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    Clinical Trial Results:
    Open-label, Multicenter Evaluation of Safety, Pharmacokinetics, and Efficacy of Recombinant Coagulation Factor IX Fc Fusion Protein, BIIB029, in the Prevention and Treatment of Bleeding Episodes in Pediatric Subjects With Hemophilia B

    Summary
    EudraCT number
    2011-003076-36
    Trial protocol
    GB   IE   NL  
    Global end of trial date
    24 Nov 2014

    Results information
    Results version number
    v2(current)
    This version publication date
    05 Feb 2016
    First version publication date
    14 Jun 2015
    Other versions
    v1
    Version creation reason
    • Correction of full data set
    Secondary enpoint #9 unit of measure correction required.

    Trial information

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    Trial identification
    Sponsor protocol code
    9HB02PED
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01440946
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Biogen
    Sponsor organisation address
    225 Binney Street, Cambridge, United States, 02142
    Public contact
    Biogen Study Medical Director, Biogen, clinicaltrials@biogen.com
    Scientific contact
    Biogen Study Medical Director, Biogen, clinicaltrials@biogen.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    EMEA-000914-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
    24 Nov 2014
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    24 Nov 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of the study is to evaluate the safety of rFIXFc in previously treated pediatric subjects with hemophilia B. Secondary objectives of this study in this study population are as follows: to evaluate the efficacy of rFIXFc for prevention and treatment of bleeding episodes; to evaluate and assess the PK of rFIXFc; to evaluate rFIXFc consumption for prevention and treatment of bleeding episodes.
    Protection of trial subjects
    Only subjects who met the eligibility criteria were enrolled into the trial. The first dose of rFIXFc was administered under medical supervision in the clinic and subjects were tested for inhibitor formation at screening and at each clinic visit prior to dosing. Medications and resuscitation equipment for the emergency management of anaphylactic reactions were available in the room where the subject's first injection was performed. In addition, the subject was provided with specific instructions by the Investigator on what to do if such an event occurred while at home, including how to seek emergency medical treatment. In addition to scheduled clinic visits, at least one telephone call was planned midway between visits for study site staff to check on each subject’s status.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    08 Jun 2012
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Netherlands: 1
    Country: Number of subjects enrolled
    United Kingdom: 7
    Country: Number of subjects enrolled
    Ireland: 3
    Country: Number of subjects enrolled
    Australia: 3
    Country: Number of subjects enrolled
    South Africa: 2
    Country: Number of subjects enrolled
    United States: 14
    Worldwide total number of subjects
    30
    EEA total number of subjects
    11
    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)
    1
    Children (2-11 years)
    29
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    0
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    -

    Pre-assignment
    Screening details
    Subject eligibility for the study was determined up to 8 weeks prior to the Baseline Visit. This period could be extended if the subject had a bleeding episode requiring factor IX (FIX) treatment within 5 days prior to the first dose of prestudy FIX. Some eligibility assessments were repeated for rescreened subjects with a >8-week screening window.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Subjects < 6 Years Old
    Arm description
    At the Baseline visit (28 ± 7 days prior to Day 1), subjects received a single IV injection of prestudy FIX over 10 (±5) minutes in the clinic under medical supervision at a dose of 50 IU/kg. A washout period with no FIX treatment was required prior to administration of prestudy FIX and prior to rFIXFc. At Day 1, subjects received a single IV injection of rFIXFc over 10 (±5) minutes at a dose of 50 IU/kg. Immediately after the last PK sampling, the first prophylactic dose of approximately 50 to 60 IU/kg was administered in clinic as an IV injection. Dose could be increased or decreased in increments of 10 IU/kg; increases to a maximum of 100 IU/kg and frequency of administration to a maximum of twice weekly, were allowed as indicated.
    Arm type
    Experimental

    Investigational medicinal product name
    rFIXFc
    Investigational medicinal product code
    rFIXFc
    Other name
    BIIB029, recombinant human coagulation factor IX Fc fusion protein, Alprolix
    Pharmaceutical forms
    Powder and solvent for solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Study site staff members were instructed to refer to the Directions for Handling and Administration (DHA) Manual located in the Investigator Site File and/or the Pharmacy Manual for specific instructions on the handling, preparation, administration, and disposal of the study treatment. Vials of rFIXFc were combined as needed, based on the actual labeled potency to achieve the subject's calculated dose. Partial vial use was allowed, in order to achieve the calculated dose.

    Investigational medicinal product name
    FIX
    Investigational medicinal product code
    Other name
    Factor IX
    Pharmaceutical forms
    Powder and solvent for solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Study site staff members were instructed to refer to the Directions for Handling and Administration (DHA) Manual located in the Investigator Site File and/or the Pharmacy Manual for specific instructions on the handling, preparation, administration, and disposal of the study treatment. Vials of prestudy FIX (provided by the subjects) were combined as needed, based on the nominal labeled potency (e.g., 250 IU, 500 IU, and 1000 IU), to achieve the subject's calculated dose.

    Arm title
    Subjects 6 to < 12 Years Old
    Arm description
    At the Baseline visit (28 ± 7 days prior to Day 1), subjects received a single IV injection of prestudy FIX over 10 (±5) minutes in the clinic under medical supervision at a dose of 50 IU/kg. A washout period with no FIX treatment was required prior to administration of prestudy FIX and prior to rFIXFc. At Day 1, subjects received a single IV injection of rFIXFc over 10 (±5) minutes at a dose of 50 IU/kg. Immediately after the last PK sampling, the first prophylactic dose of approximately 50 to 60 IU/kg was administered in clinic as an IV injection. Dose could be increased or decreased in increments of 10 IU/kg; increases to a maximum of 100 IU/kg and frequency of administration to a maximum of twice weekly, were allowed as indicated.
    Arm type
    Experimental

    Investigational medicinal product name
    rFIXFc
    Investigational medicinal product code
    rFIXFc
    Other name
    BIIB029, recombinant human coagulation factor IX Fc fusion protein, Alprolix
    Pharmaceutical forms
    Powder and solvent for solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Study site staff members were instructed to refer to the Directions for Handling and Administration (DHA) Manual located in the Investigator Site File and/or the Pharmacy Manual for specific instructions on the handling, preparation, administration, and disposal of the study treatment. Vials of rFIXFc were combined as needed, based on the actual labeled potency to achieve the subject's calculated dose. Partial vial use was allowed, in order to achieve the calculated dose.

