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    Clinical Trial Results:
    A Phase 3, Randomized, Double-Blind, Placebo-Controlled, Multicenter Clinical Study Evaluating the Safety and Efficacy of Icatibant as a Treatment for Angiotensin-Converting Enzyme Inhibitor (ACE-I)-Induced Angioedema in Adults

    Summary
    EudraCT number
    2014-001213-12
    Trial protocol
    GB  
    Global end of trial date
    22 Aug 2015

    Results information
    Results version number
    v1(current)
    This version publication date
    02 Sep 2016
    First version publication date
    02 Sep 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    HGT-FIR-096
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    -
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Shire
    Sponsor organisation address
    300 Shire Way, Lexington, Massachusetts, United States, 02421
    Public contact
    Study Physician, Shire, +1 1 866-842-5335,
    Scientific contact
    Study Physician, Shire, +1 1 866-842-5335,
    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
    22 Aug 2015
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    22 Aug 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The main objective was to compare the efficacy of icatibant with placebo in the treatment of angiotensin-converting enzyme inhibitor (ACE-I)-induced angioedema based on the time to meeting discharge criteria (TMDC) endpoint.
    Protection of trial subjects
    This study was conducted in accordance with International Conference on Harmonisation (ICH) of Good Clinical Practice, the principles of the Declaration of Helsinki, as well as other applicable local ethical and legal requirements.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    02 Dec 2013
    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
    United States: 105
    Country: Number of subjects enrolled
    Canada: 10
    Country: Number of subjects enrolled
    United Kingdom: 5
    Country: Number of subjects enrolled
    Israel: 1
    Worldwide total number of subjects
    121
    EEA total number of subjects
    5
    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)
    70
    From 65 to 84 years
    51
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    The study was conducted at 59 sites in the United States, United Kingdom, Israel and Canada.

    Pre-assignment
    Screening details
    Overall 121 subjects were randomized, of which 118 received the study medication, and 117 completed the study.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Icatibant 30 mg
    Arm description
    Subjects received a single dose of icatibant 30 milligram (mg) subcutaneous (SC) injection within 12 hours after the onset of the angiotensin-converting enzyme inhibitor (ACE-I) induced angioedema attack.
    Arm type
    Experimental

    Investigational medicinal product name
    Icatibant
    Investigational medicinal product code
    Other name
    Firazyr
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subjects received a single dose of icatibant 30 mg SC injection within 12 hours after the onset of the ACE-I induced angioedema attack.

    Arm title
    Placebo
    Arm description
    Subjects received a single dose of placebo matched to icatibant SC injection within 12 hours after the onset of the ACE-I induced angioedema attack.
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subjects received a single dose of placebo matched to icatibant 30 mg SC injection within 12 hours after the onset of the ACE-I induced angioedema attack.

    Number of subjects in period 1
    Icatibant 30 mg Placebo
    Started
    61
    60
    Completed
    60
    57
    Not completed
    1
    3
         Physician decision
    -
    1
         Unspecified
    -
    1
         Consent withdrawn by subject
    1
    -
         Lost to follow-up
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Icatibant 30 mg
    Reporting group description
    Subjects received a single dose of icatibant 30 milligram (mg) subcutaneous (SC) injection within 12 hours after the onset of the angiotensin-converting enzyme inhibitor (ACE-I) induced angioedema attack.

    Reporting group title
    Placebo
    Reporting group description
    Subjects received a single dose of placebo matched to icatibant SC injection within 12 hours after the onset of the ACE-I induced angioedema attack.

    Reporting group values
    Icatibant 30 mg Placebo Total
    Number of subjects
    61 60 121
    Age categorical
    Units: Subjects
    Age Continuous
    Age was calculated as the difference between date of birth and date of informed consent, rounded to 1 decimal place.
    Units: years
        arithmetic mean (standard deviation)
    60.9 ± 12.1 61.8 ± 13.4 -
    Gender, Male/Female
    Units: subjects
        Female
    27 35 62
        Male
    34 25 59

    End points

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    End points reporting groups
    Reporting group title
    Icatibant 30 mg
    Reporting group description
    Subjects received a single dose of icatibant 30 milligram (mg) subcutaneous (SC) injection within 12 hours after the onset of the angiotensin-converting enzyme inhibitor (ACE-I) induced angioedema attack.

