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    Clinical Trial Results:
    An Open-label, Multi-centre, Un-controlled Trial to Assess Efficacy and Safety of NNC-0156-0000-0009 during Surgical Procedures in Patients with Haemophilia B.

    Summary
    EudraCT number
    2010-023070-40
    Trial protocol
    FR   GB   NL   DE   IT   ES   GR   AT  
    Global end of trial date
    02 Dec 2013

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

    Trial information

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    Trial identification
    Sponsor protocol code
    NN7999-3773
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01386528
    WHO universal trial number (UTN)
    U1111-1121-4554
    Sponsors
    Sponsor organisation name
    Novo Nordisk A/S
    Sponsor organisation address
    Novo Allé, Bagsvaerd, Denmark, 2860
    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-000731-PIP01-09
    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
    27 May 2014
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    02 Dec 2013
    Global end of trial reached?
    Yes
    Global end of trial date
    02 Dec 2013
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the haemostatic effect of nonacog beta pegol (N9-GP) during surgical procedures in patients with haemophilia B.
    Protection of trial subjects
    The trial was conducted in accordance with the Declaration of Helsinki (Seoul, October 2008), the 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
    08 Jun 2012
    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
    United Kingdom: 2
    Country: Number of subjects enrolled
    Italy: 1
    Country: Number of subjects enrolled
    Romania: 1
    Country: Number of subjects enrolled
    Malaysia: 2
    Country: Number of subjects enrolled
    South Africa: 2
    Country: Number of subjects enrolled
    Taiwan: 1
    Country: Number of subjects enrolled
    Turkey: 1
    Country: Number of subjects enrolled
    United States: 3
    Worldwide total number of subjects
    13
    EEA total number of subjects
    4
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    1
    Adults (18-64 years)
    12
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    The 10 sites in 8 countries enrolled patients: Italy (1 site), Malaysia (1 site), Romania (1 site), South Africa (1 site), Taiwan (1 site), Turkey (1 site), UK (2 sites), US (2 sites).

    Pre-assignment
    Screening details
    Patients enrolled in the present trial could be recruited from the pivotal trial (NN7999-3747) or the extension trial (NN7999-3775). In addition, new patients could also be recruited into the present trial.

    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
    Arm title
    nonacog beta pegol
    Arm description
    New patients as well as transferred patients from the pivotal trial (NN7999-3747) or the extension trial (NN7999-3775) received nonacog beta pegol at screening and followed a preventive treatment regimen with nonacog beta pegol until one week before the day of surgery. No more than 4 hours prior to the planned surgical procedure, all patients received a single bolus injection of 80 U/kg of nonacog beta pegol. Postoperatively, the patients received fixed doses of 40 U/kg repeated at the investigator’s discretion aiming for no less than the FIX levels recommended by the World Federation of Hemophilia. Nonacog beta pegol was administered intravenously (into the vein).
    Arm type
    Experimental

    Investigational medicinal product name
    nonacog beta pegol (N9-GP)
    Investigational medicinal product code
    NNC 0156-0000-009
    Other name
    Pharmaceutical forms
    Powder for solution for injection, Solvent for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    The new patients were dosed once with 40 U/kg nonacog beta pegol at screening. The FIX (coagulation factor 9) activity after 30 minutes at this visit, was used to determine if dose adjustments were necessary during the peri-operative period. For patients who had been on prophylaxis with 40 U/kg in the preceding trial, the most recent FIX activity level 30 minutes post-dose was used instead. All patients received a pre-operative dose of nonacog beta pegol 15 minutes to 4 hours prior to the surgery and before any procedures were undertaken including anaesthesia. The pre-operative dose was a single bolus injection of 80 U/kg. It was recommended to give a dose of 40 U/kg 24-48 hours after the pre-operative dose depending on the desired FIX activity level. From the day after surgery (Day 1) and through Day 6, nonacog beta pegol dosing was adjusted to aim for a FIX activity level of approximately 0.50 U/mL.

    Number of subjects in period 1
    nonacog beta pegol
    Started
    13
    Completed
    13

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Overall Study
    Reporting group description
    The demographics and baseline characteristics are presented for the full analysis set (FAS) which included all patients exposed to nonacog beta pegol.

