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    Clinical Trial Results:
    A Multinational, Open-Label, Non-Controlled Trial on Safety, Efficacy and Pharmacokinetics of NNC 0129-0000-1003 in Previously Treated Paediatric Patients with Severe Haemophilia A

    Summary
    EudraCT number
    		 2012-001711-23
    Trial protocol
    		 DE   PT   GB   IT   GR   LT  
    Global end of trial date
    28 Sep 2018

    Results information
    Results version number
    		 v1(current)
    This version publication date
    12 Apr 2019
    First version publication date
    12 Apr 2019
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    NN7088-3885
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01731600
    WHO universal trial number (UTN)
    		 U1111-1129-6009
    Other trial identifiers
    		 Japanese trial registration: 132214
    Sponsors
    Sponsor organisation name
    Novo Nordisk A/S
    Sponsor organisation address
    Novo Allé, Bagsvaerd, Denmark, 2880
    Public contact
    Clinical Reporting Anchor and Disclosure (1452), Novo Nordisk A/S, clinicaltrials@novonordisk.com
    Scientific contact
    Clinical Reporting Anchor and Disclosure (1452), Novo Nordisk A/S, clinicaltrials@novonordisk.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    		 EMEA-001174-PIP02-12
    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?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    13 Mar 2019
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    15 Sep 2014
    Global end of trial reached?
    Yes
    Global end of trial date
    28 Sep 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate immunogenicity of NNC 0129-0000-1003 (hereafter referred to as N8-GP)
    Protection of trial subjects
    The trial was conducted in accordance with the Declaration of Helsinki (Seoul, October 2008), ICH Good Clinical Practice (Geneva, May 1996), and FDA 21 CFR 312.120.
    Background therapy
    		 Not applicable
    Evidence for comparator
    		 Not applicable
    Actual start date of recruitment
    20 Feb 2013
    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
    Canada: 2
    Country: Number of subjects enrolled
    France: 7
    Country: Number of subjects enrolled
    Germany: 1
    Country: Number of subjects enrolled
    Greece: 1
    Country: Number of subjects enrolled
    Israel: 2
    Country: Number of subjects enrolled
    Italy: 1
    Country: Number of subjects enrolled
    Japan: 2
    Country: Number of subjects enrolled
    Lithuania: 5
    Country: Number of subjects enrolled
    Malaysia: 2
    Country: Number of subjects enrolled
    Portugal: 2
    Country: Number of subjects enrolled
    Switzerland: 4
    Country: Number of subjects enrolled
    Turkey: 6
    Country: Number of subjects enrolled
    Ukraine: 6
    Country: Number of subjects enrolled
    United Kingdom: 6
    Country: Number of subjects enrolled
    United States: 21
    Worldwide total number of subjects
    68
    EEA total number of subjects
    23
    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)
    6
    Children (2-11 years)
    62
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    0
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 The trial was conducted at 36 sites in 15 countries as follows: Canada (1), France (2), Germany (1), Greece (2 sites screened/1 site randomised subjects), Israel (1), Italy (1), Japan (2), Lithuania (1), Malaysia (1), Portugal (1), Switzerland (3), Turkey (3), Ukraine (2), United Kingdom (3), and United States (12).

    Pre-assignment
    Screening details
    		 Not applicable

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Younger children (0 - 5 years)
    Arm description
    		 Subjects (0 - 5 years) previously treated with FVIII received N8-GP (prophylaxis or treatment of bleeding episodes). The trial consisted of main and extension phase. Duration of main phase for each subject was approximately 26 weeks (50 exposure days). After completion of main phase, subjects could continue until the end of the extension phase, which was defined as last patient last visit (LPLV). All subjects continued twice weekly or every third day prophylaxis regimen in extension phase as prescribed for main phase. However, after 12 months' treatment with N8-GP (main phase+extension phase) the investigator was permitted to prescribe extra coverage before physical activities.
    Arm type
    		 Experimental

    Investigational medicinal product name
    N8-GP rFVIII
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder and solvent for solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Prophylaxis: N8-GP was administered as a single intravenous (iv) bolus injection 60 IU/kg twice weekly. There were two vials which were used (500 U/vial 53μg/vial, 2000 U/vial 211 μg/vial). An increase in dose frequency from twice weekly to every third day was permitted at investigator’s discretion (based on bleeding pattern). Extra doses of N8-GP were administered, if the subject experienced a treatment-requiring bleeding episode or in case of minor surgery. Treatment of bleeding episodes: Treatment-requiring bleeding episodes were treated with doses of N8-GP ranging from 20−75 IU/kg, according to the severity and location of the bleeding episode. Bleeding episodes due to abdominal, head trauma, surgery were treated with extra dose of N8-GP similar to that used for severe bleeding episodes.

    Arm title
    		 Older children (6 - 11 years)
    Arm description
    		 Subjects (6 - 11 years) previously treated with FVIII received N8-GP (prophylaxis or treatment of bleeding episodes). The trial consisted of main and extension phase. Duration of main phase for each subject was approximately 26 weeks (50 exposure days). After completion of main phase, subjects could continue until the end of the extension phase, which was defined as LPLV. All subjects continued twice weekly or every third day prophylaxis regimen in extension phase as prescribed for main phase. However, after 12 months' treatment with N8-GP (main phase+extension phase) the investigator was permitted to prescribe extra coverage before physical activities.
    Arm type
    		 Experimental

    Investigational medicinal product name
    N8-GP rFVIII
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder and solvent for solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Prophylaxis: N8-GP was administered as a single iv bolus injection 60 IU/kg twice weekly. There were two vials which were used (500 U/vial 53μg/vial, 2000 U/vial 211 μg/vial). An increase in dose frequency from twice weekly to every third day was permitted at investigator’s discretion (based on bleeding pattern). Extra doses of N8-GP were administered, if the subject experienced a treatment-requiring bleeding episode or in case of minor surgery. Treatment of bleeding episodes: Treatment-requiring bleeding episodes were treated with doses of N8-GP ranging from 20−75 IU/kg, according to the severity and location of the bleeding episode. Bleeding episodes due to abdominal, head trauma, surgery were treated with extra dose of N8-GP similar to that used for severe bleeding episodes.

