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
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Summary
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EudraCT number |
2011-003825-81 |
Trial protocol |
DE HU ES IT AT |
Global end of trial date |
12 Mar 2018
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Results information
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Results version number |
v1(current) |
This version publication date |
27 Sep 2018
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First version publication date |
27 Sep 2018
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Other versions |
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Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
HGT-FIR-086
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT01386658 | ||
WHO universal trial number (UTN) |
- | ||
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Sponsors
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Sponsor organisation name |
Shire
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Sponsor organisation address |
300 Shire Way, Lexington, United States, MA 02421
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Public contact |
Study Director, Shire, ClinicalTransparency@shire.com
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Scientific contact |
Study Director, Shire, ClinicalTransparency@shire.com
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
Yes
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EMA paediatric investigation plan number(s) |
EMEA-000408-PIP02-12 | ||
Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
Yes
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
12 Mar 2018
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Is this the analysis of the primary completion data? |
No
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Global end of trial reached? |
Yes
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Global end of trial date |
12 Mar 2018
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Was the trial ended prematurely? |
No
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General information about the trial
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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).
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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.
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
27 Jan 2012
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
Yes
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
United States: 10
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Country: Number of subjects enrolled |
Colombia: 1
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Country: Number of subjects enrolled |
Australia: 1
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Country: Number of subjects enrolled |
Hungary: 4
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Country: Number of subjects enrolled |
Israel: 7
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Country: Number of subjects enrolled |
Italy: 1
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Country: Number of subjects enrolled |
Spain: 3
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Country: Number of subjects enrolled |
Austria: 3
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Country: Number of subjects enrolled |
Germany: 2
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Worldwide total number of subjects |
32
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EEA total number of subjects |
13
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
0
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Children (2-11 years) |
15
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Adolescents (12-17 years) |
17
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Adults (18-64 years) |
0
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From 65 to 84 years |
0
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85 years and over |
0
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Recruitment
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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). | ||||||||||||||||||
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Pre-assignment
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Screening details |
A total of 32 subjects were enrolled and received treatment. | ||||||||||||||||||
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Period 1
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Period 1 title |
Initial Icatibant Exposure
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Is this the baseline period? |
Yes | ||||||||||||||||||
Allocation method |
Non-randomised - controlled
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Blinding used |
Not blinded | ||||||||||||||||||
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Arms
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Are arms mutually exclusive |
Yes
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Arm title
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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
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Investigational medicinal product code |
JE049
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Other name |
Firazyr
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Pharmaceutical forms |
Solution for injection in pre-filled syringe
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Routes of administration |
Subcutaneous use
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Dosage and administration details |
Subjects received SC injection of icatibant in the abdominal region.
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Arm title
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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
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Investigational medicinal product code |
JE049
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Other name |
Firazyr
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Pharmaceutical forms |
Solution for injection in pre-filled syringe
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Routes of administration |
Subcutaneous use
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Dosage and administration details |
Subjects received SC injection of icatibant in the abdominal region.
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Period 2
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Period 2 title |
Icatibant Exposure 2
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Is this the baseline period? |
No | ||||||||||||||||||
Allocation method |
Not applicable
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Blinding used |
Not blinded | ||||||||||||||||||
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Arms
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Arm title
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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
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Investigational medicinal product code |
JE049
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Other name |
Firazyr
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Pharmaceutical forms |
Solution for injection in pre-filled syringe
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Routes of administration |
Subcutaneous use
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Dosage and administration details |
Subjects received SC injection of icatibant in the abdominal region.
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Period 3
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Period 3 title |
Icatibant Exposure 3
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Is this the baseline period? |
No | ||||||||||||||||||
Allocation method |
Not applicable
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Blinding used |
Not blinded | ||||||||||||||||||
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Arms
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Arm title
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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
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Investigational medicinal product code |
JE049
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Other name |
Firazyr
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Pharmaceutical forms |
Solution for injection in pre-filled syringe
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Routes of administration |
Subcutaneous use
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Dosage and administration details |
Subjects received SC injection of icatibant in the abdominal region.
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Baseline characteristics reporting groups
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Reporting group title |
Prepubertal
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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
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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. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Prepubertal
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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
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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
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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
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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
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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.
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Subject analysis set title |
Pubertal/postpubertal: without acute attack
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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.
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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.
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End point type |
Primary
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End point timeframe |
Pre-dose; 0.25, 0.5, 0.75, 1, 2, 4 and 6 hours post-dose on Day 1
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| 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. |
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| No statistical analyses for this end point | |||||||||||||||||||||
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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.
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End point type |
Primary
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End point timeframe |
Pre-dose; 0.25, 0.5, 0.75, 1, 2, 4 and 6 hours post-dose on Day 1
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| 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. |
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| No statistical analyses for this end point | |||||||||||||||||||||
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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.
