Subcutaneous Treatment With Icatibant for Acute Attacks of Hereditary Angioedema (HAE) (FAST2)

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)

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

Study Overview

• Status: Completed
• Conditions: Hereditary Angioedema
• Intervention / Treatment: Drug: Icatibant; Drug: Oral Placebo; Drug: Tranexamic Acid; Drug: S.C. Placebo

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 85
• Phase: Phase 3

Contacts and Locations

Study Locations

• Italy
  • Milano, Italy, 20123
    • Università degli Studi di Milano, Dipartimento di Medicina Interna

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Randomized controlled -Icatibant; 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; Icatibant: a stable, synthetic decapeptide and specific BK B2 receptor antagonist.; Other Names: Brand name, Firazyr®; Drug: Oral Placebo; hard capsule matched to tranexamic acid; Other Names: Placebo
Active Comparator: Randomized controlled-Tranexamic acid; 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; 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.; Drug: S.C. Placebo; solution for injection, matched to icatibant for injection; Other Names: Placebo
Experimental: Controlled Open-label / laryngeal attack; Patients with laryngeal symptoms at the baseline were not randomised but treated with icatibant open label during the controlled phase.	Drug: Icatibant; Icatibant: a stable, synthetic decapeptide and specific BK B2 receptor antagonist.; Other Names: Brand name, Firazyr®
Experimental: Untreated patients at the baseline; 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; Icatibant: a stable, synthetic decapeptide and specific BK B2 receptor antagonist.; Other Names: Brand name, Firazyr®

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Shire

Publications and helpful links

General Publications

• Bas M, Bier H, Greve J, Kojda G, Hoffmann TK. Novel pharmacotherapy of acute hereditary angioedema with bradykinin B2-receptor antagonist icatibant. Allergy. 2006 Dec;61(12):1490-2. doi: 10.1111/j.1398-9995.2006.01197.x. No abstract available.
• Bas M, Greve J, Hoffmann TK, Reshef A, Aberer W, Maurer M, Kivity S, Farkas H, Floccard B, Arcoleo F, Martin L, Sitkauskiene B, Bouillet L, Schmid-Grendelmeier P, Li H, Zanichelli A. Repeat treatment with icatibant for multiple hereditary angioedema attacks: FAST-2 open-label study. Allergy. 2013 Nov;68(11):1452-9. doi: 10.1111/all.12244. Epub 2013 Sep 21.
• Cicardi M, Banerji A, Bracho F, Malbran A, Rosenkranz B, Riedl M, Bork K, Lumry W, Aberer W, Bier H, Bas M, Greve J, Hoffmann TK, Farkas H, Reshef A, Ritchie B, Yang W, Grabbe J, Kivity S, Kreuz W, Levy RJ, Luger T, Obtulowicz K, Schmid-Grendelmeier P, Bull C, Sitkauskiene B, Smith WB, Toubi E, Werner S, Anne S, Bjorkander J, Bouillet L, Cillari E, Hurewitz D, Jacobson KW, Katelaris CH, Maurer M, Merk H, Bernstein JA, Feighery C, Floccard B, Gleich G, Hebert J, Kaatz M, Keith P, Kirkpatrick CH, Langton D, Martin L, Pichler C, Resnick D, Wombolt D, Fernandez Romero DS, Zanichelli A, Arcoleo F, Knolle J, Kravec I, Dong L, Zimmermann J, Rosen K, Fan WT. Icatibant, a new bradykinin-receptor antagonist, in hereditary angioedema. N Engl J Med. 2010 Aug 5;363(6):532-41. doi: 10.1056/NEJMoa0906393. Erratum In: N Engl J Med. 2010 Oct 7;363(15):1486.

Study record dates

Study Major Dates

• Study Start (Actual): March 1, 2005
• Primary Completion (Actual): July 25, 2006
• Study Completion (Actual): July 25, 2006

Study Registration Dates

• First Submitted: July 12, 2007
• First Submitted That Met QC Criteria: July 12, 2007
• First Posted (Estimate): July 13, 2007

Study Record Updates

• Last Update Posted (Actual): June 9, 2021
• Last Update Submitted That Met QC Criteria: May 24, 2021
• Last Verified: May 1, 2021

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Skin Diseases; Immunologic Deficiency Syndromes; Immune System Diseases; Hypersensitivity, Immediate; Genetic Diseases, Inborn; Skin Diseases, Vascular; Hypersensitivity; Urticaria; Hereditary Complement Deficiency Diseases; Primary Immunodeficiency Diseases; Angioedema; Angioedemas, Hereditary; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Peripheral Nervous System Agents; Analgesics; Sensory System Agents; Anti-Inflammatory Agents, Non-Steroidal; Analgesics, Non-Narcotic; Anti-Inflammatory Agents; Antirheumatic Agents; Fibrin Modulating Agents; Immunosuppressive Agents; Immunologic Factors; Antifibrinolytic Agents; Hemostatics; Coagulants; Complement Inactivating Agents; Bradykinin B2 Receptor Antagonists; Bradykinin Receptor Antagonists; Tranexamic Acid; Icatibant
• Other Study ID Numbers: JE049 #2102; 2004-001540-71 (EudraCT Number)