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    Clinical Trial Results:
    An open-label exploratory Phase II study of the safety and prophylactic effect of a weekly 50 U/kg rC1INH treatment in asymptomatic patients with hereditary C1INH deficiency (HAE)

    Summary
    EudraCT number
    2009-010736-18
    Trial protocol
    HU  
    Global end of trial date
    19 Apr 2010

    Results information
    Results version number
    v1(current)
    This version publication date
    26 Sep 2018
    First version publication date
    26 Sep 2018
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    C1 1207
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT00851409
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Pharming Technologies BV
    Sponsor organisation address
    Darwinweg 24, Leiden, Netherlands, 2333CR
    Public contact
    Anurag Relan, MD, Pharming Technologies BV, +31 715247400, medical-information@pharming.com
    Scientific contact
    Anurag Relan, MD, Pharming Technologies BV, +31 715247400, medical-information@pharming.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
    19 Apr 2010
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    19 Apr 2010
    Global end of trial reached?
    Yes
    Global end of trial date
    19 Apr 2010
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the occurrence of HAE attacks under prophylactic administration of rhC1INH (50 U/kg, once a week)
    Protection of trial subjects
    Breakthrough angioedema acute attacks were allowed to be treated with rhC1INH at 50 U/kg with the provision of a second 50 U/kg dose. The maximum allowed total number of rhC1INH administrations within this study was 15 per patient. For the purpose of this study, patients were recruited in 3 Phases. The study commenced with the simultaneous recruitment of 4 patients (Phase 1). Safety Laboratory Data from the 4th treatment visit was analyzed for clinically significant abnormalities. If no safety problems were identified in the Phase 1 patients, the next 4 patients (Phase 2) started. Safety Laboratory Data from the last treatment visit from the Phase 1 patients along with Safety Laboratory Data from the 4th treatment visit from Phase 2 patients were analyzed for clinically significant abnormalities. If no safety problems were identified in the Phase 1 and Phase 2 patients, then the last 17 patients (Phase 3) were able to start.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    26 Aug 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
    Israel: 7
    Country: Number of subjects enrolled
    Romania: 10
    Country: Number of subjects enrolled
    Poland: 8
    Worldwide total number of subjects
    25
    EEA total number of subjects
    18
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    24
    From 65 to 84 years
    1
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    Twenty-five patients from five countries (Italy, Hungary, Romania, Poland and Israel) with a confirmed HAE diagnosis, of at least 18 years old (men and women) were planned to be included in the study.

    Pre-assignment
    Screening details
    Confirmed diagnosis of HAE with baseline plasma level of functional C1 INH activity of less than 50% of normal, and/or proven HAE mutation in C1INH gene and occurrence of HAE attacks at least fortnight. In total: 25 screened, 25 eligible, 25 treated and 24 completed patients, from Israel, Romania and Poland.

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

    Arms
    Arm title
    Treatment period
    Arm description
    -
    Arm type
    Experimental

    Investigational medicinal product name
    Recombinant Human C1 Inhibitor
    Investigational medicinal product code
    rhC1INH
    Other name
    Pharmaceutical forms
    Powder for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    rhC1INH at 50 U/kg

    Number of subjects in period 1
    Treatment period
    Started
    25
    Completed
    25
    Period 2
    Period 2 title
    Follow up
    Is this the baseline period?
    No
    Allocation method
    Not applicable
    Blinding used
    Not blinded

    Arms
    Arm title
    Follow up
    Arm description
    After the last treatment patients were followed up for 42 days. One study visit took place 7 days after the last study treatment and one visit 42 days after last study treatment.
    Arm type
    No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 2
    Follow up
    Started
    25
    Completed
    24
    Not completed
    1
         Adverse event, serious fatal
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Treatment period
    Reporting group description
    -

    Reporting group values
    Treatment period Total
    Number of subjects
    25 25
    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)
    0 0
        Adolescents (12-17 years)
    0 0
        Adults (18-64 years)
    24 24
        From 65-84 years
    1 1
        85 years and over
    0 0
    Age continuous
    Units: years
        median (standard deviation)
    37.9 ± 13.4 -
    Gender categorical
    Units: Subjects
        Female
    20 20
        Male
    5 5

    End points

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    End points reporting groups
    Reporting group title
    Treatment period
    Reporting group description
    -
    Reporting group title
    Follow up
    Reporting group description
    After the last treatment patients were followed up for 42 days. One study visit took place 7 days after the last study treatment and one visit 42 days after last study treatment.

