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    Clinical Trial Results:
    A Multicenter, Open-Label, Non-Randomized Study to Assess the Pharmacokinetics, Tolerability, and Safety of a Single Subcutaneous Administration of Icatibant in Children and Adolescents with Hereditary Angioedema

    Summary
    EudraCT number
    2011-003825-81
    Trial protocol
    DE   HU   ES   IT   AT  
    Global end of trial date
    12 Mar 2018

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

    Trial information

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    Trial identification
    Sponsor protocol code
    HGT-FIR-086
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01386658
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Shire
    Sponsor organisation address
    300 Shire Way, Lexington, United States, MA 02421
    Public contact
    Study Director, Shire, ClinicalTransparency@shire.com
    Scientific contact
    Study Director, Shire, ClinicalTransparency@shire.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    EMEA-000408-PIP02-12
    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?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    12 Mar 2018
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    12 Mar 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The main objective of the trial was to investigate the pharmacokinetics (PK), tolerability, and safety of a single subcutaneous (SC) dose of icatibant in children and adolescents with hereditary angioedema (HAE).
    Protection of trial subjects
    This study was conducted in accordance with International Conference on Harmonisation 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
    27 Jan 2012
    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
    Spain: 3
    Country: Number of subjects enrolled
    United States: 10
    Country: Number of subjects enrolled
    Australia: 1
    Country: Number of subjects enrolled
    Austria: 3
    Country: Number of subjects enrolled
    Colombia: 1
    Country: Number of subjects enrolled
    Germany: 2
    Country: Number of subjects enrolled
    Hungary: 4
    Country: Number of subjects enrolled
    Israel: 7
    Country: Number of subjects enrolled
    Italy: 1
    Worldwide total number of subjects
    32
    EEA total number of subjects
    13
    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)
    15
    Adolescents (12-17 years)
    17
    Adults (18-64 years)
    0
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    The study was conducted at 27 study centers in the United States, Germany, Israel, Spain, Argentina, Australia, Austria, Canada, Colombia, Hungary, and Italy between 27 January 2012 (first subject first visit) and 12 March 2018 (last subject last visit).

    Pre-assignment
    Screening details
    A total of 32 subjects were enrolled and received treatment.

    Period 1
    Period 1 title
    Initial Icatibant Exposure
    Is this the baseline period?
    Yes
    Allocation method
    Non-randomised - controlled
    Blinding used
    Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Prepubertal
    Arm description
    Prepubertal subjects received a single subcutaneous (SC) injection of 0.4 milligram per kilogram (mg/kg) icatibant (up to a maximal dose of 30 mg) in the abdominal region.
    Arm type
    Experimental

    Investigational medicinal product name
    Icatibant
    Investigational medicinal product code
    JE049
    Other name
    Firazyr
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subjects received SC injection of icatibant in the abdominal region.

    Arm title
    Pubertal/Postpubertal
    Arm description
    Pubertal/postpubertal subjects received a SC injection of 0.4 mg/kg icatibant (up to a maximal dose of 30 mg) in the abdominal region.
    Arm type
    Experimental

    Investigational medicinal product name
    Icatibant
    Investigational medicinal product code
    JE049
    Other name
    Firazyr
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subjects received SC injection of icatibant in the abdominal region.

    Number of subjects in period 1
    Prepubertal Pubertal/Postpubertal
    Started
    11
    21
    Completed
    11
    9
    Not completed
    0
    12
         Consent withdrawn by subject
    -
    9
         Lack of adherence and poor compliance
    -
    3
    Period 2
    Period 2 title
    Icatibant Exposure 2
    Is this the baseline period?
    No
    Allocation method
    Not applicable
    Blinding used
    Not blinded

    Arms
    Arm title
    Pubertal/Postpubertal: Exposure 2
    Arm description
    Subjects received a single SC injection of 0.4 mg/kg icatibant (up to a maximal dose of 30 mg) in the abdominal region by health care practitioner or caregiver/self, after initial exposure to icatibant during acute HAE attacks or in between attacks during Period 1 of the study.
    Arm type
    Experimental

    Investigational medicinal product name
    Icatibant
    Investigational medicinal product code
    JE049
    Other name
    Firazyr
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subjects received SC injection of icatibant in the abdominal region.

    Number of subjects in period 2
    Pubertal/Postpubertal: Exposure 2
    Started
    9
    Completed
    9
    Period 3
    Period 3 title
    Icatibant Exposure 3
    Is this the baseline period?
    No
    Allocation method
    Not applicable
    Blinding used
    Not blinded

    Arms
    Arm title
    Pubertal/Postpubertal: Exposure 3
    Arm description
    Subjects received a single SC injection of 0.4 mg/kg icatibant (up to a maximal dose of 30 mg) in the abdominal region by health care practitioner or caregiver/self, after initial 2 exposures to icatibant during acute HAE attacks or in between attacks during Period 1 of the study.
    Arm type
    Experimental

    Investigational medicinal product name
    Icatibant
    Investigational medicinal product code
    JE049
    Other name
    Firazyr
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subjects received SC injection of icatibant in the abdominal region.

    Number of subjects in period 3
    Pubertal/Postpubertal: Exposure 3
    Started
    9
    Completed
    9

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Prepubertal
    Reporting group description
    Prepubertal subjects received a single subcutaneous (SC) injection of 0.4 milligram per kilogram (mg/kg) icatibant (up to a maximal dose of 30 mg) in the abdominal region.

    Reporting group title
    Pubertal/Postpubertal
    Reporting group description
    Pubertal/postpubertal subjects received a SC injection of 0.4 mg/kg icatibant (up to a maximal dose of 30 mg) in the abdominal region.

    Reporting group values
    Prepubertal Pubertal/Postpubertal Total
    Number of subjects
    11 21
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    8.6 ± 2.97 14.3 ± 1.66 -
    Gender categorical
    Units: Subjects
        Female
    5 8 13
        Male
    6 13 19
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    0 0 0
        Asian
    0 0 0
        Native Hawaiian or Other Pacific Islander
    0 0 0
        Black or African American
    0 0 0
        White
    11 20 31
        More than one race
    0 0 0
        Unknown or Not Reported
    0 1 1
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    1 2 3
        Not Hispanic or Latino
    10 19 29
        Unknown or Not Reported
    0 0 0

    End points

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    End points reporting groups
    Reporting group title
    Prepubertal
    Reporting group description
    Prepubertal subjects received a single subcutaneous (SC) injection of 0.4 milligram per kilogram (mg/kg) icatibant (up to a maximal dose of 30 mg) in the abdominal region.

