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    Clinical Trial Results:
    A Multi-Centre, Open-Label, Single-Arm, and Multiple Dosing Trial on Safety of Monthly Replacement Therapy with Recombinant Factor XIII (rFXIII) in Subjects with Congenital Factor XIII Deficiency : Safety Extension Trial to F13CD-1725.

    Summary
    EudraCT number
    2008-007883-41
    Trial protocol
    FI   DE   GB   FR   ES   IT   AT  
    Global end of trial date
    20 Oct 2015

    Results information
    Results version number
    v1(current)
    This version publication date
    05 May 2016
    First version publication date
    05 May 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    F13CD-3720 (Mentor™2)
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT00978380
    WHO universal trial number (UTN)
    U1111-1111-9289
    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
    31 Mar 2016
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    20 Oct 2015
    Global end of trial reached?
    Yes
    Global end of trial date
    20 Oct 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To assess the long term safety of monthly replacement therapy with recombinant factor XIII (rFXIII) when used for prevention of bleeding episodes in subjects with congenital factor XIII (FXIII) deficiency.
    Protection of trial subjects
    The trial was conducted in accordance with the Declaration of Helsinki[World medical Association. Declaration of Helsinki: Ethical principles for medical research involving human subjects - Last amended by the 59th WMA General Assembly, Seoul. 2008. 2015.], ICH GCP [International Conference on Harmonisation. ICH Harmonised Tripartite Guideline. Good Clinical Practice. 01 May 1996. 2015.] and FDA 21 CFR 312, 50 and 56.
    Background therapy
    Previous participation (means up to and including end-of-trial visit) in F13CD-1725 (EudraCT no: 2006-003148-51).
    Evidence for comparator
    Not applicable
    Actual start date of recruitment
    21 Sep 2009
    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
    Austria: 1
    Country: Number of subjects enrolled
    Canada: 2
    Country: Number of subjects enrolled
    Finland: 3
    Country: Number of subjects enrolled
    France: 4
    Country: Number of subjects enrolled
    Germany: 9
    Country: Number of subjects enrolled
    Israel: 12
    Country: Number of subjects enrolled
    Italy: 1
    Country: Number of subjects enrolled
    Japan: 5
    Country: Number of subjects enrolled
    Spain: 3
    Country: Number of subjects enrolled
    Switzerland: 2
    Country: Number of subjects enrolled
    United Kingdom: 5
    Country: Number of subjects enrolled
    United States: 16
    Worldwide total number of subjects
    63
    EEA total number of subjects
    26
    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)
    8
    Adolescents (12-17 years)
    8
    Adults (18-64 years)
    46
    From 65 to 84 years
    1
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    The trial was conducted at 34 sites in 12 countries as follows: Austria: 1 site; Canada: 1 site; Finland: 1 site; France: 4 sites; Germany: 4 sites; Israel: 1 site; Italy: 1 site: Japan: 2 sites; Spain: 2 sites; Switzerland: 1 site; United Kingdom: 4 sites; United States: 12 sites.

    Pre-assignment
    Screening details
    Subjects who completed F13CD-1725 (EudraCT no: 2006-003148-51) end of trial visit were eligible to enroll in this trial. Also, new subjects diagnosed with congenital FXIII A-subunit deficiency (confirmed by genotyping at screening visit or documented results from previously performed genotyping) were enrolled to expand the safety population.

    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
    The trial was an open-label phase 3b trial.

