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

    Summary
    EudraCT number
    		 2011-003075-11
    Trial protocol
    		 GB   DE   BE   SE   PL   IT   IE   NL  
    Global end of trial date
    31 Oct 2017

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

    Trial information

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    Trial identification
    Sponsor protocol code
    9HB01EXT
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01425723
    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)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    31 Oct 2017
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    31 Oct 2017
    Global end of trial reached?
    Yes
    Global end of trial date
    31 Oct 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this study was to evaluate the long-term safety of rFIXFc in subjects with hemophilia B.
    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 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
    08 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
    Australia: 8
    Country: Number of subjects enrolled
    Belgium: 2
    Country: Number of subjects enrolled
    Brazil: 8
    Country: Number of subjects enrolled
    Canada: 2
    Country: Number of subjects enrolled
    China: 6
    Country: Number of subjects enrolled
    France: 2
    Country: Number of subjects enrolled
    Germany: 2
    Country: Number of subjects enrolled
    Hong Kong: 7
    Country: Number of subjects enrolled
    India: 7
    Country: Number of subjects enrolled
    Ireland: 3
    Country: Number of subjects enrolled
    Italy: 2
    Country: Number of subjects enrolled
    Japan: 5
    Country: Number of subjects enrolled
    Netherlands: 1
    Country: Number of subjects enrolled
    Poland: 1
    Country: Number of subjects enrolled
    South Africa: 10
    Country: Number of subjects enrolled
    Sweden: 2
    Country: Number of subjects enrolled
    United Kingdom: 19
    Country: Number of subjects enrolled
    United States: 33
    Worldwide total number of subjects
    120
    EEA total number of subjects
    34
    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)
    26
    Adolescents (12-17 years)
    9
    Adults (18-64 years)
    85
    From 65 to 84 years
    0
    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 Study (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
    		 rFIXFc [Subjects from 9HB02PED]
    Arm description
    		 Weekly prophylaxis (P): Subjects received 20 IU/kg to 100 IU/kg rFIXFc once weekly during weekly prophylaxis. Dose was based on the subject's clinical profile observed in the parent rFIXFc study and the individual pharmacokinetic profile, trough, and/or peak (recovery) values. Individualized P: 100 IU/kg rFIXFc every 8 to 16 days, or twice a month in individualized prophylaxis. Personalized P: included addition of prevention doses prior to strenuous activity; targeting a FIX trough level of greater than (>) 5%, if warranted by the bleeding history and/or activity level or dosing twice a week (25 IU/kg, twice weekly, versus 50 IU/kg, once weekly) for subjects who may have better control with such a regimen. Subjects who reached the age of 12 during the study could also choose to switch to the episodic treatment group, with dosing based on subject's clinical condition and type and severity of bleeding event; no subjects had entered the episodic treatment group as of the end of study.
    Arm type
    		 Experimental

    Investigational medicinal product name
    rFIXFc
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects received rFIXFc as weekly, individualized, personalized or episodic (on-demand) prophylaxis. Subjects could switch between treatment regimen upon enrollment into the study and at any time during the study, a subject may be included in summary analyses for more than one treatment group.

    Arm title
    		 rFIXFc [Subjects from 998HB102]
    Arm description
    		 Weekly prophylaxis: Subjects received 20 IU/kg to 100 IU/kg rFIXFc once weekly during weekly prophylaxis. Dose was based on the subject's clinical profile observed in the parent rFIXFc study and the individual pharmacokinetic profile, trough, and/or peak (recovery) values. Individual prophylaxis: Subjects received 100 IU/kg rFIXFc every 8 to 16 days, or twice a month in individualized prophylaxis. Personalized Prophylaxis: Personalized prophylaxis included addition of prevention doses prior to strenuous activity; targeting a FIX trough level of greater than (>) 5 percent (%), if warranted by the bleeding history and/or activity level or dosing twice a week (25 IU/kg, twice weekly, versus 50 IU/kg, once weekly) for subjects who may have better control with such a regimen. Episodic (On Demand): The individual dose of rFIXFc to treat bleeding episodes was based on subject's clinical condition, type and severity of the bleeding event.
    Arm type
    		 Experimental

    Investigational medicinal product name
    rFIXFc
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects received rFIXFc as weekly, individualized, personalized or episodic (on demand) prophylaxis. Subjects could switch between treatment regimen upon enrollment into the study and at any time during the study, a subject may be included in summary analyses for more than one treatment group.