    Primary: Incidence of documented HAE attacks during treatment period

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    End point title
    Incidence of documented HAE attacks during treatment period [1]
    End point description
    End point type
    Primary
    End point timeframe
    8 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: As this was an open-label single arm study, no statistical analyses could be provided. The pre defined endpoint was the number of HAE attacks during the treatment period. No comparison has been against a control or placebo group, so therefore no statistical analyses could be presented.
    End point values
    Treatment period
    Number of subjects analysed
    25
    Units: Amount of attacks
        arithmetic mean (standard deviation)
    3.3 ± 2.8
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    All treatment emergent adverse events have been listed, including any events that happened in the follow up period.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    13
    Reporting groups
    Reporting group title
    Treatment phase
    Reporting group description
    Administrations of rhC1INH were given once weekly over an 8-week period.

    Serious adverse events
    Treatment phase
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 25 (8.00%)
         number of deaths (all causes)
    1
         number of deaths resulting from adverse events
    1
    Respiratory, thoracic and mediastinal disorders
    Laryncheal edema
         subjects affected / exposed
    1 / 25 (4.00%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    1 / 1
    Infections and infestations
    Appendicitis
         subjects affected / exposed
    1 / 25 (4.00%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 4%
    Non-serious adverse events
    Treatment phase
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    10 / 25 (40.00%)
    Vascular disorders
    Hypotension
         subjects affected / exposed
    1 / 25 (4.00%)
         occurrences all number
    1
    Investigations
    White blood cell count increased
         subjects affected / exposed
    1 / 25 (4.00%)
         occurrences all number
    1
    Respiratory, thoracic and mediastinal disorders
    Laryngeal oedema
         subjects affected / exposed
    1 / 25 (4.00%)
         occurrences all number
    1
    Blood and lymphatic system disorders
    Anemia
         subjects affected / exposed
    2 / 25 (8.00%)
         occurrences all number
    2
    Nervous system disorders
    Headache
         subjects affected / exposed
    1 / 25 (4.00%)
         occurrences all number
    1
    Migraine
         subjects affected / exposed
    1 / 25 (4.00%)
         occurrences all number
    1
    Dizziness
         subjects affected / exposed
    1 / 25 (4.00%)
         occurrences all number
    1
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    1 / 25 (4.00%)
         occurrences all number
    1
    Gastrointestinal disorders
    Abdominal pain upper
         subjects affected / exposed
    1 / 25 (4.00%)
         occurrences all number
    1
    Diarrhoea
         subjects affected / exposed
    1 / 25 (4.00%)
         occurrences all number
    1
    Dry mouth
         subjects affected / exposed
    1 / 25 (4.00%)
         occurrences all number
    1
    Reproductive system and breast disorders
    Cervical polyp
         subjects affected / exposed
    1 / 25 (4.00%)
         occurrences all number
    1
    Vaginal haemorrhage
         subjects affected / exposed
    1 / 25 (4.00%)
         occurrences all number
    1
    Skin and subcutaneous tissue disorders
    Pruritus
         subjects affected / exposed
    1 / 25 (4.00%)
         occurrences all number
    1
    Musculoskeletal and connective tissue disorders
    Arthritis
         subjects affected / exposed
    1 / 25 (4.00%)
         occurrences all number
    1
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    2 / 25 (8.00%)
         occurrences all number
    2
    Tooth infection
         subjects affected / exposed
    2 / 25 (8.00%)
         occurrences all number
    2
    Upper respiratory tract infection
         subjects affected / exposed
    4 / 25 (16.00%)
         occurrences all number
    4
    Appendicitis
         subjects affected / exposed
    1 / 25 (4.00%)
         occurrences all number
    1
    Cervicitis
         subjects affected / exposed
    1 / 25 (4.00%)
         occurrences all number
    1
    Tooth abscess
         subjects affected / exposed
    1 / 25 (4.00%)
         occurrences all number
    1

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    24 Sep 2009
    This amendment is written to make the protocol more clear and to rectify any discrepancies in the text body or between the text body and appendix. Also to reflect changes that occurred in the time between the first final protocol and this amendment 1.
    10 Dec 2009
    This amendment was written to clarify the methodology for immunology testing. To avoid inconsistencies, the body text needed adaptation in some points.

    Interruptions (globally)

    Were there any global interruptions to the trial? No

    Limitations and caveats

    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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