    Reporting group title
    Placebo
    Reporting group description
    Subjects received a single dose of placebo matched to icatibant SC injection within 12 hours after the onset of the ACE-I induced angioedema attack.

    Subject analysis set title
    Metabolite M1
    Subject analysis set type
    Full analysis
    Subject analysis set description
    Subjects received a single dose of icatibant 30 mg sc injection within 12 hours after the onset of the ACE-I induced angioedema attack and assessed for metabolite M1.

    Subject analysis set title
    Metabolite M2
    Subject analysis set type
    Full analysis
    Subject analysis set description
    Subjects received a single dose of icatibant 30 mg sc injection within 12 hours after the onset of the ACE-I induced angioedema attack and assessed for metabolite M2.

    Primary: Time to Meeting Discharge Criteria (TMDC)

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    End point title
    Time to Meeting Discharge Criteria (TMDC)
    End point description
    TMDC was based on the investigator-assessed angioedema-associated upper airway symptom assessments. It was calculated from the time of study drug administration to the earliest time point at which the symptoms of difficulty breathing and difficulty swallowing were absent and the symptoms of voice change and tongue swelling were mild or absent and all subsequent assessments continued to satisfy these conditions. These symptoms were evaluated by the investigator using a 5-point grading scale (0=absent, 1=mild, 2=moderate, 3=severe, and 4=very severe). TMDC was analysed using Kaplan-Meier estimates. Intent-to-treat (ITT) population included all randomized subjects.
    End point type
    Primary
    End point timeframe
    Day 0 up to Day 5
    End point values
    Icatibant 30 mg Placebo
    Number of subjects analysed
    61
    60
    Units: days
        median (inter-quartile range (Q1-Q3))
    4.03 (2.03 to 6)
    4 (1.03 to 6)
    Statistical analysis title
    TMDC
    Statistical analysis description
    A total of 121 subjects were analysed, however 3 subjects did not receive the study medication and were censored at time 0.
    Comparison groups
    Icatibant 30 mg v Placebo
    Number of subjects included in analysis
    121
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.633 [1]
    Method
    Adjusted Peto-Prentice
    Confidence interval
    Notes
    [1] - Test was performed using a weighted log-rank test called the Peto-Prentice test with a global 2-sided significance level of 5 percent (%) after adjusting for stratification factors (race, and severity) in the ITT population.

    Primary: Number of Subjects With Treatment-emergent Adverse Events (TEAE) and Treatment-emergent Serious Adverse Events (TESAEs)

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    End point title
    Number of Subjects With Treatment-emergent Adverse Events (TEAE) and Treatment-emergent Serious Adverse Events (TESAEs) [2]
    End point description
    An adverse event (AE) was any untoward medical occurrence in a subject who received study drug without regard to possibility of causal relationship. An serious adverse event (SAE) was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. TEAEs were defined as adverse events/serious adverse events that started or worsened after the study drug treatment. Safety population included all subjects who received the study drug.
    End point type
    Primary
    End point timeframe
    From start of study drug administration (Day 0) up to follow-up (Day 5)
    Notes
    [2] - 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: Descriptive statistics were planned to report and inferential statistics were not planned.
    End point values
    Icatibant 30 mg Placebo
    Number of subjects analysed
    60
    58
    Units: subjects
    number (not applicable)
        Participants with TEAEs
    27
    21
        Participants with TESAEs
    2
    1
    No statistical analyses for this end point

    Primary: Number of Subjects with Treatment Emergent Injection Site Reaction

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    End point title
    Number of Subjects with Treatment Emergent Injection Site Reaction [3]
    End point description
    Injection site reaction included erythema, swelling, cutaneous pain, burning sensation, itching and warm sensation. Safety population included all subjects who received the study drug.
    End point type
    Primary
    End point timeframe
    Day 0 to Day 5
    Notes
    [3] - 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: Descriptive statistics were planned to report and inferential statistics were not planned.
    End point values
    Icatibant 30 mg Placebo
    Number of subjects analysed
    60
    58
    Units: subjects
    number (not applicable)
        Erythema
    31
    13
        Swelling
    17
    13
        Cutaneous pain
    10
    7
        Burning sensation
    15
    7
        Itching
    13
    6
        Warm sensation
    16
    8
    No statistical analyses for this end point

