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    Clinical Trial Results:
    A Multi-Centre Trial Evaluating Efficacy and Safety of Prophylactic Administration of Concizumab in Patients with Severe Haemophilia A without Inhibitors

    Summary
    EudraCT number
    2016-000614-29
    Trial protocol
    SE   DE   ES   FR   GB   IT  
    Global end of trial date
    03 Jun 2020

    Results information
    Results version number
    v1(current)
    This version publication date
    20 Jun 2021
    First version publication date
    20 Jun 2021
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    NN7415-4255
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT03196297
    WHO universal trial number (UTN)
    U1111-1179-3872
    Other trial identifiers
    Japanese trial registration number: JapicCTI-173682
    Sponsors
    Sponsor organisation name
    Novo Nordisk A/S
    Sponsor organisation address
    Novo Allé, Bagsvaerd, Denmark, 2880
    Public contact
    Clinical Transparency and Medical Writing (1452), Novo Nordisk A/S, clinicaltrials@novonordisk.com
    Scientific contact
    Clinical Transparency and Medical Writing (1452), Novo Nordisk A/S, clinicaltrials@novonordisk.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    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
    08 Jan 2021
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    22 Jun 2018
    Global end of trial reached?
    Yes
    Global end of trial date
    03 Jun 2020
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The main objective of the trial was to assess the efficacy of concizumab administered subcutaneously (s.c.) once daily in preventing bleeding episodes in patients with severe haemophilia A without inhibitors.
    Protection of trial subjects
    The trial was conducted in accordance with the Declaration of Helsinki (64th World Medical Association [WMA] 2013) and The International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) Good Clinical Practice, including archiving of essential documents (2016), and Food and Drug Administration (FDA) 21 Code of Federal Regulations (CFR) 312.120.
    Background therapy
    Not applicable
    Evidence for comparator
    Not applicable
    Actual start date of recruitment
    16 Aug 2017
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    France: 3
    Country: Number of subjects enrolled
    Germany: 6
    Country: Number of subjects enrolled
    Italy: 1
    Country: Number of subjects enrolled
    Spain: 3
    Country: Number of subjects enrolled
    Sweden: 2
    Country: Number of subjects enrolled
    United Kingdom: 4
    Country: Number of subjects enrolled
    Ukraine: 2
    Country: Number of subjects enrolled
    Thailand: 2
    Country: Number of subjects enrolled
    Turkey: 4
    Country: Number of subjects enrolled
    Japan: 4
    Country: Number of subjects enrolled
    United States: 5
    Worldwide total number of subjects
    36
    EEA total number of subjects
    15
    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)
    0
    Adults (18-64 years)
    34
    From 65 to 84 years
    2
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    The trial was conducted at 26 sites in 11 countries: France(3), Germany(2), Italy(1), Japan(3), Spain(3), Sweden(2), Thailand(1), Turkey(3), the United Kingdom(4), Ukraine(1) and the United States(3). In addition, 5 sites were approved by the IRB/IEC and/or local health authority but did not screen or assign any participants to treatment.

    Pre-assignment
    Screening details
    The trial consisted of two treatment periods: main part which lasted at least 24 weeks for all participants in the trial and an extension part which was up to 102 weeks.

    Period 1
    Period 1 title
    Main part
    Is this the baseline period?
    Yes
    Allocation method
    Not applicable
    Blinding used
    Not blinded

    Arms
    Arm title
    Concizumab- Main part
    Arm description
    Subjects were to receive subcutaneous (s.c.) injection of concizumab once daily for at least 24 weeks. The initial dose was 0.15 milligrams per kilogram (mg/kg) and then the dose was escalated to 0.20 and 0.25 mg/kg based on the number of spontaneous bleeding episodes. Breakthrough bleeding episodes occurring to the participants during the trial were treated with turoctocog at home.
    Arm type
    Experimental

    Investigational medicinal product name
    Concizumab B 100 mg/mL
    Investigational medicinal product code
    Other name
    concizumab
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subjects were to receive a s.c. injection of concizumab once daily. At the first treatment visit (week 0) concizumab was administered at the trial site supervised by medically trained trial staff. After visit 2, the subject self administered concizumab daily preferably at the same time in the morning, at home.