    Number of subjects in period 1
    		rFIXFc [Subjects from 9HB02PED] rFIXFc [Subjects from 998HB102]
    Started
    27
    93
    Completed
    23
    75
    Not completed
    4
    18
         Physician decision
    2
    -
         Consent withdrawn by subject
    1
    4
         Other
    1
    10
         Lost to follow-up
    -
    3
         Lack of efficacy
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    rFIXFc [Subjects from 9HB02PED]
    Reporting group description
    		 Weekly prophylaxis (P): Subjects received 20 IU/kg to 100 IU/kg rFIXFc once weekly during weekly prophylaxis. Dose was based on the subject's clinical profile observed in the parent rFIXFc study and the individual pharmacokinetic profile, trough, and/or peak (recovery) values. Individualized P: 100 IU/kg rFIXFc every 8 to 16 days, or twice a month in individualized prophylaxis. Personalized P: included addition of prevention doses prior to strenuous activity; targeting a FIX trough level of greater than (>) 5%, if warranted by the bleeding history and/or activity level or dosing twice a week (25 IU/kg, twice weekly, versus 50 IU/kg, once weekly) for subjects who may have better control with such a regimen. Subjects who reached the age of 12 during the study could also choose to switch to the episodic treatment group, with dosing based on subject's clinical condition and type and severity of bleeding event; no subjects had entered the episodic treatment group as of the end of study.

    Reporting group title
    rFIXFc [Subjects from 998HB102]
    Reporting group description
    		 Weekly prophylaxis: Subjects received 20 IU/kg to 100 IU/kg rFIXFc once weekly during weekly prophylaxis. Dose was based on the subject's clinical profile observed in the parent rFIXFc study and the individual pharmacokinetic profile, trough, and/or peak (recovery) values. Individual prophylaxis: Subjects received 100 IU/kg rFIXFc every 8 to 16 days, or twice a month in individualized prophylaxis. Personalized Prophylaxis: Personalized prophylaxis included addition of prevention doses prior to strenuous activity; targeting a FIX trough level of greater than (>) 5 percent (%), if warranted by the bleeding history and/or activity level or dosing twice a week (25 IU/kg, twice weekly, versus 50 IU/kg, once weekly) for subjects who may have better control with such a regimen. Episodic (On Demand): The individual dose of rFIXFc to treat bleeding episodes was based on subject's clinical condition, type and severity of the bleeding event.

    Reporting group values
    		 rFIXFc [Subjects from 9HB02PED] rFIXFc [Subjects from 998HB102] Total
    Number of subjects
    		 27 93 120
    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)
    		 26 0 26
        Adolescents (12-17 years)
    		 1 8 9
        Adults (18-64 years)
    		 0 85 85
        From 65-84 years
    		 0 0 0
        85 years and over
    		 0 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 6.7 ( 3.22 ) 32.7 ( 14.09 ) -
    Gender categorical
    Units: Subjects
        Female
    		 0 0 0
        Male
    		 27 93 120

    End points

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    End points reporting groups
    Reporting group title
    rFIXFc [Subjects from 9HB02PED]
    Reporting group description
    		 Weekly prophylaxis (P): Subjects received 20 IU/kg to 100 IU/kg rFIXFc once weekly during weekly prophylaxis. Dose was based on the subject's clinical profile observed in the parent rFIXFc study and the individual pharmacokinetic profile, trough, and/or peak (recovery) values. Individualized P: 100 IU/kg rFIXFc every 8 to 16 days, or twice a month in individualized prophylaxis. Personalized P: included addition of prevention doses prior to strenuous activity; targeting a FIX trough level of greater than (>) 5%, if warranted by the bleeding history and/or activity level or dosing twice a week (25 IU/kg, twice weekly, versus 50 IU/kg, once weekly) for subjects who may have better control with such a regimen. Subjects who reached the age of 12 during the study could also choose to switch to the episodic treatment group, with dosing based on subject's clinical condition and type and severity of bleeding event; no subjects had entered the episodic treatment group as of the end of study.

