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    Clinical Trial Results:
    A Multi-Centre, Randomised, Open-Label, Controlled Trial Evaluating the Efficacy and Safety of Prophylactic Administration of Concizumab in Haemophilia A and B Patients with Inhibitors

    Summary
    EudraCT number
    2016-000510-30
    Trial protocol
    SE   DK   GB   GR   ES   AT   HR   IT  
    Global end of trial date
    31 Jan 2020

    Results information
    Results version number
    v1(current)
    This version publication date
    14 Feb 2021
    First version publication date
    14 Feb 2021
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    NN7415-4310
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT03196284
    WHO universal trial number (UTN)
    U1111-1179-2925
    Other trial identifiers
    Japanese trial registration number: JapicCTI-173681
    Sponsors
    Sponsor organisation name
    Novo Nordisk A/S
    Sponsor organisation address
    Novo Allé, Bagsvaerd, Denmark, 2880
    Public contact
    Clinical Reporting Anchor and Disclosure (1452), Novo Nordisk A/S, +1 866 8677178, clinicaltrials@novonordisk.com
    Scientific contact
    Clinical Reporting Anchor and Disclosure (1452), Novo Nordisk A/S, +1 866 8677178, 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
    24 Jun 2020
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    19 Sep 2018
    Global end of trial reached?
    Yes
    Global end of trial date
    31 Jan 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 haemophilia A and B patients with inhibitors.
    Protection of trial subjects
    The trial was conducted in accordance with the Declaration of Helsinki (64th World Medical Association (WMA) 2013), International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) Good Clinical Practice, including archiving of essential documents (2016) and Code of Federal Regulations - Title 21 - Food and Drugs (FDA 21 CFR) 312.120.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    10 Aug 2017
    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: 2
    Country: Number of subjects enrolled
    Croatia: 3
    Country: Number of subjects enrolled
    Denmark: 2
    Country: Number of subjects enrolled
    Italy: 2
    Country: Number of subjects enrolled
    Spain: 4
    Country: Number of subjects enrolled
    Sweden: 1
    Country: Number of subjects enrolled
    United Kingdom: 1
    Country: Number of subjects enrolled
    Israel: 1
    Country: Number of subjects enrolled
    Malaysia: 3
    Country: Number of subjects enrolled
    Ukraine: 3
    Country: Number of subjects enrolled
    Japan: 2
    Country: Number of subjects enrolled
    United States: 2
    Worldwide total number of subjects
    26
    EEA total number of subjects
    14
    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)
    26
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    The trial was conducted at 17 sites in 12 countries as follows: Austria (1), Croatia (1), Denmark (1), Italy (2), Spain (2), Sweden (1), the United Kingdom (1), Israel (1), Malaysia (2), Ukraine (1), Japan (2) and the United States (2).

    Pre-assignment
    Screening details
    The trial consisted of two treatment periods: main part which lasted 24 weeks for participants randomised to eptacog alfa and at least 24 weeks for patients randomised to concizumab and an extension part which lasted up to 94 weeks.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Concizumab- Main part
    Arm description
    Subjects were to receive a subcutaneous (s.c.) injection of concizumab once daily for 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. A loading dose of 0.5 mg/kg was given as the first concizumab dose. A single injection of 90 micrograms per kilogram (μg/kg) eptacog alfa (rFVIIa) was administered in a non-bleeding state one week after dosing with concizumab had initiated.
    Arm type
    Experimental

    Investigational medicinal product name
    Eptacog alfa (activated)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder and solvent for solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    A single injection of 90 μg/kg eptacog alfa (rFVIIa) was administered in a non-bleeding state one week after dosing with concizumab had initiated.

    Investigational medicinal product name
    Concizumab B 100 mg/mL
    Investigational medicinal product code
    Other name
    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 for 24 weeks. The initial dose was 0.15 mg/kg and then the dose was escalated to 0.20 and 0.25 mg/kg based on the number of spontaneous bleeding episodes. A loading dose of 0.5 mg/kg was given as the first concizumab dose.

    Arm title
    Eptacog alfa- Main part
    Arm description
    Subjects were to receive eptacog alfa on-demand treatment for 24 weeks.
    Arm type
    Experimental

    Investigational medicinal product name
    Eptacog alfa (activated)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder and solvent for solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects were to receive eptacog alfa on-demand treatment for 24 weeks.