    Number of subjects in period 1
    Concizumab- Main part
    Started
    36
    Full Analysis set (FAS)
    36
    Subject analysis set (SAS)
    36
    Completed
    32
    Not completed
    4
         Consent withdrawn by subject
    4
    Period 2
    Period 2 title
    Extension part
    Is this the baseline period?
    No
    Allocation method
    Not applicable
    Blinding used
    Not blinded

    Arms
    Arm title
    Concizumab- Extension part
    Arm description
    Patients continued the extension phase at the same dose of concizumab once daily they have reached at the end of main part for 52-102 weeks with the potential dose escalation based on the number of spontaneous bleeding episodes. Breakthrough bleeding episodes occurring to the patients during the trial were treated with turoctocog at home.
    Arm type
    Experimental

    Investigational medicinal product name
    Concizumab B 100 mg/mL
    Investigational medicinal product code
    Other name
    concizumab
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subjects who received concizumab during the main part were to continue with their treatment at last dose by the end of main part with s.c. injection of concizumab once daily for 52-102 weeks with the potential dose escalation based on the number of spontaneous bleeding episodes.

    Number of subjects in period 2
    Concizumab- Extension part
    Started
    32
    FAS
    32
    SAS
    32
    Completed
    29
    Not completed
    3
         Consent withdrawn by subject
    1
         Lack of efficacy
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Concizumab- Main part
    Reporting group description
    Subjects were to receive subcutaneous (s.c.) injection of concizumab once daily for at least 24 weeks. The initial dose was 0.15 milligrams per kilogram (mg/kg) and then the dose was escalated to 0.20 and 0.25 mg/kg based on the number of spontaneous bleeding episodes. Breakthrough bleeding episodes occurring to the participants during the trial were treated with turoctocog at home.

    Reporting group values
    Concizumab- Main part Total
    Number of subjects
    36 36
    Age Categorical
    Units:
    Age Continuous
    Full analysis set (FAS) included all randomised subjects.
    Units: years
        arithmetic mean (standard deviation)
    36.9 ( 12.9 ) -
    Gender Categorical
    Units: Subjects
        Female
    0 0
        Male
    36 36

    End points

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    End points reporting groups
    Reporting group title
    Concizumab- Main part
    Reporting group description
    Subjects were to receive subcutaneous (s.c.) injection of concizumab once daily for at least 24 weeks. The initial dose was 0.15 milligrams per kilogram (mg/kg) and then the dose was escalated to 0.20 and 0.25 mg/kg based on the number of spontaneous bleeding episodes. Breakthrough bleeding episodes occurring to the participants during the trial were treated with turoctocog at home.
    Reporting group title
    Concizumab- Extension part
    Reporting group description
    Patients continued the extension phase at the same dose of concizumab once daily they have reached at the end of main part for 52-102 weeks with the potential dose escalation based on the number of spontaneous bleeding episodes. Breakthrough bleeding episodes occurring to the patients during the trial were treated with turoctocog at home.

    Subject analysis set title
    Concizumab 0.15 mg/kg- Main part
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Participants received s.c. injection of 0.15 mg/kg concizumab once daily for at least 24 weeks. Breakthrough bleeding episodes occurring to the participants during the trial were treated with turoctocog at home.

    Subject analysis set title
    Concizumab 0.20 mg/kg- Main part
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Participants received s.c. injection of concizumab once daily for at least 24 weeks. The initial dose was 0.15 mg/kg which was then escalated to 0.20 mg/kg based on the number of spontaneous bleeding episodes. Breakthrough bleeding episodes occurring to the participants during the trial were treated with turoctocog at home.

    Subject analysis set title
    Concizumab 0.25 mg/kg- Main part
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Participants received s.c. injection of concizumab once daily for at least 24 weeks. The initial dose was 0.15 mg/kg which was then escalated 0.25 mg/kg based on the number of spontaneous bleeding episodes. Breakthrough bleeding episodes occurring to the participants during the trial were treated with turoctocog at home.

