Clinical Trial Results:
A Phase 3, Randomized, Double-Blind, Placebo-Controlled, Multicenter Clinical Study Evaluating the Safety and Efficacy of Icatibant as a Treatment for Angiotensin-Converting Enzyme Inhibitor (ACE-I)-Induced Angioedema in Adults
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Summary
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EudraCT number |
2014-001213-12 |
Trial protocol |
GB |
Global end of trial date |
22 Aug 2015
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Results information
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Results version number |
v1(current) |
This version publication date |
02 Sep 2016
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First version publication date |
02 Sep 2016
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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-096
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
- | ||
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, Massachusetts, United States, 02421
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Public contact |
Study Physician, Shire, +1 1 866-842-5335,
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Scientific contact |
Study Physician, Shire, +1 1 866-842-5335,
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
No
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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? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
22 Aug 2015
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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 |
22 Aug 2015
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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 was to compare the efficacy of icatibant with placebo in the treatment of angiotensin-converting enzyme inhibitor (ACE-I)-induced angioedema based on the time to meeting discharge criteria (TMDC) endpoint.
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Protection of trial subjects |
This study was conducted in accordance with International Conference on Harmonisation (ICH) of Good Clinical Practice, the principles of the Declaration of Helsinki, as well as other applicable local ethical and legal requirements.
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
02 Dec 2013
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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: 105
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Country: Number of subjects enrolled |
Canada: 10
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Country: Number of subjects enrolled |
United Kingdom: 5
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Country: Number of subjects enrolled |
Israel: 1
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Worldwide total number of subjects |
121
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EEA total number of subjects |
5
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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) |
0
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Adolescents (12-17 years) |
0
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Adults (18-64 years) |
70
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From 65 to 84 years |
51
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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 59 sites in the United States, United Kingdom, Israel and Canada. | ||||||||||||||||||||||||
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Pre-assignment
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Screening details |
Overall 121 subjects were randomized, of which 118 received the study medication, and 117 completed the study. | ||||||||||||||||||||||||
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Period 1
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Period 1 title |
Overall Study (overall period)
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Is this the baseline period? |
Yes | ||||||||||||||||||||||||
Allocation method |
Randomised - controlled
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Blinding used |
Double blind | ||||||||||||||||||||||||
Roles blinded |
Subject, Investigator, Carer, Assessor | ||||||||||||||||||||||||
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Arms
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Are arms mutually exclusive |
Yes
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Arm title
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Icatibant 30 mg | ||||||||||||||||||||||||
Arm description |
Subjects received a single dose of icatibant 30 milligram (mg) subcutaneous (SC) injection within 12 hours after the onset of the angiotensin-converting enzyme inhibitor (ACE-I) induced angioedema attack. | ||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||
Investigational medicinal product name |
Icatibant
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Investigational medicinal product code |
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Other name |
Firazyr
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Pharmaceutical forms |
Solution for injection
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Routes of administration |
Subcutaneous use
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Dosage and administration details |
Subjects received a single dose of icatibant 30 mg SC injection within 12 hours after the onset of the ACE-I induced angioedema attack.
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Arm title
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Placebo | ||||||||||||||||||||||||
Arm description |
Subjects received a single dose of placebo matched to icatibant SC injection within 12 hours after the onset of the ACE-I induced angioedema attack. | ||||||||||||||||||||||||
Arm type |
Placebo | ||||||||||||||||||||||||
Investigational medicinal product name |
Placebo
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Solution for injection
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Routes of administration |
Subcutaneous use
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Dosage and administration details |
Subjects received a single dose of placebo matched to icatibant 30 mg SC injection within 12 hours after the onset of the ACE-I induced angioedema attack.