    Reporting group title
    Pubertal/Postpubertal
    Reporting group description
    Pubertal/postpubertal subjects received a SC injection of 0.4 mg/kg icatibant (up to a maximal dose of 30 mg) in the abdominal region.
    Reporting group title
    Pubertal/Postpubertal: Exposure 2
    Reporting group description
    Subjects received a single SC injection of 0.4 mg/kg icatibant (up to a maximal dose of 30 mg) in the abdominal region by health care practitioner or caregiver/self, after initial exposure to icatibant during acute HAE attacks or in between attacks during Period 1 of the study.
    Reporting group title
    Pubertal/Postpubertal: Exposure 3
    Reporting group description
    Subjects received a single SC injection of 0.4 mg/kg icatibant (up to a maximal dose of 30 mg) in the abdominal region by health care practitioner or caregiver/self, after initial 2 exposures to icatibant during acute HAE attacks or in between attacks during Period 1 of the study.

    Subject analysis set title
    Pubertal/postpubertal: with acute attack
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Subjects with acute attack received a SC injection of 0.4 mg/kg icatibant (up to a maximal dose of 30 mg) in the abdominal region.

    Subject analysis set title
    Pubertal/postpubertal: without acute attack
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Subjects without acute attack received a SC injection of 0.4 mg/kg icatibant (up to a maximal dose of 30 mg) in the abdominal region.

    Primary: Time to Peak Concentration (Tmax) of a Single Subcutaneous (SC) Dose of Icatibant

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    End point title
    Time to Peak Concentration (Tmax) of a Single Subcutaneous (SC) Dose of Icatibant [1] [2]
    End point description
    Time to peak concentration (Tmax) of a single SC dose of icatibant was reported. Pharmacokinetic (PK) population consisted of subjects who were treated with icatibant and had sufficient icatibant plasma concentration-time measurements to derive primary PK parameters. In the below table, the number of subjects analyzed signifies subjects who were evaluable for this measure.
    End point type
    Primary
    End point timeframe
    Pre-dose; 0.25, 0.5, 0.75, 1, 2, 4 and 6 hours post-dose on Day 1
    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: Descriptive statistics were done, no inferential statistical analyses were performed.
    [2] - 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: The PK analysis was performed for prepubertal subjects with an acute attack of HAE and pubertal/postpubertal subjects with or without an acute attack of HAE.
    End point values
    Prepubertal Pubertal/postpubertal: with acute attack Pubertal/postpubertal: without acute attack
    Number of subjects analysed
    9
    11
    10
    Units: Hour (h)
    arithmetic mean (standard deviation)
        Hour (h)
    0.42 ± 0.13
    0.55 ± 0.19
    0.57 ± 0.17
    No statistical analyses for this end point

    Primary: Maximum Plasma Concentration (Cmax) of a Single Subcutaneous (SC) Dose of Icatibant

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    End point title
    Maximum Plasma Concentration (Cmax) of a Single Subcutaneous (SC) Dose of Icatibant [3] [4]
    End point description
    Maximum plasma concentration (Cmax) of a single SC dose of icatibant was reported. PK population consisted of subjects who were treated with icatibant and had sufficient icatibant plasma concentration-time measurements to derive primary PK parameters. In the below table, the number of subjects analyzed signifies subjects who were evaluable for this measure.
    End point type
    Primary
    End point timeframe
    Pre-dose; 0.25, 0.5, 0.75, 1, 2, 4 and 6 hours post-dose on Day 1
    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 done, no inferential statistical analyses were performed.
    [4] - 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: The PK analysis was performed for prepubertal subjects with an acute attack of HAE and pubertal/postpubertal subjects with or without an acute attack of HAE.
    End point values
    Prepubertal Pubertal/postpubertal: with acute attack Pubertal/postpubertal: without acute attack
    Number of subjects analysed
    9
    11
    10
    Units: Nanogram per milliliter (ng/mL)
    arithmetic mean (standard deviation)
        Nanogram per milliliter (ng/mL)
    659 ± 158
    805 ± 125
    761 ± 133
    No statistical analyses for this end point

    Primary: Total Plasma Clearance (CL/F) of a Single Subcutaneous (SC) Dose of Icatibant

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    End point title
    Total Plasma Clearance (CL/F) of a Single Subcutaneous (SC) Dose of Icatibant [5] [6]
    End point description
    Total plasma clearance (CL/F) of a single SC dose of icatibant was reported. PK population consisted of subjects who were treated with icatibant and had sufficient icatibant plasma concentration-time measurements to derive primary PK parameters. In the below table, the number of subjects analyzed signifies subjects who were evaluable for this measure.
    End point type
    Primary
    End point timeframe
    Pre-dose; 0.25, 0.5, 0.75, 1, 2, 4 and 6 hours post-dose on Day 1
    Notes
    [5] - 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 done, no inferential statistical analyses were performed.
    [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: The PK analysis was performed for prepubertal subjects with an acute attack of HAE and pubertal/postpubertal subjects with or without an acute attack of HAE.
    End point values
    Prepubertal Pubertal/postpubertal: with acute attack Pubertal/postpubertal: without acute attack
    Number of subjects analysed
    6
    11
    10
    Units: Milliliters per minute (mL/min)
    arithmetic mean (standard deviation)
        Milliliters per minute (mL/min)
    10.8 ± 4.63
    13.1 ± 3.42
    19.3 ± 4.84
    No statistical analyses for this end point

    Primary: Area Under the Plasma Concentration-time Curve From Time Zero to 4 Hours Post-dose (AUC0-4) of a Single Subcutaneous (SC) Dose of Icatibant

