Blinded Safety & Efficacy Placebo Controlled Study of Icatibant for Angiotensin Converting Enzyme Inhibitor Induced Angioedema

Phase III, Randomized, Double-Blind, Placebo-Controlled, Multicenter Clinical Study Evaluating the Safety & Efficacy of Icatibant as a Treatment for Angiotensin-Converting Enzyme Inhibitor (ACE-I)-Induced Angioedema in Adults

This study is being conducted to compare the safety and efficacy of icatibant with placebo in the treatment for Angiotensin-Converting Enzyme Inhibitor (ACE-I)-Induced Angioedema in Adults.

Study Overview

• Status: Completed
• Conditions: Angiotensin Converting Enzyme Inhibitor Induced Angioedema
• Intervention / Treatment: Drug: Placebo; Drug: Icatibant

Detailed Description

Angiotensin-converting enzyme inhibitors (ACE-Is) are the class of medications prescribed most frequently for the treatment of hypertension. They are also used post myocardial infarction as well as in patients with heart failure, diabetes mellitus, and chronic kidney disease. Approximately 35 to 40 million patients are on ACE-Is worldwide.

Study HGT-FIR-096 is a multicenter, Phase III, randomized, double-blind, two-armed, placebo-controlled trial. The study population will consist of 118 adult patients, 18 years of age or older, who present with an acute ACE-I-induced angioedema attack. The primary aim of the study is to demonstrate that icatibant is significantly more effective than placebo in resolving attacks of angioedema caused by ACE-I based on the Time to Meeting Discharge Criteria (TMDC). Safety and tolerability, as well as the pharmacokinetics (PK), of icatibant will also be evaluated. Eligible patients will be randomized at a 1:1 ratio to receive a single sub-cutaneous injection of either 30 mg icatibant or placebo.

• Study Type: Interventional
• Enrollment (Actual): 118
• Phase: Phase 3

Contacts and Locations

Study Locations

• Canada
  • Nova Scotia
    • Halifax, Nova Scotia, Canada, B3H 3A7
      • Queen Elizabeth II Health Sciences Center
  • Ontario
    • Kingston, Ontario, Canada, K7L 2V7
      • Kingston General Hospital
    • Kingston, Ontario, Canada, K7L 5G2
      • Hotel Dieu Hospital
• Israel
  • Beer Sheva, Israel, 84101
    • Soroka University Medical Center
  • Haifa, Israel, 31048
    • Bnai Zion Medical Center
  • Safed, Israel, 13100
    • Ziv Medical Center
  • Tel Aviv, Israel, 64239
    • Tel-Aviv Sourasky Medical Center
• United Kingdom
  • Brighton, United Kingdom, BN2 5BE
    • Brighton and Sussex University Hospitals NHS Trust
  • Exeter, United Kingdom, EX2 5DW
    • Royal Devon and Exeter Hospital NHS Trust
  • Liverpool, United Kingdom, L9 7AL
    • University Hospital Aintree
  • Manchester, United Kingdom, M13 9WL
    • Manchester Royal Infirmary
  • Nottingham, United Kingdom, NG7 2UH
    • Queen's Medical Centre
• United States
  • California
    • La Jolla, California, United States, 92037
      • University of California San Diego Medical Center
    • La Jolla, California, United States, 92093
      • University of California San Diego
  • District of Columbia
    • Washington, District of Columbia, United States, 20010
      • Washington Hospital Center
  • Florida
    • Gainesville, Florida, United States, 32610
      • UF Health Shands Hospital
    • Orlando, Florida, United States, 32806
      • Orlando Health
    • Tampa, Florida, United States, 33606
      • Tampa General Hospital
  • Illinois
    • Chicago, Illinois, United States, 60612
      • Cook County Hospital
    • Chicago, Illinois, United States, 60064-3048
      • Federal Health Care Center
  • Kansas
    • Kansas City, Kansas, United States, 66160
      • University of Kansas Cancer Center
  • Louisiana
    • New Orleans, Louisiana, United States, 70121
      • Ochsner Medical Center
  • Maryland
    • Baltimore, Maryland, United States, 21201
      • University of Maryland School of Medicine
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Massachusetts General Hospital
    • Boston, Massachusetts, United States, 02115
      • Brigham and Womens Hospital
    • Springfield, Massachusetts, United States, 01199
      • Baystate Medical Center
  • Michigan
    • Detroit, Michigan, United States, 48202
      • Henry Ford Health System
    • Detroit, Michigan, United States, 48201
      • Sinai Grace Hospital
    • Detroit, Michigan, United States, 48201
      • Detroit Receiving Hospital and University Health Center
    • Royal Oak, Michigan, United States, 48073
      • William Beaumont Hospital
    • Troy, Michigan, United States, 48085
      • William Beaumont Hospital
  • Minnesota
    • Minneapolis, Minnesota, United States, 55415
      • Hennepin County Medical Center
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Barnes Jewish Hospital
    • Saint Louis, Missouri, United States, 63141
      • Washington University
  • New Jersey
    • Vineland, New Jersey, United States, 08360
      • Inspira Health Network
  • New Mexico
    • Albuquerque, New Mexico, United States, 87106
      • University of New Mexico
  • New York
    • Brooklyn, New York, United States, 11203
      • SUNY Downstate Medical Center
    • Brooklyn, New York, United States, 11203
      • Kings County Hospital Center
    • New York, New York, United States, 10021
      • Weill Medical College of Cornell University
  • North Carolina
    • Greenville, North Carolina, United States, 27835
      • East Carolina University
  • Ohio
    • Cincinnati, Ohio, United States, 45219
      • University of Cincinnati
    • Cleveland, Ohio, United States, 44195
      • Cleveland Clinic Foundation
    • Gahanna, Ohio, United States, 43230
      • Ohio State University Hospital - East
  • Pennsylvania
    • Chambersburg, Pennsylvania, United States, 17201
      • Summit Health
    • Philadelphia, Pennsylvania, United States, 19141
      • Albert Einstein Medical Center
    • Philadelphia, Pennsylvania, United States, 19140
      • Temple University Hospital
    • Philadelphia, Pennsylvania, United States, 19102
      • Hahnemann University Hospital
    • Pittsburgh, Pennsylvania, United States, 15143
      • Allegheny General Hospital
  • Rhode Island
    • Providence, Rhode Island, United States, 02903
      • Rhode Island Hospital
  • South Carolina
    • Columbia, South Carolina, United States, 29203
      • University of South Carolina School of Medicine
  • Texas
    • Dallas, Texas, United States, 75246
      • Baylor University Medical Center
    • Fort Worth, Texas, United States, 76104
      • John Peter Smith Hospital
    • Galveston, Texas, United States, 77555-0561
      • University of Texas Medical Branch
    • Houston, Texas, United States, 77030
      • Baylor College of Medicine
  • Virginia
    • Charlottesville, Virginia, United States, 22903
      • University of Virginia