    Reporting group title
    rFIXFc [Subjects from 998HB102]
    Reporting group description
    		 Weekly prophylaxis: Subjects received 20 IU/kg to 100 IU/kg rFIXFc once weekly during weekly prophylaxis. Dose was based on the subject's clinical profile observed in the parent rFIXFc study and the individual pharmacokinetic profile, trough, and/or peak (recovery) values. Individual prophylaxis: Subjects received 100 IU/kg rFIXFc every 8 to 16 days, or twice a month in individualized prophylaxis. Personalized Prophylaxis: Personalized prophylaxis included addition of prevention doses prior to strenuous activity; targeting a FIX trough level of greater than (>) 5 percent (%), if warranted by the bleeding history and/or activity level or dosing twice a week (25 IU/kg, twice weekly, versus 50 IU/kg, once weekly) for subjects who may have better control with such a regimen. Episodic (On Demand): The individual dose of rFIXFc to treat bleeding episodes was based on subject's clinical condition, type and severity of the bleeding event.

    Subject analysis set title
    rFIXFc [9HB02PED (<6 years old age cohort)]
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Subjects enrolled from the study 9HB02PED with <6 years old age.

    Subject analysis set title
    rFIXFc [9HB02PED (6 - <12 years old age cohort)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Subjects enrolled from the study 9HB02PED with 6 - <12 years old age.

    Subject analysis set title
    rFIXFc [Subjects from 998HB102]
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Subjects enrolled from the study 998HB102.

    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, confirmed on 2 separate samples drawn 2 to 4 weeks apart, was considered positive. Both tests were to be performed by the central laboratory using the Nijmegen-modified Bethesda Assay. Safety Analysis Set included subjects who received at least 1 dose of rFIXFc in study 9HB01EXT.
    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
    		 rFIXFc [Subjects from 9HB02PED] rFIXFc [Subjects from 998HB102]
    Number of subjects analysed
    27
    93
    Units: subjects with any positive inhibitor
    0
    0
    No statistical analyses for this end point

    Secondary: Annualized Bleeding Rate (ABR)

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    End point title
    		 Annualized Bleeding Rate (ABR)
    End point description
    ABR is annualized number of bleeding episodes (spontaneous or traumatic) per subject. 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. FAS=all subjects who received at least 1 dose of rFIXFc. "n"= number of subject analyzed in specified treatment regimen. "99999" indicates that data was not analyzed for the arm in specified category. Annualized bleeding episodes=(Number of bleeding episodes during efficacy period/number of days during efficacy period)*365.25. Efficacy period reflects the sum of all intervals of time during which subjects were treated with rFIXFc 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
    		 rFIXFc [9HB02PED (<6 years old age cohort)] rFIXFc [9HB02PED (6 - <12 years old age cohort) rFIXFc [Subjects from 998HB102]
    Number of subjects analysed
    13
    14
    93
    Units: episodes per subject per year
    median (inter-quartile range (Q1-Q3))
        Weekly Prophylaxis (n= 13, 10, 51)
    1.04 (0.00 to 2.28)
    1.14 (0.54 to 2.34)
    2.26 (0.40 to 5.16)
        Individualized Prophylaxis (n= 0, 5, 31)
    99999 (99999 to 99999)
    3.69 (3.54 to 5.21)
    1.85 (0.76 to 4.00)
        Personalized Prophylaxis (n= 1, 1, 16)
    0.54 (0.54 to 0.54)
    3.13 (3.13 to 3.13)
    2.91 (1.14 to 5.36)
        Episodic (n= 0, 0, 15)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    11.64 (5.12 to 18.54)
    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 rFIXFc. 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
    		 rFIXFc [9HB02PED (<6 years old age cohort)] rFIXFc [9HB02PED (6 - <12 years old age cohort) rFIXFc [Subjects from 998HB102]
    Number of subjects analysed
    13
    14
    93
    Units: episodes per subject per year
    median (inter-quartile range (Q1-Q3))
        Weekly Prophylaxis (n= 13, 10, 51)
    0.00 (0.00 to 1.06)
    0.00 (0.00 to 1.40)
    0.38 (0.00 to 2.25)
        Individualized Prophylaxis (n= 0, 5, 31)
    99999 (99999 to 99999)
    0.00 (0.00 to 0.29)
    0.38 (0.00 to 1.43)
        Personalized Prophylaxis (n= 1, 1, 16)
    0.00 (0.00 to 0.00)
    0.00 (0.00 to 0.00)
    0.30 (0.00 to 1.37)
        Episodic (n= 0, 0, 15)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    2.15 (0.58 to 11.68)
    No statistical analyses for this end point