    Number of subjects in period 1
    		Younger children (0 - 5 years) Older children (6 - 11 years)
    Started
    34
    34
    Completed
    28
    34
    Not completed
    6
    0
         Adverse event, non-fatal
    2
    -
         Withdrawal criteria
    1
    -
         Other reasons
    3
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Younger children (0 - 5 years)
    Reporting group description
    		 Subjects (0 - 5 years) previously treated with FVIII received N8-GP (prophylaxis or treatment of bleeding episodes). The trial consisted of main and extension phase. Duration of main phase for each subject was approximately 26 weeks (50 exposure days). After completion of main phase, subjects could continue until the end of the extension phase, which was defined as last patient last visit (LPLV). All subjects continued twice weekly or every third day prophylaxis regimen in extension phase as prescribed for main phase. However, after 12 months' treatment with N8-GP (main phase+extension phase) the investigator was permitted to prescribe extra coverage before physical activities.

    Reporting group title
    Older children (6 - 11 years)
    Reporting group description
    		 Subjects (6 - 11 years) previously treated with FVIII received N8-GP (prophylaxis or treatment of bleeding episodes). The trial consisted of main and extension phase. Duration of main phase for each subject was approximately 26 weeks (50 exposure days). After completion of main phase, subjects could continue until the end of the extension phase, which was defined as LPLV. All subjects continued twice weekly or every third day prophylaxis regimen in extension phase as prescribed for main phase. However, after 12 months' treatment with N8-GP (main phase+extension phase) the investigator was permitted to prescribe extra coverage before physical activities.

    Reporting group values
    		 Younger children (0 - 5 years) Older children (6 - 11 years) Total
    Number of subjects
    		 34 34 68
    Age Categorical
    Units: Subjects
        Infants and toddlers (28 days-23 months)
    		 6 0 6
        Children (2-11 years)
    		 28 34 62
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 3.0 ( 1.3 ) 8.9 ( 1.7 ) -
    Gender Categorical
    Units: Subjects
        Female
    		 0 0 0
        Male
    		 34 34 68
    Subject analysis sets

    Subject analysis set title
    Younger children (0 - 5 years) [Main trial]
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Subjects (0 - 5 years) previously treated with FVIII received N8-GP (prophylaxis or treatment of bleeding episodes). The trial consisted of main and extension phase. Duration of main phase for each subject was approximately 26 weeks (50 exposure days).

    Subject analysis set title
    Older children (6 - 11 years) [Main trial]
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Subjects (6 - 11 years) previously treated with FVIII received N8-GP (prophylaxis or treatment of bleeding episodes). The trial consisted of main and extension phase. Duration of main phase for each subject was approximately 26 weeks (50 exposure days).

    Subject analysis set title
    Younger children (0 - 5 years) [Full trial]
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Subjects (0 - 5 years) previously treated with FVIII received N8-GP (prophylaxis or treatment of bleeding episodes). The trial consisted of main and extension phase. Duration of main phase for each subject was approximately 26 weeks (50 exposure days). After completion of main phase, subjects could continue until the end of the extension phase, which was defined as LPLV. All subjects continued twice weekly or every third day prophylaxis regimen in extension phase as prescribed for main phase. However, after 12 months treatment with N8-GP (main phase+extension phase) the investigator was permitted to prescribe extra coverage before physical activities.

    Subject analysis set title
    Older children (6 - 11 years) [Full trial]
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Subjects (6 - 11 years) previously treated with FVIII received N8-GP (prophylaxis or treatment of bleeding episodes). The trial consisted of main and extension phase. Duration of main phase for each subject was approximately 26 weeks (50 exposure days). After completion of main phase, subjects could continue until the end of the extension phase, which was defined as LPLV. All subjects continued twice weekly or every third day prophylaxis regimen in extension phase as prescribed for main phase. However, after 12 months treatment with N8-GP (main phase+extension phase) the investigator was permitted to prescribe extra coverage before physical activities.

    Subject analysis sets values
    		 Younger children (0 - 5 years) [Main trial] Older children (6 - 11 years) [Main trial] Younger children (0 - 5 years) [Full trial] Older children (6 - 11 years) [Full trial]
    Number of subjects
    34
    34
    34
    34
    Age Categorical
    Units: Subjects
        Infants and toddlers (28 days-23 months)
        Children (2-11 years)
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    ( )
    ( )
    ( )
    ( )
    Gender Categorical
    Units: Subjects
        Female
    0
    0
    0
    0
        Male
    34
    34
    34
    34

    End points

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    End points reporting groups
    Reporting group title
    Younger children (0 - 5 years)
    Reporting group description
    		 Subjects (0 - 5 years) previously treated with FVIII received N8-GP (prophylaxis or treatment of bleeding episodes). The trial consisted of main and extension phase. Duration of main phase for each subject was approximately 26 weeks (50 exposure days). After completion of main phase, subjects could continue until the end of the extension phase, which was defined as last patient last visit (LPLV). All subjects continued twice weekly or every third day prophylaxis regimen in extension phase as prescribed for main phase. However, after 12 months' treatment with N8-GP (main phase+extension phase) the investigator was permitted to prescribe extra coverage before physical activities.

    Reporting group title
    Older children (6 - 11 years)
    Reporting group description
    		 Subjects (6 - 11 years) previously treated with FVIII received N8-GP (prophylaxis or treatment of bleeding episodes). The trial consisted of main and extension phase. Duration of main phase for each subject was approximately 26 weeks (50 exposure days). After completion of main phase, subjects could continue until the end of the extension phase, which was defined as LPLV. All subjects continued twice weekly or every third day prophylaxis regimen in extension phase as prescribed for main phase. However, after 12 months' treatment with N8-GP (main phase+extension phase) the investigator was permitted to prescribe extra coverage before physical activities.

    Subject analysis set title
    Younger children (0 - 5 years) [Main trial]
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Subjects (0 - 5 years) previously treated with FVIII received N8-GP (prophylaxis or treatment of bleeding episodes). The trial consisted of main and extension phase. Duration of main phase for each subject was approximately 26 weeks (50 exposure days).

    Subject analysis set title
    Older children (6 - 11 years) [Main trial]
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Subjects (6 - 11 years) previously treated with FVIII received N8-GP (prophylaxis or treatment of bleeding episodes). The trial consisted of main and extension phase. Duration of main phase for each subject was approximately 26 weeks (50 exposure days).