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Baseline characteristics reporting groups
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Reporting group title |
Icatibant 30 mg
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Reporting group description |
Subjects received a single dose of icatibant 30 milligram (mg) subcutaneous (SC) injection within 12 hours after the onset of the angiotensin-converting enzyme inhibitor (ACE-I) induced angioedema attack. | ||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Placebo
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Reporting group description |
Subjects received a single dose of placebo matched to icatibant SC injection within 12 hours after the onset of the ACE-I induced angioedema attack. | ||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Icatibant 30 mg
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Reporting group description |
Subjects received a single dose of icatibant 30 milligram (mg) subcutaneous (SC) injection within 12 hours after the onset of the angiotensin-converting enzyme inhibitor (ACE-I) induced angioedema attack. | ||
Reporting group title |
Placebo
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Reporting group description |
Subjects received a single dose of placebo matched to icatibant SC injection within 12 hours after the onset of the ACE-I induced angioedema attack. | ||
Subject analysis set title |
Metabolite M1
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Subject analysis set type |
Full analysis | ||
Subject analysis set description |
Subjects received a single dose of icatibant 30 mg sc injection within 12 hours after the onset of the ACE-I induced angioedema attack and assessed for metabolite M1.
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Subject analysis set title |
Metabolite M2
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Subject analysis set type |
Full analysis | ||
Subject analysis set description |
Subjects received a single dose of icatibant 30 mg sc injection within 12 hours after the onset of the ACE-I induced angioedema attack and assessed for metabolite M2.
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End point title |
Time to Meeting Discharge Criteria (TMDC) | ||||||||||||
End point description |
TMDC was based on the investigator-assessed angioedema-associated upper airway symptom assessments. It was calculated from the time of study drug administration to the earliest time point at which the symptoms of difficulty breathing and difficulty swallowing were absent and the symptoms of voice change and tongue swelling were mild or absent and all subsequent assessments continued to satisfy these conditions. These symptoms were evaluated by the investigator using a 5-point grading scale (0=absent, 1=mild, 2=moderate, 3=severe, and 4=very severe). TMDC was analysed using Kaplan-Meier estimates. Intent-to-treat (ITT) population included all randomized subjects.
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End point type |
Primary
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End point timeframe |
Day 0 up to Day 5
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Statistical analysis title |
TMDC | ||||||||||||
Statistical analysis description |
A total of 121 subjects were analysed, however 3 subjects did not receive the study medication and were censored at time 0.
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Comparison groups |
Icatibant 30 mg v Placebo
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Number of subjects included in analysis |
121
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
P-value |
= 0.633 [1] | ||||||||||||
Method |
Adjusted Peto-Prentice | ||||||||||||
Confidence interval |
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| Notes [1] - Test was performed using a weighted log-rank test called the Peto-Prentice test with a global 2-sided significance level of 5 percent (%) after adjusting for stratification factors (race, and severity) in the ITT population. |
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End point title |
Number of Subjects With Treatment-emergent Adverse Events (TEAE) and Treatment-emergent Serious Adverse Events (TESAEs) [2] | ||||||||||||||||||
End point description |
An adverse event (AE) was any untoward medical occurrence in a subject who received study drug without regard to possibility of causal relationship. An serious adverse event (SAE) was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. TEAEs were defined as adverse events/serious adverse events that started or worsened after the study drug treatment. Safety population included all subjects who received the study drug.
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End point type |
Primary
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End point timeframe |
From start of study drug administration (Day 0) up to follow-up (Day 5)
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| Notes [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Descriptive statistics were planned to report and inferential statistics were not planned. |
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| No statistical analyses for this end point | |||||||||||||||||||
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End point title |
Number of Subjects with Treatment Emergent Injection Site Reaction [3] | ||||||||||||||||||||||||||||||
End point description |
Injection site reaction included erythema, swelling, cutaneous pain, burning sensation, itching and warm sensation. Safety population included all subjects who received the study drug.
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End point type |
Primary
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End point timeframe |
Day 0 to Day 5
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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 planned to report and inferential statistics were not planned. |
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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 Laboratory Evaluation, Vital Signs, Electrocardiogram (ECG) and Physical Examination [4] | ||||||||||||
End point description |
Safety population included all subjects who received the study drug.