    Secondary: Total Number of Days of Exposure per Subject

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    End point title
    		 Total Number of Days of Exposure per Subject
    End point description
    An exposure day is a 24-hour period in which one or more rFIXFc injections are given. The total number of days of exposure to rFIXFc were summarized. Safety Analysis Set included subjects who received at least 1 dose of rFIXFc in study 9HB01EXT. 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
    		 rFIXFc [9HB02PED (<6 years old age cohort)] rFIXFc [9HB02PED (6 - <12 years old age cohort) rFIXFc [Subjects from 998HB102]
    Number of subjects analysed
    13
    14
    93
    Units: days
    median (full range (min-max))
        Weekly Prophylaxis (n= 13, 10, 51)
    55.00 (8.0 to 176.0)
    165.00 (3.0 to 202.0)
    169.00 (4.0 to 327.0)
        Individualized Prophylaxis (n= 0, 5, 31)
    99999 (99999 to 99999)
    54.00 (4.0 to 141.0)
    110.00 (9.0 to 369.0)
        Personalized Prophylaxis (n= 1, 1, 17)
    157.00 (157.00 to 157.00)
    90.00 (90.00 to 90.00)
    146.00 (7.0 to 431.0)
        Episodic (n= 0, 0, 15)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    52.00 (0.0 to 164.0)
    No statistical analyses for this end point

    Secondary: Annualized rFIXFc Consumption per Kilogram per Subject per Year

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    End point title
    		 Annualized rFIXFc Consumption per Kilogram 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 rFIXFc. 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
    		 rFIXFc [9HB02PED (<6 years old age cohort)] rFIXFc [9HB02PED (6 - <12 years old age cohort) rFIXFc [Subjects from 998HB102]
    Number of subjects analysed
    13
    14
    93
    Units: dose per kilogram per subject per year
    median (inter-quartile range (Q1-Q3))
        Weekly Prophylaxis (n= 13, 10, 51)
    3382.5 (2930.9 to 3667.4)
    3212.0 (2838.5 to 3344.4)
    2598.0 (2129.8 to 3370.9)
        Individualized Prophylaxis (n= 0, 5, 31)
    99999 (99999 to 99999)
    3700.7 (3689.2 to 3716.5)
    2894.8 (2520.0 to 4023.5)
        Personalized Prophylaxis (n= 1, 1, 16)
    3331.7 (3331.7 to 3331.7)
    8931.2 (8931.2 to 8931.2)
    3671.2 (2394.8 to 5563.3)
        Episodic (n= 0, 0, 15)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    595.6 (363.8 to 1024.5)
    No statistical analyses for this end point

    Secondary: Physicians' Global Assessment of Response to Treatment With rFIXFc Using a 4-Point Scale