    Subject analysis set title
    Younger children (0 - 5 years) [Full trial]
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Subjects (0 - 5 years) previously treated with FVIII received N8-GP (prophylaxis or treatment of bleeding episodes). The trial consisted of main and extension phase. Duration of main phase for each subject was approximately 26 weeks (50 exposure days). After completion of main phase, subjects could continue until the end of the extension phase, which was defined as LPLV. All subjects continued twice weekly or every third day prophylaxis regimen in extension phase as prescribed for main phase. However, after 12 months treatment with N8-GP (main phase+extension phase) the investigator was permitted to prescribe extra coverage before physical activities.

    Subject analysis set title
    Older children (6 - 11 years) [Full trial]
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Subjects (6 - 11 years) previously treated with FVIII received N8-GP (prophylaxis or treatment of bleeding episodes). The trial consisted of main and extension phase. Duration of main phase for each subject was approximately 26 weeks (50 exposure days). After completion of main phase, subjects could continue until the end of the extension phase, which was defined as LPLV. All subjects continued twice weekly or every third day prophylaxis regimen in extension phase as prescribed for main phase. However, after 12 months treatment with N8-GP (main phase+extension phase) the investigator was permitted to prescribe extra coverage before physical activities.

    Primary: Incidence of inhibitory antibodies against coagulation factor VIII (FVIII) ≥0.6 Bethesda units

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    End point title
    		 Incidence of inhibitory antibodies against coagulation factor VIII (FVIII) ≥0.6 Bethesda units
    End point description
    The incidence of inhibitory antibodies was calculated as number of patients with inhibitors during the main phase of the trial divided by number of patients in the main phase of the trial. Results were based on safety analysis set (SAS). The SAS consists of all patients exposed to at least one dose of turoctocog alfa pegol.
    End point type
    Primary
    End point timeframe
    During the main phase of the trial (from 0-26 weeks of treatment)
    End point values
    		 Younger children (0 - 5 years) [Main trial] Older children (6 - 11 years) [Main trial]
    Number of subjects analysed
    34
    34
    Units: Proportion of subjects
    0
    0
    Statistical analysis title
    		 Statistical analysis 1
    Statistical analysis description
    A one-sided, upper 97.5% confidence limit was provided based on an exact calculation in the binomial distribution.
    Comparison groups
    Older children (6 - 11 years) [Main trial] v Younger children (0 - 5 years) [Main trial]
    Number of subjects included in analysis
    68
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Incidence rate
    Point estimate
    0
    Confidence interval
         level
    		 97.5%
         sides
    1-sided
         lower limit
    		 -
         upper limit
    		 0.067

    Secondary: Frequency of adverse events including serious adverse events reported during the trial period

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    End point title
    		 Frequency of adverse events including serious adverse events reported during the trial period
    End point description
    The frequency of adverse events including serious adverse events reported during the main and extension phase of the trial. Results were based on SAS.
    End point type
    Secondary
    End point timeframe
    Main phase: (from 0-26 weeks of treatment) and full trial: (0 weeks to last patient’s completion of the trial)
    End point values
    		 Younger children (0 - 5 years) [Main trial] Older children (6 - 11 years) [Main trial] Younger children (0 - 5 years) [Full trial] Older children (6 - 11 years) [Full trial]
    Number of subjects analysed
    34
    34
    34
    34
    Units: Events per patient years of exposure
        number (not applicable)
    4.87
    4.74
    3.09
    2.45
    No statistical analyses for this end point

    Secondary: Haemostatic effect of N8-GP when used for treatment of bleeding episodes and assessed as: Excellent, Good, Moderate, or None

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    End point title
    		 Haemostatic effect of N8-GP when used for treatment of bleeding episodes and assessed as: Excellent, Good, Moderate, or None
    End point description
    Haemostatic effect of turoctocog alfa pegol for treatment of bleeding episodes was assessed by 4-point response scale: none, moderate, good or excellent. Evaluation during trial was done by patient and/or parent(s)/caregiver 8 hours after first injection as follows: Excellent: Abrupt pain relief and/or clear improvement in objective signs of bleeding within approximately 8 hours after a single injection; Good: Definite pain relief and/or improvement in signs of bleeding within approximately 8 hours after a single injection, but possibly requiring more than one injection for complete resolution; Moderate: Probable or slight beneficial effect within approximately 8 hours after the first injection, but usually requiring more than one injection; None: No improvement, or worsening of symptoms. Results were based on full analysis set (FAS). All trial patients allocated to treatment, for which at least one of the pharmacokinetic or efficacy endpoints was assessed, were included in the FAS.
    End point type
    Secondary
    End point timeframe
    Main phase: (from 0-26 weeks of treatment) and full trial: (0 weeks to last patient’s completion of the trial)
    End point values
    		 Younger children (0 - 5 years) [Main trial] Older children (6 - 11 years) [Main trial] Younger children (0 - 5 years) [Full trial] Older children (6 - 11 years) [Full trial]
    Number of subjects analysed
    30 [1]
    40 [2]
    108 [3]
    222 [4]
    Units: Bleeding episodes
        Excellent
    11
    12
    47
    96
        Good
    13
    19
    48
    74
        Moderate
    4
    7
    9
    44
        None
    1
    0
    2
    2
        Missing
    1
    2
    2
    6
    Notes
    [1] - "Number of subjects analyzed” = number of bleeds in subjects
    [2] - "Number of subjects analyzed” = number of bleeds in subjects
    [3] - "Number of subjects analyzed” = number of bleeds in subjects
    [4] - "Number of subjects analyzed” = number of bleeds in subjects
    No statistical analyses for this end point

    Secondary: Number of bleeding episodes during prophylactic treatment with N8-GP (annualised bleeding rate)