    Investigational medicinal product name
    FIX
    Investigational medicinal product code
    Other name
    Factor IX
    Pharmaceutical forms
    Powder and solvent for solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Study site staff members were instructed to refer to the Directions for Handling and Administration (DHA) Manual located in the Investigator Site File and/or the Pharmacy Manual for specific instructions on the handling, preparation, administration, and disposal of the study treatment. Vials of prestudy FIX (provided by the subjects) were combined as needed, based on the nominal labeled potency (e.g., 250 IU, 500 IU, and 1000 IU), to achieve the subject's calculated dose.

    Number of subjects in period 1
    Subjects < 6 Years Old Subjects 6 to < 12 Years Old
    Started
    15
    15
    Completed
    13
    14
    Not completed
    2
    1
         Physician decision
    1
    -
         Lost to follow-up
    1
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Subjects < 6 Years Old
    Reporting group description
    At the Baseline visit (28 ± 7 days prior to Day 1), subjects received a single IV injection of prestudy FIX over 10 (±5) minutes in the clinic under medical supervision at a dose of 50 IU/kg. A washout period with no FIX treatment was required prior to administration of prestudy FIX and prior to rFIXFc. At Day 1, subjects received a single IV injection of rFIXFc over 10 (±5) minutes at a dose of 50 IU/kg. Immediately after the last PK sampling, the first prophylactic dose of approximately 50 to 60 IU/kg was administered in clinic as an IV injection. Dose could be increased or decreased in increments of 10 IU/kg; increases to a maximum of 100 IU/kg and frequency of administration to a maximum of twice weekly, were allowed as indicated.

    Reporting group title
    Subjects 6 to < 12 Years Old
    Reporting group description
    At the Baseline visit (28 ± 7 days prior to Day 1), subjects received a single IV injection of prestudy FIX over 10 (±5) minutes in the clinic under medical supervision at a dose of 50 IU/kg. A washout period with no FIX treatment was required prior to administration of prestudy FIX and prior to rFIXFc. At Day 1, subjects received a single IV injection of rFIXFc over 10 (±5) minutes at a dose of 50 IU/kg. Immediately after the last PK sampling, the first prophylactic dose of approximately 50 to 60 IU/kg was administered in clinic as an IV injection. Dose could be increased or decreased in increments of 10 IU/kg; increases to a maximum of 100 IU/kg and frequency of administration to a maximum of twice weekly, were allowed as indicated.

    Reporting group values
    Subjects < 6 Years Old Subjects 6 to < 12 Years Old Total
    Number of subjects
    15 15 30
    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)
    1 0 1
        Children (2-11 years)
    14 15 29
        Adolescents (12-17 years)
    0 0 0
        Adults (18-64 years)
    0 0 0
        From 65-84 years
    0 0 0
        85 years and over
    0 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    2.6 ± 0.99 8.3 ± 1.45 -
    Gender categorical
    Units: Subjects
        Female
    0 0 0
        Male
    15 15 30
    Subject analysis sets

    Subject analysis set title
    All subjects
    Subject analysis set type
    Full analysis
    Subject analysis set description
    All subjects

    Subject analysis sets values
    All subjects
    Number of subjects
    30
    Age categorical
    Units: Subjects
        In utero
    0
        Preterm newborn infants (gestational age < 37 wks)
    0
        Newborns (0-27 days)
    0
        Infants and toddlers (28 days-23 months)
    1
        Children (2-11 years)
    29
        Adolescents (12-17 years)
    0
        Adults (18-64 years)
    0
        From 65-84 years
    0
        85 years and over
    0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    5.5 ± 3.16
    Gender categorical
    Units: Subjects
        Female
    0
        Male
    30

    End points

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    End points reporting groups
    Reporting group title
    Subjects < 6 Years Old
    Reporting group description
    At the Baseline visit (28 ± 7 days prior to Day 1), subjects received a single IV injection of prestudy FIX over 10 (±5) minutes in the clinic under medical supervision at a dose of 50 IU/kg. A washout period with no FIX treatment was required prior to administration of prestudy FIX and prior to rFIXFc. At Day 1, subjects received a single IV injection of rFIXFc over 10 (±5) minutes at a dose of 50 IU/kg. Immediately after the last PK sampling, the first prophylactic dose of approximately 50 to 60 IU/kg was administered in clinic as an IV injection. Dose could be increased or decreased in increments of 10 IU/kg; increases to a maximum of 100 IU/kg and frequency of administration to a maximum of twice weekly, were allowed as indicated.

    Reporting group title
    Subjects 6 to < 12 Years Old
    Reporting group description
    At the Baseline visit (28 ± 7 days prior to Day 1), subjects received a single IV injection of prestudy FIX over 10 (±5) minutes in the clinic under medical supervision at a dose of 50 IU/kg. A washout period with no FIX treatment was required prior to administration of prestudy FIX and prior to rFIXFc. At Day 1, subjects received a single IV injection of rFIXFc over 10 (±5) minutes at a dose of 50 IU/kg. Immediately after the last PK sampling, the first prophylactic dose of approximately 50 to 60 IU/kg was administered in clinic as an IV injection. Dose could be increased or decreased in increments of 10 IU/kg; increases to a maximum of 100 IU/kg and frequency of administration to a maximum of twice weekly, were allowed as indicated.

