A Study of Icatibant in Patients With Acute Attacks of Hereditary Angioedema (FAST-3)

A Phase III Randomized, Double-Blind,Placebo-Controlled, Multicenter Study of Icatibant for Subcutaneous Injection in Patients With Acute Attacks of Hereditary Angioedema (HAE)

This study is being conducted to evaluate the efficacy and safety of icatibant compared to placebo in patients experiencing acute attacks of hereditary angioedema (HAE).

Study Overview

• Status: Completed
• Conditions: Hereditary Angioedema
• Intervention / Treatment: Drug: Icatibant; Drug: Placebo

Detailed Description

This Phase III study consisted of two parts: A controlled phase and an open label extension (OLE) phase.

The controlled phase describes the double blind part of the study and was intended to evaluate the efficacy and safety of icatibant compared with placebo for the first treated cutaneous and/or abdominal attack.

Patients with moderate to severe abdominal or cutaneous attacks were randomized to receive a single, blinded, subcutaneous injection of icatibant (30 mg) or placebo. After a protocol amendment, patients with mild to moderate laryngeal HAE attacks were also randomized to receive a single, blinded subcutaneous injection of icatibant (30 mg) or placebo in order to obtain blinded, controlled efficacy and safety data for this subset of subjects. Patients experiencing severe laryngeal attacks (post-amendment) or mild to severe laryngeal attacks (pre-amendment) were to receive open-label icatibant.

After treatment of the first attack in the controlled phase, patients were eligible to enter the OLE phase. In the OLE phase, patients who experienced angioedema attacks severe enough to warrant treatment were to be treated with s.c. icatibant as appropriate until the study was discontinued or the product was commercially available.