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    End point title
    		 Number of bleeding episodes during prophylactic treatment with N8-GP (annualised bleeding rate)
    End point description
    The number of bleeding episodes per year reported during the prophylactic treatment with N8-GP. Results were based on FAS.
    End point type
    Secondary
    End point timeframe
    Main phase: (from 0-26 weeks of treatment) and full trial: (0 weeks to last patient’s completion of the trial)
    End point values
    		 Younger children (0 - 5 years) [Main trial] Older children (6 - 11 years) [Main trial] Younger children (0 - 5 years) [Full trial] Older children (6 - 11 years) [Full trial]
    Number of subjects analysed
    34
    34
    34
    34
    Units: bleeds/patient/year
        median (inter-quartile range (Q1-Q3))
    1.94 (0.00 to 2.08)
    1.97 (0.00 to 3.91)
    0.61 (0.20 to 1.19)
    0.93 (0.20 to 2.11)
    No statistical analyses for this end point

    Secondary: Consumption of N8-GP per bleeding episode (number of injections)

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    End point title
    		 Consumption of N8-GP per bleeding episode (number of injections)
    End point description
    The mean number of injections of turoctocog alfa pegol used for treatment of a bleed from start to stop of a bleed. Results were based on FAS.
    End point type
    Secondary
    End point timeframe
    Main phase: (from 0-26 weeks of treatment) and full trial: (0 weeks to last patient’s completion of the trial)
    End point values
    		 Younger children (0 - 5 years) [Main trial] Older children (6 - 11 years) [Main trial] Younger children (0 - 5 years) [Full trial] Older children (6 - 11 years) [Full trial]
    Number of subjects analysed
    30 [5]
    40 [6]
    108 [7]
    222 [8]
    Units: Number of injections
        arithmetic mean (standard deviation)
    1.9 ( 1.5 )
    1.6 ( 0.9 )
    1.6 ( 1.3 )
    1.5 ( 1.1 )
    Notes
    [5] - "Number of subjects analyzed"=number of bleeds
    [6] - "Number of subjects analyzed"=number of bleeds
    [7] - "Number of subjects analyzed"=number of bleeds
    [8] - "Number of subjects analyzed"=number of bleeds
    No statistical analyses for this end point

    Secondary: Consumption of N8-GP per bleeding episode (U/kg)

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    End point title
    		 Consumption of N8-GP per bleeding episode (U/kg)
    End point description
    The mean consumption of turoctocog alfa pegol used for treatment of a bleed from start to stop of a bleed. Results were based on FAS.
    End point type
    Secondary
    End point timeframe
    Main phase: (from 0-26 weeks of treatment) and full trial: (0 weeks to last patient’s completion of the trial)
    End point values
    		 Younger children (0 - 5 years) [Main trial] Older children (6 - 11 years) [Main trial] Younger children (0 - 5 years) [Full trial] Older children (6 - 11 years) [Full trial]
    Number of subjects analysed
    30
    40
    108
    222
    Units: IU/kg/bleed
        arithmetic mean (standard deviation)
    123 ( 104.9 )
    99.0 ( 54.4 )
    102.8 ( 81.0 )
    91.0 ( 58.3 )
    No statistical analyses for this end point

    Secondary: Consumption of N8-GP during prophylaxis (number of injections)

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    End point title
    		 Consumption of N8-GP during prophylaxis (number of injections)
    End point description
    The mean number of injections of turoctocog alfa pegol used for treatment of a bleed from start to stop of a bleed during prophylaxis. Results were based on FAS.
    End point type
    Secondary
    End point timeframe
    Main phase: (from 0-26 weeks of treatment) and full trial: (0 weeks to last patient’s completion of the trial)
    End point values
    		 Younger children (0 - 5 years) [Main trial] Older children (6 - 11 years) [Main trial] Younger children (0 - 5 years) [Full trial] Older children (6 - 11 years) [Full trial]
    Number of subjects analysed
    1592 [9]
    1799 [10]
    14442 [11]
    17243 [12]
    Units: Number of injections
        arithmetic mean (standard deviation)
    65.3 ( 6.5 )
    62.3 ( 7.4 )
    65.4 ( 7.5 )
    64.1 ( 5.3 )
    Notes
    [9] - "Number of subjects analyzed"=Number of injections"
    [10] - "Number of subjects analyzed"=Number of injections"
    [11] - "Number of subjects analyzed"=Number of injections"
    [12] - "Number of subjects analyzed"=Number of injections"
    No statistical analyses for this end point

    Secondary: Consumption of N8-GP during prophylaxis (U/kg per month)

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    End point title
    		 Consumption of N8-GP during prophylaxis (U/kg per month)
    End point description
    The mean consumption of turoctocog alfa pegol used for treatment of a bleed from start to stop of a bleed during prophylaxis (per month per subject). Results were based on FAS. Consumption used for treatment includes all doses given (prophylaxis, treatment of bleed, minor surgery and pharmacokinetics [PK])
    End point type
    Secondary
    End point timeframe
    Main phase: (from 0-26 weeks of treatment) and full trial: (0 weeks to last patient’s completion of the trial)
    End point values
    		 Younger children (0 - 5 years) [Main trial] Older children (6 - 11 years) [Main trial] Younger children (0 - 5 years) [Full trial] Older children (6 - 11 years) [Full trial]
    Number of subjects analysed
    34
    34
    34
    34
    Units: U/kg/month
        arithmetic mean (standard deviation)
    572.5 ( 97.4 )
    555.8 ( 44.6 )
    564.9 ( 86.6 )
    563.4 ( 15.1 )
    No statistical analyses for this end point

    Secondary: Consumption of N8-GP during prophylaxis (U/kg per year)

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    End point title
    		 Consumption of N8-GP during prophylaxis (U/kg per year)
    End point description
    The mean consumption of turoctocog alfa pegol used for treatment of a bleed from start to stop of a bleed during prophylaxis (per year per subject). Results were based on FAS. Consumption used for treatment includes all doses given (prophylaxis, treatment of bleed, minor surgery and pharmacokinetics)
    End point type
    Secondary
    End point timeframe
    Main phase: (from 0-26 weeks of treatment) and full trial: (0 weeks to last patient’s completion of the trial).
    End point values
    		 Younger children (0 - 5 years) [Main trial] Older children (6 - 11 years) [Main trial] Younger children (0 - 5 years) [Full trial] Older children (6 - 11 years) [Full trial]
    Number of subjects analysed
    34
    34
    34
    34
    Units: U/kg/year
        arithmetic mean (standard deviation)
    6870.3 ( 1169 )
    6669.6 ( 535.8 )
    6778.6 ( 1039 )
    6760.4 ( 181.8 )
    No statistical analyses for this end point