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    End point title
    		 Physicians' Global Assessment of Response to Treatment With rFIXFc Using a 4-Point Scale
    End point description
    Subjects were assessed for response to their rFIXFc 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 rFIXFc, 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 rFIXFc. 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
    		 rFIXFc [Subjects from 9HB02PED] rFIXFc [Subjects from 998HB102]
    Number of subjects analysed
    27
    93
    Units: percentage of visits
    number (not applicable)
        Excellent
    86.8
    76.3
        Effective
    12.6
    22.6
        Partially Effective
    0.7
    1.1
        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 rFIXFc 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
    		 rFIXFc [9HB02PED (<6 years old age cohort)] rFIXFc [9HB02PED (6 - <12 years old age cohort) rFIXFc [Subjects from 998HB102]
    Number of subjects analysed
    13
    14
    93
    Units: % of first inj. with evaluations for BE
    number (not applicable)
        Weekly Prophylaxis (n= 13, 10, 51)
    81.1
    82.5
    74.2
        Individualized Prophylaxis (n= 0, 5, 31)
    99999
    80.6
    87.0
        Personalized Prophylaxis (n= 1, 1, 16)
    0
    50.0
    75.8
        Episodic (n= 0, 0, 15)
    99999
    99999
    97.1
    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 [14 (+7) days after the last dose of rFIXFc] 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 rFIXFc 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
    rFIXFc [Subjects from 9HB02PED]
    Reporting group description
    		 Weekly prophylaxis (P): Subjects received 20 IU/kg to 100 IU/kg rFIXFc once weekly during weekly prophylaxis. Dose was based on the subject's clinical profile observed in the parent rFIXFc study and the individual pharmacokinetic profile, trough, and/or peak (recovery) values. Individualized P: 100 IU/kg rFIXFc every 8 to 16 days, or twice a month in individualized prophylaxis. Personalized P: included addition of prevention doses prior to strenuous activity; targeting a FIX trough level of greater than (>) 5%, if warranted by the bleeding history and/or activity level or dosing twice a week (25 IU/kg, twice weekly, versus 50 IU/kg, once weekly) for subjects who may have better control with such a regimen. Subjects who reached the age of 12 during the study could also choose to switch to the episodic treatment group, with dosing based on subject's clinical condition and type and severity of bleeding event; no subjects had entered the episodic treatment group as of the end of study.

    Reporting group title
    rFIXFc [Subjects from 998HB102]
    Reporting group description
    		 Weekly prophylaxis: Subjects received 20 IU/kg to 100 IU/kg rFIXFc once weekly during weekly prophylaxis. Dose was based on the subject's clinical profile observed in the parent rFIXFc study and the individual pharmacokinetic profile, trough, and/or peak (recovery) values. Individual prophylaxis: Subjects received 100 IU/kg rFIXFc every 8 to 16 days, or twice a month in individualized prophylaxis. Personalized Prophylaxis: Personalized prophylaxis included addition of prevention doses prior to strenuous activity; targeting a FIX trough level of greater than (>) 5 percent (%), if warranted by the bleeding history and/or activity level or dosing twice a week (25 IU/kg, twice weekly, versus 50 IU/kg, once weekly) for subjects who may have better control with such a regimen. Episodic (On Demand): The individual dose of rFIXFc to treat bleeding episodes was based on subject's clinical condition, type and severity of the bleeding event.

    Reporting group title
    Overall rFIXFc
    Reporting group description
    		 -