    Subject analysis set title
    All subjects
    Subject analysis set type
    Full analysis
    Subject analysis set description
    All subjects

    Primary: Occurrence of Factor IX (FIX) Inhibitor Development

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    End point title
    Occurrence of Factor IX (FIX) Inhibitor Development [1]
    End point description
    An inhibitor test result ≥0.6 BU/mL, identified and confirmed by re-testing of a second sample obtained within 2 to 4 weeks, was considered positive. Both tests were to be performed using the Nijmegen-modified Bethesda Assay by the central laboratory. The incidence rates along with the 95% CI were summarized for all titers for subjects with 50 or more EDs to rFIXFc and a valid inhibitor test after the 50th exposure. In addition, the incidence rates for all subjects regardless of their EDs to rFIXFc were also summarized. The 95% CI was calculated using Clopper-Pearson exact method. Safety Analysis Set: subjects who received at least 1 dose of prestudy FIX, or at least 1 dose of rFIXFc; n=number of subjects with given number of EDs who had a valid inhibitor test.
    End point type
    Primary
    End point timeframe
    Up to 50 weeks +/- 7 days, or up to 50 EDs if reached prior to Week 50
    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: The incidence of confirmed inhibitor formation from the central laboratory was summarized for each age cohort and a 95% CI was calculated for each incidence for this endpoint, as presented in this data table. No further statistical analyses were planned.
    End point values
    Subjects < 6 Years Old Subjects 6 to < 12 Years Old All subjects
    Number of subjects analysed
    15 [2]
    15 [3]
    30 [4]
    Units: percentage of subjects
    number (confidence interval 95%)
        Subjects with ≥ 50 EDs; n=10, 13, 23
    0 (0 to 30.85)
    0 (0 to 23.16)
    0 (0 to 14.25)
        All subjects regardless of # of EDs; n=15, 15, 30
    0 (0 to 21.8)
    0 (0 to 21.8)
    0 (0 to 11.57)
    Notes
    [2] - Safety Analysis Set; n=subjects with given number of exposure days who had a valid inhibitor test.
    [3] - Safety Analysis Set; n=subjects with given number of exposure days who had a valid inhibitor test.
    [4] - Safety Analysis Set; n=subjects with given number of exposure days who had a valid inhibitor test.
    No statistical analyses for this end point

    Secondary: Annualized Bleeding Rate

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    End point title
    Annualized Bleeding Rate
    End point description
    Annualized bleeding rate=(number of bleeding episodes during the efficacy period/total number of days during the efficacy period)*365.25. Efficacy period begins with the first prophylactic dose of rFIXFc and ends with the last dose (for prophylaxis or a bleeding episode). Surgery/rehabilitation periods and PK evaluation periods are not included in the efficacy period. A bleeding episode started from the first sign of bleeding and ended ≤72 hours after the last treatment for the bleeding episode, within which any symptoms of bleeding at the same location or injections ≤72 hours apart were considered the same bleeding episode. Any injection to treat the bleeding episode taken >72 hours after the preceding 1 was considered the first injection to treat a new bleeding episode at the same location. Any bleeding at a different location was considered a separate bleeding episode, regardless of time from last injection. Full Analysis Set: subjects who received at least 1 dose of rFIXFc.
    End point type
    Secondary
    End point timeframe
    Up to 50 weeks +/- 7 days (efficacy period as defined in description)
    End point values
    Subjects < 6 Years Old Subjects 6 to < 12 Years Old
    Number of subjects analysed
    15 [5]
    15 [6]
    Units: bleeding episodes per participant per yr
        median (inter-quartile range (Q1-Q3))
    1.09 (0 to 2.9)
    2.13 (0 to 4.17)
    Notes
    [5] - Full Analysis Set; based on the number of subjects whose efficacy period was ≥ 1 day in duration.
    [6] - Full Analysis Set; based on the number of subjects whose efficacy period was ≥ 1 day in duration.
    No statistical analyses for this end point

    Secondary: Annualized Joint Bleeding Rate (AJBR; Spontaneous)

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    End point title
    Annualized Joint Bleeding Rate (AJBR; Spontaneous)
    End point description
    AJBR for spontaneous joint bleeding episode=(number of bleeding episodes during the efficacy period/total number of days during the efficacy period)*365.25. Efficacy period begins with the first prophylactic dose of rFIXFc and ends with the last dose (for prophylaxis or a bleeding episode). Surgery/rehabilitation and PK evaluation periods are not included in the efficacy period. A bleeding episode started from the first sign of bleeding and ended ≤72 hours after the last treatment for the bleeding episode, within which any symptoms of bleeding at the same location or injections ≤72 hours apart were considered the same bleeding episode. Any injection to treat the bleeding episode taken >72 hours after the preceding 1 was considered the first injection to treat a new bleeding episode at the same location. Any bleeding at a different location was considered a separate bleeding episode, regardless of time from last injection. Full Analysis Set: subjects who received ≥ 1 dose of rFIXFc.
    End point type
    Secondary
    End point timeframe
    Up to 50 weeks +/- 7 days (efficacy period as defined in description)
    End point values
    Subjects < 6 Years Old Subjects 6 to < 12 Years Old
    Number of subjects analysed
    15 [7]
    15 [8]
    Units: bleeding episodes per participant per yr
        median (inter-quartile range (Q1-Q3))
    0 (0 to 1.2)
    0 (0 to 2.2)
    Notes
    [7] - Full Analysis Set; based on the number of subjects whose efficacy period was ≥1 day in duration.
    [8] - Full Analysis Set; based on the number of subjects whose efficacy period was ≥1 day in duration.
    No statistical analyses for this end point

