Subcutaneous Treatment With Icatibant for Acute Attacks of Hereditary Angioedema (HAE)

Study Overview
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Brief Summary
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Primary Outcome Measures: The primary endpoint was the time to onset of symptom relief of the first attack in the double blind phase. H0: λ icatibant/λ tranexamic acid =1 versus H1: λ icatibant/λ tranexamic acid ≠1 Where: λ icatibant refers to the hazard rate under icatibant and λ tranexamic acid refers to the hazard rate under tranexamic acid. Secondary Outcome Measures: Additional efficacy assessments (Time to Almost Complete Symptom Relief) Safety and tolerability Pharmacoeconomics

Detailed Description
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This was a Phase III, randomised, double blind, double dummy, multicentre, controlled,parallel group study of a 30 mg s.c. formulation of icatibant for the treatment of patients with moderate to very severe symptoms of cutaneous and/or abdominal symptoms of HAE. The study consisted of two parts: controlled phase and OLE phase. For the primary endpoint, Efficacy was determined by evaluating the differences in study outcomes using a Visual Analogue Scale for patients treated with icatibant and tranexamic acid.

Official Title
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Randomised Double Blind, Controlled, Parallel Group, Multicentre Study of a Subcutaneous Formulation of Icatibant Versus Oral Tranexamic Acid for the Treatment of Hereditary Angioedema (HAE)

Conditions
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Hereditary Angioedema

Intervention / Treatment
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* Drug: Icatibant
* Drug: Tranexamic Acid
* Drug: Oral Placebo
* Drug: S.C. Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age above 18 years; Documented diagnosis of HAE Type I or II (confirmed C1-INH deficiency); Current edema in the cutaneous, abdominal and/or laryngeal areas; Current edema moderate to severe according to the investigator's Symptom Score. Exclusion Criteria: Diagnosis of angioedema other than HAE, Participation in a clinical trial of another investigational medicinal product (IMP)within the past month Treatment with any pain medication since onset of the current angioedema attack Treatment with replacement therapy, including C1-INH products, less than 3 days before onset of the current angioedema attack Treatment with Tranexamic acid replacement therapy within a week before onset of the current angioedema attack Treatment with ACE inhibitors Contraindications for Tranexamic acid Evidence of coronary artery disease based on medical history or Screening examination in particular unstable angina pectoris or severe coronary heart disease Congestive heart failure (class 3 and 4) Serum creatinine level of ≥ 250 μmol/L Serious concomitant illness that the investigator considered to be a contraindication for participation in the trial Pregnancy (as assessed prior to treatment) and/or breast-feeding

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Randomized controlled -Icatibant<br>Subjects received S.C icatibant+ oral placebo Icatibant Form: solution for injection, 3 mL, 10 mg/mL Single dose: 30 mg (3 mL) Placebo Form: hard capsule Single dose: 2 capsules Frequency: 3 x 2 capsules for 2 days, taken orally, 6 to 8 hours apart | Drug: Icatibant<br>* Icatibant: a stable, synthetic decapeptide and specific BK B2 receptor antagonist.<br>* Other names: Brand name, Firazyr®;Drug: Oral Placebo<br>* hard capsule matched to tranexamic acid<br>* Other names: Placebo;|
| Active Comparator: Randomized controlled-Tranexamic acid<br>Subjects received oral Tranexamic acid+ S.C. placebo Tranexamic acid Form: over encapsulated film tablet Single dose: 1000 mg (2 capsules) Frequency: 3 x 2 capsules for 2 days, taken orally, 6 to 8 hours apart Placebo Form: solution for injection, matched to icatibant for injection Single dose: 3 mL Frequency: one subcutaneous injection in the abdominal region | Drug: Tranexamic Acid<br>* over encapsulated film tablet an anti-fibrinolytic agent,is used in some European countries for the treatment of acute oedema episodes and the continuous prophylaxis of HAE.<br>Drug: S.C. Placebo<br>* solution for injection, matched to icatibant for injection<br>* Other names: Placebo;|
| Experimental: Controlled Open-label / laryngeal attack<br>Patients with laryngeal symptoms at the baseline were not randomised but treated with icatibant open label during the controlled phase. | Drug: Icatibant<br>* Icatibant: a stable, synthetic decapeptide and specific BK B2 receptor antagonist.<br>* Other names: Brand name, Firazyr®;|
| Experimental: Untreated patients at the baseline<br>Patients who were screened and found eligible but did not experience an angioedema attack, or had an attack that was not severe enough to merit treatment while the controlled phase was ongoing were treated in the open label phase with icatibant | Drug: Icatibant<br>* Icatibant: a stable, synthetic decapeptide and specific BK B2 receptor antagonist.<br>* Other names: Brand name, Firazyr®;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to Onset of Symptom Relief. | The primary efficacy endpoint was Time to onset of symptom relief (TOSR) following treatment with either icatibant or tranexamic acid. The median time to onset of symptom relief for the icatibant group was compared to the the median time to onset of symptom relief for the tranexamic acid group. TOSR was defined as the time between time of injection to time of first documented onset of symptom relief for the three primary symptoms: cutaneous swelling, cutaneous skin, and abdominal pain. The primary symptom was based on the type of attack. For abdominal attacks, the single primary symptom was abdominal pain. For cutaneous attacks, the single primary symptom was either skin swelling or skin pain, whichever was most severe. | 2 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to Almost Complete Symptom Relief | Almost complete symptom relief was defined as a score between 0 and 10 mm on the VAS for at least three consecutive measurements for all symptoms. | 48 hours |