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End point type |
Primary
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End point timeframe |
Pre-dose; 0.25, 0.5, 0.75, 1, 2, 4 and 6 hours post-dose on Day 1
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| 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. |
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| No statistical analyses for this end point | |||||||||||||||||||||
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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.
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End point type |
Primary
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End point timeframe |
Pre-dose; 0.25, 0.5, 0.75, 1, 2, 4 and 6 hours post-dose on Day 1
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| 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. |
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| No statistical analyses for this end point | |||||||||||||||||||||
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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.
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End point type |
Primary
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End point timeframe |
Pre-dose; 0.25, 0.5, 0.75, 1, 2, 4 and 6 hours post-dose on Day 1
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| 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. |
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| No statistical analyses for this end point | |||||||||||||||||||||
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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.
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End point type |
Primary
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End point timeframe |
Pre-dose; 0.25, 0.5, 0.75, 1, 2, 4 and 6 hours post-dose on Day 1
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| 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. |
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| No statistical analyses for this end point | |||||||||||||||||||||
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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.
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End point type |
Primary
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End point timeframe |
Pre-dose; 0.25, 0.5, 0.75, 1, 2, 4 and 6 hours post-dose on Day 1
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| 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. |
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| No statistical analyses for this end point | |||||||||||||||||||||
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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.
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End point type |
Primary
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End point timeframe |
Pre-dose; 0.25, 0.5, 0.75, 1, 2, 4 and 6 hours post-dose on Day 1
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| 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. |
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| No statistical analyses for this end point | |||||||||||||||||||||
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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.
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End point type |
Primary
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End point timeframe |
Pre-dose up to 97 days post-dose
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| 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. |
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| No statistical analyses for this end point | |||||||||||||
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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.
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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. |
|||||||||||||
|
|||||||||||||
| No statistical analyses for this end point | |||||||||||||
|
|||||||||||||
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. |
|||||||||||||
|
|||||||||||||
| No statistical analyses for this end point | |||||||||||||
|
|||||||||||||
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. |
|||||||||||||
|
|||||||||||||
| No statistical analyses for this end point | |||||||||||||
|
|||||||||||||
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. |
|||||||||||||
|
|||||||||||||
| No statistical analyses for this end point | |||||||||||||
|
||||||||||||||||
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. |
||||||||||||||||
|
||||||||||||||||
| No statistical analyses for this end point | ||||||||||||||||
|
||||||||||||||||||||||
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. |
||||||||||||||||||||||
|
||||||||||||||||||||||
| No statistical analyses for this end point | ||||||||||||||||||||||
|
|||||||||||||
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. |
|||||||||||||
|
|||||||||||||
| No statistical analyses for this end point | |||||||||||||
|
||||||||||||||||
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
|
|||||||||||||||
|
||||||||||||||||
| No statistical analyses for this end point | ||||||||||||||||
|
|||||||||||||||||||
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
|
||||||||||||||||||
|
|||||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||||
|
||||||||||||||||
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
|
|||||||||||||||
|
||||||||||||||||
| No statistical analyses for this end point | ||||||||||||||||
|
|||||||||||||||||||
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
|
||||||||||||||||||
|
|||||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||||
|
|||||||||||
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. |
|||||||||||
|
|||||||||||
| No statistical analyses for this end point | |||||||||||
|
||||||||||||||||
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
|
|||||||||||||||
|
||||||||||||||||
| No statistical analyses for this end point | ||||||||||||||||
|
|||||||||||||||||||
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
|
||||||||||||||||||
|
|||||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||||
|
||||||||||||||||
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
|
|||||||||||||||
|
||||||||||||||||
| No statistical analyses for this end point | ||||||||||||||||
|
|||||||||||||||||||
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
|
||||||||||||||||||
|
|||||||||||||||||||
| No statistical analyses for this end point | |||||||||||||||||||
|
|||||||||||
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. |
|||||||||||
|
|||||||||||
| No statistical analyses for this end point | |||||||||||
|
||||||||||||||||
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
|
|||||||||||||||
|
||||||||||||||||
| Notes [27] - This analysis was not performed. [28] - This analysis was not performed. |
||||||||||||||||
| No statistical analyses for this end point | ||||||||||||||||
|
||||||||||||||||||||||||||||||||||
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
|
|||||||||||||||||||||||||||||||||
|
||||||||||||||||||||||||||||||||||
| No statistical analyses for this end point | ||||||||||||||||||||||||||||||||||
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| No statistical analyses for this end point | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
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
|
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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. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Frequency threshold for reporting non-serious adverse events: 5% | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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| Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
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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. |
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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. |
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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. |
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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. |
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Interruptions (globally) |
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| Were there any global interruptions to the trial? No | |||
Limitations and caveats |
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| Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
| None reported | |||
