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    Clinical Trial Results:
    A Multi-Centre, Open-Label, Single-Arm and Multiple Dosing Trial on Efficacy and Safety of Monthly Replacement Therapy with Recombinant Factor XIII (rFXIII) in Subjects with Congenital Factor XIII Deficiency.

    Summary
    EudraCT number
    2006-003148-51
    Trial protocol
    GB   FR   DE   AT   ES   FI   IT  
    Global end of trial date
    15 Apr 2010

    Results information
    Results version number
    v1
    This version publication date
    16 Mar 2016
    First version publication date
    21 Jul 2015
    Other versions
    v2

    Trial information

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    Trial identification
    Sponsor protocol code
    F13CD-1725
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT00713648
    WHO universal trial number (UTN)
    -
    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-000185-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
    17 Nov 2010
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    15 Apr 2010
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the efficacy of monthly replacement therapy with rFXIII on prevention of bleeding episodes in subjects with congenital FXIII deficiency.
    Protection of trial subjects
    The trial was conducted in accordance with the Declaration of Helsinki and ICH Good Clinical Practice.
    Background therapy
    Subjects who had received regular replacement therapy before entering the trial, were to have initiated this treatment at least 6 months prior to screening.
    Evidence for comparator
    Not applicable.
    Actual start date of recruitment
    18 Aug 2008
    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
    Spain: 2
    Country: Number of subjects enrolled
    United Kingdom: 5
    Country: Number of subjects enrolled
    Austria: 1
    Country: Number of subjects enrolled
    Finland: 2
    Country: Number of subjects enrolled
    France: 1
    Country: Number of subjects enrolled
    Germany: 6
    Country: Number of subjects enrolled
    Italy: 1
    Country: Number of subjects enrolled
    Canada: 3
    Country: Number of subjects enrolled
    Israel: 8
    Country: Number of subjects enrolled
    United States: 10
    Country: Number of subjects enrolled
    Switzerland: 2
    Worldwide total number of subjects
    41
    EEA total number of subjects
    18
    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)
    9
    Adolescents (12-17 years)
    6
    Adults (18-64 years)
    26
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    Of a total of 29 initiated trial sites, 23 sites enrolled and dosed at least one patient. The country distribution was (number of actively recruiting sites per country in parenthesis): Austria (1), Canada (1), Finland (1), France (1), Germany (3), Israel (2), Italy (1), Spain (1), Switzerland (1), UK (3) and United States of America (8).

    Pre-assignment
    Screening details
    After screening, eligible subjects entered a 4-week run-in period followed by a 52-week recombinant factor XIII (rFXIII) treatment period. Subjects who before entering the trial were receiving regular replacement therapy with a FXIII-containing product were to receive their last standard replacement dose just before the screening visit.

    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
    rFXIII
    Arm description
    Subjects received 35 IU/kg rFXIII every 4th week (28±2 days) during a treatment period of 52 weeks. In case of acute bleeding episodes, any additional treatment as per investigator judgment was to be according to local standard practice. Additional doses of rFXIII could therefore not be used to treat such breakthrough bleedings.
    Arm type
    Experimental

    Investigational medicinal product name
    Recombinant Factor XIII
    Investigational medicinal product code
    F13CD
    Other name
    Coagulation factor XIII
    Pharmaceutical forms
    Powder for solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Monthly administration of recombinant factor XIII as preventative treatment of bleeding episodes. Dose: 35 IU/kg body weight intravenous (into the vein).

    Number of subjects in period 1
    rFXIII
    Started
    41
    Completed
    33
    Not completed
    8
         Other Reason
    2
         Non-Neutralising Antibodies
    3
         Adverse event, non-fatal
    1
         Withdrawal Criteria
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    rFXIII
    Reporting group description
    Subjects received 35 IU/kg rFXIII every 4th week (28±2 days) during a treatment period of 52 weeks. In case of acute bleeding episodes, any additional treatment as per investigator judgment was to be according to local standard practice. Additional doses of rFXIII could therefore not be used to treat such breakthrough bleedings.

    Reporting group values
    rFXIII Total
    Number of subjects
    41 41
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    26.4 ± 15.9 -
    Gender categorical
    Units: Subjects
        Female
    18 18
        Male
    23 23
    Race
    Units: Subjects
        Black or African American
    2 2
        White
    28 28
        Asian
    5 5
        Other
    5 5
        Unknown
    1 1

    End points

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    End points reporting groups
    Reporting group title
    rFXIII
    Reporting group description
    Subjects received 35 IU/kg rFXIII every 4th week (28±2 days) during a treatment period of 52 weeks. In case of acute bleeding episodes, any additional treatment as per investigator judgment was to be according to local standard practice. Additional doses of rFXIII could therefore not be used to treat such breakthrough bleedings.