    Number of subjects in period 1
    Concizumab- Main part Eptacog alfa- Main part
    Started
    17
    9
    Completed
    17
    8
    Not completed
    0
    1
         Consent withdrawn by subject
    -
    1
    Period 2
    Period 2 title
    Extension part
    Is this the baseline period?
    No
    Allocation method
    Randomised - controlled
    Blinding used
    Not blinded

    Arms
    Arm title
    Concizumab- Extension part
    Arm description
    Subjects who completed main part treatment were to receive a s.c. injection of concizumab once daily for 52-94 weeks. Subjects who received concizumab during the main part were to continue with their treatment at last dose by the end of main part and those received eptacog alfa during the main part were to start their treatment with 0.15 mg/kg of concizumab. The dose was then escalated to 0.20 and 0.25 mg/kg based on the number of spontaneous bleeding episodes. A loading dose of 0.5 mg/kg was given as the first concizumab dose.
    Arm type
    Experimental

    Investigational medicinal product name
    Concizumab B 100 mg/mL
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subjects who completed main part treatment were to receive a s.c. injection of concizumab once daily for 52-94 weeks. Subjects who received concizumab during the main part were to continue with their treatment at last dose by the end of main part and those received eptacog alfa during the main part were to start their treatment with 0.15 mg/kg of concizumab. The dose was then escalated to 0.20 and 0.25 mg/kg based on the number of spontaneous bleeding episodes. A loading dose of 0.5 mg/kg was given as the first concizumab dose.

    Number of subjects in period 2
    Concizumab- Extension part
    Started
    25
    Completed
    22
    Not completed
    3
         Consent withdrawn by subject
    1
         Physician decision
    1
         Lack of efficacy
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Concizumab- Main part
    Reporting group description
    Subjects were to receive a subcutaneous (s.c.) injection of concizumab once daily for 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. A loading dose of 0.5 mg/kg was given as the first concizumab dose. A single injection of 90 micrograms per kilogram (μg/kg) eptacog alfa (rFVIIa) was administered in a non-bleeding state one week after dosing with concizumab had initiated.

    Reporting group title
    Eptacog alfa- Main part
    Reporting group description
    Subjects were to receive eptacog alfa on-demand treatment for 24 weeks.

    Reporting group values
    Concizumab- Main part Eptacog alfa- Main part Total
    Number of subjects
    17 9 26
    Age Categorical
    Units: Subjects
    Age Continuous
    Full analysis set (FAS) included all randomised subjects.
    Units: years
        arithmetic mean (standard deviation)
    34.1 ± 11.1 41.1 ± 15.0 -
    Gender Categorical
    Units: Subjects
        Female
    0 0 0
        Male
    17 9 26

    End points

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    End points reporting groups
    Reporting group title
    Concizumab- Main part
    Reporting group description
    Subjects were to receive a subcutaneous (s.c.) injection of concizumab once daily for 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. A loading dose of 0.5 mg/kg was given as the first concizumab dose. A single injection of 90 micrograms per kilogram (μg/kg) eptacog alfa (rFVIIa) was administered in a non-bleeding state one week after dosing with concizumab had initiated.

    Reporting group title
    Eptacog alfa- Main part
    Reporting group description
    Subjects were to receive eptacog alfa on-demand treatment for 24 weeks.
    Reporting group title
    Concizumab- Extension part
    Reporting group description
    Subjects who completed main part treatment were to receive a s.c. injection of concizumab once daily for 52-94 weeks. Subjects who received concizumab during the main part were to continue with their treatment at last dose by the end of main part and those received eptacog alfa during the main part were to start their treatment with 0.15 mg/kg of concizumab. The dose was then escalated to 0.20 and 0.25 mg/kg based on the number of spontaneous bleeding episodes. A loading dose of 0.5 mg/kg was given as the first concizumab dose.

    Subject analysis set title
    Concizumab 0.15 mg/kg- Main part
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Subjects received s.c. injection of 0.15 mg/kg concizumab once daily for 24 weeks. A loading dose of 0.5 mg/kg was given as the first concizumab dose.

    Subject analysis set title
    Concizumab 0.20 mg/kg- Main part
    Subject analysis set type
    Sub-group analysis
    Subject analysis set 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. A loading dose of 0.5 mg/kg was given as the first concizumab dose.

    Subject analysis set title
    Eptacog alfa- Main part
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Subjects were to receive eptacog alfa on-demand treatment for 24 weeks.