    Secondary: Incremental recovery (defined as the peak level recorded 60 min after end of injection) evaluated for previous FVIII product

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    End point title
    		 Incremental recovery (defined as the peak level recorded 60 min after end of injection) evaluated for previous FVIII product
    End point description
    The incremental recovery was defined as the increase in plasma FVIII activity per IU/kg of factor administered recorded 60 minutes after end of injection. It was calculated as (Factor VIII procoagulant [FVIII:C] activity measured in plasma 60 min after dosing - FVIII:C activity measured in plasma immediately before dosing) / (dose injected at time 0 min), where the dose was expressed as U FVIII product per kg body weight. A chromogenic assay with normal human plasma (NHP) as calibrator was used. Results were based on FAS.
    End point type
    Secondary
    End point timeframe
    2-6 weeks prior to initial dosing with N8-GP and up to 30 hours after administration of previous FVIII product
    End point values
    		 Younger children (0 - 5 years) [Main trial] Older children (6 - 11 years) [Main trial]
    Number of subjects analysed
    13 [13]
    12 [14]
    Units: (IU/mL)/(U/kg)
        least squares mean (confidence interval 95%)
    0.017 (0.014 to 0.021)
    0.022 (0.018 to 0.027)
    Notes
    [13] - "Number of subjects analysed"=subjects with available data
    [14] - "Number of subjects analysed"=subjects with available data
    No statistical analyses for this end point

    Secondary: Incremental recovery (defined as the peak level recorded 60 min after end of injection) evaluated for N8-GP

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    End point title
    		 Incremental recovery (defined as the peak level recorded 60 min after end of injection) evaluated for N8-GP
    End point description
    The incremental recovery was defined as the peak level recorded 60 min after end of injection and dose-normalised. It was calculated as (FVIII:C activity measured in plasma 60 min after dosing - FVIII:C activity measured in plasma immediately before dosing) / (dose injected at time 0 min), where the dose was expressed as U FVIII product per kg body weight. A chromogenic assay with product specific calibrator (PSS) as calibrator was used. Results were based on FAS.
    End point type
    Secondary
    End point timeframe
    From 1 hour prior to and up to 96 hours after initial administration of N8-GP.
    End point values
    		 Younger children (0 - 5 years) [Full trial] Older children (6 - 11 years) [Full trial]
    Number of subjects analysed
    13 [15]
    12 [16]
    Units: (IU/mL)/(U/kg)
        least squares mean (confidence interval 95%)
    0.018 (0.015 to 0.022)
    0.020 (0.016 to 0.024)
    Notes
    [15] - "Number of subjects analyzed"=subjects with available data
    [16] - "Number of subjects analyzed"=subjects with available data
    No statistical analyses for this end point

    Secondary: Area under the curve evaluated for previous FVIII product

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    End point title
    		 Area under the curve evaluated for previous FVIII product
    End point description
    Area under the curve (AUC) versus time from zero to infinity. This is calculated as AUC = AUClast + (C(t) / λz), where C(t) is the last measurable concentration. A chromogenic assay with NHP as calibrator was used. Results were based on FAS.
    End point type
    Secondary
    End point timeframe
    2-6 weeks prior to initial dosing with N8-GP and up to 30 hours after administration of previous FVIII product
    End point values
    		 Younger children (0 - 5 years) [Full trial] Older children (6 - 11 years) [Full trial]
    Number of subjects analysed
    14 [17]
    11 [18]
    Units: IU×h/mL
        least squares mean (confidence interval 95%)
    11.628 (9.170 to 14.744)
    12.203 (9.336 to 15.951)
    Notes
    [17] - "Number of subjects analyzed"=subjects with available data
    [18] - "Number of subjects analyzed"=subjects with available data
    No statistical analyses for this end point

    Secondary: Area under the curve evaluated for N8-GP

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    End point title
    		 Area under the curve evaluated for N8-GP
    End point description
    Area under the curve versus time from zero to infinity. This is calculated as AUC = AUClast + (C(t) / λz), where C(t) is the last measurable concentration. A chromogenic assay with PSS as calibrator was used. Results were based on FAS.
    End point type
    Secondary
    End point timeframe
    From 1 hour prior to and up to 96 hours after initial administration of N8-GP
    End point values
    		 Younger children (0 - 5 years) [Full trial] Older children (6 - 11 years) [Full trial]
    Number of subjects analysed
    13 [19]
    11 [20]
    Units: IU*h/mL
        least squares mean (confidence interval 95%)
    21.489 (16.785 to 27.511)
    25.026 (19.145 to 32.713)
    Notes
    [19] - "Number of subjects analyzed"=subjects with available data
    [20] - "Number of subjects analyzed"=subjects with available data
    No statistical analyses for this end point

    Secondary: Terminal half-life evaluated for previous FVIII product

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    End point title
    		 Terminal half-life evaluated for previous FVIII product
    End point description
    t½ = ln(2) / λz, where λz is the terminal elimination rate. The terminal elimination rate was planned estimated using linear regression on the terminal part of the time versus log(concentration) curve. A population-based method simultaneously estimating individual t½ values for all patients was applied, including patients with few values above the lower limit of quantification (LLOQ). This was estimated using time points from 1h to 30h. A chromogenic assay with PSS as calibrator was used. Results were based on FAS.
    End point type
    Secondary
    End point timeframe
    2-6 weeks prior to initial dosing with N8-GP and up to 30 hours after administration of previous FVIII product
    End point values
    		 Younger children (0 - 5 years) [Full trial] Older children (6 - 11 years) [Full trial]
    Number of subjects analysed
    14 [21]
    12 [22]
    Units: hours
        geometric mean (geometric coefficient of variation)
    7.2 ( 20.1 )
    7.5 ( 19.1 )
    Notes
    [21] - "Number of subjects analyzed"=subjects with available data
    [22] - "Number of subjects analyzed"=subjects with available data
    No statistical analyses for this end point