    Primary: The number of bleeding episodes

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    End point title
    The number of bleeding episodes [1]
    End point description
    The number of bleeding episodes that were treated during at least 24 weeks from treatment onset are presented. The data is presented while on last dose level when the bleed occurred. Results are based on the FAS which included all randomised subjects.
    End point type
    Primary
    End point timeframe
    During at least 24 weeks from treatment onset
    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 was evaluated using descriptive statistics. Thus, no statistical analysis was performed.
    End point values
    Concizumab 0.15 mg/kg- Main part Concizumab 0.20 mg/kg- Main part Concizumab 0.25 mg/kg- Main part
    Number of subjects analysed
    21
    7
    8
    Units: Episodes
    43
    13
    14
    No statistical analyses for this end point

    Secondary: The number of spontaneous bleeding episodes

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    End point title
    The number of spontaneous bleeding episodes
    End point description
    Bleeds that were not linked to a specific, known action or event are called spontaneous bleeding episodes. The number of spontaneous bleeding episodes that were treated during at least 24 weeks from treatment onset are presented. The data is presented while on last dose level when the bleed occurred. Results are based on the FAS which included all randomised subjects.
    End point type
    Secondary
    End point timeframe
    During at least 24 weeks from treatment onset
    End point values
    Concizumab 0.15 mg/kg- Main part Concizumab 0.20 mg/kg- Main part Concizumab 0.25 mg/kg- Main part
    Number of subjects analysed
    21
    7
    8
    Units: episodes
    16
    8
    2
    No statistical analyses for this end point

    Secondary: The number of treatment emergent adverse events (TEAEs)

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    End point title
    The number of treatment emergent adverse events (TEAEs)
    End point description
    An adverse event (AE) was any untoward medical occurrence in a subject administered a medicinal product, and which does not necessarily had a causal relationship with this treatment. A TEAE was defined as an event that had onset from the first exposure to treatment until the last visit in the trial. Number of TEAEs that occurred during at least 24 weeks from treatment onset (week 0) are presented. The data is presented per dose level subjects were on at the time of onset of the adverse event. Results are based on the safety analysis set (SAS) which included all randomised subjects.
    End point type
    Secondary
    End point timeframe
    During at least 24 weeks from treatment onset
    End point values
    Concizumab 0.15 mg/kg- Main part Concizumab 0.20 mg/kg- Main part Concizumab 0.25 mg/kg- Main part
    Number of subjects analysed
    36
    15
    8
    Units: events
    105
    16
    9
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From start of study drug administration (week 0) up to 134 weeks. All presented adverse events are treatment emergent adverse events (TEAEs). TEAE is an event that had onset from the first exposure to treatment until the last visit in the trial.
    Adverse event reporting additional description
    Results are based on the safety analysis set which included all dosed subjects. The data is presented per dose level subjects were on at the time of onset of the adverse event. MedDRA versions 21.0 and 22.1 were used for the main and extension phases respectively.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    22
    Reporting groups
    Reporting group title
    Concizumab 0.15 mg/kg - Main part
    Reporting group description
    Subjects received s.c. injection of 0.15 mg/kg concizumab once daily for 24 weeks. Breakthrough bleeding episodes occurring to the subjects during the trial were treated with turoctocog at home.

    Reporting group title
    Concizumab 0.20 mg/kg - Main part
    Reporting group description
    Subjects received s.c. injection of concizumab once daily for 24 weeks. The initial dose was 0.15 mg/kg which was then escalated to 0.20 mg/kg based on the number of spontaneous bleeding episodes. Breakthrough bleeding episodes occurring to the subjects during the trial were treated with turoctocog at home.

    Reporting group title
    Concizumab 0.25 mg/kg - Main part
    Reporting group description
    Subjects received s.c. injection of concizumab once daily for 24 weeks. The initial dose was 0.15 mg/kg which was then escalated to 0.20 and 0.25 mg/kg based on the number of spontaneous bleeding episodes. Breakthrough bleeding episodes occurring to the subjects during the trial were treated with turoctocog at home.

    Reporting group title
    Concizumab 0.15 mg/kg - Extension part
    Reporting group description
    Subjects were to receive s.c. injection of 0.15 mg/kg of concizumab once daily. Subjects who completed the main part (24 weeks) of the study were continued the same dose regimen for concizumab once daily for 52-102 weeks with the potential dose escalation based on the number of spontaneous bleeding episodes. Breakthrough bleeding episodes occurring to the subjects during the trial were treated with turoctocog at home

    Reporting group title
    Concizumab 0.20 mg/kg - Extension part
    Reporting group description
    Subjects were to receive s.c. injection of concizumab once daily. Subjects who completed the main part (24 weeks) of the study were continued the same dose regimen for concizumab once daily for 52-102 weeks. The initial dose was 0.15 mg/kg which was then escalated to 0.20 mg/kg based on the number of spontaneous bleeding episodes. Breakthrough bleeding episodes occurring to the subjects during the trial were treated with turoctocog at home.