    Primary: Rate (Number Per Subject Year) of Bleeding Episodes Requiring Treatment With a FXIII Containing Product During the Treatment Period

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    End point title
    Rate (Number Per Subject Year) of Bleeding Episodes Requiring Treatment With a FXIII Containing Product During the Treatment Period [1]
    End point description
    The rate (Number Per Subject Year) of bleeding episodes represents the incidence of bleeding episodes requiring treatment with a FXIII-containing product.
    End point type
    Primary
    End point timeframe
    For a period of 322 days (approximately one year) comprised of a screening visit (Visit 1), treatment period (Visits 2-15), unscheduled visit and end-of-trial visit (Visit 16).
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: The low bleeding incidence and frequency for patients currently on regular replacement therapy (on average approximately 0.3 bleeds/year) and the low number of patients diagnosed with congenital FXIII deficiency (400-700 patients worldwide) did not allow a statistical comparison of clinical outcome parameters (bleeding events) between rFXIII and any other type of regular replacement therapy with sufficient statistical power.
    End point values
    rFXIII
    Number of subjects analysed
    41
    Units: bleeding episodes per subject per year
        arithmetic mean (full range (min-max))
    0.138 (0 to 2)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events (AEs) were collected and reported during the entire study period i.e. approximately one year (322 days)
    Adverse event reporting additional description
    All AEs observed by the investigator or reported spontaneously by the subjects, were recorded by the investigator at each contact with the site (visit or telephone, excluding safety visits, where the subject was not seeing the Investigator or his staff (e.g.visits to the laboratory))
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    13.0
    Reporting groups
    Reporting group title
    rFXIII
    Reporting group description
    Subjects received 35 IU/kg rFXIII every 4th week (28±2 days) during a treatment period of 52 weeks. In case of acute bleeding episodes, any additional treatment as per investigator judgment was to be according to local standard practice. Additional doses of rFXIII could therefore not be used to treat such breakthrough bleedings.

    Serious adverse events
    rFXIII
    Total subjects affected by serious adverse events
         subjects affected / exposed
    6 / 41 (14.63%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Injury, poisoning and procedural complications
    Road traffic accident
         subjects affected / exposed
    1 / 41 (2.44%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Investigations
    Antibody test positive
         subjects affected / exposed
    3 / 41 (7.32%)
         occurrences causally related to treatment / all
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    Nervous system disorders
    Headache
         subjects affected / exposed
    1 / 41 (2.44%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    General disorders and administration site conditions
    Non-cardiac chest pain
         subjects affected / exposed
    1 / 41 (2.44%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorders
    Small intestinal obstruction
         subjects affected / exposed
    1 / 41 (2.44%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Diverticulitis
         subjects affected / exposed
    1 / 41 (2.44%)
         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
    rFXIII
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    32 / 41 (78.05%)
    Injury, poisoning and procedural complications
    Excoriation
         subjects affected / exposed
    3 / 41 (7.32%)
         occurrences all number
    3
    Incorrect dose administered
         subjects affected / exposed
    4 / 41 (9.76%)
         occurrences all number
    11
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    3 / 41 (7.32%)
         occurrences all number
    4
    Nasal congestion
         subjects affected / exposed
    5 / 41 (12.20%)
         occurrences all number
    6
    Oropharyngeal pain
         subjects affected / exposed
    4 / 41 (9.76%)
         occurrences all number
    6
    Nervous system disorders
    Headache
         subjects affected / exposed
    12 / 41 (29.27%)
         occurrences all number
    21
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    7 / 41 (17.07%)
         occurrences all number
    7
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    3 / 41 (7.32%)
         occurrences all number
    3
    Toothache
         subjects affected / exposed
    3 / 41 (7.32%)
         occurrences all number
    5
    Vomiting
         subjects affected / exposed
    3 / 41 (7.32%)
         occurrences all number
    3
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    5 / 41 (12.20%)
         occurrences all number
    5
    Pain In Extremity
         subjects affected / exposed
    4 / 41 (9.76%)
         occurrences all number
    4
    Infections and infestations
    Influenza
         subjects affected / exposed
    4 / 41 (9.76%)
         occurrences all number
    4
    Nasopharyngitis
         subjects affected / exposed
    8 / 41 (19.51%)
         occurrences all number
    11
    Urinary tract infection
         subjects affected / exposed
    3 / 41 (7.32%)
         occurrences all number
    3

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    27 Jun 2008
    The FXIII genotyping will not be made again for those patients if it can be confirmed that the they have Congenital A-subunit deficiency and provided that the results can be made available to NN at screening or prior to administration of trial product. The text in the protocol and Subject Information / Informed Consent were updated accordingly. Regarding the participating countries the protocol will be updated according to the result for the country feasibility. The safety information in the protocol and SI/IC has been updated to include data from recently finalised trial F13CARD-1660. The remaining changes are editorial.
    12 Dec 2008
    A few subject selection criteria were slightly reworded or modified as described in Section 9.3. Furthermore, lack of efficacy of rFXIII (as judged by the investigator) was added as a withdrawal criterion. A sensitivity analysis for the primary endpoint excluding centres that contributed with more than 20% of the total number of subjects was specified.
    27 Jan 2009
    No major changes were implemented with this amendment, which specifies precautionary measures related to pregnancy.
    10 Jun 2009
    It was specified that if the Novo Nordisk Safety Committee decided to stop treatment of a subject with rFXIII for safety reasons, the subject could continue in the trial for continued blood and urine sampling for safety evaluation. In addition to recording of bleeding episode and adverse event details, sampling for haematology, biochemistry, urinalysis, FXIII laboratory parameters, immunology, coagulation parameters and clot solubility testing was to be performed prior to administration of standard replacement therapy.
    25 Nov 2009
    The subject information/informed consent form was slightly modified due to the fact that two additional subjects had developed non-neutralising antibodies after initiation of treatment with rFXIII.
    02 Dec 2009
    This amendment enabled further characterisation of anti-FXIII antibodies. Samples from any subjects in whom anti-FXIII antibodies had been observed following dosing with rFXIII were to be further characterised in order to determine the immunoglobulin isotype of the detected anti-rFXIII antibodies. Additionally, cross-reactivity of subject antibody to plasma-derived FXIII was to be assessed. These analyses were exploratory and were to be presented separately.

    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

    Online references

    http://www.ncbi.nlm.nih.gov/pubmed/22451421
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