    Arms
    Arm title
    Recombinant factor XIII (rFXIII)
    Arm description
    All subjects received 35 IU/kg bodyweight of rFXIII every 4 weeks (28 days±2 days) until the end of trial for a minimum period of 52 weeks. The dose was identical to the dose administered in the F13CD-1725 trial. Additional haemostatic rescue medication as per local standard of care was to be intiated in subjects with the consent of the investigator, where haemostatic control could not be achieved with a single dose of rFXIII 35 IU/kg. A total of 60 unique subjects were enrolled and exposed in the trial, but 3 of these subjects were later withdrawn and subsequently re-enrolled with new subject IDs, giving rise to a total of N=63 subjects. The unique subjects (N=60) were presented as full analysis set while summarising adverse events to avoid double-counting.
    Arm type
    Experimental

    Investigational medicinal product name
    Recombinant factor XIII (rFXIII)
    Investigational medicinal product code
    Other name
    Catridecacog
    Pharmaceutical forms
    Powder and solvent for solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Monthly administration of recombinant factor XIII (rFXIII) as preventative treatment of bleeding episodes of dose: 35 IU/kg body weight intravenous (into the vein). Sterile, freeze-dried powder rFXIII was reconstituted with 3.2 mL of sterile water for injection at room temperature. The solution was administered by syringe as a slow bolus injection at a rate not higher than 1−2 mL/minute within 6 hours after reconstitution. The correct dosing was calculated and adjusted based on the actual weight of the subject.

    Number of subjects in period 1
    Recombinant factor XIII (rFXIII)
    Started
    63
    Completed
    44
    Not completed
    19
         Protocol deviation
    2
         withdrawal criteria
    9
         Unclassified
    8

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Recombinant factor XIII (rFXIII)
    Reporting group description
    All subjects received 35 IU/kg bodyweight of rFXIII every 4 weeks (28 days±2 days) until the end of trial for a minimum period of 52 weeks. The dose was identical to the dose administered in the F13CD-1725 trial. Additional haemostatic rescue medication as per local standard of care was to be intiated in subjects with the consent of the investigator, where haemostatic control could not be achieved with a single dose of rFXIII 35 IU/kg. A total of 60 unique subjects were enrolled and exposed in the trial, but 3 of these subjects were later withdrawn and subsequently re-enrolled with new subject IDs, giving rise to a total of N=63 subjects. The unique subjects (N=60) were presented as full analysis set while summarising adverse events to avoid double-counting.

    Reporting group values
    Recombinant factor XIII (rFXIII) Total
    Number of subjects
    63 63
    Age categorical
    Units: Subjects
        In utero
    0 0
        Preterm newborn infants (gestational age < 37 wks)
    0 0
        Newborns (0-27 days)
    0 0
        Infants and toddlers (28 days-23 months)
    0 0
        Children (2-11 years)
    8 8
        Adolescents (12-17 years)
    8 8
        Adults (18-64 years)
    46 46
        From 65-84 years
    1 1
        85 years and over
    0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    31 ± 16.8 -
    Gender categorical
    Units: Subjects
        Female
    23 23
        Male
    40 40
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    7 7
        Not Hispanic or Latino
    52 52
        Unknown
    4 4
    Race
    Units: Subjects
        Black or African American
    6 6
        American Indian or Alaska Native
    1 1
        White
    37 37
        Asian
    9 9
        Other
    6 6
        Unknown
    4 4

    End points

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    End points reporting groups
    Reporting group title
    Recombinant factor XIII (rFXIII)
    Reporting group description
    All subjects received 35 IU/kg bodyweight of rFXIII every 4 weeks (28 days±2 days) until the end of trial for a minimum period of 52 weeks. The dose was identical to the dose administered in the F13CD-1725 trial. Additional haemostatic rescue medication as per local standard of care was to be intiated in subjects with the consent of the investigator, where haemostatic control could not be achieved with a single dose of rFXIII 35 IU/kg. A total of 60 unique subjects were enrolled and exposed in the trial, but 3 of these subjects were later withdrawn and subsequently re-enrolled with new subject IDs, giving rise to a total of N=63 subjects. The unique subjects (N=60) were presented as full analysis set while summarising adverse events to avoid double-counting.

