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    Clinical Trial Results:
    A Multi-Centre, Open-Label, Non-Controlled Trial on Safety and Efficacy of N8 in Previously Treated Paediatric Patients with Haemophilia A

    Summary
    EudraCT number
    2009-016383-36
    Trial protocol
    IT   LT  
    Global end of trial date
    21 Nov 2011

    Results information
    Results version number
    v1(current)
    This version publication date
    15 Mar 2016
    First version publication date
    26 Jul 2015
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    NN7008-3545
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01138501
    WHO universal trial number (UTN)
    U1111-1113-7182
    Sponsors
    Sponsor organisation name
    Novo Nordisk A/S
    Sponsor organisation address
    Novo Allé, Bagsvaerd, Denmark, 2880
    Public contact
    Global Clinical Registry (GCR, 1452), Novo Nordisk A/S, clinicaltrials@novonordisk.com
    Scientific contact
    Global Clinical Registry (GCR, 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-000428-PIP01-08
    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
    20 Mar 2012
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    21 Nov 2011
    Global end of trial reached?
    Yes
    Global end of trial date
    21 Nov 2011
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate safety of N8 (turoctocog alfa) in paediatric previously treated patients (PTPs) <12 years of age with haemophilia A
    Protection of trial subjects
    The trial was conducted in accordance with the Declaration of Helsinki (2008) and ICH Good Clinical Practice (1996). The results presented reflect data available in the clinical database as of 13 -Dec-2011. The database was updated on 1-Feb-2012 in order to change the coding of one adverse event coded as ‘anti-factor VIII antibody positive’. The results of a second separately drawn sample from this patient was negative, meaning that the definition of FVIII inhibitors was not met and the coding of the event was therefore changed to ‘anti-factor VIII antibody test’.
    Background therapy
    Not applicable
    Evidence for comparator
    Not applicable
    Actual start date of recruitment
    18 Jun 2010
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    Safety, Efficacy
    Long term follow-up duration
    53 Months
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Brazil: 9
    Country: Number of subjects enrolled
    Italy: 2
    Country: Number of subjects enrolled
    Lithuania: 4
    Country: Number of subjects enrolled
    Macedonia, the former Yugoslav Republic of: 5
    Country: Number of subjects enrolled
    Malaysia: 5
    Country: Number of subjects enrolled
    Poland: 5
    Country: Number of subjects enrolled
    Russian Federation: 8
    Country: Number of subjects enrolled
    Serbia: 5
    Country: Number of subjects enrolled
    Taiwan: 1
    Country: Number of subjects enrolled
    Turkey: 7
    Country: Number of subjects enrolled
    United States: 12
    Worldwide total number of subjects
    63
    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)
    4
    Children (2-11 years)
    59
    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
    A total of 26 sites enrolled and dosed at least one patient. The country distribution was as follows (number of actively recruiting sites per country in parenthesis): Brazil (3), Italy (1), Lithuania (1), Macedonia (1), Malaysia (1), Poland (2), Russia (2), Serbia (1), Taiwan (1), Turkey (3) and the US (10)

    Pre-assignment
    Screening details
    Not Applicable

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

    Arms
    Arm title
    All subjects treated with Turoctocog Alfa
    Arm description
    The patients received bleeding preventive treatment with a single dose of turoctocog alfa of 25-50 IU/kg every second day or 25-60 IU/kg three times weekly. Turoctocog alfa was administered as a slow bolus i.v. injection (approximately 1-2 mL/min). Pharmacokinetic assessments were performed in at least 13 patients from each age cohort. Each patient participating in the pharmacokinetic assessments received one dose of previous factor VIII (FVIII) and one dose of turoctocog alfa.
    Arm type
    Experimental

    Investigational medicinal product name
    N8
    Investigational medicinal product code
    Other name
    Turoctocog Alfa
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous bolus use
    Dosage and administration details
    A single dose of turoctocog alfa of 25-50 IU/kg every second day or 25-60 IU/kg three times weekly was administered as a slow bolus i.v. injection (approximately 1-2 mL/min). Each patient participating in the pharmacokinetic assessments received one dose of previous FVIII and one dose of turoctocog alfa.