    Reporting group title
    Concizumab 0.25 mg/kg - Extension part
    Reporting group description
    Subjects were to receive s.c. injection of concizumab once daily. Subjects who completed the main part (24 weeks) of the study were continued the same dose regimen for concizumab once daily for 52-102 weeks. The initial dose was 0.15 mg/kg which was then escalated to 0.25 mg/kg based on the number of spontaneous bleeding episodes. Breakthrough bleeding episodes occurring to the subjects during the trial were treated with turoctocog at home.

    Serious adverse events
    Concizumab 0.15 mg/kg - Main part Concizumab 0.20 mg/kg - Main part Concizumab 0.25 mg/kg - Main part Concizumab 0.15 mg/kg - Extension part Concizumab 0.20 mg/kg - Extension part Concizumab 0.25 mg/kg - Extension part
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 15 (0.00%)
    0 / 8 (0.00%)
    2 / 19 (10.53%)
    1 / 14 (7.14%)
    2 / 10 (20.00%)
         number of deaths (all causes)
    0
    0
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    0
    0
    Injury, poisoning and procedural complications
    Ligament sprain
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 15 (0.00%)
    0 / 8 (0.00%)
    0 / 19 (0.00%)
    1 / 14 (7.14%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 15 (0.00%)
    0 / 8 (0.00%)
    0 / 19 (0.00%)
    0 / 14 (0.00%)
    1 / 10 (10.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pharyngeal haemorrhage
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 15 (0.00%)
    0 / 8 (0.00%)
    1 / 19 (5.26%)
    0 / 14 (0.00%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Atypical pneumonia
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 15 (0.00%)
    0 / 8 (0.00%)
    0 / 19 (0.00%)
    0 / 14 (0.00%)
    1 / 10 (10.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal infection
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 15 (0.00%)
    0 / 8 (0.00%)
    1 / 19 (5.26%)
    0 / 14 (0.00%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Concizumab 0.15 mg/kg - Main part Concizumab 0.20 mg/kg - Main part Concizumab 0.25 mg/kg - Main part Concizumab 0.15 mg/kg - Extension part Concizumab 0.20 mg/kg - Extension part Concizumab 0.25 mg/kg - Extension part
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    26 / 36 (72.22%)
    7 / 15 (46.67%)
    3 / 8 (37.50%)
    16 / 19 (84.21%)
    9 / 14 (64.29%)
    7 / 10 (70.00%)
    Surgical and medical procedures
    Tooth repair
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 15 (0.00%)
    0 / 8 (0.00%)
    1 / 19 (5.26%)
    0 / 14 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    General disorders and administration site conditions
    Exercise tolerance decreased
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 15 (0.00%)
    0 / 8 (0.00%)
    1 / 19 (5.26%)
    0 / 14 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Granuloma
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 15 (0.00%)
    0 / 8 (0.00%)
    1 / 19 (5.26%)
    0 / 14 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Influenza like illness
         subjects affected / exposed
    2 / 36 (5.56%)
    0 / 15 (0.00%)
    0 / 8 (0.00%)
    0 / 19 (0.00%)
    0 / 14 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    2
    0
    0
    0
    0
    0
    Injection site bruising
         subjects affected / exposed
    5 / 36 (13.89%)
    0 / 15 (0.00%)
    0 / 8 (0.00%)
    1 / 19 (5.26%)
    0 / 14 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    8
    0
    0
    2
    0
    0
    Injection site haematoma
         subjects affected / exposed
    4 / 36 (11.11%)
    0 / 15 (0.00%)
    0 / 8 (0.00%)
    1 / 19 (5.26%)
    0 / 14 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    5
    0
    0
    2
    0
    0
    Injection site haemorrhage
         subjects affected / exposed
    3 / 36 (8.33%)
    0 / 15 (0.00%)
    0 / 8 (0.00%)
    0 / 19 (0.00%)
    1 / 14 (7.14%)
    1 / 10 (10.00%)
         occurrences all number
    6
    0
    0
    0
    1
    1
    Injection site induration
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 15 (6.67%)
    0 / 8 (0.00%)
    0 / 19 (0.00%)
    0 / 14 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Injection site pruritus
         subjects affected / exposed
    2 / 36 (5.56%)
    0 / 15 (0.00%)
    0 / 8 (0.00%)
    0 / 19 (0.00%)
    0 / 14 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    2
    0
    0
    0
    0
    0
    Pyrexia
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 15 (6.67%)
    0 / 8 (0.00%)
    0 / 19 (0.00%)
    2 / 14 (14.29%)