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    End point title
    Area Under the Plasma Concentration-time Curve From Time Zero to 4 Hours Post-dose (AUC0-4) of a Single Subcutaneous (SC) Dose of Icatibant [7] [8]
    End point description
    Area under the plasma concentration-time curve from time zero to 4 hours post-dose (AUC0-4) of a single SC dose of icatibant was reported. PK population consisted of subjects who were treated with icatibant and had sufficient icatibant plasma concentration-time measurements to derive primary PK parameters. In the below table, the number of subjects analyzed signifies subjects who were evaluable for this measure.
    End point type
    Primary
    End point timeframe
    Pre-dose; 0.25, 0.5, 0.75, 1, 2, 4 and 6 hours post-dose on Day 1
    Notes
    [7] - 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 done, no inferential statistical analyses were performed.
    [8] - 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: The PK analysis was performed for prepubertal subjects with an acute attack of HAE and pubertal/postpubertal subjects with or without an acute attack of HAE.
    End point values
    Prepubertal Pubertal/postpubertal: with acute attack Pubertal/postpubertal: without acute attack
    Number of subjects analysed
    9
    11
    10
    Units: Hour*nanogram per milliliter (h*ng/mL)
    arithmetic mean (standard deviation)
        Hour*nanogram per milliliter (h*ng/mL)
    1241 ± 319
    1448 ± 304
    1335 ± 211
    No statistical analyses for this end point

    Primary: Area Under the Plasma Concentration-time Curve From Time Zero to 6 Hours Post-dose (AUC0-t) of a Single Subcutaneous (SC) Dose of Icatibant

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    End point title
    Area Under the Plasma Concentration-time Curve From Time Zero to 6 Hours Post-dose (AUC0-t) of a Single Subcutaneous (SC) Dose of Icatibant [9] [10]
    End point description
    Area under the plasma concentration-time curve from time zero to 6 hours post-dose (AUC0-t) of a single SC dose of icatibant was reported. PK population consisted of subjects who were treated with icatibant and had sufficient icatibant plasma concentration-time measurements to derive primary PK parameters. In the below table, the number of subjects analyzed signifies subjects who were evaluable for this measure.
    End point type
    Primary
    End point timeframe
    Pre-dose; 0.25, 0.5, 0.75, 1, 2, 4 and 6 hours post-dose on Day 1
    Notes
    [9] - 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 done, no inferential statistical analyses were performed.
    [10] - 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: The PK analysis was performed for prepubertal subjects with an acute attack of HAE and pubertal/postpubertal subjects with or without an acute attack of HAE.
    End point values
    Prepubertal Pubertal/postpubertal: with acute attack Pubertal/postpubertal: without acute attack
    Number of subjects analysed
    9
    11
    10
    Units: h*ng/mL
    arithmetic mean (standard deviation)
        h*ng/mL
    1289 ± 325
    1573 ± 372
    1398 ± 225
    No statistical analyses for this end point

    Primary: Area Under the Plasma Concentration-time Curve From Time Zero to Infinity (AUC0-inf) of a Single Subcutaneous (SC) Dose of Icatibant

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    End point title
    Area Under the Plasma Concentration-time Curve From Time Zero to Infinity (AUC0-inf) of a Single Subcutaneous (SC) Dose of Icatibant [11] [12]
    End point description
    Area under the plasma concentration-time curve from time zero to infinity (AUC0-inf) of a single SC dose of icatibant was reported. PK population consisted of subjects who were treated with icatibant and had sufficient icatibant plasma concentration-time measurements to derive primary PK parameters. In the below table, the number of subjects analyzed signifies subjects who were evaluable for this measure.
    End point type
    Primary
    End point timeframe
    Pre-dose; 0.25, 0.5, 0.75, 1, 2, 4 and 6 hours post-dose on Day 1
    Notes
    [11] - 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 done, no inferential statistical analyses were performed.
    [12] - 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: The PK analysis was performed for prepubertal subjects with an acute attack of HAE and pubertal/postpubertal subjects with or without an acute attack of HAE.
    End point values
    Prepubertal Pubertal/postpubertal: with acute attack Pubertal/postpubertal: without acute attack
    Number of subjects analysed
    6
    11
    10
    Units: h*ng/mL
    arithmetic mean (standard deviation)
        h*ng/mL
    1243 ± 244
    1710 ± 569
    1416 ± 229
    No statistical analyses for this end point

    Primary: Volume of Distribution (Vz/F) of a Single Subcutaneous (SC) Dose of Icatibant

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    End point title
    Volume of Distribution (Vz/F) of a Single Subcutaneous (SC) Dose of Icatibant [13] [14]
    End point description
    Volume of distribution (Vz/F) of a single SC dose of icatibant was reported. PK population consisted of subjects who were treated with icatibant and had sufficient icatibant plasma concentration-time measurements to derive primary PK parameters. In the below table, the number of subjects analyzed signifies subjects who were evaluable for this measure.
    End point type
    Primary
    End point timeframe
    Pre-dose; 0.25, 0.5, 0.75, 1, 2, 4 and 6 hours post-dose on Day 1
    Notes
    [13] - 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 done, no inferential statistical analyses were performed.
    [14] - 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: The PK analysis was performed for prepubertal subjects with an acute attack of HAE and pubertal/postpubertal subjects with or without an acute attack of HAE.
    End point values
    Prepubertal Pubertal/postpubertal: with acute attack Pubertal/postpubertal: without acute attack
    Number of subjects analysed
    6
    11
    10
    Units: Liters (L)
    arithmetic mean (standard deviation)
        Liters (L)
    12.5 ± 5.28
    23.5 ± 13.9
    25.4 ± 8.87
    No statistical analyses for this end point

    Primary: Elimination Half-life (t1/2) of a Single Subcutaneous (SC) Dose of Icatibant

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    End point title
    Elimination Half-life (t1/2) of a Single Subcutaneous (SC) Dose of Icatibant [15] [16]
    End point description
    Elimination half-life (t1/2) of a single SC dose of icatibant was reported. PK population consisted of subjects who were treated with icatibant and had sufficient icatibant plasma concentration-time measurements to derive primary PK parameters. In the below table, the number of subjects analyzed signifies subjects who were evaluable for this measure.
    End point type
    Primary
    End point timeframe
    Pre-dose; 0.25, 0.5, 0.75, 1, 2, 4 and 6 hours post-dose on Day 1
    Notes
    [15] - 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 done, no inferential statistical analyses were performed.
    [16] - 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: The PK analysis was performed for prepubertal subjects with an acute attack of HAE and pubertal/postpubertal subjects with or without an acute attack of HAE.
    End point values
    Prepubertal Pubertal/postpubertal: with acute attack Pubertal/postpubertal: without acute attack
    Number of subjects analysed
    6
    11
    10
    Units: Hour (h)
    arithmetic mean (standard deviation)
        Hour (h)
    0.80 ± 0.04
    1.34 ± 0.96
    0.90 ± 0.10
    No statistical analyses for this end point