    Primary: Adverse events (serious and non-serious) occurring from first trial related activity after signing the informed consent to the end of subject’s participation in the trial

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    End point title
    Adverse events (serious and non-serious) occurring from first trial related activity after signing the informed consent to the end of subject’s participation in the trial [1]
    End point description
    An adverse events (AEs) was defined as any unfavourable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. Trial AEs included any event that occurred from the time of informed consent until the post-treatment followup period as specified in the protocol.
    End point type
    Primary
    End point timeframe
    All adverse events were collected and reported from screening (visit 1) and until the end of trial visit for a minimum period of 52 weeks.
    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 primary endpoint investigated safety and was analysed using descriptive statistics, and thus no statistical analysis was performed.
    End point values
    Recombinant factor XIII (rFXIII)
    Number of subjects analysed
    60
    Units: Events
        All adverse events
    920
        Serious adverse events
    19
        Non-serious adverse events
    901
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    All adverse events (AEs) were collected and reported from screening (visit 1) and until the end of trial visit for a minimum period of 52 weeks.
    Adverse event reporting additional description
    All AEs either observed by the investigator or reported spontaneously by the subjects were recorded by the investigator and evaluated at each contact with the trial site (visit or telephone). The full analysis set included all subjects who received at least one dose of the trial product.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    18.1
    Reporting groups
    Reporting group title
    rFXIII Novo Nordisk
    Reporting group description
    Subjects in this arm received identical dose of 35 IU/kg bodyweight of rFXIII every 4 weeks (28 days±2 days) until the end of trial for a minimum period of 52 weeks. In the early stage of the trial, a contract manufacturing facility (Avecia) produced the rFXIII drug substance (rFXIII Avecia) and subsequently, Novo Nordisk took over production of the rFXIII drug substance (rFXIII Novo Nordisk). Characterisation testing between the two products confirmed that rFXIII Novo Nordisk and rFXIII Avecia had identical structures, and similar physico-chemical properties. The recombinant factor XIII (rFXIII) reporting group was segregated as rFXIII Novo Nordisk and rFXIII Avecia while reporting endpoints and AEs.

    Reporting group title
    rFXIII Avecia
    Reporting group description
    Subjects in this arm received 35 IU/kg bodyweight of rFXIII every 4 weeks (28 days±2 days) until the end of trial for a minimum period of 52 weeks. Early on in the trial, a contract manufacturing facility (Avecia) produced the rFXIII drug substance (rFXIII Avecia). Subsequently, Novo Nordisk took over production of the rFXIII drug substance (substance referred to as rFXIII Novo Nordisk). Characterisation testing between two products confirmed that rFXIII Novo Nordisk and rFXIII Avecia had identical structures and similar physico-chemical properties. The recombinant factor XIII (rFXIII) reporting group was segregated as rFXIII Novo Nordisk and rFXIII Avecia while reporting endpoints and AEs.