    Primary: Number of Subjects with Clinically Significant Changes in Laboratory Evaluation, Vital Signs, Electrocardiogram (ECG) and Physical Examination

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    End point title
    Number of Subjects with Clinically Significant Changes in Laboratory Evaluation, Vital Signs, Electrocardiogram (ECG) and Physical Examination [4]
    End point description
    Safety population included all subjects who received the study drug.
    End point type
    Primary
    End point timeframe
    Day 0 to Day 5
    Notes
    [4] - 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: Descriptive statistics were planned to report and inferential statistics were not planned.
    End point values
    Icatibant 30 mg Placebo
    Number of subjects analysed
    60
    58
    Units: subjects
        number (not applicable)
    0
    0
    No statistical analyses for this end point

    Secondary: Time to Onset of Symptom Relief (TOSR)

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    End point title
    Time to Onset of Symptom Relief (TOSR)
    End point description
    TOSR was calculated for the individual symptoms with pre-treatment scores of 2 (moderate) or more improved by at least 1 severity grade and the individual symptoms with pretreatment scores of 0 or 1 (absent or mild) were scored again at 0 or 1 and all the subsequent assessments continued to satisfy this condition. Time-to-event data were summarized using Kaplan-Meier estimates. ITT population included all randomized participants.
    End point type
    Secondary
    End point timeframe
    Day 0 up to Day 5
    End point values
    Icatibant 30 mg Placebo
    Number of subjects analysed
    61
    60
    Units: days
        median (inter-quartile range (Q1-Q3))
    2 (0.58 to 3.08)
    1.55 (0.5 to 3.88)
    No statistical analyses for this end point

    Secondary: Number of Subjects Experienced Airway Intervention due to ACE-I-induced Angioedema

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    End point title
    Number of Subjects Experienced Airway Intervention due to ACE-I-induced Angioedema
    End point description
    Airway Intervention included intubation, tracheotomy, cricothyrotomy. Modified Intent to treat (mITT) population included all randomized participants who received the study drug.
    End point type
    Secondary
    End point timeframe
    Day 0 up to Day 5
    End point values
    Icatibant 30 mg Placebo
    Number of subjects analysed
    60
    58
    Units: subjects
        number (not applicable)
    1
    0
    No statistical analyses for this end point

    Secondary: Number of Subjects Admitted to Hospital or Intensive Care Unit (ICU)

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    End point title
    Number of Subjects Admitted to Hospital or Intensive Care Unit (ICU)
    End point description
    Number of subjects with and without an occurrence of admission to the hospital (inpatient) or ICU post-treatment due to the ACE-I-induced angioedema attack were described. mITT population included all randomized subjects who received the study drug.
    End point type
    Secondary
    End point timeframe
    Day 0 up to Day 5
    End point values
    Icatibant 30 mg Placebo
    Number of subjects analysed
    60
    58
    Units: subjects
        number (not applicable)
    22
    22
    No statistical analyses for this end point

    Secondary: Number of Subjects Experienced ACE-I-induced Angioedema Attack Following Study Drug Administration

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    End point title
    Number of Subjects Experienced ACE-I-induced Angioedema Attack Following Study Drug Administration
    End point description
    Number of subjects with the use of conventional medications (corticosteroids, antihistamines, epinephrine) for the treatment of symptoms of the ACE-I- induced angioedema attack following study drug administration were presented. mITT population included all randomized subjects who received the study drug.
    End point type
    Secondary
    End point timeframe
    Day 0 up to Day 5
    End point values
    Icatibant 30 mg Placebo
    Number of subjects analysed
    60
    58
    Units: subjects
        number (not applicable)
    35
    35
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With Time to Meeting Discharge Criteria (TMDC) at specified time points

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    End point title
    Percentage of Subjects With Time to Meeting Discharge Criteria (TMDC) at specified time points
    End point description
    mITT population included all randomized subjects.
    End point type
    Secondary
    End point timeframe
    4, 6, and 8 hours post treatment
    End point values
    Icatibant 30 mg Placebo
    Number of subjects analysed
    60
    58
    Units: percentage of subjects
    number (not applicable)
        At 4 hours post treatment
    55
    60.3
        At 6 hours post treatment
    78.3
    75.9
        At 8 hours post treatment
    91.7
    91.4
    No statistical analyses for this end point