    Primary: Number of Subjects With Clinically Significant Changes in Vital Signs

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    End point title
    Number of Subjects With Clinically Significant Changes in Vital Signs [17]
    End point description
    Vital signs included pulse rate, blood pressure, respiration rate, and temperature. The number of subjects who reported clinically significant changes in vital signs were reported. Safety population consisted of subjects who were treated with icatibant at least once during the study.
    End point type
    Primary
    End point timeframe
    Pre-dose up to 97 days post-dose
    Notes
    [17] - 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 done, no inferential statistical analyses were performed.
    End point values
    Prepubertal Pubertal/Postpubertal
    Number of subjects analysed
    11
    21
    Units: Subjects
        Subjects
    0
    0
    No statistical analyses for this end point

    Primary: Number of Subjects With Clinically Significant Changes in Electrocardiograms (ECGs)

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    End point title
    Number of Subjects With Clinically Significant Changes in Electrocardiograms (ECGs) [18]
    End point description
    A standard 12-lead ECG was performed after 10 minutes at rest when the subject was seated or supine following treatment. The number of subjects who reported clinically significant changes in ECGs were reported. Safety population consisted of subjects who were treated with icatibant at least once during the study.
    End point type
    Primary
    End point timeframe
    6 - 8 hours post-dose on Day 1
    Notes
    [18] - 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 done, no inferential statistical analyses were performed.
    End point values
    Prepubertal Pubertal/Postpubertal
    Number of subjects analysed
    11
    21
    Units: Subjects
        Subjects
    0
    0
    No statistical analyses for this end point

    Primary: Number of Subjects With Clinically Significant Changes in Clinical Laboratory Evaluations

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    End point title
    Number of Subjects With Clinically Significant Changes in Clinical Laboratory Evaluations [19]
    End point description
    Clinical laboratory evaluations included clinical chemistry (including liver function tests), hematology, urinalysis. The number of subjects who reported clinically significant changes in clinical laboratory evaluations were reported. Safety population consisted of subjects who were treated with icatibant at least once during the study.
    End point type
    Primary
    End point timeframe
    Pre-dose up to 97 days post-dose
    Notes
    [19] - 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 done, no inferential statistical analyses were performed.
    End point values
    Prepubertal Pubertal/Postpubertal
    Number of subjects analysed
    11
    21
    Units: Subjects
        Subjects
    0
    0
    No statistical analyses for this end point

    Primary: Number of Subjects who Reported Presence of Anti-icatibant Antibodies

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    End point title
    Number of Subjects who Reported Presence of Anti-icatibant Antibodies [20]
    End point description
    The number of subjects who reported anti-icatibant antibodies were reported. Safety population consisted of subjects who were treated with icatibant at least once during the study.
    End point type
    Primary
    End point timeframe
    Pre-dose up to 97 days post-dose
    Notes
    [20] - 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 done, no inferential statistical analyses were performed.
    End point values
    Prepubertal Pubertal/Postpubertal
    Number of subjects analysed
    11
    21
    Units: Subjects
        Subjects
    0
    0
    No statistical analyses for this end point

    Primary: Number of Subjects With Adverse Events (AEs)

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    End point title
    Number of Subjects With Adverse Events (AEs) [21]
    End point description
    An AE was any noxious, pathologic, or unintended change in anatomical, physiologic, or metabolic function as indicated by physical signs, symptoms, or laboratory changes occurring in a clinical study, whether or not considered investigational product related. Safety population consisted of subjects who were treated with icatibant at least once during the study.
    End point type
    Primary
    End point timeframe
    From the start of study drug administration up to 97 days post-dose
    Notes
    [21] - 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 done, no inferential statistical analyses were performed.
    End point values
    Prepubertal Pubertal/Postpubertal
    Number of subjects analysed
    11
    21
    Units: Subjects
        Subjects
    2
    11
    No statistical analyses for this end point

    Primary: Number of Subjects who Reported Injection Site Reactions (ISR) for Icatibant Exposure Number 1

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    End point title
    Number of Subjects who Reported Injection Site Reactions (ISR) for Icatibant Exposure Number 1 [22]
    End point description
    The number of subjects with injection site reactions (erythema, swelling, burning sensation, itching/pruritus, warm sensation, cutaneous pain, or other) that occured after initial icatibant administration was reported. Safety population consisted of subjects who were treated with icatibant at least once during the study.
    End point type
    Primary
    End point timeframe
    1 h post-dose on Day 1 up to 9 days post-dose
    Notes
    [22] - 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 done, no inferential statistical analyses were performed.
    End point values
    Prepubertal Pubertal/Postpubertal
    Number of subjects analysed
    11
    21
    Units: Subjects
        Any Reaction
    9
    20
        Any Severe Reaction
    0
    2
    No statistical analyses for this end point

    Primary: Number of Subjects who Reported Injection Site Reactions (ISR) for Icatibant Exposure Number 2 and 3

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    End point title
    Number of Subjects who Reported Injection Site Reactions (ISR) for Icatibant Exposure Number 2 and 3 [23]
    End point description
    The number of subjects with injection site reactions (erythema, swelling, burning sensation, itching/pruritus, warm sensation, cutaneous pain, or other) that occurred after subsequent icatibant administration by study-site personnel (health care practitioner [HCP] administration) or by caregiver/self (caregiver administration) was reported. In the below table, ASR refers to any severe reaction and "n" indicates the number of subjects evaluable for this endpoint. Safety population consisted of subjects who were treated with icatibant at least once during the study.
    End point type
    Primary
    End point timeframe
    1 h post-dose up to 9 days post-dose
    Notes
    [23] - 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 done, no inferential statistical analyses were performed.
    End point values
    Pubertal/Postpubertal: Exposure 2 Pubertal/Postpubertal: Exposure 3
    Number of subjects analysed
    9
    9
    Units: Subjects
        HCP Administration: Any Reaction (n=1,1)
    1
    1
        HCP Administration: ASR (n=1,1)
    0
    0
        Caregiver Administration: Any Reaction (n=8,8)
    8
    7
        Caregiver Administration: ASR (n=8,8)
    3
    1
    No statistical analyses for this end point

    Primary: Number of Subjects With Clinically Significant Changes in Reproductive Hormones