    Serious adverse events
    rFXIII Novo Nordisk rFXIII Avecia
    Total subjects affected by serious adverse events
         subjects affected / exposed
    12 / 59 (20.34%)
    0 / 26 (0.00%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Injury, poisoning and procedural complications
    Chest injury
         subjects affected / exposed
    1 / 59 (1.69%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fall
         subjects affected / exposed
    2 / 59 (3.39%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Head injury
         subjects affected / exposed
    2 / 59 (3.39%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Multiple fractures
         subjects affected / exposed
    1 / 59 (1.69%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Laceration
         subjects affected / exposed
    1 / 59 (1.69%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Road traffic accident
         subjects affected / exposed
    2 / 59 (3.39%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal cord injury
         subjects affected / exposed
    1 / 59 (1.69%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Congenital, familial and genetic disorders
    Atrial septal defect
         subjects affected / exposed
    1 / 59 (1.69%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Patent ductus arteriosus
         subjects affected / exposed
    1 / 59 (1.69%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebral ischaemia
         subjects affected / exposed
    1 / 59 (1.69%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    1 / 59 (1.69%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pregnancy, puerperium and perinatal conditions
    Ectopic pregnancy
         subjects affected / exposed
    1 / 59 (1.69%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Suicide attempt
         subjects affected / exposed
    1 / 59 (1.69%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Inguinal hernia
         subjects affected / exposed
    1 / 59 (1.69%)
    0 / 26 (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
    Diverticulitis
         subjects affected / exposed
    1 / 59 (1.69%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Otitis media chronic
         subjects affected / exposed
    1 / 59 (1.69%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    rFXIII Novo Nordisk rFXIII Avecia
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    54 / 59 (91.53%)
    15 / 26 (57.69%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    3 / 59 (5.08%)
    0 / 26 (0.00%)
         occurrences all number
    4
    0
    Immune system disorders
    Seasonal allergy
         subjects affected / exposed
    3 / 59 (5.08%)
    0 / 26 (0.00%)
         occurrences all number
    4
    0
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    3 / 59 (5.08%)
    0 / 26 (0.00%)
         occurrences all number
    3
    0
    Pain
         subjects affected / exposed
    3 / 59 (5.08%)
    0 / 26 (0.00%)
         occurrences all number
    4
    0
    Pyrexia
         subjects affected / exposed
    6 / 59 (10.17%)
    0 / 26 (0.00%)
         occurrences all number
    11
    0
    Injury, poisoning and procedural complications
    Arthropod bite
         subjects affected / exposed
    4 / 59 (6.78%)
    0 / 26 (0.00%)
         occurrences all number
    4
    0
    Contusion
         subjects affected / exposed
    11 / 59 (18.64%)
    2 / 26 (7.69%)
         occurrences all number
    18
    2
    Fall
         subjects affected / exposed
    8 / 59 (13.56%)
    1 / 26 (3.85%)
         occurrences all number
    10
    1
    Head injury
         subjects affected / exposed
    3 / 59 (5.08%)
    1 / 26 (3.85%)
         occurrences all number
    4
    1
    Incorrect dose administered
         subjects affected / exposed
    6 / 59 (10.17%)
    1 / 26 (3.85%)
         occurrences all number
    9
    1
    Injury
         subjects affected / exposed
    4 / 59 (6.78%)
    0 / 26 (0.00%)
         occurrences all number
    4
    0
    Joint injury
         subjects affected / exposed
    4 / 59 (6.78%)
    0 / 26 (0.00%)
         occurrences all number
    6
    0
    Laceration
         subjects affected / exposed
    4 / 59 (6.78%)
    1 / 26 (3.85%)
         occurrences all number
    4
    1
    Ligament sprain
         subjects affected / exposed
    6 / 59 (10.17%)
    2 / 26 (7.69%)
         occurrences all number
    9
    2
    Limb injury
         subjects affected / exposed
    5 / 59 (8.47%)
    3 / 26 (11.54%)
         occurrences all number
    8
    3
    Post-traumatic pain
         subjects affected / exposed
    3 / 59 (5.08%)
    0 / 26 (0.00%)
         occurrences all number
    4
    0
    Procedural pain
         subjects affected / exposed
    3 / 59 (5.08%)
    0 / 26 (0.00%)
         occurrences all number
    3
    0
    Road traffic accident
         subjects affected / exposed
    3 / 59 (5.08%)
    0 / 26 (0.00%)
         occurrences all number
    3
    0
    Skin abrasion
         subjects affected / exposed
    3 / 59 (5.08%)
    1 / 26 (3.85%)
         occurrences all number
    4
    1
    Thermal burn
         subjects affected / exposed
    6 / 59 (10.17%)
    2 / 26 (7.69%)
         occurrences all number