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

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    End point title
    Subject Assessment of Response to Injections to Treat a Bleeding Episode
    End point description
    Subject's assessment of the response (provided by the caregiver) to the first rFIXFc injection for each bleeding episode. Percentages were based on the number of bleeding episodes for which a response was provided for the first injection, using the following 4-point scale: excellent=abrupt pain relief and/or improvement in signs of bleeding within approximately 8 hours after the initial injection; good=definite pain relief and/or improvement in signs of bleeding within approximately 8 hours after an injection, but possibly requiring more than one injection after 24 to 48 hours for complete resolution; moderate=probable or slight beneficial effect within 8 hours after the initial injection and requiring more than one injection; no response=no improvement, or condition worsened, within approximately 8 hours after the initial injection. Full Analysis Set: subjects who received at least 1 dose of rFIXFc and had ≥ 1 bleeding episode; based on the number of injections with an evaluation.
    End point type
    Secondary
    End point timeframe
    Up to 50 weeks +/- 7 days
    End point values
    Subjects < 6 Years Old Subjects 6 to < 12 Years Old
    Number of subjects analysed
    9 [9]
    11 [10]
    Units: percent of 1st injections w/ a response
    number (not applicable)
        Excellent or Good
    89.5
    88.2
        Excellent
    52.6
    41.2
        Good
    36.8
    47.1
        Moderate
    5.3
    11.8
        No Response
    5.3
    0
    Notes
    [9] - Full Analysis Set; percentages are based on the number of injections (total number of injections=19)
    [10] - Full Analysis Set; percentages are based on the number of injections (total number of injections=34)
    No statistical analyses for this end point

    Secondary: Annualized rFIXFc Consumption by Type of Injection

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    End point title
    Annualized rFIXFc Consumption by Type of Injection
    End point description
    Annualized consumption of rFIXFc for prevention of bleeding (prophylactic), treatment of bleeding, and other rFIXFc injections. Consumption is calculated for the efficacy period. The efficacy period began with the first prophylactic dose of rFIXFc and ended with the last dose (regardless of the reason for dosing). Surgery/rehabilitation and PK evaluation periods were not included in the efficacy period. Annualized consumption = (total IU/kg of study treatment received during the efficacy period / total number of days during the efficacy period)*365.25. Subjects who did not have a particular injection type are counted as having zero injections for that type.
    End point type
    Secondary
    End point timeframe
    Up to 50 weeks +/- 7 days (efficacy period as defined in description)
    End point values
    Subjects < 6 Years Old Subjects 6 to < 12 Years Old
    Number of subjects analysed
    15 [11]
    15 [12]
    Units: IU/kg rFIXFc per year
    arithmetic mean (standard deviation)
        Prophylactic injections
    3041.5 ± 577.55
    3185.6 ± 683.71
        Injections for bleeding
    147.9 ± 209.89
    293.8 ± 515.59
        Other injections
    29.2 ± 48.93
    16.9 ± 44.9
    Notes
    [11] - Full Analysis Set: subjects who received at least 1 dose of rFIXFc.
    [12] - Full Analysis Set: subjects who received at least 1 dose of rFIXFc.
    No statistical analyses for this end point

    Secondary: Number of Days From the Last Prophylaxis Injection to a Spontaneous Bleeding Episode

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    End point title
    Number of Days From the Last Prophylaxis Injection to a Spontaneous Bleeding Episode
    End point description
    The number of days from the last prophylaxis injection to the onset of a new spontaneous bleeding episode, analyzed across all evaluable bleeding episodes per subject and per episode, based on the efficacy period. Evaluable bleeding episodes are those for which both a date and time are available for both the onset of the bleeding episode and the previous prophylactic injection. The efficacy period begins with the first prophylactic dose of rFIXFc and ends with the last dose (for prophylaxis or a bleeding episode). Surgery/rehabilitation periods and PK evaluation periods are not included in the efficacy period. For 'Per subject' values, the number of days from the last prophylactic injection to a spontaneous bleeding episode is averaged across all evaluable spontaneous bleeding episodes per subject. Full Analysis Set: subjects who received at least 1 dose of rFIXFc; number of subjects and number of episodes were determined for subjects with at least 1 evaluable spontaneous episode.
    End point type
    Secondary
    End point timeframe
    Up to 50 weeks +/- 7 days (efficacy period as defined in description)
    End point values
    Subjects < 6 Years Old Subjects 6 to < 12 Years Old
    Number of subjects analysed
    4 [13]
    6 [14]
    Units: days
    median (inter-quartile range (Q1-Q3))
        Per spontaneous bleeding episode
    3.97 (0.71 to 4.27)
    5.55 (3.3 to 6.04)
        Per subject
    4.12 (2.33 to 5.3)
    5.52 (4.41 to 6.04)
    Notes
    [13] - Full Analysis Set; the number of evaluable spontaneous bleeding episodes analyzed was 5.
    [14] - Full Analysis Set; the number of evaluable spontaneous bleeding episodes analyzed was 11.
    No statistical analyses for this end point