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    End point title
    Number of Subjects With Clinically Significant Changes in Reproductive Hormones [24]
    End point description
    Reproductive hormone levels of follicle-stimulating hormone (FSH), luteinizing hormone (LH), estradiol, and progesterone in females, and FSH, LH, and testosterone in males were measured. The number of subjects with clinically significant changes in reproductive hormones was reported. Safety population consisted of subjects who were treated with icatibant at least once during the study.
    End point type
    Primary
    End point timeframe
    Pre-dose up to 97 days post-dose
    Notes
    [24] - 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 done, no inferential statistical analyses were performed.
    End point values
    Prepubertal Pubertal/Postpubertal
    Number of subjects analysed
    11
    21
    Units: Subjects
        Subjects
    0
    0
    No statistical analyses for this end point

    Secondary: Time to Onset of Symptom Relief (TOSR) for Composite Investigator-Assessed Symptom Scores for Icatibant Exposure Number 1

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    End point title
    Time to Onset of Symptom Relief (TOSR) for Composite Investigator-Assessed Symptom Scores for Icatibant Exposure Number 1
    End point description
    TOSR was defined as the duration of time in hours from study drug administration to the earliest time post-treatment at which there was at least a 20 percent(%) improvement in the average post-treatment symptom score with no worsening of any single component score for the initial icatibant exposure. The investigator used a symptom score to assess the severities of symptoms of acute cutaneous, abdominal, and laryngeal attacks of HAE using the following 5-point scale: 0=none, 1=mild, 2=moderate, 3=severe and 4=very severe. TOSR for subjects received initial icatibant administration was reported. In the below table, number of subjects analyzed indicates the subjects evaluable for this endpoint. Efficacy population consisted of subjects who were treated with icatibant attacks during the study.
    End point type
    Secondary
    End point timeframe
    From start of study drug administration up to 8.5 hours post-dose
    End point values
    Prepubertal Pubertal/Postpubertal
    Number of subjects analysed
    11
    11
    Units: Hour (h)
    median (confidence interval 95%)
        Hour (h)
    1.0 (1.0 to 2.0)
    1.0 (1.0 to 2.0)
    No statistical analyses for this end point

    Secondary: Time to Onset of Symptom Relief (TOSR) for Composite Investigator-Assessed Symptom Scores for Icatibant Exposure Number 2 and 3

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    End point title
    Time to Onset of Symptom Relief (TOSR) for Composite Investigator-Assessed Symptom Scores for Icatibant Exposure Number 2 and 3
    End point description
    TOSR was defined as the duration of time in hours from study drug administration to the earliest time post-treatment at which there was at least a 20% improvement in the composite (or average) post-treatment symptom score with no worsening of any single component score. The investigator used a symptom score to assess the severities of symptoms of acute cutaneous, abdominal, and laryngeal attacks of HAE using the following 5-point scale: 0=none, 1=mild, 2=moderate, 3=severe and 4=very severe. In the below table, HCP refers to health care practitioner administration and "n" indicates the number of subjects evaluable for this endpoint. Efficacy population consisted of subjects who were treated with icatibant for their first and any additional attacks during the study.
    End point type
    Secondary
    End point timeframe
    From start of study drug administration up to 12 hours post-dose
    End point values
    Pubertal/Postpubertal: Exposure 2 Pubertal/Postpubertal: Exposure 3
    Number of subjects analysed
    9
    9
    Units: Hour (h)
    median (confidence interval 95%)
        HCP Administration (n=1,1)
    4.0 (4.0 to 4.0)
    1.0 (1.0 to 1.0)
        Caregiver Administration (n=8,7)
    1.0 (1.0 to 2.3)
    1.1 (1.0 to 3.0)
    No statistical analyses for this end point

    Secondary: Time to Onset of Symptom Relief (TOSR) for Faces Pain Scale-Revised (FPS-R) Scores for Icatibant Exposure Number 1

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    End point title
    Time to Onset of Symptom Relief (TOSR) for Faces Pain Scale-Revised (FPS-R) Scores for Icatibant Exposure Number 1
    End point description
    TOSR was defined as the earliest time at which the post-treatment score improved by at least one level. Subjects of 4 years age and older self-assessed their HAE-related pain using the FPS-R instrument. FPS-R is a self-reported measure used to assess the intensity of children's pain and it is scored using a 0 to 10 scale (0=no pain to 10=very much pain). TOSR for subjects who received initial icatibant administration was reported. In the below table, the number of subjects analyzed signifies subjects who were evaluable for this measure. Efficacy population consisted of subjects who were treated with icatibant for their first and any additional attacks during the study.
    End point type
    Secondary
    End point timeframe
    From start of study drug administration up to 52 hours post-dose
    End point values
    Prepubertal Pubertal/Postpubertal
    Number of subjects analysed
    6
    9
    Units: Hour (h)
    median (confidence interval 95%)
        Hour (h)
    0.9 (0.8 to 1.0)
    1.0 (0.6 to 1.0)
    No statistical analyses for this end point

    Secondary: Time to Onset of Symptom Relief (TOSR) for Faces Pain Scale-Revised (FPS-R) Scores for Icatibant Exposure Number 2 and 3

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    End point title
    Time to Onset of Symptom Relief (TOSR) for Faces Pain Scale-Revised (FPS-R) Scores for Icatibant Exposure Number 2 and 3
    End point description
    TOSR was defined as the earliest time at which the post-treatment score improved by at least one level. Subjects of 4 years age and older self-assessed their HAE-related pain using the FPS-R instrument. FPS-R is a self-reported measure used to assess the intensity of children's pain and it is scored using a 0 to 10 scale (0=no pain to 10=very much pain). TOSR for subjects who received subsequent icatibant administration by HCP administration or by caregiver/ self-administration was reported. In the below table, HCP refers to health care practitioner administration and "n" indicates the number of subjects with FPS-R data. Efficacy population consisted of subjects who were treated with icatibant for their first and any additional attacks during the study.
    End point type
    Secondary
    End point timeframe
    From start of study drug administration up to 28 hours post-dose
    End point values
    Pubertal/Postpubertal: Exposure 2 Pubertal/Postpubertal: Exposure 3
    Number of subjects analysed
    9
    9
    Units: Hour (h)
    median (confidence interval 95%)
        HCP Administration (n=1,1)
    3.0 (3.0 to 3.0)
    1.0 (1.0 to 1.0)
        Caregiver Administration (n=7,7)
    1.0 (1.0 to 1.2)
    1.1 (1.0 to 1.2)
    No statistical analyses for this end point