    Serious adverse events
    		 rFIXFc [Subjects from 9HB02PED] rFIXFc [Subjects from 998HB102] Overall rFIXFc
    Total subjects affected by serious adverse events
         subjects affected / exposed
    5 / 27 (18.52%)
    31 / 93 (33.33%)
    36 / 120 (30.00%)
         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 / 27 (0.00%)
    1 / 93 (1.08%)
    1 / 120 (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
    Haemorrhage intracranial
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 93 (1.08%)
    1 / 120 (0.83%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Posterior interosseous syndrome
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 93 (1.08%)
    1 / 120 (0.83%)
         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
    Haematoma
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 93 (1.08%)
    1 / 120 (0.83%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Surgical and medical procedures
    Knee arthroplasty
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 93 (1.08%)
    1 / 120 (0.83%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tonsillectomy
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 93 (1.08%)
    1 / 120 (0.83%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Pain
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 93 (1.08%)
    1 / 120 (0.83%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Social circumstances
    Victim of crime
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 93 (1.08%)
    1 / 120 (0.83%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Epistaxis
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 93 (1.08%)
    1 / 120 (0.83%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tonsillar haemorrhage
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 93 (1.08%)
    1 / 120 (0.83%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Concussion
         subjects affected / exposed
    1 / 27 (3.70%)
    0 / 93 (0.00%)
    1 / 120 (0.83%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Extradural haematoma
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 93 (1.08%)
    1 / 120 (0.83%)
         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
    3 / 27 (11.11%)
    4 / 93 (4.30%)
    7 / 120 (5.83%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 4
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Femoral neck fracture
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 93 (1.08%)
    1 / 120 (0.83%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Foreign body
         subjects affected / exposed
    1 / 27 (3.70%)
    0 / 93 (0.00%)
    1 / 120 (0.83%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Head injury
         subjects affected / exposed
    1 / 27 (3.70%)
    0 / 93 (0.00%)
    1 / 120 (0.83%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Laceration
         subjects affected / exposed
    1 / 27 (3.70%)
    0 / 93 (0.00%)
    1 / 120 (0.83%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Post procedural haematoma
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 93 (1.08%)
    1 / 120 (0.83%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Post procedural haemorrhage
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 93 (1.08%)
    1 / 120 (0.83%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Rib fracture
         subjects affected / exposed
    0 / 27 (0.00%)
    2 / 93 (2.15%)
    2 / 120 (1.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Road traffic accident
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 93 (1.08%)
    1 / 120 (0.83%)
         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 / 27 (0.00%)
    1 / 93 (1.08%)
    1 / 120 (0.83%)
         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 intracranial haemorrhage
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 93 (1.08%)
    1 / 120 (0.83%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Upper limb fracture
         subjects affected / exposed
    1 / 27 (3.70%)
    0 / 93 (0.00%)
    1 / 120 (0.83%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Epilepsy
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 93 (1.08%)
    1 / 120 (0.83%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 27 (3.70%)
    0 / 93 (0.00%)
    1 / 120 (0.83%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Necrotising retinitis
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 93 (1.08%)
    1 / 120 (0.83%)
         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
    Enterocolitis
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 93 (1.08%)
    1 / 120 (0.83%)
         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 haemorrhage
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 93 (1.08%)
    1 / 120 (0.83%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Calculus ureteric
         subjects affected / exposed
    0 / 27 (0.00%)
    2 / 93 (2.15%)
    2 / 120 (1.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haematuria
         subjects affected / exposed
    0 / 27 (0.00%)
    2 / 93 (2.15%)
    2 / 120 (1.67%)
         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 colic