    6
    2
    Wound
         subjects affected / exposed
    2 / 59 (3.39%)
    2 / 26 (7.69%)
         occurrences all number
    2
    2
    Investigations
    White blood cells urine positive
         subjects affected / exposed
    3 / 59 (5.08%)
    0 / 26 (0.00%)
         occurrences all number
    3
    0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    4 / 59 (6.78%)
    0 / 26 (0.00%)
         occurrences all number
    6
    0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    12 / 59 (20.34%)
    0 / 26 (0.00%)
         occurrences all number
    29
    0
    Nasal congestion
         subjects affected / exposed
    7 / 59 (11.86%)
    0 / 26 (0.00%)
         occurrences all number
    20
    0
    Oropharyngeal pain
         subjects affected / exposed
    11 / 59 (18.64%)
    0 / 26 (0.00%)
         occurrences all number
    31
    0
    Rhinorrhoea
         subjects affected / exposed
    3 / 59 (5.08%)
    0 / 26 (0.00%)
         occurrences all number
    4
    0
    Nervous system disorders
    Headache
         subjects affected / exposed
    19 / 59 (32.20%)
    2 / 26 (7.69%)
         occurrences all number
    72
    4
    Ear and labyrinth disorders
    Ear pain
         subjects affected / exposed
    4 / 59 (6.78%)
    0 / 26 (0.00%)
         occurrences all number
    4
    0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    5 / 59 (8.47%)
    0 / 26 (0.00%)
         occurrences all number
    6
    0
    Constipation
         subjects affected / exposed
    5 / 59 (8.47%)
    0 / 26 (0.00%)
         occurrences all number
    5
    0
    Dental caries
         subjects affected / exposed
    3 / 59 (5.08%)
    0 / 26 (0.00%)
         occurrences all number
    4
    0
    Diarrhoea
         subjects affected / exposed
    3 / 59 (5.08%)
    1 / 26 (3.85%)
         occurrences all number
    3
    1
    Dyspepsia
         subjects affected / exposed
    6 / 59 (10.17%)
    0 / 26 (0.00%)
         occurrences all number
    14
    0
    Nausea
         subjects affected / exposed
    7 / 59 (11.86%)
    0 / 26 (0.00%)
         occurrences all number
    8
    0
    Toothache
         subjects affected / exposed
    4 / 59 (6.78%)
    0 / 26 (0.00%)
         occurrences all number
    6
    0
    Vomiting
         subjects affected / exposed
    3 / 59 (5.08%)
    0 / 26 (0.00%)
         occurrences all number
    4
    0
    Renal and urinary disorders
    Haematuria
         subjects affected / exposed
    3 / 59 (5.08%)
    1 / 26 (3.85%)
         occurrences all number
    3
    1
    Skin and subcutaneous tissue disorders
    Acne
         subjects affected / exposed
    4 / 59 (6.78%)
    0 / 26 (0.00%)
         occurrences all number
    5
    0
    Dermatitis contact
         subjects affected / exposed
    3 / 59 (5.08%)
    0 / 26 (0.00%)
         occurrences all number
    3
    0
    Pruritus
         subjects affected / exposed
    3 / 59 (5.08%)
    0 / 26 (0.00%)
         occurrences all number
    5
    0
    Rash
         subjects affected / exposed
    5 / 59 (8.47%)
    0 / 26 (0.00%)
         occurrences all number
    8
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    11 / 59 (18.64%)
    1 / 26 (3.85%)
         occurrences all number
    24
    1
    Back pain
         subjects affected / exposed
    9 / 59 (15.25%)
    2 / 26 (7.69%)
         occurrences all number
    12
    2
    Musculoskeletal pain
         subjects affected / exposed
    6 / 59 (10.17%)
    0 / 26 (0.00%)
         occurrences all number
    7
    0
    Musculoskeletal stiffness
         subjects affected / exposed
    4 / 59 (6.78%)
    0 / 26 (0.00%)
         occurrences all number
    4
    0
    Myalgia
         subjects affected / exposed
    3 / 59 (5.08%)
    0 / 26 (0.00%)
         occurrences all number
    5
    0
    Neck pain
         subjects affected / exposed
    3 / 59 (5.08%)
    1 / 26 (3.85%)
         occurrences all number
    3
    1
    Pain in extremity
         subjects affected / exposed
    12 / 59 (20.34%)
    1 / 26 (3.85%)
         occurrences all number
    32
    1
    Infections and infestations
    Folliculitis
         subjects affected / exposed
    3 / 59 (5.08%)
    0 / 26 (0.00%)
         occurrences all number
    4
    0
    Gastroenteritis
         subjects affected / exposed
    8 / 59 (13.56%)
    0 / 26 (0.00%)
         occurrences all number
    10
    0
    Influenza
         subjects affected / exposed
    7 / 59 (11.86%)
    0 / 26 (0.00%)
         occurrences all number
    8
    0
    Nasopharyngitis
         subjects affected / exposed
    19 / 59 (32.20%)
    2 / 26 (7.69%)
         occurrences all number
    48
    2
    Sinusitis
         subjects affected / exposed
    11 / 59 (18.64%)
    1 / 26 (3.85%)
         occurrences all number
    17
    1
    Tonsillitis
         subjects affected / exposed
    5 / 59 (8.47%)
    0 / 26 (0.00%)
         occurrences all number
    8
    0
    Upper respiratory tract infection
         subjects affected / exposed
    14 / 59 (23.73%)
    0 / 26 (0.00%)
         occurrences all number
    25
    0
    Viral infection
         subjects affected / exposed
    3 / 59 (5.08%)
    0 / 26 (0.00%)
         occurrences all number
    4
    0