    Secondary: Time to Onset of Symptom Relief (TOSR) for Faces, Legs, Activity, Cry, and Consolability (FLACC) Scores

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    End point title
    Time to Onset of Symptom Relief (TOSR) for Faces, Legs, Activity, Cry, and Consolability (FLACC) Scores [25]
    End point description
    TOSR was defined as the earliest time at which a 20% improvement was seen in the total post-treatment score. Subjects of 4 years age and young underwent investigator assessment of HAE-related pain (cutaneous, abdominal, and laryngeal) using the FLACC comportmental pain scale. Each of the 5 categories was scored from 0 to 2. Face(F): 0 (no particular expression/smile) - 2 (frequent to constant frown clenched jaw quivering chin); Legs(L): 0 (normal position/relaxed) - 2 (kicking/legs drawn up); Activity(A): 0 (lying quietly, normal position, moves easily) - 2 (arched rigid/jerking); Cry(C): 0 (No cry [awake/asleep]) - 2 (crying steadily/screams/sobs or frequent complaints); Consolability(C): 0 (content/relaxed) - 2 (difficult to console/comfort), resulting in a total score between 0 and 10. In the below table, the number of subjects analyzed signifies subjects with FLACC data. Efficacy population was analyzed.
    End point type
    Secondary
    End point timeframe
    From start of study drug administration up to 8.5 hours post-dose
    Notes
    [25] - 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: This endpoint was analyzed for subjects of 4 years age and younger.
    End point values
    Prepubertal
    Number of subjects analysed
    1
    Units: Hour (h)
    median (confidence interval 95%)
        Hour (h)
    1.0 (1.0 to 1.0)
    No statistical analyses for this end point

    Secondary: Time to Minimum Symptoms for Composite Investigator-Assessed Symptom Scores for Icatibant Exposure Number 1

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    End point title
    Time to Minimum Symptoms for Composite Investigator-Assessed Symptom Scores for Icatibant Exposure Number 1
    End point description
    Time to minimum symptom was defined as the duration of time in hours from study drug administration to the earliest time post-treatment at which all symptoms were either mild or absent for the investigator-reported symptom score. The investigator used a symptom score to assess the severities of symptoms of acute cutaneous, abdominal, and laryngeal attacks of HAE using the following 5-point scale: 0=none, 1=mild, 2=moderate, 3=severe and 4=very severe. Time to minimum symptom for subjects who received initial icatibant administration was reported. In the below table, the number of subjects analyzed signifies those evaluable for this measure. Efficacy population consisted of subjects who were treated with icatibant for their first and any additional attacks during the study.
    End point type
    Secondary
    End point timeframe
    From start of study drug administration up to 8.5 hours post-dose
    End point values
    Prepubertal Pubertal/Postpubertal
    Number of subjects analysed
    11
    10
    Units: Hour (h)
    median (confidence interval 95%)
        Hour (h)
    1.9 (1.0 to 2.0)
    1.0 (1.0 to 2.0)
    No statistical analyses for this end point

    Secondary: Time to Minimum Symptoms for Composite Investigator-Assessed Symptom Scores for Icatibant Exposure Number 2 and 3

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    End point title
    Time to Minimum Symptoms for Composite Investigator-Assessed Symptom Scores for Icatibant Exposure Number 2 and 3
    End point description
    Time to minimum symptom was defined as the duration of time in hours from study drug administration to the earliest time post-treatment at which all symptoms were either mild or absent for the investigator-reported symptom score. The investigator used a symptom score to assess the severities of symptoms of acute cutaneous, abdominal, and laryngeal attacks of HAE using the following 5-point scale: 0=none, 1=mild, 2=moderate, 3=severe and 4=very severe. Time to minimum symptom for subjects who received subsequent icatibant administration by HCP administration or by caregiver/ self-administration was reported. In the below table, HCP refers to health care practitioner administration, "99999" indicates that the data was not calculated due to less number of subjects, "88888" indicates that the data was not calculated due to analysis method limitation and "n" indicates the number of subjects evaluable for this endpoint. Efficacy population was analyzed.
    End point type
    Secondary
    End point timeframe
    From start of study drug administration up to 12 hours post-dose
    End point values
    Pubertal/Postpubertal: Exposure 2 Pubertal/Postpubertal: Exposure 3
    Number of subjects analysed
    9
    9
    Units: Hour (h)
    median (confidence interval 95%)
        HCP Administration (n=0,0)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
        Caregiver Administration (n=7,7)
    1.2 (1.0 to 2.0)
    2.2 (1.0 to 88888)
    No statistical analyses for this end point

    Secondary: Time to Minimum Symptom for Faces Pain Scale-Revised (FPS-R) Scores for Icatibant Exposure Number 1

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    End point title
    Time to Minimum Symptom for Faces Pain Scale-Revised (FPS-R) Scores for Icatibant Exposure Number 1
    End point description
    Time to minimum symptoms was defined as the duration of time in hours from study drug administration to the earliest time at which post-treatment score improved to zero (or no pain). Subjects of 4 years of age and older self-assessed their HAE-related pain using the FPS-R instrument. FPS-R is a self-reported measure used to assess the intensity of children's pain and it is scored using a 0 to 10 scale (0=no pain to 10=very much pain). Time to minimum symptom for subjects who received initial icatibant administration was reported. In the below table, the number of subjects analyzed signifies subjects with FPS-R data. Efficacy population consisted of subjects who were treated with icatibant for their first and any additional attacks during the study.
    End point type
    Secondary
    End point timeframe
    From start of study drug administration up to 52 hours post-dose
    End point values
    Prepubertal Pubertal/Postpubertal
    Number of subjects analysed
    6
    11
    Units: Hour (h)
    median (confidence interval 95%)
        Hour (h)
    2.4 (1.9 to 5.3)
    3.8 (1.0 to 6.8)
    No statistical analyses for this end point

    Secondary: Time to Minimum Symptom for Faces Pain Scale-Revised (FPS-R) Scores for Icatibant Exposure Number 2 and 3