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

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    End point title
    Number of Injections Required for Resolution of a Bleeding Episode
    End point description
    The number of injections required to resolve a bleeding episode per subject and per episode, based on the efficacy period. The efficacy period begins with the first prophylactic dose of rFIXFc and ends with the last dose (for prophylaxis or a bleeding episode). Surgery/rehabilitation periods and PK evaluation periods are not included in the efficacy period. All injections given from the initial sign of a bleeding episode, until the last date/time within the bleeding episode window are counted. The resolution of a bleeding episode is defined as no sign of bleeding following injection for the bleeding episode. For 'Per subject' values, the number of injections required to resolve each bleeding episode is averaged across all bleeding episodes per subject. Full Analysis Set: subjects who received at least 1 dose of rFVIIIFc; number of subjects and number of episodes were determined for subjects with at least 1 evaluable bleeding episode.
    End point type
    Secondary
    End point timeframe
    Up to 50 weeks +/- 7 days (efficacy period as defined in description)
    End point values
    Subjects < 6 Years Old Subjects 6 to < 12 Years Old
    Number of subjects analysed
    9 [15]
    11 [16]
    Units: injections
    median (inter-quartile range (Q1-Q3))
        Per bleeding episode
    1 (1 to 1)
    1 (1 to 2)
        Per participant
    1 (1 to 1.2)
    1 (1 to 1.7)
    Notes
    [15] - Full Analysis Set; the number of bleeding episodes analyzed was 22.
    [16] - Full Analysis Set; the number of bleeding episodes analyzed was 38.
    No statistical analyses for this end point

    Secondary: Total Dose Required for Resolution of a Bleeding Episode

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    End point title
    Total Dose Required for Resolution of a Bleeding Episode
    End point description
    The total dose required to resolve a bleeding episode per subject and per episode, based on the efficacy period. The efficacy period begins with the first prophylactic dose of rFIXFc and ends with the last dose (for prophylaxis or a bleeding episode). Surgery/rehabilitation periods and PK evaluation periods are not included in the efficacy period. For 'Per bleeding episode' values, for each bleeding episode, the total dose is the sum of the doses (IU/kg) administered across all injections given to treat that bleeding episode. For 'Per subject' values, the total dose (IU/kg) used to resolve each bleeding episode is averaged across all bleeding episodes per subject. Full Analysis Set: subjects who received at least 1 dose of rFVIIIFc; number of subjects and number of episodes were determined for subjects who had complete information on the dose administered to treat a bleeding episode.
    End point type
    Secondary
    End point timeframe
    Up to 50 weeks +/- 7 days (efficacy period as defined in description)
    End point values
    Subjects < 6 Years Old Subjects 6 to < 12 Years Old
    Number of subjects analysed
    9 [17]
    11 [18]
    Units: IU/kg
    median (inter-quartile range (Q1-Q3))
        Per bleeding episode
    65.37 (50.68 to 125)
    89.77 (50.92 to 140.86)
        Per subject
    70.22 (55.4 to 97.22)
    52.22 (27.03 to 161.06)
    Notes
    [17] - Full Analysis Set; the number of bleeding episodes analyzed was 22.
    [18] - Full Analysis Set; the number of bleeding episodes analyzed was 38.
    No statistical analyses for this end point

    Secondary: Maximum Plasma Activity (Cmax; One-stage Activated Partial Thromboplastin Time [aPTT] Clotting Assay)

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    End point title
    Maximum Plasma Activity (Cmax; One-stage Activated Partial Thromboplastin Time [aPTT] Clotting Assay)
    End point description
    Cmax: maximum plasma FIX activity during a dosing interval. The values for Cmax were adjusted to the nominal dose of 50 IU/kg. The 95% confidence interval on the geometric mean is based on the t-statistic back-transformed from the log scale. PK Analysis Set: all subjects with adequate PK data, defined as complete and evaluable PK samples through 168 hours after rFIXFc dosing. Complete means the availability of the 168-hour sample and at least enough other samples to allow for all the PK parameters to be estimated.
    End point type
    Secondary
    End point timeframe
    Baseline (28±7 days before Day 1) Prestudy FIX Dosing: predose; 30±5 min, 3 hrs±30 min, 10±2 hrs, 24±3 hrs, 48±4 hrs postdose. Day 1 rFIXFc Dosing: predose; 30±5 min, 3 hrs ±30 min, 10±2 hrs, 24±3 hrs, 72±7 hrs, 120±12 hrs, 168±16 hrs postdose.
    End point values
    Subjects < 6 Years Old Subjects 6 to < 12 Years Old
    Number of subjects analysed
    11 [19]
    13 [20]
    Units: IU/dL
        geometric mean (confidence interval 95%)
    29.78 (26.18 to 33.87)
    35.84 (30.56 to 42.03)
    Notes
    [19] - All subjects in the PK subgroup with adequate PK data
    [20] - All subjects in the PK subgroup with adequate PK data
    No statistical analyses for this end point

    Secondary: Terminal Half Life (t1/2; One-stage aPTT Clotting Assay)

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    End point title
    Terminal Half Life (t1/2; One-stage aPTT Clotting Assay)
    End point description
    t1/2: time required for the concentration of the drug to reach half of its original value in the body. Non-compartmental methods. The 95% confidence interval on the geometric mean is based on the t-statistic back-transformed from the log scale. PK Analysis Set: all subjects with adequate PK data, defined as complete and evaluable PK samples through 168 hours after rFIXFc dosing. Complete means the availability of the 168-hour sample and at least enough other samples to allow for all the PK parameters to be estimated.
    End point type
    Secondary
    End point timeframe
    Baseline (28±7 days before Day 1) Prestudy FIX Dosing: predose; 30±5 min, 3 hrs±30 min, 10±2 hrs, 24±3 hrs, 48±4 hrs postdose. Day 1 rFIXFc Dosing: predose; 30±5 min, 3 hrs ±30 min, 10±2 hrs, 24±3 hrs, 72±7 hrs, 120±12 hrs, 168±16 hrs postdose.
    End point values
    Subjects < 6 Years Old Subjects 6 to < 12 Years Old
    Number of subjects analysed
    11 [21]
    13 [22]
    Units: hours
        geometric mean (confidence interval 95%)
    66.49 (55.86 to 79.14)
    70.34 (60.95 to 81.17)
    Notes
    [21] - All subjects in the PK subgroup with adequate PK data
    [22] - All subjects in the PK subgroup with adequate PK data
    No statistical analyses for this end point