    Secondary: Terminal half-life evaluated for N8-GP

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    End point title
    		 Terminal half-life evaluated for N8-GP
    End point description
    t½ = ln(2) / λz, where λz is the terminal elimination rate. The terminal elimination rate was planned estimated using linear regression on the terminal part of the time versus log(concentration) curve. A population-based method simultaneously estimating individual t½ values for all patients was applied, including patients with few values above the LLOQ. This was estimated using time points from 6h to 96h. A chromogenic assay with PSS as calibrator was used. Results were based on FAS.
    End point type
    Secondary
    End point timeframe
    From 1 hour prior to and up to 96 hours after initial administration of N8-GP
    End point values
    		 Younger children (0 - 5 years) [Full trial] Older children (6 - 11 years) [Full trial]
    Number of subjects analysed
    13 [23]
    12 [24]
    Units: hours
        geometric mean (geometric coefficient of variation)
    13.6 ( 20.4 )
    14.1 ( 25.0 )
    Notes
    [23] - "Number of subjects analyzed"=subjects with available data
    [24] - "Number of subjects analyzed"=subjects with available data
    No statistical analyses for this end point

    Secondary: Clearance evaluated for previous FVIII product

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    End point title
    		 Clearance evaluated for previous FVIII product
    End point description
    Total plasma clearance of drug after intravenous administration measured as actual dose/AUC. A chromogenic assay with NHP as calibrator was used. Results were based on FAS.
    End point type
    Secondary
    End point timeframe
    2-6 weeks prior to initial dosing with N8-GP and up to 30 hours after administration of previous FVIII product
    End point values
    		 Younger children (0 - 5 years) [Full trial] Older children (6 - 11 years) [Full trial]
    Number of subjects analysed
    14 [25]
    11 [26]
    Units: mL/h/kg
        least squares mean (confidence interval 95%)
    4.322 (3.404 to 5.486)
    3.867 (2.955 to 5.061)
    Notes
    [25] - "Number of subjects analyzed"=subjects with available data
    [26] - "Number of subjects analyzed"=subjects with available data
    No statistical analyses for this end point

    Secondary: Clearance evaluated for N8-GP

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    End point title
    		 Clearance evaluated for N8-GP
    End point description
    Total plasma clearance of drug after intravenous administration measured as actual dose/AUC. A chromogenic assay with PSS as calibrator was used. Results were based on FAS.
    End point type
    Secondary
    End point timeframe
    From 1 hour prior to and up to 96 hours after initial administration of N8-GP.
    End point values
    		 Younger children (0 - 5 years) [Full trial] Older children (6 - 11 years) [Full trial]
    Number of subjects analysed
    13
    11
    Units: mL/h/kg
        least squares mean (confidence interval 95%)
    2.601 (2.030 to 3.333)
    2.386 (1.823 to 3.123)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From first exposure to N8-GP (visit 2) of main phase to end of extension phase (>=4 days after last dose of N8-GP).
    Adverse event reporting additional description
    The safety analysis set consists of all patients exposed to at least one dose of N8-GP.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    21
    Reporting groups
    Reporting group title
    Younger children (0-5 years)
    Reporting group description
    		 Subjects (0 - 5 years) previously treated with FVIII received N8-GP (prophylaxis or treatment of bleeding episodes). The trial consisted of main and extension phase. Duration of main phase for each subject was approximately 26 weeks (50 exposure days). After completion of main phase, subjects could continue until the end of the extension phase, which was defined as LPLV. All subjects continued twice weekly or every third day prophylaxis regimen in extension phase as prescribed for main phase. However, after 12 months treatment with N8-GP (main phase+extension phase) the investigator was permitted to prescribe extra coverage before physical activities.

    Reporting group title
    Older children (6-11 years)
    Reporting group description
    		 Subjects (6 - 11 years) previously treated with FVIII received N8-GP (prophylaxis or treatment of bleeding episodes). The trial consisted of main and extension phase. Duration of main phase for each subject was approximately 26 weeks (50 exposure days). After completion of main phase, subjects could continue until the end of the extension phase, which was defined as LPLV. All subjects continued twice weekly or every third day prophylaxis regimen in extension phase as prescribed for main phase. However, after 12 months treatment with N8-GP (main phase+extension phase) the investigator was permitted to prescribe extra coverage before physical activities.