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    End point title
    Time to Minimum Symptom for Faces Pain Scale-Revised (FPS-R) Scores for Icatibant Exposure Number 2 and 3
    End point description
    Time to minimum symptoms was defined as the duration of time in hours from study drug administration to the earliest time at which post-treatment score improved to zero (or no pain). Subjects of 4 years of age and older self-assessed their HAE-related pain using the FPS-R instrument. FPS-R is a self-reported measure used to assess the intensity of children's pain and it is scored using a 0 to 10 scale (0=no pain to 10=very much pain). Time to minimum symptom for subjects who received subsequent icatibant administration by HCP administration or by caregiver/ self-administration was reported. In the below table, HCP refers to health care practitioner administration and "n" indicates the number of subjects with FPS-R data. Efficacy population was analyzed.
    End point type
    Secondary
    End point timeframe
    From start of study drug administration up to 28 hours post-dose
    End point values
    Pubertal/Postpubertal: Exposure 2 Pubertal/Postpubertal: Exposure 3
    Number of subjects analysed
    9
    9
    Units: Hour (h)
    median (confidence interval 95%)
        HCP Administration (n=1,1)
    3.0 (3.0 to 3.0)
    5.8 (5.8 to 5.8)
        Caregiver Administration (n=7,7)
    2.1 (1.0 to 4.0)
    24.0 (3.8 to 24.2)
    No statistical analyses for this end point

    Secondary: Time to Minimum Symptom for Faces, Legs, Activity, Cry, and Consolability (FLACC) Scores

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    End point title
    Time to Minimum Symptom for Faces, Legs, Activity, Cry, and Consolability (FLACC) Scores [26]
    End point description
    Time to minimum symptoms was defined as the duration of time in hours from study drug administration to the earliest time at which the total post-treatment score improved to zero. Subjects of 4 years age and younger underwent investigator assessment of HAE-related pain (cutaneous, abdominal, and laryngeal) using the FLACC comportmental pain scale. Each of the 5 categories was scored from 0 to 2. (F) Face: 0 (no particular expression/smile) - 2 (frequent to constant frown clenched jaw quivering chin); (L) Legs: 0 (normal position/relaxed) - 2 (kicking/legs drawn up); (A) Activity: 0 (lying quietly, normal position, moves easily) - 2 (arched rigid/jerking); (C) Cry: 0 (No cry [awake/asleep]) - 2 (crying steadily/screams/sobs or frequent complaints); (C) Consolability: 0 (content/relaxed) - 2 (difficult to console/comfort), resulting in a total score between 0 and 10. In the below table, the number of subjects analyzed signifies subjects with FLACC data. Efficacy population was analyzed.
    End point type
    Secondary
    End point timeframe
    From start of study drug administration up to 8.5 hours post-dose
    Notes
    [26] - 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: This endpoint was analyzed for subjects of 4 years age and younger.
    End point values
    Prepubertal
    Number of subjects analysed
    1
    Units: Hour (h)
    median (confidence interval 95%)
        Hour (h)
    1.0 (1.0 to 1.0)
    No statistical analyses for this end point

    Secondary: Time to Use of Rescue Medication for the Treatment of Symptoms of the HAE Attack Following Study Drug Administration

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    End point title
    Time to Use of Rescue Medication for the Treatment of Symptoms of the HAE Attack Following Study Drug Administration
    End point description
    Rescue medication was any medication used after the administration of icatibant which, in the opinion of the investigator, was immediately necessary to alleviate acute symptoms which are judged by the investigator as resultant from the current HAE attack. Time to first use of rescue medication prior to the onset of symptom relief was calculated from the time of study drug administration to the first use of rescue medication prior to the onset of symptom relief. This analysis was not performed since as per protocol, "This analysis will only be performed if there are at least 5 subjects for a given attack who used rescue medication prior to attaining symptom relief". In the below table, the number of subjects analyzed signifies subjects who were evaluable for this measure. Efficacy population consisted of subjects who were treated with icatibant for their first and any additional attacks during the study.
    End point type
    Secondary
    End point timeframe
    From the start of study drug administration up to 52 hours post-dose
    End point values
    Prepubertal Pubertal/Postpubertal
    Number of subjects analysed
    0 [27]
    0 [28]
    Units: Hour (h)
    median (confidence interval 95%)
        Hour (h)
    ( to )
    ( to )
    Notes
    [27] - This analysis was not performed.
    [28] - This analysis was not performed.
    No statistical analyses for this end point

    Secondary: Number of Subjects With Worsened Intensity of Clinical HAE Symptoms Between 2 and 4 Hours After Treatment With Icatibant Exposure Number 1

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    End point title
    Number of Subjects With Worsened Intensity of Clinical HAE Symptoms Between 2 and 4 Hours After Treatment With Icatibant Exposure Number 1
    End point description
    The investigator used a symptom score to assess the severities of symptoms of acute cutaneous, abdominal, and laryngeal attacks of HAE using the following 5-point scale: 0=none (absence of symptoms), 1=mild (no to mild interference with daily activities), 2=moderate (moderate interference with daily activities), 3=severe (severe interference with daily activities) and 4=very severe (very severe interference with daily activities). The number of subjects with a worsened severity of HAE symptoms at 4 hours post-dose from 2 hours post-dose were reported. In the below table, "n" indicates the number of subjects evaluable for this endpoint. Efficacy population consisted of subjects who were treated with icatibant for their first and any additional attacks during the study.
    End point type
    Secondary
    End point timeframe
    From 2 hours post-dose to 4 hours post-dose
    End point values
    Prepubertal Pubertal/Postpubertal
    Number of subjects analysed
    11
    11
    Units: Subjects
        Abdominal Tenderness
    0
    1
        Nausea
    0
    0
        Vomiting
    0
    0
        Diarrhea
    0
    0
        Skin Pain
    0
    0
        Erythema
    0
    0
        Skin Irritation
    0
    0
        Skin Swelling
    0
    0
    No statistical analyses for this end point

    Secondary: Number of Subjects With Worsened Intensity of Clinical HAE Symptoms Between 2 and 4 Hours After Treatment With Icatibant Exposure Number 2 and 3