    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 (week 0) are presented. 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: Inferential statistics was not performed.
    End point values
    Concizumab- Main part Eptacog alfa- Main part
    Number of subjects analysed
    17
    9
    Units: Count of episodes
    47
    77
    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 (week 0) are presented. The data is presented per the last dose level which the subjects have reached at the time of assessment. 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 Eptacog alfa- Main part
    Number of subjects analysed
    15
    2
    9
    Units: Count of episodes
    19
    5
    69
    No statistical analyses for this end point

    Secondary: Number of treatment emergent adverse events (TEAEs)

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    End point title
    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 the last dose level which the subjects have reached at the time of event. Results are based on the safety analysis set (SAS) 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 Eptacog alfa- Main part
    Number of subjects analysed
    15
    2
    9
    Units: Count of events
    39
    4
    18
    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 126 weeks
    Adverse event reporting additional description
    Results are based on the safety analysis set which included all randomized subjects. All presented adverse events are treatment emergent adverse events (TEAEs). TEAE was defined as an event that had onset from the first exposure to treatment (randomisation date, in case of on-demand arm) until the last visit in the trial.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    22
    Reporting groups
    Reporting group title
    Eptacog alfa - Main part
    Reporting group description
    Subjects were to receive eptacog alfa on-demand treatment for 24 weeks.

    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. A loading dose of 0.5 mg/kg was given as the first concizumab dose.

    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. A loading dose of 0.5 mg/kg was given as the first concizumab dose.

    Reporting group title
    Concizumab 0.15 mg/kg - Extension part
    Reporting group description
    Subjects who were on treatment with concizumab once daily at the end of main part of the study continued their treatment in the extension part. Subjects who received eptacog alfa in the main part switched to treatment with concizumab in the extension part (a loading dose of 0.5 mg/kg was given as the first concizumab dose). The dose of concizumab was 0.15 mg/kg.

    Reporting group title
    Concizumab 0.20 mg/kg - Extension part
    Reporting group description
    Subjects who were on treatment with concizumab once daily at the end of main part of the study continued their treatment in the extension part. Subjects who received eptacog alfa in the main part switched to treatment with concizumab in the extension part (a loading dose of 0.5 mg/kg was given as the first concizumab dose). The initial dose of concizumab was 0.15 mg/kg which was then escalated to 0.20 mg/kg based on the number of spontaneous bleeding episodes.

    Reporting group title
    Concizumab 0.25 mg/kg - Extension part
    Reporting group description
    Subjects who were on treatment with concizumab once daily at the end of main part of the study continued their treatment in the extension part. Subjects who received eptacog alfa in the main part switched to treatment with concizumab in the extension part (a loading dose of 0.5 mg/kg was given as the first concizumab dose). The initial dose of concizumab was 0.15 mg/kg which was then escalated to 0.25 mg/kg based on the number of spontaneous bleeding episodes.