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 93 (1.08%)
    1 / 120 (0.83%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthropathy
         subjects affected / exposed
    0 / 27 (0.00%)
    2 / 93 (2.15%)
    2 / 120 (1.67%)
         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
    0 / 27 (0.00%)
    1 / 93 (1.08%)
    1 / 120 (0.83%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haemophilic arthropathy
         subjects affected / exposed
    0 / 27 (0.00%)
    4 / 93 (4.30%)
    4 / 120 (3.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 5
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Intervertebral disc protrusion
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 93 (1.08%)
    1 / 120 (0.83%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Slipping rib syndrome
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 93 (1.08%)
    1 / 120 (0.83%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Spinal column stenosis
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 93 (1.08%)
    1 / 120 (0.83%)
         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
    Anal abscess
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 93 (1.08%)
    1 / 120 (0.83%)
         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
    0 / 27 (0.00%)
    3 / 93 (3.23%)
    3 / 120 (2.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatitis C
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 93 (1.08%)
    1 / 120 (0.83%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Orchitis
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 93 (1.08%)
    1 / 120 (0.83%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pilonidal cyst
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 93 (1.08%)
    1 / 120 (0.83%)
         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
    0 / 27 (0.00%)
    1 / 93 (1.08%)
    1 / 120 (0.83%)
         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 bacteraemia
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 93 (1.08%)
    1 / 120 (0.83%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tonsillitis
         subjects affected / exposed
    1 / 27 (3.70%)
    0 / 93 (0.00%)
    1 / 120 (0.83%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tooth abscess
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 93 (1.08%)
    1 / 120 (0.83%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Wound infection
         subjects affected / exposed
    1 / 27 (3.70%)
    0 / 93 (0.00%)
    1 / 120 (0.83%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    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
    		 rFIXFc [Subjects from 9HB02PED] rFIXFc [Subjects from 998HB102] Overall rFIXFc
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    23 / 27 (85.19%)
    66 / 93 (70.97%)
    89 / 120 (74.17%)
    Investigations
    Serum ferritin decreased
         subjects affected / exposed
    2 / 27 (7.41%)
    0 / 93 (0.00%)
    2 / 120 (1.67%)
         occurrences all number
    2
    0
    2
    Injury, poisoning and procedural complications
    Excoriation
         subjects affected / exposed
    2 / 27 (7.41%)
    1 / 93 (1.08%)
    3 / 120 (2.50%)
         occurrences all number
    2
    2
    4
    Fall
         subjects affected / exposed
    7 / 27 (25.93%)
    4 / 93 (4.30%)
    11 / 120 (9.17%)
         occurrences all number
    9
    15
    24
    Head injury
         subjects affected / exposed
    2 / 27 (7.41%)
    2 / 93 (2.15%)
    4 / 120 (3.33%)
         occurrences all number
    2
    2
    4
    Joint dislocation
         subjects affected / exposed
    2 / 27 (7.41%)
    0 / 93 (0.00%)
    2 / 120 (1.67%)
         occurrences all number
    2
    0
    2
    Joint injury
         subjects affected / exposed
    2 / 27 (7.41%)
    2 / 93 (2.15%)
    4 / 120 (3.33%)
         occurrences all number
    3
    3
    6
    Laceration
         subjects affected / exposed
    3 / 27 (11.11%)
    5 / 93 (5.38%)
    8 / 120 (6.67%)
         occurrences all number
    3
    5
    8
    Ligament sprain
         subjects affected / exposed
    2 / 27 (7.41%)
    4 / 93 (4.30%)
    6 / 120 (5.00%)
         occurrences all number
    2
    4
    6
    Vascular disorders
    Hypertension
         subjects affected / exposed
    0 / 27 (0.00%)
    7 / 93 (7.53%)
    7 / 120 (5.83%)
         occurrences all number
    0
    7
    7
    Nervous system disorders
    Headache
         subjects affected / exposed
    3 / 27 (11.11%)
    15 / 93 (16.13%)
    18 / 120 (15.00%)
         occurrences all number
    6
    17
    23
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    6 / 27 (22.22%)
    5 / 93 (5.38%)
    11 / 120 (9.17%)
         occurrences all number
    9
    6
    15
    Immune system disorders
    Seasonal allergy
         subjects affected / exposed
    4 / 27 (14.81%)
    3 / 93 (3.23%)
    7 / 120 (5.83%)
         occurrences all number
    6
    4
    10
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    2 / 27 (7.41%)
    4 / 93 (4.30%)
    6 / 120 (5.00%)
         occurrences all number
    2
    4
    6
    Gastrooesophageal reflux disease