    1 / 10 (10.00%)
         occurrences all number
    0
    1
    0
    0
    2
    1
    Respiratory, thoracic and mediastinal disorders
    Catarrh
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 15 (0.00%)
    0 / 8 (0.00%)
    1 / 19 (5.26%)
    0 / 14 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Cough
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 15 (0.00%)
    0 / 8 (0.00%)
    2 / 19 (10.53%)
    0 / 14 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    0
    2
    0
    1
    Haemoptysis
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 15 (0.00%)
    0 / 8 (0.00%)
    1 / 19 (5.26%)
    0 / 14 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Oropharyngeal pain
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 15 (6.67%)
    0 / 8 (0.00%)
    1 / 19 (5.26%)
    0 / 14 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    1
    0
    1
    0
    3
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 15 (0.00%)
    0 / 8 (0.00%)
    1 / 19 (5.26%)
    0 / 14 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Product issues
    Device physical property issue
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 15 (0.00%)
    0 / 8 (0.00%)
    1 / 19 (5.26%)
    0 / 14 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Investigations
    Activated partial thromboplastin time prolonged
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 15 (0.00%)
    1 / 8 (12.50%)
    0 / 19 (0.00%)
    0 / 14 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Antithrombin III decreased
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 15 (0.00%)
    0 / 8 (0.00%)
    0 / 19 (0.00%)
    1 / 14 (7.14%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    0
    0
    2
    0
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 15 (0.00%)
    0 / 8 (0.00%)
    1 / 19 (5.26%)
    0 / 14 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Basophil count increased
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 15 (0.00%)
    0 / 8 (0.00%)
    0 / 19 (0.00%)
    1 / 14 (7.14%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Blood bilirubin increased
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 15 (0.00%)
    0 / 8 (0.00%)
    1 / 19 (5.26%)
    0 / 14 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Blood fibrinogen decreased
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 15 (0.00%)
    0 / 8 (0.00%)
    0 / 19 (0.00%)
    0 / 14 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    C-reactive protein increased
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 15 (0.00%)
    0 / 8 (0.00%)
    1 / 19 (5.26%)
    0 / 14 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Fibrin D dimer increased
         subjects affected / exposed
    3 / 36 (8.33%)
    2 / 15 (13.33%)
    2 / 8 (25.00%)
    1 / 19 (5.26%)
    1 / 14 (7.14%)
    2 / 10 (20.00%)
         occurrences all number
    4
    2
    2
    1
    1
    2
    Hepatic enzyme increased
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 15 (0.00%)
    0 / 8 (0.00%)
    0 / 19 (0.00%)
    1 / 14 (7.14%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Platelet count decreased
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 15 (0.00%)
    1 / 8 (12.50%)
    0 / 19 (0.00%)
    0 / 14 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Prothrombin fragment 1.2 increased
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 15 (0.00%)
    0 / 8 (0.00%)
    0 / 19 (0.00%)
    1 / 14 (7.14%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Prothrombin level increased
         subjects affected / exposed
    3 / 36 (8.33%)
    2 / 15 (13.33%)
    2 / 8 (25.00%)
    0 / 19 (0.00%)
    0 / 14 (0.00%)
    2 / 10 (20.00%)
         occurrences all number
    4
    2
    3
    0
    0
    3
    Soluble fibrin monomer complex increased
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 15 (0.00%)
    0 / 8 (0.00%)
    0 / 19 (0.00%)
    1 / 14 (7.14%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Thrombin-antithrombin III complex increased
         subjects affected / exposed
    2 / 36 (5.56%)
    0 / 15 (0.00%)
    0 / 8 (0.00%)
    1 / 19 (5.26%)
    0 / 14 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    3
    0
    0
    2
    0
    0
    Vitamin D decreased
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 15 (0.00%)
    0 / 8 (0.00%)
    1 / 19 (5.26%)
    0 / 14 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    1 / 36 (2.78%)
    1 / 15 (6.67%)
    0 / 8 (0.00%)
    0 / 19 (0.00%)
    0 / 14 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    1
    1
    0