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    End point title
    Number of Subjects With Worsened Intensity of Clinical HAE Symptoms Between 2 and 4 Hours After Treatment With Icatibant Exposure Number 2 and 3
    End point description
    The investigator used a symptom score to assess the severities of symptoms of acute cutaneous, abdominal, and laryngeal attacks of HAE using the following 5-point scale: 0=none (absence of symptoms), 1=mild (no to mild interference with daily activities), 2=moderate (moderate interference with daily activities), 3=severe (severe interference with daily activities) and 4=very severe (very severe interference with daily activities). The number of subjects with a worsened severity of HAE symptoms at 4 hours post-dose from 2 hours post-dose were reported. In the below table, HCPA refers to health care practitioner administration, CA refers to caregiver/ self-administration and "n" indicates the number of subjects evaluable for this endpoint. Efficacy population consisted of subjects who were treated with icatibant for their first and any additional attacks during the study.
    End point type
    Secondary
    End point timeframe
    From 2 hours post-dose to 4 hours post-dose
    End point values
    Pubertal/Postpubertal: Exposure 2 Pubertal/Postpubertal: Exposure 3
    Number of subjects analysed
    9
    9
    Units: Subjects
        HCPA: Abdominal Tenderness (n=1,1)
    0
    0
        CA: Abdominal Tenderness (n=8,8)
    0
    1
        HCPA: Nausea (n=1,1)
    0
    0
        CA: Nausea (n=8,8)
    0
    0
        HCPA: Vomiting (n=1,1)
    0
    0
        CA: Vomiting (n=8,8)
    0
    0
        HCPA: Diarrhea (n=1,1)
    0
    0
        CA: Diarrhea (n=8,8)
    0
    1
        HCPA: Skin Pain (n=1,1)
    0
    0
        CA: Skin Pain (n=8,8)
    0
    0
        HCPA: Erythema (n=1,1)
    0
    0
        CA: Erythema (n=8,8)
    0
    0
        HCPA: Skin Irritation (n=1,1)
    0
    0
        CA: Skin Irritation (n=8,8)
    0
    0
        HCPA: Skin Swelling (n=1,1)
    0
    0
        CA: Skin Swelling (n=8,8)
    0
    0
        HCPA: Dysphagia (n=1,1)
    0
    0
        CA: Dysphagia (n=8,8)
    0
    0
        HCPA: Voice Change (n=1,1)
    0
    0
        CA: Voice Change (n=8,8)
    0
    0
        HCPA: Breathing Difficulties (n=1,1)
    0
    0
        CA: Breathing Difficulties (n=8,8)
    0
    0
        HCPA: Stridor (n=1,1)
    0
    0
        CA: Stridor (n=8,8)
    0
    0
        HCPA: Asphyxia (n=1,1)
    0
    0
        CA: Asphyxia (n=8,8)
    0
    0
    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 up to 187 days
    Assessment type
    Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    16.0
    Reporting groups
    Reporting group title
    Prepubertal
    Reporting group description
    Prepubertal subjects received a single SC injection of 0.4 mg/kg icatibant (up to a maximal dose of 30 mg) in the abdominal region.

    Reporting group title
    Pubertal/Post-pubertal
    Reporting group description
    Pubertal/postpubertal subjects received an SC injection of 0.4 mg/kg icatibant (up to a maximal dose of 30 mg) in the abdominal region; and subjects after initial exposure to icatibant during acute HAE attacks or in between attacks during Period 1 of the study, who subsequently experienced an acute hereditary angioedema (HAE) attack continued to receive treatment with icatibant as a single SC administration per attack for a total of 3 eligible icatibant exposures.

    Serious adverse events
    Prepubertal Pubertal/Post-pubertal
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 21 (0.00%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Prepubertal Pubertal/Post-pubertal
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    4 / 11 (36.36%)
    8 / 21 (38.10%)
    Injury, poisoning and procedural complications
    Epiphyseal fracture
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 21 (0.00%)
         occurrences all number
    1
    0
    Thermal burn
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 21 (0.00%)
         occurrences all number
    1
    0
    Investigations
    Nitrite urine present
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 21 (0.00%)
         occurrences all number
    1
    0
    Respiratory, thoracic and mediastinal disorders
    Bronchospasm
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 21 (0.00%)
         occurrences all number
    2
    0
    Oropharyngeal pain
         subjects affected / exposed
    0 / 11 (0.00%)
    2 / 21 (9.52%)
         occurrences all number
    0
    2
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 21 (0.00%)
         occurrences all number
    1
    0
    Nervous system disorders
    Headache
         subjects affected / exposed
    1 / 11 (9.09%)
    1 / 21 (4.76%)
         occurrences all number
    2
    1
    Eye disorders
    Conjunctivitis
         subjects affected / exposed
    0 / 11 (0.00%)
    2 / 21 (9.52%)
         occurrences all number
    0
    5
    Conjunctivitis allergic
         subjects affected / exposed
    0 / 11 (0.00%)
    2 / 21 (9.52%)
         occurrences all number
    0
    9
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    0 / 11 (0.00%)
    2 / 21 (9.52%)
         occurrences all number
    0
    2
    Gastrointestinal disorders
    Toothache
         subjects affected / exposed
    0 / 11 (0.00%)
    2 / 21 (9.52%)
         occurrences all number
    0
    2
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 21 (0.00%)
         occurrences all number
    1
    0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 21 (0.00%)
         occurrences all number
    1
    0
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    0 / 11 (0.00%)
    3 / 21 (14.29%)
         occurrences all number
    0
    4
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 11 (9.09%)
    2 / 21 (9.52%)
         occurrences all number
    1
    3

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    05 Aug 2011
    - Safety assessments were amended to include ECG evaluations. - An investigator assessment utilizing a comportmental pain scale (FLACC) was added for the evaluation of abdominal symptoms of acute HAE in children below 4 years of age.
    06 Mar 2012
    - Determination of Tanner stage was eliminated in favor of simply stratifying subjects by pubertal status. - Clarifications were made to inclusion criterion pertaining to the definition of C1-INH deficiency. - Clarification to exclusion criterion was made to ensure that the text clearly prohibits subjects from participating in another concurrent interventional clinical study and to exclude subjects with a physical condition that interfered with pubertal status determination.
    19 Jun 2013
    - The number of adolescent subjects participating in the study remained at 20; however, 10 subjects were to be treated with icatibant during an HAE attack while the other 10 subjects were to be treated without an attack. - The number of prepubertal subjects was reduced from 16 to 10. - Adolescent subjects, including both those treated during an attack or not, could be offered further open-label treatment with icatibant for any subsequent HAE attacks that occurred at least 7 days after prior treatment.
    18 Mar 2016
    - A parent/legal guardian/caregiver was allowed to administer or the subject (under the supervision of a parent/legal guardian/caregiver) was allowed to self-administer the investigational product after having received appropriate training.

    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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