• Study Type: Interventional
• Enrollment (Actual): 98
• Phase: Phase 3

Contacts and Locations

Study Locations

• Australia
  • Adelaide, Australia
    • Royal Adelaide Hospital
  • Australian Capital Territory
    • Garran, Australian Capital Territory, Australia
      • Canberra Hospital Department of Immunology
  • New South Wales
    • Campbelltown, New South Wales, Australia, 2560
      • Dept of Medicine Immunology & Allergy Campbelltown Hospital
  • Victoria
    • Parkville, Victoria, Australia, 3050
      • Royal Melbourne Hospital Department of Immunology
• Canada
  • Alberta
    • Edmonton, Alberta, Canada, T6G 2H7
      • NACTRC
  • Ontario
    • Ottawa, Ontario, Canada, K1Y 4G2
      • Allergy & Asthma Research Centre
  • Quebec
    • Quebec City, Quebec, Canada, G1V 5M6
      • Centre De Recherche Appliquée en Allergie De Québec
• Hungary
  • Budapest, Hungary, 1125
    • 3rd Department of Internal Medicine Semmelweis University
• Israel
  • Haifa, Israel, 31048
    • Bnai-Zion Medical Center Division of Immunology & Allergy
  • Tel Aviv, Israel, 64239
    • Tel Aviv Medical Center
  • Tel Hashomer, Israel, 52621
    • The Chaim Sheba Medical Center
• Romania
  • Transylvania
    • Targu Mures, Transylvania, Romania, 540103
      • Spitalul Clinic Judetean Mures Sectia Medicina Interna
• Russian Federation
  • Moscow, Russian Federation, 115446
    • State Healthcare Institution of City of Moscow
  • Moscow, Russian Federation, 115478
    • State Enterprise State Scientific Centre
  • Moscow, Russian Federation, 123182
    • State Educational Institution of Additional Profess. Edu. Moscow
  • Smolensk, Russian Federation, 214001
    • Municipal Medical & Preventive Treatment Institution
  • Vladivostok, Russian Federation, 690091
    • Regional Clinical Center of Specialized Medical Treatment
  • Saint Petersburg
    • St Petersburg, Saint Petersburg, Russian Federation, 194291
      • Medical Academy of Postgraduate Education
    • St Petersburg, Saint Petersburg, Russian Federation, 198216
      • Autonomous Non Commercial Organization
• South Africa
  • Mowbray
    • Cape Town, Mowbray, South Africa, 7700
      • Allergy Diagnostic and Clinical Research Unit (ADCRU)
• Ukraine
  • Ivano-Frankivsk, Ukraine, 76018
    • Ivano-Frankivsk National Medical University
  • Kyiv, Ukraine, 01133
    • National Medical Academy for Postgraduate Education
  • Kyiv, Ukraine, 03680
    • Institute of Otolaryngology
  • Poltava, Ukraine, 36039
    • Ukranian Medical Stomatological Academy Dept of Int Diseases
  • Vinnitsa, Ukraine, 21029
    • Vinnitsa Medical Academy Chair of Internal Disease
• United States
  • Alabama
    • Alabaster, Alabama, United States, 35007
      • Primary Care Associates of Alabaster
    • Birmingham, Alabama, United States, 35294
      • UAB Lung Health Center
  • Arizona
    • Scottsdale, Arizona, United States, 85251
      • Medical Research of AZ A Division of Allergy & Immunology Assoc
  • Arkansas
    • Little Rock, Arkansas, United States, 72205
      • Little Rock Allergy & Asthma Clinic, PA
  • California
    • Granada Hills, California, United States, 91344
      • Allergy and Asthma Insititute of the Valley
    • La Jolla, California, United States, 92093
      • University of California San Diego
    • Los Angeles, California, United States, 90095
      • UCLA - Clinical Immunology & Allergy
    • Stanford, California, United States, 27330
      • Speciality Medical Clinic & Research Center
    • Stanford, California, United States, 94305
      • Standford University
  • Colorado
    • Colorado Springs, Colorado, United States, 80907
      • Asthma & Allergy Associates, PC
  • Florida
    • Melbourne, Florida, United States, 32935
      • Medical Associates of Brevard
    • Tampa, Florida, United States, 33613
      • University of South Florida Division of Allergy and Immunology
  • Georgia
    • Atlanta, Georgia, United States, 30342
      • Family Allergy and Asthma Center, PC
  • Illinois
    • Chicago, Illinois, United States, 60612
      • Rush University Medical Center
  • Indiana
    • Evansville, Indiana, United States, 47713
      • Research Institute of Deaconess Clinic
  • Iowa
    • Iowa City, Iowa, United States, 52242
      • University of Iowa Asthma Center/ Hospitals & Clinics
  • Louisiana
    • Shreveport, Louisiana, United States, 71130
      • LSUHSC Allergy & Immunology
  • Maryland
    • Chevy Chase, Maryland, United States, 20815-6901
      • Institute for Asthman & Allergy, P.C.
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Massachusetts General Hospital
  • Missouri
    • Saint Louis, Missouri, United States, 63141
      • The Asthma Center
  • Nevada
    • Reno, Nevada, United States, 89503
      • University of Reno Nevada School of Medicine
  • New Jersey
    • Edison, New Jersey, United States, 08820
      • Starx Research Center, LLC
  • New York
    • Bronx, New York, United States, 10461
      • Montefiore Medical Center/Albert Einstein College of Medicine
    • Mineola, New York, United States, 11501
      • Winthrop University Hospital Clinical Trials Center
    • New York, New York, United States, 10029
      • Mount Sinai School of Medicine
  • North Carolina
    • Asheville, North Carolina, United States, 28801
      • Allergy Partners of Western North Carolina
    • Durham, North Carolina, United States, 27710
      • Duke University Medical Center
  • Ohio
    • Cincinnati, Ohio, United States, 45267
      • University of Cincinnati Division of Immunology/Allergy
    • Columbus, Ohio, United States, 43235
      • Optimed Research, LTD
  • Oklahoma
    • Tulsa, Oklahoma, United States, 74133
      • Tulsa Allergy Clinic
  • Oregon
    • Lake Oswego, Oregon, United States, 97035
      • Baker Allergy, Asthma & Dermatology Research Center LLC
  • Pennsylvania
    • Bethlehem, Pennsylvania, United States, 18020
      • Valley Clinical Research Center
    • Hershey, Pennsylvania, United States, 17033
      • Penn State Hershey Medical Center
    • Pittsburgh, Pennsylvania, United States, 15224
      • Children's Hospital of Pittsburgh (of UMPC)
  • Texas
    • Dallas, Texas, United States, 75231
      • AARA Research Center
    • Galveston, Texas, United States, 77555-0561
      • University of Texas Medical Branch (UTMB)
    • Houston, Texas, United States, 77030
      • Texas A&M Health Science Center College of Medicine
    • San Antonio, Texas, United States, 78229
      • Allergy and Asthma Research Center, P.A.
  • Utah
    • Salt Lake City, Utah, United States, 84132
      • University of Utah