    Secondary: Clearance (CL; One-stage aPTT Clotting Assay)

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    End point title
    Clearance (CL; One-stage aPTT Clotting Assay)
    End point description
    CL: the measure of the efficiency of the body to remove the drug and the unit is the volume of the plasma or blood cleared of drug per unit time. Non-compartmental methods. The 95% confidence interval on the geometric mean is based on the t-statistic back-transformed from the log scale. PK Analysis Set: all subjects with adequate PK data, defined as complete and evaluable PK samples through 168 hours after rFIXFc dosing. Complete means the availability of the 168-hour sample and at least enough other samples to allow for all the PK parameters to be estimated.
    End point type
    Secondary
    End point timeframe
    Baseline (28±7 days before Day 1) Prestudy FIX Dosing: predose; 30±5 min, 3 hrs±30 min, 10±2 hrs, 24±3 hrs, 48±4 hrs postdose. Day 1 rFIXFc Dosing: predose; 30±5 min, 3 hrs ±30 min, 10±2 hrs, 24±3 hrs, 72±7 hrs, 120±12 hrs, 168±16 hrs postdose.
    End point values
    Subjects < 6 Years Old Subjects 6 to < 12 Years Old
    Number of subjects analysed
    11 [23]
    13 [24]
    Units: mL/h/kg
        geometric mean (confidence interval 95%)
    4.365 (3.901 to 4.885)
    3.505 (3.006 to 4.087)
    Notes
    [23] - All subjects in the PK subgroup with adequate PK data
    [24] - All subjects in the PK subgroup with adequate PK data
    No statistical analyses for this end point

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

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    End point title
    Volume of Distribution at Steady State (Vss; One-stage aPTT Clotting Assay)
    End point description
    Vss: volume of distribution at steady state. Non-compartmental methods. The 95% confidence interval on the geometric mean is based on the t-statistic back-transformed from the log scale. PK Analysis Set: all subjects with adequate PK data, defined as complete and evaluable PK samples through 168 hours after rFIXFc dosing. Complete means the availability of the 168-hour sample and at least enough other samples to allow for all the PK parameters to be estimated.
    End point type
    Secondary
    End point timeframe
    Baseline (28±7 days before Day 1) Prestudy FIX Dosing: predose; 30±5 min, 3 hrs±30 min, 10±2 hrs, 24±3 hrs, 48±4 hrs postdose. Day 1 rFIXFc Dosing: predose; 30±5 min, 3 hrs ±30 min, 10±2 hrs, 24±3 hrs, 72±7 hrs, 120±12 hrs, 168±16 hrs postdose.
    End point values
    Subjects < 6 Years Old Subjects 6 to < 12 Years Old
    Number of subjects analysed
    11 [25]
    13 [26]
    Units: mL/kg
        geometric mean (confidence interval 95%)
    365.1 (316.2 to 421.6)
    289 (236.7 to 352.9)
    Notes
    [25] - All subjects in the PK subgroup with adequate PK data
    [26] - All subjects in the PK subgroup with adequate PK data
    No statistical analyses for this end point

    Secondary: Dose Normalized Area Under the Curve (DNAUC; One-stage aPTT Clotting Assay)

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    End point title
    Dose Normalized Area Under the Curve (DNAUC; One-stage aPTT Clotting Assay)
    End point description
    DNAUC: dose normalized area under the drug concentration-time curve (extent of unmetabolized drug in circulation). Non-compartmental methods. The 95% confidence interval on the geometric mean is based on the t-statistic backtransformed from the log scale. PK Analysis Set: all subjects with adequate PK data, defined as complete and evaluable PK samples through 168 hours after rFIXFc dosing. Complete means the availability of the 168-hour sample and at least enough other samples to allow for all the PK parameters to be estimated.
    End point type
    Secondary
    End point timeframe
    Baseline (28±7 days before Day 1) Prestudy FIX Dosing: predose; 30±5 min, 3 hrs±30 min, 10±2 hrs, 24±3 hrs, 48±4 hrs postdose. Day 1 rFIXFc Dosing: predose; 30±5 min, 3 hrs ±30 min, 10±2 hrs, 24±3 hrs, 72±7 hrs, 120±12 hrs, 168±16 hrs postdose.
    End point values
    Subjects < 6 Years Old Subjects 6 to < 12 Years Old
    Number of subjects analysed
    11 [27]
    13 [28]
    Units: IU*h/dL per IU/kg
        geometric mean (confidence interval 95%)
    22.71 (20.32 to 25.38)
    28.53 (24.47 to 33.27)
    Notes
    [27] - All subjects in the PK subgroup with adequate PK data
    [28] - All subjects in the PK subgroup with adequate PK data
    No statistical analyses for this end point

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

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    End point title
    Mean Residence Time (MRT; One-stage aPTT Clotting Assay)
    End point description
    MRT: the average time for all the drug molecules to reside in the body. Non-compartmental methods. The 95% confidence interval on the geometric mean is based on the t-statistic backtransformed from the log scale. PK Analysis Set: all subjects with adequate PK data, defined as complete and evaluable PK samples through 168 hours after rFIXFc dosing. Complete means the availability of the 168-hour sample and at least enough other samples to allow for all the PK parameters to be estimated.
    End point type
    Secondary
    End point timeframe
    Baseline (28±7 days before Day 1) Prestudy FIX Dosing: predose; 30±5 min, 3 hrs±30 min, 10±2 hrs, 24±3 hrs, 48±4 hrs postdose. Day 1 rFIXFc Dosing: predose; 30±5 min, 3 hrs ±30 min, 10±2 hrs, 24±3 hrs, 72±7 hrs, 120±12 hrs, 168±16 hrs postdose.
    End point values
    Subjects < 6 Years Old Subjects 6 to < 12 Years Old
    Number of subjects analysed
    11 [29]
    13 [30]
    Units: hours
        geometric mean (confidence interval 95%)
    83.65 (71.76 to 97.51)
    82.46 (72.65 to 93.6)
    Notes
    [29] - All subjects in the PK subgroup with adequate PK data
    [30] - All subjects in the PK subgroup with adequate PK data
    No statistical analyses for this end point