         subjects affected / exposed
    1 / 27 (3.70%)
    7 / 93 (7.53%)
    8 / 120 (6.67%)
         occurrences all number
    1
    8
    9
    Gingival bleeding
         subjects affected / exposed
    2 / 27 (7.41%)
    0 / 93 (0.00%)
    2 / 120 (1.67%)
         occurrences all number
    2
    0
    2
    Nausea
         subjects affected / exposed
    0 / 27 (0.00%)
    5 / 93 (5.38%)
    5 / 120 (4.17%)
         occurrences all number
    0
    6
    6
    Toothache
         subjects affected / exposed
    0 / 27 (0.00%)
    5 / 93 (5.38%)
    5 / 120 (4.17%)
         occurrences all number
    0
    6
    6
    Vomiting
         subjects affected / exposed
    5 / 27 (18.52%)
    7 / 93 (7.53%)
    12 / 120 (10.00%)
         occurrences all number
    5
    8
    13
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    3 / 27 (11.11%)
    5 / 93 (5.38%)
    8 / 120 (6.67%)
         occurrences all number
    3
    6
    9
    Epistaxis
         subjects affected / exposed
    5 / 27 (18.52%)
    0 / 93 (0.00%)
    5 / 120 (4.17%)
         occurrences all number
    6
    0
    6
    Nasal congestion
         subjects affected / exposed
    5 / 27 (18.52%)
    0 / 93 (0.00%)
    5 / 120 (4.17%)
         occurrences all number
    5
    0
    5
    Skin and subcutaneous tissue disorders
    Acne
         subjects affected / exposed
    0 / 27 (0.00%)
    5 / 93 (5.38%)
    5 / 120 (4.17%)
         occurrences all number
    0
    5
    5
    Renal and urinary disorders
    Haematuria
         subjects affected / exposed
    0 / 27 (0.00%)
    5 / 93 (5.38%)
    5 / 120 (4.17%)
         occurrences all number
    0
    7
    7
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    4 / 27 (14.81%)
    10 / 93 (10.75%)
    14 / 120 (11.67%)
         occurrences all number
    4
    13
    17
    Pain in extremity
         subjects affected / exposed
    2 / 27 (7.41%)
    1 / 93 (1.08%)
    3 / 120 (2.50%)
         occurrences all number
    2
    1
    3
    Infections and infestations
    Ear infection
         subjects affected / exposed
    3 / 27 (11.11%)
    1 / 93 (1.08%)
    4 / 120 (3.33%)
         occurrences all number
    3
    2
    5
    Hepatitis c
         subjects affected / exposed
    0 / 27 (0.00%)
    5 / 93 (5.38%)
    5 / 120 (4.17%)
         occurrences all number
    0
    5
    5
    Influenza
         subjects affected / exposed
    1 / 27 (3.70%)
    8 / 93 (8.60%)
    9 / 120 (7.50%)
         occurrences all number
    1
    9
    10
    Lower respiratory tract infection
         subjects affected / exposed
    3 / 27 (11.11%)
    1 / 93 (1.08%)
    4 / 120 (3.33%)
         occurrences all number
    5
    1
    6
    Nasopharyngitis
         subjects affected / exposed
    3 / 27 (11.11%)
    14 / 93 (15.05%)
    17 / 120 (14.17%)
         occurrences all number
    4
    18
    22
    Paronychia
         subjects affected / exposed
    2 / 27 (7.41%)
    0 / 93 (0.00%)
    2 / 120 (1.67%)
         occurrences all number
    2
    0
    2
    Sinusitis
         subjects affected / exposed
    1 / 27 (3.70%)
    5 / 93 (5.38%)
    6 / 120 (5.00%)
         occurrences all number
    2
    6
    8
    Tonsillitis
         subjects affected / exposed
    2 / 27 (7.41%)
    0 / 93 (0.00%)
    2 / 120 (1.67%)
         occurrences all number
    3
    0
    3
    Upper respiratory tract infection
         subjects affected / exposed
    2 / 27 (7.41%)
    6 / 93 (6.45%)
    8 / 120 (6.67%)
         occurrences all number
    3
    7
    10
    Varicella
         subjects affected / exposed
    2 / 27 (7.41%)
    1 / 93 (1.08%)
    3 / 120 (2.50%)
         occurrences all number
    2
    1
    3
    Viral infection
         subjects affected / exposed
    2 / 27 (7.41%)
    3 / 93 (3.23%)
    5 / 120 (4.17%)
         occurrences all number
    2
    3
    5

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    05 Aug 2011
    The primary reason for this amendment was to clarify the duration and planned end of the study.
    20 Jun 2012
    The main reasons for this amendment were: to include various clarifications to the protocol (including a Protocol Clarification Letter), correction of errors, and additions to enhance understanding of the protocol, e.g., in Section 5.3.3 the list of assessments to be performed at the Last Postoperative Visit for subjects who entered the extension study following major surgery in Study 9HB02PED was added; addition of information on dispensation of study treatment between study visits to maintain adequate drug supplies for the subject’s study treatment.
    13 Nov 2013
    The main reason of this amendment were: to amend dose regimen to be appropriate for subjects <12 years of age to accommodate the transition of subjects from the pediatric study (9HB02PED) to this study (Study 9HB01EXT); ·specify that subjects will be followed through at least 100 EDs; update of statistical section; modification of text to note that major surgeries are to be classified as SAEs; addition of anti-rFIXFc antibody assessment.

    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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