    Serious adverse events
    		 Younger children (0-5 years) Older children (6-11 years)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    11 / 34 (32.35%)
    5 / 34 (14.71%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    1 / 34 (2.94%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hand fracture
         subjects affected / exposed
    1 / 34 (2.94%)
    0 / 34 (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
    0 / 34 (0.00%)
    1 / 34 (2.94%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Haemorrhage
         subjects affected / exposed
    1 / 34 (2.94%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    1 / 34 (2.94%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Hypersensitivity
         subjects affected / exposed
    1 / 34 (2.94%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal hernia
         subjects affected / exposed
    0 / 34 (0.00%)
    1 / 34 (2.94%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastritis
         subjects affected / exposed
    0 / 34 (0.00%)
    1 / 34 (2.94%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Acquired phimosis
         subjects affected / exposed
    1 / 34 (2.94%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Adenoidal hypertrophy
         subjects affected / exposed
    0 / 34 (0.00%)
    1 / 34 (2.94%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Asthma
         subjects affected / exposed
    1 / 34 (2.94%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Muscle haemorrhage
         subjects affected / exposed
    1 / 34 (2.94%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Device related infection
         subjects affected / exposed
    1 / 34 (2.94%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    1 / 34 (2.94%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Encephalitis
         subjects affected / exposed
    1 / 34 (2.94%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis syndrome
         subjects affected / exposed
    1 / 34 (2.94%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tonsillitis
         subjects affected / exposed
    0 / 34 (0.00%)
    1 / 34 (2.94%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Younger children (0-5 years) Older children (6-11 years)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    33 / 34 (97.06%)
    33 / 34 (97.06%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Skin papilloma
         subjects affected / exposed
    2 / 34 (5.88%)
    0 / 34 (0.00%)
         occurrences all number
    2
    0
    Vascular disorders
    Haematoma
         subjects affected / exposed
    2 / 34 (5.88%)
    0 / 34 (0.00%)
         occurrences all number
    2
    0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    7 / 34 (20.59%)
    6 / 34 (17.65%)
         occurrences all number
    16
    9
    Hyperthermia
         subjects affected / exposed
    2 / 34 (5.88%)
    1 / 34 (2.94%)
         occurrences all number
    2
    1
    Peripheral swelling
         subjects affected / exposed
    0 / 34 (0.00%)
    3 / 34 (8.82%)
         occurrences all number
    0
    3
    Immune system disorders
    Seasonal allergy
         subjects affected / exposed
    2 / 34 (5.88%)
    2 / 34 (5.88%)
         occurrences all number
    2
    2
    Food allergy
         subjects affected / exposed
    1 / 34 (2.94%)
    2 / 34 (5.88%)
         occurrences all number
    2
    4
    Reproductive system and breast disorders
    Penile adhesion
         subjects affected / exposed
    2 / 34 (5.88%)
    0 / 34 (0.00%)
         occurrences all number
    2
    0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    14 / 34 (41.18%)
    6 / 34 (17.65%)
         occurrences all number
    26
    6
    Oropharyngeal pain
         subjects affected / exposed
    2 / 34 (5.88%)
    8 / 34 (23.53%)
         occurrences all number
    2
    10
    Rhinorrhoea
         subjects affected / exposed
    4 / 34 (11.76%)
    3 / 34 (8.82%)
         occurrences all number
    4
    4
    Asthma
         subjects affected / exposed
    2 / 34 (5.88%)
    1 / 34 (2.94%)
         occurrences all number
    4
    1
    Epistaxis
         subjects affected / exposed
    4 / 34 (11.76%)
    1 / 34 (2.94%)
         occurrences all number
    28
    3
    Nasal congestion
         subjects affected / exposed
    2 / 34 (5.88%)
    2 / 34 (5.88%)
         occurrences all number
    3
    2
    Rhinitis allergic
         subjects affected / exposed
    3 / 34 (8.82%)
    1 / 34 (2.94%)
         occurrences all number
    3
    1
    Psychiatric disorders
    Attention deficit/hyperactivity disorder
         subjects affected / exposed
    3 / 34 (8.82%)
    1 / 34 (2.94%)
         occurrences all number
    3
    1
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    4 / 34 (11.76%)
    4 / 34 (11.76%)
         occurrences all number
    4
    4
    Joint injury
         subjects affected / exposed
    2 / 34 (5.88%)
    3 / 34 (8.82%)
         occurrences all number
    2
    4
    Ligament sprain
         subjects affected / exposed
    0 / 34 (0.00%)
    5 / 34 (14.71%)
         occurrences all number
    0
    6
    Limb injury
         subjects affected / exposed
    5 / 34 (14.71%)
    4 / 34 (11.76%)
         occurrences all number
    5
    12
    Skin abrasion
         subjects affected / exposed
    2 / 34 (5.88%)
    3 / 34 (8.82%)
         occurrences all number
    2
    4
    Arthropod bite
         subjects affected / exposed
    1 / 34 (2.94%)
    2 / 34 (5.88%)
         occurrences all number
    2
    2
    Arthropod sting
         subjects affected / exposed
    1 / 34 (2.94%)
    3 / 34 (8.82%)
         occurrences all number
    3
    3
    Face injury
         subjects affected / exposed
    1 / 34 (2.94%)
    2 / 34 (5.88%)
         occurrences all number
    1
    3
    Fall
         subjects affected / exposed
    5 / 34 (14.71%)
    3 / 34 (8.82%)
         occurrences all number
    8
    4
    Head injury
         subjects affected / exposed
    3 / 34 (8.82%)
    4 / 34 (11.76%)
         occurrences all number
    4
    5
    Laceration
         subjects affected / exposed
    2 / 34 (5.88%)
    4 / 34 (11.76%)
         occurrences all number
    2
    4
    Nervous system disorders
    Headache
         subjects affected / exposed
    5 / 34 (14.71%)
    9 / 34 (26.47%)
         occurrences all number
    6
    16
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    2 / 34 (5.88%)
    1 / 34 (2.94%)
         occurrences all number
    2
    1
    Ear and labyrinth disorders
    Cerumen impaction
         subjects affected / exposed
    2 / 34 (5.88%)
    0 / 34 (0.00%)
         occurrences all number
    2
    0
    Ear pain
         subjects affected / exposed
    4 / 34 (11.76%)
    1 / 34 (2.94%)
         occurrences all number
    5
    2
    Eye disorders
    Conjunctivitis allergic
         subjects affected / exposed
    0 / 34 (0.00%)
    3 / 34 (8.82%)
         occurrences all number
    0
    4
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    5 / 34 (14.71%)
    2 / 34 (5.88%)
         occurrences all number
    7
    2
    Diarrhoea
         subjects affected / exposed
    5 / 34 (14.71%)
    4 / 34 (11.76%)
         occurrences all number
    7
    5
    Nausea
         subjects affected / exposed
    0 / 34 (0.00%)
    2 / 34 (5.88%)
         occurrences all number
    0
    2
    Vomiting
         subjects affected / exposed
    9 / 34 (26.47%)
    3 / 34 (8.82%)
         occurrences all number
    10
    7
    Chapped lips
         subjects affected / exposed
    0 / 34 (0.00%)
    2 / 34 (5.88%)
         occurrences all number
    0
    2
    Constipation
         subjects affected / exposed
    2 / 34 (5.88%)
    3 / 34 (8.82%)
         occurrences all number
    2
    5
    Dental caries
         subjects affected / exposed
    3 / 34 (8.82%)
    1 / 34 (2.94%)
         occurrences all number
    5
    1
    Skin and subcutaneous tissue disorders
    Acne
         subjects affected / exposed
    0 / 34 (0.00%)
    4 / 34 (11.76%)
         occurrences all number
    0
    5
    Dermatitis contact
         subjects affected / exposed
    1 / 34 (2.94%)
    2 / 34 (5.88%)
         occurrences all number
    1
    2
    Eczema
         subjects affected / exposed
    2 / 34 (5.88%)
    5 / 34 (14.71%)
         occurrences all number
    2
    5
    Rash
         subjects affected / exposed
    7 / 34 (20.59%)
    0 / 34 (0.00%)
         occurrences all number
    11
    0
    Dermatitis
         subjects affected / exposed
    0 / 34 (0.00%)
    2 / 34 (5.88%)
         occurrences all number
    0
    3
    Erythema
         subjects affected / exposed
    3 / 34 (8.82%)
    1 / 34 (2.94%)
         occurrences all number
    5
    1
    Rash pruritic
         subjects affected / exposed
    0 / 34 (0.00%)
    2 / 34 (5.88%)
         occurrences all number
    0
    2
    Skin lesion
         subjects affected / exposed
    1 / 34 (2.94%)
    2 / 34 (5.88%)
         occurrences all number
    1
    2
    Urticaria
         subjects affected / exposed
    1 / 34 (2.94%)
    2 / 34 (5.88%)
         occurrences all number
    1
    2
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    3 / 34 (8.82%)
    4 / 34 (11.76%)
         occurrences all number
    4
    5
    Pain in extremity
         subjects affected / exposed
    5 / 34 (14.71%)
    6 / 34 (17.65%)
         occurrences all number
    11
    8
    Tendonitis
         subjects affected / exposed
    0 / 34 (0.00%)
    2 / 34 (5.88%)
         occurrences all number
    0
    2
    Joint swelling
         subjects affected / exposed
    3 / 34 (8.82%)
    0 / 34 (0.00%)
         occurrences all number
    3
    0
    Infections and infestations
    Conjunctivitis
         subjects affected / exposed
    2 / 34 (5.88%)
    2 / 34 (5.88%)
         occurrences all number
    2
    2
    Gastroenteritis
         subjects affected / exposed
    7 / 34 (20.59%)
    9 / 34 (26.47%)
         occurrences all number
    10
    13
    Influenza
         subjects affected / exposed
    5 / 34 (14.71%)
    6 / 34 (17.65%)
         occurrences all number
    9
    10
    Nasopharyngitis
         subjects affected / exposed
    11 / 34 (32.35%)
    10 / 34 (29.41%)
         occurrences all number
    21
    16
    Pharyngitis
         subjects affected / exposed
    2 / 34 (5.88%)
    1 / 34 (2.94%)
         occurrences all number
    2
    2
    Rhinitis
         subjects affected / exposed
    8 / 34 (23.53%)
    4 / 34 (11.76%)
         occurrences all number
    8
    7
    Sinusitis
         subjects affected / exposed
    1 / 34 (2.94%)
    2 / 34 (5.88%)
         occurrences all number
    1
    2
    Tonsillitis
         subjects affected / exposed
    2 / 34 (5.88%)
    2 / 34 (5.88%)
         occurrences all number
    2
    5
    Upper respiratory tract infection
         subjects affected / exposed
    10 / 34 (29.41%)
    13 / 34 (38.24%)
         occurrences all number
    20
    31
    Acute sinusitis
         subjects affected / exposed
    0 / 34 (0.00%)
    2 / 34 (5.88%)
         occurrences all number
    0
    2
    Bronchitis
         subjects affected / exposed
    3 / 34 (8.82%)
    3 / 34 (8.82%)
         occurrences all number
    5
    3
    Ear infection
         subjects affected / exposed
    5 / 34 (14.71%)
    3 / 34 (8.82%)
         occurrences all number
    5
    5
    Gastroenteritis viral
         subjects affected / exposed
    0 / 34 (0.00%)
    2 / 34 (5.88%)
         occurrences all number
    0
    2
    Molluscum contagiosum
         subjects affected / exposed
    2 / 34 (5.88%)
    1 / 34 (2.94%)
         occurrences all number
    2
    1
    Otitis media
         subjects affected / exposed
    4 / 34 (11.76%)
    5 / 34 (14.71%)
         occurrences all number
    4
    5
    Pharyngitis streptococcal
         subjects affected / exposed
    2 / 34 (5.88%)
    1 / 34 (2.94%)
         occurrences all number
    2
    2
    Pharyngotonsillitis
         subjects affected / exposed
    0 / 34 (0.00%)
    2 / 34 (5.88%)
         occurrences all number
    0
    2
    Pneumonia
         subjects affected / exposed
    1 / 34 (2.94%)
    2 / 34 (5.88%)
         occurrences all number
    1
    2
    Varicella
         subjects affected / exposed
    6 / 34 (17.65%)
    1 / 34 (2.94%)
         occurrences all number
    6
    1
    Viral infection
         subjects affected / exposed
    4 / 34 (11.76%)
    3 / 34 (8.82%)
         occurrences all number
    5
    3
    Viral pharyngitis
         subjects affected / exposed
    2 / 34 (5.88%)
    0 / 34 (0.00%)
         occurrences all number
    2
    0
    Viral upper respiratory tract infection
         subjects affected / exposed
    4 / 34 (11.76%)
    3 / 34 (8.82%)
         occurrences all number
    5
    5