    Secondary: Incremental Recovery (IR; One-stage aPTT Clotting Assay)

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    End point title
    Incremental Recovery (IR; One-stage aPTT Clotting Assay)
    End point description
    IR for FIX activity following rFIXFc dosing: IU/dL rise in plasma FIX per IU/kg drug administered. Non-compartmental methods. The 95% confidence interval on the geometric mean is based on the t-statistic back-transformed from the log scale.PK Analysis Set: all subjects with adequate PK data, defined as complete and evaluable PK samples through 168 hours after rFIXFc dosing. Complete means the availability of the 168-hour sample and at least enough other samples to allow for all the PK parameters to be estimated.
    End point type
    Secondary
    End point timeframe
    Baseline (28±7 days before Day 1) Prestudy FIX Dosing: predose; 30±5 min, 3 hrs±30 min, 10±2 hrs, 24±3 hrs, 48±4 hrs postdose. Day 1 rFIXFc Dosing: predose; 30±5 min, 3 hrs ±30 min, 10±2 hrs, 24±3 hrs, 72±7 hrs, 120±12 hrs, 168±16 hrs postdose.
    End point values
    Subjects < 6 Years Old Subjects 6 to < 12 Years Old
    Number of subjects analysed
    11 [31]
    13 [32]
    Units: IU/dL per IU/kg
        geometric mean (confidence interval 95%)
    0.5898 (0.5152 to 0.6752)
    0.717 (0.6115 to 0.8407)
    Notes
    [31] - All subjects in the PK subgroup with adequate PK data
    [32] - All subjects in the PK subgroup with adequate PK data
    No statistical analyses for this end point

    Secondary: Physician's Global Assessment of the Subject's Response to His rFIXFc Regimen

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    End point title
    Physician's Global Assessment of the Subject's Response to His rFIXFc Regimen
    End point description
    Investigators assessed each subject's response to his rFIXFc regimen using a 4-point scale: excellent=bleeding episodes responded 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 bleeding; 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; ineffective=routine failure to control hemostasis, or hemostatic control required additional agents. Percentages are based on the total number of responses; multiple responses per subject are counted. Full Analysis Set: subjects who received ≥ 1 dose of rFIXFc.
    End point type
    Secondary
    End point timeframe
    Up to 50 weeks +/- 7 days
    End point values
    Subjects < 6 Years Old Subjects 6 to < 12 Years Old
    Number of subjects analysed
    15 [33]
    15 [34]
    Units: percentage of responses
    number (not applicable)
        Excellent
    85.4
    89.8
        Effective
    14.6
    10.2
        Partially Effective
    0
    0
        Ineffective
    0
    0
    Notes
    [33] - percentages based on the number of responses (n=48)
    [34] - percentages are based on the number of responses (n=59)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Serious adverse events (AEs): from informed consent up to 21 days after last dose; AEs: from Baseline (28 ± 7 days prior to Day 1) up to 14 (+7) days after last dose.
    Adverse event reporting additional description
    Length of rFIXFc dosing was up to 50 weeks ± 7 days. Serious and non-serious AEs that were treatment-emergent with respect to rFIXFc are presented for those subjects in the Safety Analysis Set who were treated with rFIXFc.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    15.0
    Reporting groups
    Reporting group title
    Subjects < 6 Years Old
    Reporting group description
    At the Baseline visit (28 ± 7 days prior to Day 1), subjects received a single IV injection of prestudy FIX over 10 (±5) minutes in the clinic under medical supervision at a dose of 50 IU/kg. A washout period with no FIX treatment was required prior to administration of prestudy FIX and prior to rFIXFc. At Day 1, subjects received a single IV injection of rFIXFc over 10 (±5) minutes at a dose of 50 IU/kg. Immediately after the last PK sampling, the first prophylactic dose of approximately 50 to 60 IU/kg was administered in clinic as an IV injection. Dose could be increased or decreased in increments of 10 IU/kg; increases to a maximum of 100 IU/kg and frequency of administration to a maximum of twice weekly, were allowed as indicated.

    Reporting group title
    Subjects 6 to < 12 Years Old
    Reporting group description
    At the Baseline visit (28 ± 7 days prior to Day 1), subjects received a single IV injection of prestudy FIX over 10 (±5) minutes in the clinic under medical supervision at a dose of 50 IU/kg. A washout period with no FIX treatment was required prior to administration of prestudy FIX and prior to rFIXFc. At Day 1, subjects received a single IV injection of rFIXFc over 10 (±5) minutes at a dose of 50 IU/kg. Immediately after the last PK sampling, the first prophylactic dose of approximately 50 to 60 IU/kg was administered in clinic as an IV injection. Dose could be increased or decreased in increments of 10 IU/kg; increases to a maximum of 100 IU/kg and frequency of administration to a maximum of twice weekly, were allowed as indicated.