    Serious adverse events
    Eptacog alfa - Main part Concizumab 0.15 mg/kg - Main part Concizumab 0.20 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
    3 / 9 (33.33%)
    1 / 17 (5.88%)
    0 / 2 (0.00%)
    3 / 23 (13.04%)
    1 / 13 (7.69%)
    0 / 4 (0.00%)
         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
    Hand fracture
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
    1 / 23 (4.35%)
    0 / 13 (0.00%)
    0 / 4 (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
    Subdural haemorrhage
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
    1 / 23 (4.35%)
    0 / 13 (0.00%)
    0 / 4 (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
    Vascular disorders
    Shock haemorrhagic
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
    1 / 23 (4.35%)
    0 / 13 (0.00%)
    0 / 4 (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
    Surgical and medical procedures
    Central venous catheter removal
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 17 (5.88%)
    0 / 2 (0.00%)
    0 / 23 (0.00%)
    0 / 13 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Congestive cardiomyopathy
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
    0 / 23 (0.00%)
    0 / 13 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Loss of consciousness
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
    1 / 23 (4.35%)
    0 / 13 (0.00%)
    0 / 4 (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
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
    0 / 23 (0.00%)
    0 / 13 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Puncture site haemorrhage
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
    1 / 23 (4.35%)
    0 / 13 (0.00%)
    0 / 4 (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
    Respiratory, thoracic and mediastinal disorders
    Sleep apnoea syndrome
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
    0 / 23 (0.00%)
    1 / 13 (7.69%)
    0 / 4 (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
    Musculoskeletal and connective tissue disorders
    Arthropathy
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
    1 / 23 (4.35%)
    0 / 13 (0.00%)
    0 / 4 (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
    Muscle haemorrhage
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
    1 / 23 (4.35%)
    0 / 13 (0.00%)
    0 / 4 (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
    Hordeolum
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
    0 / 23 (0.00%)
    0 / 13 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    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
    Eptacog alfa - Main part Concizumab 0.15 mg/kg - Main part Concizumab 0.20 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
    7 / 9 (77.78%)
    13 / 17 (76.47%)
    2 / 2 (100.00%)
    13 / 23 (56.52%)
    9 / 13 (69.23%)
    2 / 4 (50.00%)
    Investigations
    Eosinophil count increased
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
    0 / 23 (0.00%)
    1 / 13 (7.69%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Fibrin D dimer increased
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 17 (5.88%)
    0 / 2 (0.00%)
    0 / 23 (0.00%)
    1 / 13 (7.69%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    0
    1
    0
    Prothrombin fragment 1.2 increased
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
    0 / 23 (0.00%)
    1 / 13 (7.69%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Prothrombin level increased
         subjects affected / exposed
    0 / 9 (0.00%)
    2 / 17 (11.76%)
    0 / 2 (0.00%)
    0 / 23 (0.00%)
    0 / 13 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    2
    0
    0
    0
    0
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    2 / 9 (22.22%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
    0 / 23 (0.00%)
    0 / 13 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    3
    0
    0
    0
    0
    0
    Overdose
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 17 (5.88%)
    0 / 2 (0.00%)
    0 / 23 (0.00%)
    0 / 13 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Post-traumatic pain
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 17 (5.88%)
    0 / 2 (0.00%)
    0 / 23 (0.00%)
    0 / 13 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Cardiac disorders
    Congestive cardiomyopathy
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
    0 / 23 (0.00%)
    1 / 13 (7.69%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Nervous system disorders
    Carpal tunnel syndrome
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 17 (5.88%)
    0 / 2 (0.00%)
    0 / 23 (0.00%)
    0 / 13 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Headache
         subjects affected / exposed
    0 / 9 (0.00%)
    2 / 17 (11.76%)
    0 / 2 (0.00%)
    0 / 23 (0.00%)
    0 / 13 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    2
    0
    0
    0
    0
    Ulnar nerve palsy
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
    0 / 23 (0.00%)
    0 / 13 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    General disorders and administration site conditions
    Injection site bruising
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
    2 / 23 (8.70%)
    0 / 13 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    0
    3
    0
    0
    Injection site erythema
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 17 (5.88%)
    0 / 2 (0.00%)
    0 / 23 (0.00%)
    0 / 13 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Injection site haematoma
         subjects affected / exposed
    0 / 9 (0.00%)
    3 / 17 (17.65%)
    0 / 2 (0.00%)
    1 / 23 (4.35%)
    1 / 13 (7.69%)
    0 / 4 (0.00%)
         occurrences all number
    0
    6
    0
    1
    3
    0
    Injection site haemorrhage
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 17 (5.88%)
    0 / 2 (0.00%)
    0 / 23 (0.00%)
    0 / 13 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    5
    0
    0
    0
    0
    Pyrexia
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
    1 / 23 (4.35%)
    0 / 13 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    0
    1
    0
    1
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 17 (0.00%)
    1 / 2 (50.00%)
    0 / 23 (0.00%)
    0 / 13 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Constipation