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    14 Dec 2012
    1) Changes introduced to the dose table in order to extend weight predictions. 2) Port restrictions text in connection with blood samplings removed. Included together with detailed instructions for laboratory sampling in other trial documents (e.g., in the laboratory manual). 3) Inconsistencies and typing errors corrected.
    11 Mar 2014
    1) Withdrawal criteria amended to allow patients with a low titre inhibitor (≤ 5 BU), that does not result in clinically ineffective treatment with N8-GP, to continue in the trial. 2) Reference unit for inhibitors has been aligned to BU. 3) Lupus anticoagulant added to flowchart main and extension phase. 4) Patients allowed continuing in the extension phase as soon as minimum 25 patients for each cohort had completed the main phase. 5) List of participating countries updated. 6) FVIII results to investigators changed to one-stage clotting assay to align across N8-GP project. 7) Inclusion of an assay to analyse for antibodies towards polyethylene glycol (PEG). 8) Clarification that FVIII activity should be analysed in case of severe allergic reaction. 9) Labelling allowed by third party vendors. 10) Section added: suspected transmission of infectious agents to the serious adverse event (SAE) definition. 11) Extension of monitoring window during extension phase to reflect the visit scheduled. 12) Multiple bleeding from the same event or time point counted as one bleeding episode. 13) Minor updates to the interim analysis
    14 Apr 2014
    1) Patients with low titre inhibitors who continue on N8-GP treatment are followed systematically and should attend an unscheduled visit monthly. 2) Novo Nordisk safety committee consulted by the investigator to determine the best management of individual patients with low titre inhibitors.

    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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