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    24 Aug 2009
    The number of subjects who had developed non-neutralising antirFXIII antibodies in trial F13CD-1725 was modified from two to ‘a few’. As an exception, the United States (US) was excluded from this protocol amendment.
    21 Oct 2009
    Evaluation of subjects for exclusion to use platelet count from visit 15 in F13CD-1725. Added requirement that subjects who develop antibodies must visit the clinic for administration of trial product. Additional blood sampling for antibody analysis will be performed at these visits to further characterise the antibodies.
    09 Nov 2009
    Subject Information/Informed Consent updated according to the changes implemented in the protocol following Substantial Amendment no. 4, dated 21-October-2009.
    02 Dec 2009
    Allowance for additional laboratory testing when the Novo Nordisk produced rFXIII is administrated to subjects in the trial.
    16 Feb 2010
    Introduced additional blood sampling prior to all monthly rFXIII administrations (and cessation of home treatments). Instituted that interim analyses were to be performed after 3 and 6 months of exposure data with Novo Nordisk-produced rFXIII had been obtained. For Canada only: post-reconstitution in-use shelf life period of rFXIII was changed from 6 hours at room temperature and 24 hours at 2-8˚C (as currently written in consolidated protocol no. 2) to 3 hours at room temperature.
    08 Sep 2010
    Allowed all subjects who had participated in Trial F13CD-1725 (not only those who completed the study) and additional subjects with FXIII A-subunit deficiency into the extension Trial if eligible. Recruitment period was extended and the total number of subjects for inclusion increased.
    02 Sep 2011
    Allowed the central laboratory to report to the investigator additional analyses not required by the protocol but produced in connection with the requested analyses.
    22 Feb 2012
    Withdrawal criterion no. 6 “Routine treatment with any antithrombotic drug” was rephrased to allow use of antithrombotic drugs. Japan added to the list of participating countries and text related to Japan’s participation updated. Number of visits until end-of-trial increased from 16 to 24.
    14 May 2012
    Steady-state PK assessment added as well as offer to treat with rFXIII in case of treatment-requiring breakthrough bleeding. The conditions for treatment with rFXIII in relation to treatment requiring bleeding episodes were specified.

    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.
    Limitations of the trial include small number of children and adolescents (16 subjects), and the sensitivity of the Berichrome® FXIII activity assay. However, mean FXIII activity levels were consistent with few bleeds requiring haemostatic treatment.
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