    Serious adverse events
    Subjects < 6 Years Old Subjects 6 to < 12 Years Old
    Total subjects affected by serious adverse events
         subjects affected / exposed
    3 / 15 (20.00%)
    1 / 15 (6.67%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    2 / 15 (13.33%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Device occlusion
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Head injury
         subjects affected / exposed
    2 / 15 (13.33%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Duodenal ulcer haemorrhage
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 15 (6.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Gastroenteritis
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    Subjects < 6 Years Old Subjects 6 to < 12 Years Old
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    12 / 15 (80.00%)
    14 / 15 (93.33%)
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    Pyrexia
         subjects affected / exposed
    4 / 15 (26.67%)
    0 / 15 (0.00%)
         occurrences all number
    7
    0
    Immune system disorders
    Seasonal allergy
         subjects affected / exposed
    1 / 15 (6.67%)
    1 / 15 (6.67%)
         occurrences all number
    1
    1
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    1 / 15 (6.67%)
    1 / 15 (6.67%)
         occurrences all number
    2
    1
    Cough
         subjects affected / exposed
    2 / 15 (13.33%)
    0 / 15 (0.00%)
         occurrences all number
    2
    0
    Epistaxis
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    Upper-airway cough syndrome
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    Psychiatric disorders
    Abnormal behaviour
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    Injury, poisoning and procedural complications
    Accidental drug intake by child
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    Bite
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    Contusion
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    Excoriation
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    Face injury
         subjects affected / exposed
    2 / 15 (13.33%)
    1 / 15 (6.67%)
         occurrences all number
    2
    1
    Fall
         subjects affected / exposed
    2 / 15 (13.33%)
    2 / 15 (13.33%)
         occurrences all number
    2
    2
    Head injury
         subjects affected / exposed
    1 / 15 (6.67%)
    1 / 15 (6.67%)
         occurrences all number
    1
    2
    Joint injury
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    Ligament sprain
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    Limb injury
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    Lip injury
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    Traumatic haematoma
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    Nervous system disorders
    Headache
         subjects affected / exposed
    0 / 15 (0.00%)
    2 / 15 (13.33%)
         occurrences all number
    0
    3
    Tremor
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    Blood and lymphatic system disorders
    Haemorrhagic anaemia
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    Iron deficiency anaemia
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    Ear and labyrinth disorders
    Ear pain
         subjects affected / exposed
    1 / 15 (6.67%)
    1 / 15 (6.67%)
         occurrences all number
    1
    1
    Gastrointestinal disorders
    Cheilitis
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    Constipation
         subjects affected / exposed
    2 / 15 (13.33%)
    0 / 15 (0.00%)
         occurrences all number
    2
    0
    Dental caries
         subjects affected / exposed
    2 / 15 (13.33%)
    0 / 15 (0.00%)
         occurrences all number
    2
    0
    Diarrhoea
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 15 (0.00%)
         occurrences all number
    2
    0
    Duodenal ulcer
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    Duodenal ulcer haemorrhage
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    Faeces discoloured
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    Haematochezia
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    Stomatitis
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    Toothache
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    Vomiting
         subjects affected / exposed
    2 / 15 (13.33%)
    0 / 15 (0.00%)
         occurrences all number
    3
    0
    Skin and subcutaneous tissue disorders
    Dermatitis contact
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 15 (0.00%)
         occurrences all number
    2
    0
    Eczema
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    Rash
         subjects affected / exposed
    2 / 15 (13.33%)
    0 / 15 (0.00%)
         occurrences all number
    3
    0
    Rash maculo-papular
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    Musculoskeletal stiffness
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    Infections and infestations
    Croup infectious
         subjects affected / exposed
    2 / 15 (13.33%)
    0 / 15 (0.00%)
         occurrences all number
    2
    0
    Ear infection
         subjects affected / exposed
    2 / 15 (13.33%)
    0 / 15 (0.00%)
         occurrences all number
    6
    0
    Fungal skin infection
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    Gastroenteritis norovirus
         subjects affected / exposed
    0 / 15 (0.00%)
    2 / 15 (13.33%)
         occurrences all number
    0
    2
    Gastroenteritis viral
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    Impetigo
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    Nail infection
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    Nasopharyngitis
         subjects affected / exposed
    1 / 15 (6.67%)
    6 / 15 (40.00%)
         occurrences all number
    1
    8
    Oral bacterial infection
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    Otitis media
         subjects affected / exposed
    2 / 15 (13.33%)
    0 / 15 (0.00%)
         occurrences all number
    2
    0
    Pharyngitis
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    Pharyngitis streptococcal
         subjects affected / exposed
    1 / 15 (6.67%)
    1 / 15 (6.67%)
         occurrences all number
    1
    1
    Respiratory tract infection
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 15 (0.00%)
         occurrences all number
    2
    0
    Sinusitis
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    Tonsillitis
         subjects affected / exposed
    1 / 15 (6.67%)
    1 / 15 (6.67%)
         occurrences all number
    1
    1
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 15 (6.67%)
    1 / 15 (6.67%)
         occurrences all number
    2
    1
    Upper respiratory tract infection bacterial
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    Urinary tract infection
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    Varicella
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    Viral infection
         subjects affected / exposed
    4 / 15 (26.67%)
    0 / 15 (0.00%)
         occurrences all number
    4
    0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    Food intolerance
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 15 (6.67%)
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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    07 Mar 2013
    The primary reasons for this amendment were as follows: - Added interim PK analyses. Data from the interim PK analyses were used to support marketing authorization in specific countries (e.g., United States) for individuals under the age of 12. In addition, the PK data were used to inform the design of a clinical study in previously untreated patients (PUPs) that is required by the EU. - Increased the sample size from at least 20 subjects to approximately 26 subjects to be dosed to ensure at least 10 subjects per cohort completed the study. - Recategorized endpoints for patient-reported and health utilization outcomes from secondary endpoints to exploratory endpoints, and notified that these will be analyzed in a separate report.

    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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