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

Each patient must meet the following criteria to be enrolled in this study.

1. The patient is ≥18 years old at the time of informed consent.
2. The patient has a documented diagnosis of HAE type I or II. The diagnosis will be confirmed either by documented decreased C4 levels and/or immunogenic or functional C1-INH deficiency results (<50% of normal levels) consistent with HAE types I and II or by medical history.
3. The current HAE attack must be in the cutaneous, abdominal and/or laryngeal (inclusive of laryngeal and pharyngeal) areas.
4. Cutaneous or abdominal HAE attacks must be moderate to very severe as determined by investigator global assessment at pre-treatment assessments
5. The patient must report at least 1 VAS score ≥ 30mm
6. The patient commences treatment within 6 hours of the attack becoming at least mild (laryngeal) or moderate (non-laryngeal) in severity, but not more than 12 hours after the onset of the attack.
7. Women of childbearing potential must have a negative urine pregnancy test and must use appropriate methods to prevent pregnancy during their participation in the study.

Exclusion Criteria:

Patients who meet any of the following criteria will be excluded from the study.

1. The patient has a diagnosis of angioedema other than HAE type I or II.
2. The patient has received previous treatment with icatibant.
3. The patient has participated in a clinical trial and has received treatment with another investigational medicinal product within the past 30 days.
4. The patient has received treatment with any pain medication since the onset of the current angioedema attack.
5. The patient has received replacement therapy (fresh frozen plasma [FFP], C1-INH products) less than 5 days (120 hours) from the onset of the current angioedema attack.
6. The patient is receiving treatment with angiotensin converting enzyme (ACE) inhibitors.
7. Evidence of coronary artery disease based on medical history or screening examination in particular unstable angina pectoris or severe coronary heart disease;
8. The patient has a serious concomitant illness or condition that, in the opinion of the Investigator, would be a contraindication for participation in the trial.
9. The patient is pregnant or breastfeeding.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo; Single subcutaneous injection of matching placebo	Drug: Placebo; Single subcutaneous injection of matching placebo
Experimental: Icatibant; Single subcutaneous injection of icatibant, 30 mg	Drug: Icatibant; Single subcutaneous injection of icatibant, 30 mg; Other Names: Firazyr

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time to Onset of Symptom Relief for an Acute Attack, as Assessed by the Patient	Time to onset of symptom relief was calculated from study drug administration to onset of symptom relief, where onset of symptom relief was defined as the earliest of 3 consecutive measurements in which there was a 50% reduction from pretreatment in composite VAS score. Composite VAS score comprised 3 symptoms, including skin swelling, skin pain, and abdominal pain, for cutaneous and abdominal attacks and 5 symptoms, including skin swelling, skin pain, abdominal pain, difficulty swallowing, and voice change, for laryngeal attacks. Subjects who did not achieve symptom relief within the observation period were censored at the last observation time.	Up to 120 hours post-dose