    Reporting group values
    Overall Study Total
    Number of subjects
    13 13
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        median (full range (min-max))
    39 (15 to 56) -
    Gender categorical
    Units: Subjects
        Female
    0 0
        Male
    13 13

    End points

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    End points reporting groups
    Reporting group title
    nonacog beta pegol
    Reporting group description
    New patients as well as transferred patients from the pivotal trial (NN7999-3747) or the extension trial (NN7999-3775) received nonacog beta pegol at screening and followed a preventive treatment regimen with nonacog beta pegol until one week before the day of surgery. No more than 4 hours prior to the planned surgical procedure, all patients received a single bolus injection of 80 U/kg of nonacog beta pegol. Postoperatively, the patients received fixed doses of 40 U/kg repeated at the investigator’s discretion aiming for no less than the FIX levels recommended by the World Federation of Hemophilia. Nonacog beta pegol was administered intravenously (into the vein).

    Primary: Haemostatic effect during surgery evaluated by the four-point response scale, assessed by the investigator/surgeon at the day of surgery − Four-point response scale: Excellent, good, moderate, poor.

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    End point title
    Haemostatic effect during surgery evaluated by the four-point response scale, assessed by the investigator/surgeon at the day of surgery − Four-point response scale: Excellent, good, moderate, poor. [1]
    End point description
    Haemostatic effect during surgery was evaluated immediately after surgery (last stitch) using a four-point response scale: – Four-point response scale: Excellent, good, moderate, poor. The evaluation was done by the surgeon, anaesthesiologist and/or investigator based on experience as follows: 1. Excellent: Better than expected/predicted in this type of procedure. 2. Good: As expected in this type of procedure. 3. Moderate: Less than optimal for the type of procedure but haemostatic response maintained without change of treatment regimen. 4. Poor: Bleeding due to inadequate therapeutic response with adequate dosing, change of regimen required.
    End point type
    Primary
    End point timeframe
    During surgery (assessed immediately after surgery (last stitch)).
    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: Endpoint is summarised as well as listed. No statistical analyses were planned for this endpoint.
    End point values
    nonacog beta pegol
    Number of subjects analysed
    13
    Units: Frequency
    number (not applicable)
        Excellent
    10
        Good
    3
        Moderate
    0
        Poor
    0
    No statistical analyses for this end point

    Secondary: Consumption of N9-GP (U/kg BW) during surgery and post-operative period

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    End point title
    Consumption of N9-GP (U/kg BW) during surgery and post-operative period
    End point description
    Mean consumption of nonacog beta pegol (U/kg) used for treatment per patient before surgery, during surgery (the time from knife to skin until last stitch) and post-operative period.
    End point type
    Secondary
    End point timeframe
    Before surgery is defined as the time from the patient entered the trial until the surgery. During surgery is defined as the time from knife to skin until last stitch. The post-operative period is defined as the time from Day 1 to Day 13
    End point values
    nonacog beta pegol
    Number of subjects analysed
    13
    Units: U/Kg
    arithmetic mean (standard deviation)
        Consumption used for treatment per patient
    328.2 ± 113.1
    No statistical analyses for this end point

    Secondary: Transfusion requirements (fulfilling transfusion criteria) during surgery and the post-operative

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    End point title
    Transfusion requirements (fulfilling transfusion criteria) during surgery and the post-operative
    End point description
    Mean quantity of transfusion during surgery (the time from knife to skin until last stitch) and the post-operative period (Day 1-13).
    End point type
    Secondary
    End point timeframe
    During surgery is defined as the time from knife to skin until last stitch. The post-operative period is defined as the time from Day 1 to Day 13.
    End point values
    nonacog beta pegol
    Number of subjects analysed
    13 [2]
    Units: mL
    arithmetic mean (standard deviation)
        During surgery
    275 ± 35.4
        Post operative period (Days 1-6)
    266.7 ± 28.9
    Notes
    [2] - Only 2 patients received transfusions.
    No statistical analyses for this end point

    Secondary: Haemoglobin pre and post surgery start (0, 1h, 24 h)

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    End point title
    Haemoglobin pre and post surgery start (0, 1h, 24 h)
    End point description
    The mean pre-surgery and post surgery haemoglobin level.
    End point type
    Secondary
    End point timeframe
    Prior to surgery and post surgery start (0, 1h, 24 h)
    End point values
    nonacog beta pegol
    Number of subjects analysed
    13 [3]
    Units: mmol/L
    arithmetic mean (standard deviation)
        Prior to surgery
    8.98 ± 0.67
        1 hour post-surgery
    8.37 ± 0.78
        24 hours post-surgery
    7.99 ± 1.13
    Notes
    [3] - 10 and 12 subjects contributed to the analysis during 1 hour and 24 hour post-surgery respectively.
    No statistical analyses for this end point

    Secondary: Haemoglobin post surgery start - every 24 hours in the post-operative period.