    0
    0
    7
    Fall
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 15 (0.00%)
    0 / 8 (0.00%)
    0 / 19 (0.00%)
    2 / 14 (14.29%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    0
    0
    2
    0
    Ligament sprain
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 15 (6.67%)
    0 / 8 (0.00%)
    0 / 19 (0.00%)
    0 / 14 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    1
    0
    0
    0
    1
    Limb injury
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 15 (0.00%)
    0 / 8 (0.00%)
    1 / 19 (5.26%)
    0 / 14 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    0
    2
    0
    0
    Muscle rupture
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 15 (0.00%)
    0 / 8 (0.00%)
    1 / 19 (5.26%)
    0 / 14 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Radius fracture
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 15 (0.00%)
    0 / 8 (0.00%)
    0 / 19 (0.00%)
    1 / 14 (7.14%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Skin injury
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 15 (0.00%)
    0 / 8 (0.00%)
    1 / 19 (5.26%)
    0 / 14 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Tooth fracture
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 15 (0.00%)
    0 / 8 (0.00%)
    1 / 19 (5.26%)
    0 / 14 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    0
    2
    0
    0
    Cardiac disorders
    Palpitations
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 15 (0.00%)
    0 / 8 (0.00%)
    1 / 19 (5.26%)
    0 / 14 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Nervous system disorders
    Headache
         subjects affected / exposed
    7 / 36 (19.44%)
    1 / 15 (6.67%)
    0 / 8 (0.00%)
    2 / 19 (10.53%)
    1 / 14 (7.14%)
    0 / 10 (0.00%)
         occurrences all number
    7
    1
    0
    3
    1
    0
    Presyncope
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 15 (6.67%)
    0 / 8 (0.00%)
    0 / 19 (0.00%)
    1 / 14 (7.14%)
    0 / 10 (0.00%)
         occurrences all number
    0
    1
    0
    0
    1
    0
    Blood and lymphatic system disorders
    Thrombocytopenia
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 15 (0.00%)
    0 / 8 (0.00%)
    0 / 19 (0.00%)
    0 / 14 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Eye disorders
    Pinguecula
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 15 (0.00%)
    0 / 8 (0.00%)
    1 / 19 (5.26%)
    0 / 14 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Retinal detachment
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 15 (0.00%)
    0 / 8 (0.00%)
    1 / 19 (5.26%)
    0 / 14 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 15 (0.00%)
    0 / 8 (0.00%)
    1 / 19 (5.26%)
    0 / 14 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Abdominal pain lower
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 15 (0.00%)
    0 / 8 (0.00%)
    1 / 19 (5.26%)
    0 / 14 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Anal fistula
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 15 (0.00%)
    0 / 8 (0.00%)
    0 / 19 (0.00%)
    0 / 14 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Chronic gastritis
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 15 (0.00%)
    0 / 8 (0.00%)
    2 / 19 (10.53%)
    0 / 14 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    0
    2
    0
    0
    Dental caries
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 15 (0.00%)
    0 / 8 (0.00%)
    1 / 19 (5.26%)
    1 / 14 (7.14%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    0
    1
    4
    1
    Diarrhoea
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 15 (0.00%)
    0 / 8 (0.00%)
    1 / 19 (5.26%)
    0 / 14 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Gastric polyps
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 15 (0.00%)
    0 / 8 (0.00%)
    1 / 19 (5.26%)
    0 / 14 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Lip discolouration
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 15 (0.00%)
    0 / 8 (0.00%)
    0 / 19 (0.00%)
    0 / 14 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Mallory-Weiss syndrome
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 15 (0.00%)
    0 / 8 (0.00%)
    1 / 19 (5.26%)
    0 / 14 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Toothache
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 15 (6.67%)
    0 / 8 (0.00%)
    0 / 19 (0.00%)
    0 / 14 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Vomiting
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 15 (0.00%)
    0 / 8 (0.00%)