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time to Onset of Primary Symptom Relief	Time to primary symptom relief was calculated from the time of study drug administration to the onset of primary symptom relief, where onset of primary symptom relief was determined using the subject-assessed VAS score for a single primary symptom (determined by edema location) and defined as the earliest of 3 consecutive non-missing measurements in which a pre-specified reduction from the pretreatment value was met. Subjects who did not achieve primary symptom relief within the observation period were censored at the last observation time.	Up to 120 hours post-dose
Time to Almost Complete Symptom Relief	Time to almost complete symptom relief was calculated from the time of study drug administration to almost complete symptom relief, where almost complete symptom relief was defined as the earliest of 3 consecutive non-missing measurements in which all VAS scores <10 mm. Subjects who did not achieve almost complete symptom relief within the observation period were censored at the last observation time.	Up to 120 Hours post treatment
Time to Subject-Assessed Initial Symptom Improvement	Time to initial symptom improvement was calculated from the time of study drug administration to initial symptom improvement as determined by the subject as the time they felt symptoms were starting to improve. Subjects who did not achieve initial symptom improvement within the observation period were censored at the last observation time.	Up to 120 hours post-dose
Time to Investigator-Assessed Initial Symptom Improvement	Time to initial symptom improvement was calculated from the time of study drug administration to initial symptom improvement as determined by the investigator as the time they felt symptoms were starting to improve. Subjects who did not achieve initial symptom improvement within the observation period were censored at the last observation time.	Up to 120 hours post-dose

Collaborators and Investigators

• Sponsor: Shire

Publications and helpful links

General Publications

• Lumry WR, Farkas H, Moldovan D, Toubi E, Baptista J, Craig T, Riedl M. Icatibant for Multiple Hereditary Angioedema Attacks across the Controlled and Open-Label Extension Phases of FAST-3. Int Arch Allergy Immunol. 2015;168(1):44-55. doi: 10.1159/000441060. Epub 2015 Nov 11.
• Maurer M, Longhurst HJ, Fabien V, Li HH, Lumry WR. Treatment of hereditary angioedema with icatibant: efficacy in clinical trials versus effectiveness in the real-world setting. Allergy Asthma Proc. 2014 Sep-Oct;35(5):377-81. doi: 10.2500/aap.2014.35.3780. Epub 2014 Aug 6.
• Bas M. Clinical efficacy of icatibant in the treatment of acute hereditary angioedema during the FAST-3 trial. Expert Rev Clin Immunol. 2012 Nov;8(8):707-17. doi: 10.1586/eci.12.67.
• Lumry WR, Li HH, Levy RJ, Potter PC, Farkas H, Moldovan D, Riedl M, Li H, Craig T, Bloom BJ, Reshef A. Randomized placebo-controlled trial of the bradykinin B(2) receptor antagonist icatibant for the treatment of acute attacks of hereditary angioedema: the FAST-3 trial. Ann Allergy Asthma Immunol. 2011 Dec;107(6):529-37. doi: 10.1016/j.anai.2011.08.015. Epub 2011 Oct 5.

Study record dates

Study Major Dates

• Study Start (Actual): July 16, 2009
• Primary Completion (Actual): October 1, 2010
• Study Completion (Actual): October 1, 2010

Study Registration Dates

• First Submitted: June 2, 2009
• First Submitted That Met QC Criteria: June 2, 2009
• First Posted (Estimate): June 3, 2009

Study Record Updates

• Last Update Posted (Actual): June 11, 2021
• Last Update Submitted That Met QC Criteria: June 3, 2021
• Last Verified: June 1, 2021

More Information

Terms related to this study

• Keywords: HAE; Type I HAE; Type II HAE
• 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; Immunosuppressive Agents; Immunologic Factors; Complement Inactivating Agents; Bradykinin B2 Receptor Antagonists; Bradykinin Receptor Antagonists; Icatibant
• Other Study ID Numbers: HGT-FIR-054; 2009-015606-19 (EudraCT Number)