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
    1 / 23 (4.35%)
    0 / 13 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    1
    0
    0
    Dental caries
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
    0 / 23 (0.00%)
    1 / 13 (7.69%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    0
    0
    1
    1
    Diarrhoea
         subjects affected / exposed
    1 / 9 (11.11%)
    1 / 17 (5.88%)
    0 / 2 (0.00%)
    2 / 23 (8.70%)
    1 / 13 (7.69%)
    0 / 4 (0.00%)
         occurrences all number
    1
    1
    0
    3
    1
    0
    Flatulence
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
    1 / 23 (4.35%)
    0 / 13 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    1
    0
    0
    Food poisoning
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
    0 / 23 (0.00%)
    1 / 13 (7.69%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Gastritis
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
    1 / 23 (4.35%)
    1 / 13 (7.69%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    0
    1
    1
    0
    Haemorrhoids
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 17 (5.88%)
    0 / 2 (0.00%)
    0 / 23 (0.00%)
    0 / 13 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Nausea
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
    0 / 23 (0.00%)
    0 / 13 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Toothache
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 17 (5.88%)
    0 / 2 (0.00%)
    1 / 23 (4.35%)
    0 / 13 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    1
    0
    0
    Vomiting
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 17 (0.00%)
    1 / 2 (50.00%)
    1 / 23 (4.35%)
    0 / 13 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    1
    1
    0
    0
    Hepatobiliary disorders
    Hepatic cyst
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
    0 / 23 (0.00%)
    0 / 13 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Skin and subcutaneous tissue disorders
    Skin ulcer
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 17 (5.88%)
    0 / 2 (0.00%)
    0 / 23 (0.00%)
    0 / 13 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
    1 / 23 (4.35%)
    1 / 13 (7.69%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    0
    1
    1
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 17 (5.88%)
    0 / 2 (0.00%)
    2 / 23 (8.70%)
    0 / 13 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    2
    0
    0
    Groin pain
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 17 (5.88%)
    0 / 2 (0.00%)
    0 / 23 (0.00%)
    0 / 13 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Haemophilic arthropathy
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 17 (5.88%)
    0 / 2 (0.00%)
    0 / 23 (0.00%)
    0 / 13 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Osteoarthritis
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 17 (5.88%)
    0 / 2 (0.00%)
    0 / 23 (0.00%)
    0 / 13 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Osteoporosis
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 17 (5.88%)
    0 / 2 (0.00%)
    0 / 23 (0.00%)
    0 / 13 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Synovitis
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
    0 / 23 (0.00%)
    0 / 13 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    2
    0
    0
    0
    0
    0
    Infections and infestations
    Cellulitis
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
    1 / 23 (4.35%)
    0 / 13 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    1
    0
    0
    Gastroenteritis
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
    0 / 23 (0.00%)
    0 / 13 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Gastroenteritis viral
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 17 (0.00%)
    1 / 2 (50.00%)
    1 / 23 (4.35%)
    0 / 13 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    1
    1
    0
    0
    Influenza
         subjects affected / exposed
    1 / 9 (11.11%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
    0 / 23 (0.00%)
    1 / 13 (7.69%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    0
    0
    1
    0
    Nasopharyngitis
         subjects affected / exposed
    0 / 9 (0.00%)
    3 / 17 (17.65%)
    0 / 2 (0.00%)
    1 / 23 (4.35%)
    0 / 13 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    3
    0
    3
    0
    0
    Pharyngitis
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 17 (5.88%)
    1 / 2 (50.00%)
    0 / 23 (0.00%)
    0 / 13 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    1
    0
    0
    0
    Respiratory tract infection
         subjects affected / exposed
    1 / 9 (11.11%)
    1 / 17 (5.88%)
    0 / 2 (0.00%)
    0 / 23 (0.00%)
    1 / 13 (7.69%)
    0 / 4 (0.00%)
         occurrences all number
    1
    1
    0
    0
    1
    0
    Rhinitis
         subjects affected / exposed
    0 / 9 (0.00%)
    0 / 17 (0.00%)
    0 / 2 (0.00%)
    1 / 23 (4.35%)
    1 / 13 (7.69%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    0
    1
    1
    0
    Sinusitis
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 17 (5.88%)
    0 / 2 (0.00%)
    0 / 23 (0.00%)
    0 / 13 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Skin infection
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 17 (5.88%)
    0 / 2 (0.00%)
    0 / 23 (0.00%)
    0 / 13 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 9 (11.11%)
    1 / 17 (5.88%)
    0 / 2 (0.00%)
    3 / 23 (13.04%)
    1 / 13 (7.69%)
    0 / 4 (0.00%)
         occurrences all number
    1
    2
    0
    5
    1
    0
    Metabolism and nutrition disorders
    Vitamin D deficiency
         subjects affected / exposed
    0 / 9 (0.00%)
    1 / 17 (5.88%)
    0 / 2 (0.00%)
    0 / 23 (0.00%)
    0 / 13 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    29 May 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.
    22 Nov 2017
    This protocol amendment was prepared to obtain pharmacokinetic (PK)-profile of daily dosing with concizumab after initiation of multiple dosing.
    12 Sep 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).

    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/31444162
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