    1 / 19 (5.26%)
    0 / 14 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Skin and subcutaneous tissue disorders
    Angioedema
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 15 (0.00%)
    0 / 8 (0.00%)
    0 / 19 (0.00%)
    1 / 14 (7.14%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Blister
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 15 (0.00%)
    0 / 8 (0.00%)
    1 / 19 (5.26%)
    0 / 14 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Hyperkeratosis
         subjects affected / exposed
    1 / 36 (2.78%)
    0 / 15 (0.00%)
    0 / 8 (0.00%)
    0 / 19 (0.00%)
    0 / 14 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    1
    0
    0
    0
    0
    1
    Penile ulceration
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 15 (0.00%)
    0 / 8 (0.00%)
    1 / 19 (5.26%)
    0 / 14 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Pruritus
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 15 (0.00%)
    0 / 8 (0.00%)
    1 / 19 (5.26%)
    0 / 14 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Rash
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 15 (0.00%)
    0 / 8 (0.00%)
    1 / 19 (5.26%)
    0 / 14 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Urticaria
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 15 (0.00%)
    0 / 8 (0.00%)
    0 / 19 (0.00%)
    1 / 14 (7.14%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Renal and urinary disorders
    Crystalluria
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 15 (0.00%)
    0 / 8 (0.00%)
    1 / 19 (5.26%)
    0 / 14 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Haematuria
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 15 (0.00%)
    0 / 8 (0.00%)
    1 / 19 (5.26%)
    0 / 14 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    1 / 36 (2.78%)
    0 / 15 (0.00%)
    1 / 8 (12.50%)
    0 / 19 (0.00%)
    2 / 14 (14.29%)
    1 / 10 (10.00%)
         occurrences all number
    1
    0
    1
    0
    2
    2
    Arthropathy
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 15 (6.67%)
    0 / 8 (0.00%)
    0 / 19 (0.00%)
    0 / 14 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Back pain
         subjects affected / exposed
    4 / 36 (11.11%)
    0 / 15 (0.00%)
    0 / 8 (0.00%)
    1 / 19 (5.26%)
    2 / 14 (14.29%)
    0 / 10 (0.00%)
         occurrences all number
    4
    0
    0
    1
    2
    0
    Groin pain
         subjects affected / exposed
    1 / 36 (2.78%)
    0 / 15 (0.00%)
    1 / 8 (12.50%)
    0 / 19 (0.00%)
    0 / 14 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    2
    0
    1
    0
    0
    0
    Haemophilic arthropathy
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 15 (6.67%)
    0 / 8 (0.00%)
    1 / 19 (5.26%)
    0 / 14 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    1
    0
    2
    0
    0
    Muscle spasms
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 15 (0.00%)
    0 / 8 (0.00%)
    1 / 19 (5.26%)
    0 / 14 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Muscle tightness
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 15 (0.00%)
    0 / 8 (0.00%)
    1 / 19 (5.26%)
    0 / 14 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Musculoskeletal chest pain
         subjects affected / exposed
    1 / 36 (2.78%)
    0 / 15 (0.00%)
    0 / 8 (0.00%)
    1 / 19 (5.26%)
    0 / 14 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    0
    2
    0
    0
    Musculoskeletal pain
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 15 (0.00%)
    0 / 8 (0.00%)
    0 / 19 (0.00%)
    1 / 14 (7.14%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Myalgia
         subjects affected / exposed
    1 / 36 (2.78%)
    0 / 15 (0.00%)
    0 / 8 (0.00%)
    0 / 19 (0.00%)
    1 / 14 (7.14%)
    0 / 10 (0.00%)
         occurrences all number
    2
    0
    0
    0
    1
    0
    Neck pain
         subjects affected / exposed
    1 / 36 (2.78%)
    0 / 15 (0.00%)
    0 / 8 (0.00%)
    1 / 19 (5.26%)
    0 / 14 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    0
    8
    0
    0
    Infections and infestations
    Conjunctivitis
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 15 (0.00%)
    1 / 8 (12.50%)
    0 / 19 (0.00%)
    0 / 14 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Fungal skin infection
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 15 (0.00%)
    0 / 8 (0.00%)
    1 / 19 (5.26%)
    0 / 14 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Gastroenteritis viral
         subjects affected / exposed
    1 / 36 (2.78%)
    0 / 15 (0.00%)
    0 / 8 (0.00%)