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    End point title
    Haemoglobin post surgery start - every 24 hours in the post-operative period.
    End point description
    Mean haemoglobin level, every 24 hours in the post-operative period.
    End point type
    Secondary
    End point timeframe
    Every 24 hours in the post-operative period.
    End point values
    nonacog beta pegol
    Number of subjects analysed
    0 [4]
    Units: mmol/L
        arithmetic mean (standard deviation)
    ±
    Notes
    [4] - Patients could be discharged on Day 3 and so Hb could not be measured every 24 hrs post surgery.
    No statistical analyses for this end point

    Secondary: AE and SAEs reported during the trial period until the last visit.

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    End point title
    AE and SAEs reported during the trial period until the last visit.
    End point description
    The number of adverse events and serious adverse events per patient years of exposure, reported during the trial period.
    End point type
    Secondary
    End point timeframe
    Adverse events from the first trial related activity after the patient had signed the informed consent and until post treatment follow-up period.
    End point values
    nonacog beta pegol
    Number of subjects analysed
    13
    Units: Events per patient year of exposure
    number (not applicable)
        Adverse events
    12.12
        Serious adverse events
    0
    No statistical analyses for this end point

    Secondary: Incidence of inhibitors against FIX (≥0.6 BU) until the last visit

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    End point title
    Incidence of inhibitors against FIX (≥0.6 BU) until the last visit
    End point description
    Number of patients with inhibitory antibodies.
    End point type
    Secondary
    End point timeframe
    During the trial from screening until last visit. The last visit is defined as the end of trial visit if the patient continues in the extension trial and as the follow-up visit if the patient does not continue in the extension trial.
    End point values
    nonacog beta pegol
    Number of subjects analysed
    13
    Units: Number of patients
    0
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    AEs from screening visit (day 0) and until post treatment follow-up period. Patients not continuing in the extension trial attended a follow-up visit 4 weeks ± 2 weeks after the last dose of nonacog beta pegol.
    Adverse event reporting additional description
    The safety analysis set consists of all patients exposed to nonacog beta pegol.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    unknown
    Reporting groups
    Reporting group title
    Nonacog beta pegol
    Reporting group description
    New patients as well as transferred patients from Paradigm™ 2 (NN7999-3747) or Paradigm™ 4 (NN7999-3775) trials received nonacog beta pegol at screening, just prior to and during surgical intervention, administered intravenously (into the vein).

    Serious adverse events
    Nonacog beta pegol
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 13 (0.00%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Nonacog beta pegol
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    9 / 13 (69.23%)
    Vascular disorders
    Haemorrhage
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    1
    Hypertension
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    1
    Injury, poisoning and procedural complications
    Excoriation
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    1
    Fall
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    1
    Investigations
    Serum ferritin increased
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    1
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    1
    Eye disorders
    Conjunctival haemorrhage
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    1
    General disorders and administration site conditions
    Face oedema
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    1
    Pyrexia
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    1
    Gastrointestinal disorders
    Epigastric discomfort
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    1
    Nausea
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    1
    Oral mucosal erythema
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    1
    Vomiting
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    1
    Skin and subcutaneous tissue disorders
    Pruritus
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    1
    Musculoskeletal and connective tissue disorders
    Musculoskeletal discomfort
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    1
    Pain in extremity
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    1

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    10 Jan 2012
    Linguistic revision to one of the stopping rules. In addition, the protocol was amended on some operational issues and inconsistencies.
    11 May 2012
    Changes in the visual appearance of the trial product. Information on stop time of bleeding episode. Information on number of months on on-demand treatment. Information on screening of antibodies.
    02 Jan 2013
    The following countries were added to the list of participating countries: Austria, Greece, Latvia, Lithuania and Romania.

    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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