    Other pre-specified: Maximum Observed Serum Concentration (Cmax) of Icatibant and its Metabolites (M1 and M2)

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    End point title
    Maximum Observed Serum Concentration (Cmax) of Icatibant and its Metabolites (M1 and M2) [5]
    End point description
    Cmax is the peak plasma concentration of a drug after administration. Pharmacokinetic (PK) analysis included all subjects in the safety population who received study drug and provided evaluable plasma drug concentrations.
    End point type
    Other pre-specified
    End point timeframe
    0.75 and 2 hours post-dose
    Notes
    [5] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Descriptive statistics were planned to report and inferential statistics were not planned.
    End point values
    Icatibant 30 mg
    Number of subjects analysed
    21
    Units: nanogram per milliliter (ng/mL)
    arithmetic mean (standard deviation)
        Icatibant: 0.75 hours
    613 ± 198
        Icatibant: 2 hours
    484 ± 194
        Metabolite M1: 0.75 hours
    98.7 ± 52.6
        Metabolite M1: 2 hours
    182 ± 82.1
        Metabolite M2: 0.75 hours
    116 ± 56.7
        Metabolite M2: 2 hours
    223 ± 94.2
    No statistical analyses for this end point

    Other pre-specified: Area Under the Plasma Concentration Versus Time Curve (AUC[0-24]) of Icatibant and its Metabolites (M1 and M2)

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    End point title
    Area Under the Plasma Concentration Versus Time Curve (AUC[0-24]) of Icatibant and its Metabolites (M1 and M2) [6]
    End point description
    Area under the plasma concentration-time curve from time zero to 24 hours post-dose (AUC[0-24]). PK analysis included all subjects in the safety population who received study drug and provided evaluable plasma drug concentrations.
    End point type
    Other pre-specified
    End point timeframe
    0.75 and 2 hours post-dose
    Notes
    [6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Descriptive statistics were planned to report and inferential statistics were not planned.
    End point values
    Icatibant 30 mg
    Number of subjects analysed
    21
    Units: hours*nanogram per milliliter (h*ng/mL)
    arithmetic mean (standard deviation)
        Icatibant
    2530 ± 786
        Metabolite M1
    2890 ± 813
        Metabolite M2
    3180 ± 931
    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 treatment up to Day 5
    Adverse event reporting additional description
    Injection site reactions were reported separately from general reports of adverse events as they were considered as adverse events of special interest.
    Assessment type
    Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    16.0
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    Subjects received a single dose of placebo matched to icatibant SC injection within 12 hours after the onset of the ACEI induced angioedema attack.

    Reporting group title
    Icatibant 30 mg
    Reporting group description
    Subjects received a single dose of icatibant 30 mg SC injection within 12 hours after the onset of the ACE-I-induced angioedema attack.

    Serious adverse events
    Placebo Icatibant 30 mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 58 (1.72%)
    2 / 60 (3.33%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    Respiratory, thoracic and mediastinal disorders
    Hypoxia
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 60 (1.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Laryngeal oedema
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 60 (1.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Rash pruritic
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Placebo Icatibant 30 mg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    11 / 58 (18.97%)
    14 / 60 (23.33%)
    Respiratory, thoracic and mediastinal disorders
    Dysphonia
         subjects affected / exposed
    2 / 58 (3.45%)
    3 / 60 (5.00%)
         occurrences all number
    2
    4
    Dyspnoea
         subjects affected / exposed
    3 / 58 (5.17%)
    1 / 60 (1.67%)
         occurrences all number
    3
    1
    Nervous system disorders
    Headache
         subjects affected / exposed
    4 / 58 (6.90%)
    7 / 60 (11.67%)
         occurrences all number
    4
    7
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    3 / 58 (5.17%)
    0 / 60 (0.00%)
         occurrences all number
    3
    0
    Skin and subcutaneous tissue disorders
    Angioedema
         subjects affected / exposed
    2 / 58 (3.45%)
    7 / 60 (11.67%)
         occurrences all number
    4
    9

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    02 Sep 2014
    -Added a new exclusion criterion. -Text were made to clarify an existing exclusion criterion and several operational aspects of the study and to describe the secondary packaging of the study drug.

    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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