    Number of subjects in period 1
    All subjects treated with Turoctocog Alfa
    Started
    63
    Completed
    60
    Not completed
    3
         Protocol deviation
    1
         Treatment with FVIII concentrates other than N8
    1
         Consent withdrawn by subject
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    All subjects treated with Turoctocog Alfa
    Reporting group description
    The patients received bleeding preventive treatment with a single dose of turoctocog alfa of 25-50 IU/kg every second day or 25-60 IU/kg three times weekly. Turoctocog alfa was administered as a slow bolus i.v. injection (approximately 1-2 mL/min). Pharmacokinetic assessments were performed in at least 13 patients from each age cohort. Each patient participating in the pharmacokinetic assessments received one dose of previous factor VIII (FVIII) and one dose of turoctocog alfa.

    Reporting group values
    All subjects treated with Turoctocog Alfa Total
    Number of subjects
    63 63
    Age categorical
    Units: Subjects
    Age continuous
    Male patients of age <12 years with severe (FVIII ≤1%) haemophilia A were enrolled in this trial.
    Units: years
        arithmetic mean (standard deviation)
    6.08 ± 2.91 -
    Gender categorical
    Male patients of age <12 years with severe (FVIII ≤1%) haemophilia A were enrolled in this trial.
    Units: Subjects
        Female
    0 0
        Male
    63 63

    End points

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    End points reporting groups
    Reporting group title
    All subjects treated with Turoctocog Alfa
    Reporting group description
    The patients received bleeding preventive treatment with a single dose of turoctocog alfa of 25-50 IU/kg every second day or 25-60 IU/kg three times weekly. Turoctocog alfa was administered as a slow bolus i.v. injection (approximately 1-2 mL/min). Pharmacokinetic assessments were performed in at least 13 patients from each age cohort. Each patient participating in the pharmacokinetic assessments received one dose of previous factor VIII (FVIII) and one dose of turoctocog alfa.

    Primary: The incidence rate of FVIII inhibitors (≥0.6 BU/mL)

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    End point title
    The incidence rate of FVIII inhibitors (≥0.6 BU/mL) [1]
    End point description
    The incidence rate of FVIII inhibitors was calculated by having all patients with inhibitors in the nominator and including all patients with a minimum 50 exposure plus any patients with less than 50 exposures but with inhibitors in denominator.
    End point type
    Primary
    End point timeframe
    The adverse events were collected throughout the trial which corresponded to an average of 138 days per subject.
    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: A one-sided 97.5% upper confidence limit for the incidence rate of FVIII inhibitors was provided based on an exact calculation for a binomial distribution. Adequate safety with regard to inhibitors was concluded if the upper one-sided 97.5% confidence limit was below 10.7%. Result : The one-sided 97.5% upper confidence limit for the inhibitor incidence rate of zero was 6.06%.
    End point values
    All subjects treated with Turoctocog Alfa
    Number of subjects analysed
    59
    Units: N with Inhibitors / N with ≥50 EDs
    0
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    The adverse events were collected throughout the trial, corresponding to an average of 138 days per subject.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    14.1
    Reporting groups
    Reporting group title
    All subjects treated with Turoctocog Alfa
    Reporting group description
    The patients received bleeding preventive treatment with a single dose of turoctocog alfa of 25-50 IU/kg every second day or 25-60 IU/kg three times weekly. Turoctocog alfa was administered as a slow bolus i.v. injection (approximately 1-2 mL/min). Pharmacokinetic assessments were performed in at least 13 patients from each age cohort. Each patient participating in the pharmacokinetic assessments received one dose of previous factor VIII (FVIII) and one dose of turoctocog alfa.

    Serious adverse events
    All subjects treated with Turoctocog Alfa
    Total subjects affected by serious adverse events
         subjects affected / exposed
    3 / 63 (4.76%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Injury, poisoning and procedural complications
    Soft tissue injury
         subjects affected / exposed
    1 / 63 (1.59%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Device related infection
         subjects affected / exposed
    1 / 63 (1.59%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastroenteritis viral
         subjects affected / exposed
    1 / 63 (1.59%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    All subjects treated with Turoctocog Alfa
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    14 / 63 (22.22%)
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    4 / 63 (6.35%)
         occurrences all number
    4
    Nervous system disorders
    Headache
         subjects affected / exposed
    4 / 63 (6.35%)
         occurrences all number
    5
    Gastrointestinal disorders
    Vomiting
         subjects affected / exposed
    4 / 63 (6.35%)
         occurrences all number
    4
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    5 / 63 (7.94%)
         occurrences all number
    6
    Upper respiratory tract infection
         subjects affected / exposed
    5 / 63 (7.94%)
         occurrences all number
    5

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? No

    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.
    Not applicable
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