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End point type |
Primary
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End point timeframe |
Day 0 to Day 5
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| Notes [4] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Descriptive statistics were planned to report and inferential statistics were not planned. |
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Time to Onset of Symptom Relief (TOSR) | ||||||||||||
End point description |
TOSR was calculated for the individual symptoms with pre-treatment scores of 2 (moderate) or more improved by at least 1 severity grade and the individual symptoms with pretreatment scores of 0 or 1 (absent or mild) were scored again at 0 or 1 and all the subsequent assessments continued to satisfy this condition. Time-to-event data were summarized using Kaplan-Meier estimates. ITT population included all randomized participants.
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End point type |
Secondary
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End point timeframe |
Day 0 up to Day 5
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Number of Subjects Experienced Airway Intervention due to ACE-I-induced Angioedema | ||||||||||||
End point description |
Airway Intervention included intubation, tracheotomy, cricothyrotomy. Modified Intent to treat (mITT) population included all randomized participants who received the study drug.
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End point type |
Secondary
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End point timeframe |
Day 0 up to Day 5
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Number of Subjects Admitted to Hospital or Intensive Care Unit (ICU) | ||||||||||||
End point description |
Number of subjects with and without an occurrence of admission to the hospital (inpatient) or ICU post-treatment due to the ACE-I-induced angioedema attack were described. mITT population included all randomized subjects who received the study drug.
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End point type |
Secondary
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End point timeframe |
Day 0 up to Day 5
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Number of Subjects Experienced ACE-I-induced Angioedema Attack Following Study Drug Administration | ||||||||||||
End point description |
Number of subjects with the use of conventional medications (corticosteroids, antihistamines, epinephrine) for the treatment of symptoms of the ACE-I- induced angioedema attack following study drug administration were presented. mITT population included all randomized subjects who received the study drug.
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End point type |
Secondary
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End point timeframe |
Day 0 up to Day 5
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Percentage of Subjects With Time to Meeting Discharge Criteria (TMDC) at specified time points | |||||||||||||||||||||
End point description |
mITT population included all randomized subjects.
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End point type |
Secondary
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End point timeframe |
4, 6, and 8 hours post treatment
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| No statistical analyses for this end point | ||||||||||||||||||||||
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End point title |
Maximum Observed Serum Concentration (Cmax) of Icatibant and its Metabolites (M1 and M2) [5] | ||||||||||||||||||||
End point description |
Cmax is the peak plasma concentration of a drug after administration. Pharmacokinetic (PK) analysis included all subjects in the safety population who received study drug and provided evaluable plasma drug concentrations.
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End point type |
Other pre-specified
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End point timeframe |
0.75 and 2 hours post-dose
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| Notes [5] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: Descriptive statistics were planned to report and inferential statistics were not planned. |
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| No statistical analyses for this end point | |||||||||||||||||||||
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End point title |
Area Under the Plasma Concentration Versus Time Curve (AUC[0-24]) of Icatibant and its Metabolites (M1 and M2) [6] | ||||||||||||||
End point description |
Area under the plasma concentration-time curve from time zero to 24 hours post-dose (AUC[0-24]). PK analysis included all subjects in the safety population who received study drug and provided evaluable plasma drug concentrations.
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End point type |
Other pre-specified
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End point timeframe |
0.75 and 2 hours post-dose
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| Notes [6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period. Justification: Descriptive statistics were planned to report and inferential statistics were not planned. |
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| No statistical analyses for this end point | |||||||||||||||
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Adverse events information
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Timeframe for reporting adverse events |
From start of study treatment up to Day 5
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Adverse event reporting additional description |
Injection site reactions were reported separately from general reports of adverse events as they were considered as adverse events of special interest.
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Assessment type |
Non-systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
16.0
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Reporting groups
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Reporting group title |
Placebo
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Reporting group description |
Subjects received a single dose of placebo matched to icatibant SC injection within 12 hours after the onset of the ACEI induced angioedema attack. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Icatibant 30 mg
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Reporting group description |
Subjects received a single dose of icatibant 30 mg SC injection within 12 hours after the onset of the ACE-I-induced angioedema attack. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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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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02 Sep 2014 |
-Added a new exclusion criterion.
-Text were made to clarify an existing exclusion criterion and several operational aspects of the study and to describe the secondary packaging of the study drug. |
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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 | |||
