    Vomiting
         subjects affected / exposed
    8 / 61 (13.11%)
    6 / 179 (3.35%)
    14 / 240 (5.83%)
         occurrences all number
    9
    6
    15
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    8 / 61 (13.11%)
    9 / 179 (5.03%)
    17 / 240 (7.08%)
         occurrences all number
    9
    10
    19
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    7 / 61 (11.48%)
    20 / 179 (11.17%)
    27 / 240 (11.25%)
         occurrences all number
    11
    26
    37
    Pain in extremity
         subjects affected / exposed
    5 / 61 (8.20%)
    11 / 179 (6.15%)
    16 / 240 (6.67%)
         occurrences all number
    6
    12
    18
    Infections and infestations
    Gastroenteritis viral
         subjects affected / exposed
    6 / 61 (9.84%)
    2 / 179 (1.12%)
    8 / 240 (3.33%)
         occurrences all number
    8
    2
    10
    Influenza
         subjects affected / exposed
    3 / 61 (4.92%)
    14 / 179 (7.82%)
    17 / 240 (7.08%)
         occurrences all number
    3
    16
    19
    Nasopharyngitis
         subjects affected / exposed
    6 / 61 (9.84%)
    37 / 179 (20.67%)
    43 / 240 (17.92%)
         occurrences all number
    13
    61
    74
    Pharyngitis
         subjects affected / exposed
    4 / 61 (6.56%)
    2 / 179 (1.12%)
    6 / 240 (2.50%)
         occurrences all number
    9
    2
    11
    Tonsillitis
         subjects affected / exposed
    12 / 61 (19.67%)
    2 / 179 (1.12%)
    14 / 240 (5.83%)
         occurrences all number
    14
    2
    16
    Upper respiratory tract infection
         subjects affected / exposed
    13 / 61 (21.31%)
    19 / 179 (10.61%)
    32 / 240 (13.33%)
         occurrences all number
    34
    27
    61
    Viral infection
         subjects affected / exposed
    4 / 61 (6.56%)
    3 / 179 (1.68%)
    7 / 240 (2.92%)
         occurrences all number
    4
    4
    8
    Viral upper respiratory tract infection
         subjects affected / exposed
    7 / 61 (11.48%)
    0 / 179 (0.00%)
    7 / 240 (2.92%)
         occurrences all number
    22
    0
    22

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    26 Aug 2013
    This amendment was commenced to allow interim analyses of safety and/or efficacy data to support regulatory submissions and planning of future clinical studies, mandate tailored or personalized prophylaxis for pediatric subjects <12 years of age, update the maximum dose and minimum interval for prophylaxis dosing in pediatric subjects, mandate that subjects first dosed with rFVIIIFc when <12 years of age would be followed to at least 100 EDs and update the statistical section.

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

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