    0 / 19 (0.00%)
    1 / 14 (7.14%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    0
    0
    1
    0
    Gastrointestinal infection
         subjects affected / exposed
    1 / 36 (2.78%)
    0 / 15 (0.00%)
    0 / 8 (0.00%)
    1 / 19 (5.26%)
    0 / 14 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    0
    1
    0
    0
    Gingivitis
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 15 (0.00%)
    0 / 8 (0.00%)
    0 / 19 (0.00%)
    0 / 14 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Influenza
         subjects affected / exposed
    1 / 36 (2.78%)
    0 / 15 (0.00%)
    0 / 8 (0.00%)
    2 / 19 (10.53%)
    1 / 14 (7.14%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    0
    2
    1
    0
    Laryngitis
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 15 (0.00%)
    0 / 8 (0.00%)
    1 / 19 (5.26%)
    0 / 14 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Nasopharyngitis
         subjects affected / exposed
    9 / 36 (25.00%)
    1 / 15 (6.67%)
    0 / 8 (0.00%)
    6 / 19 (31.58%)
    1 / 14 (7.14%)
    0 / 10 (0.00%)
         occurrences all number
    11
    1
    0
    8
    1
    0
    Otitis externa
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 15 (6.67%)
    0 / 8 (0.00%)
    0 / 19 (0.00%)
    0 / 14 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Periodontitis
         subjects affected / exposed
    1 / 36 (2.78%)
    0 / 15 (0.00%)
    0 / 8 (0.00%)
    1 / 19 (5.26%)
    0 / 14 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    0
    1
    0
    0
    Pharyngitis
         subjects affected / exposed
    1 / 36 (2.78%)
    0 / 15 (0.00%)
    0 / 8 (0.00%)
    1 / 19 (5.26%)
    0 / 14 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    1
    0
    0
    1
    0
    1
    Pyoderma
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 15 (0.00%)
    0 / 8 (0.00%)
    1 / 19 (5.26%)
    0 / 14 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Respiratory tract infection
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 15 (0.00%)
    0 / 8 (0.00%)
    1 / 19 (5.26%)
    0 / 14 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Rhinitis
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 15 (0.00%)
    0 / 8 (0.00%)
    2 / 19 (10.53%)
    0 / 14 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    0
    2
    0
    0
    Tooth abscess
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 15 (0.00%)
    0 / 8 (0.00%)
    0 / 19 (0.00%)
    1 / 14 (7.14%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Upper respiratory tract infection
         subjects affected / exposed
    2 / 36 (5.56%)
    0 / 15 (0.00%)
    0 / 8 (0.00%)
    1 / 19 (5.26%)
    2 / 14 (14.29%)
    1 / 10 (10.00%)
         occurrences all number
    2
    0
    0
    2
    2
    1
    Metabolism and nutrition disorders
    Diabetes mellitus
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 15 (6.67%)
    0 / 8 (0.00%)
    0 / 19 (0.00%)
    0 / 14 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Type 2 diabetes mellitus
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 15 (0.00%)
    0 / 8 (0.00%)
    2 / 19 (10.53%)
    0 / 14 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    0
    2
    0
    0

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    08 Jun 2017
    This protocol amendment was prepared to address VHP1081 requirements to clarify individual discontinuation criteria, holding rules for the trial and protocol deviations in order to improve safety and rights of the patients.
    20 Oct 2017
    This protocol amendment was prepared to obtain 24 hours pharmacokinetic (PK)-profile under daily dosing with concizumab after initiation of multiple dosing.
    02 Mar 2018
    This protocol amendment was finalised to prolong the extension part of trial ensuring additional safety data and providing the option for the patients to be enrolled into a subsequent trial if eligible. Furthermore, patients who permanently prematurely discontinue trial product due to a safety concern can now be followed after completion of visit 17 (end of trial) by unscheduled visits until Last Patient Last Visit (LPLV) ( global).

    Interruptions (globally)

    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    16 Mar 2020
    The decision to pause the trial was a result of the occurrence of non-fatal thrombotic events in three patients enrolled in the ongoing phase 3 programme. The trial was completed as planned.
    -

    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/31444162
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