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:

1. Male or female, 18 years of age or older.
2. Patient is currently being treated with an ACE inhibitor.
3. Patient presenting with an ACE inhibitor-induced angioedema attack of the head and/or neck region within 12 hours of onset (must be sufficiently less than 12 hours to allow study drug to be given with 12 hours of attack onset).
4. Angioedema must be considered at least moderate in severity for at least one of the four angioedema-associated airway symptoms (difficulty breathing, difficulty swallowing, voice changes, tongue swelling).
5. Patient must have voluntarily signed an Institutional Review Board/Independent Ethics Committee-approved informed consent form after all relevant aspects of the study have been explained and discussed with the patient.
6. Females must have a negative urine pregnancy test prior to administration of the study medication, with the exception of those females who have had a total hysterectomy or bilateral oophorectomy, or who are 2 years post-menopausal.

Exclusion Criteria:

1. Patient has a diagnosis of angioedema of other etiology (eg, hereditary or acquired angioedema, allergic angioedema [eg, food, insect bite or sting, evident clinical response to antihistamines and/or corticosteroids], anaphylaxis, trauma, abscess or infection or associated disease, local inflammation, local tumor, post-operative or post-radiogenic edema, salivary gland disorders, other [non-ACE inhibitor] drug-induced angioedema).
2. Patients with a family history of recurrent angioedema.
3. Patients who have had a previous episode(s) of angioedema while not on ACE inhibitor therapy.
4. Patients with acute urticaria (itchy, erythematous wheals).
5. Patients who have an intervention to support the airway (eg, intubation, tracheotomy, cricothyrotomy) due to the current attack of angioedema.

6. Patient has any of the following vascular conditions that, in the judgment of the investigator, would be a contraindication to participation in the study.

   • Unstable angina pectoris or acute myocardial ischemia
   • Hypertensive urgency or emergency (diastolic blood pressure [DBP] >120 mm Hg or systolic blood pressure [SBP] >180 mm Hg)
   • Within 1 month of a stroke or transient ischemic attack
   • New York Heart Association (NYHA) heart failure class IV
7. Patient has a serious or acute condition or illness that, in the judgment of the investigator, would interfere with evaluating the safety and/or efficacy assessments of the study (eg, a condition or illness requiring hemodialysis).
8. Patient is pregnant or breast feeding.
9. Patient has participated in another investigational study in the past 30 days.
10. Patient is unable to understand the nature, scope, and possible consequences of the protocol, or is unlikely or unable to comply with the protocol assessments, or is unlikely to complete the study for any reason.
11. Patients who are not suitable for the study in the opinion of the investigator.
12. Patient has experienced hypersensitivity to the active substance of the investigational product or to any of its excipients.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Icatibant; Icatibant at a dose of 30 mg will be administered as a single subcutaneous injection	Drug: Icatibant; Single dose of 30 mg icatibant administered within 12 hours of the onset of an acute attack of ACE-I-induced angioedema; Other Names: Firazyr
Placebo Comparator: Placebo; Placebo will be administered as a single subcutaneous injection	Drug: Placebo

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time to Meeting Discharge Criteria (TMDC)	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.	Day 0 up to Day 5
Number of Participants With Treatment-emergent Adverse Events (TEAE) and Treatment-emergent Serious Adverse Events (TESAEs)	An adverse event (AE) was any untoward medical occurrence in a participant 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.	From start of study drug administration (Day 0) up to follow-up (Day 5)
Number of Participants With Treatment Emergent Injection Site Reaction	Injection site reaction included erythema, swelling, cutaneous pain, burning sensation, itching and warm sensation	Day 0 to Day 5
Number of Participants With Clinically Significant Changes in Laboratory Evaluation, Vital Signs, Electrocardiogram (ECG) and Physical Examination	During laboratory evaluation, serum chemistry and hematology blood tests, and urinalysis were performed. Vital signs parameters included evaluation of pulse rate and systolic and diastolic blood pressure. Standard 12-lead ECGs were performed and ECG recordings were read locally at the study site by a cardiologist. Physical examination was performed with examination of major body systems per routine clinical practice.	Day 0 to Day 5

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time to Onset of Symptom Relief (TOSR)	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.	Day 0 up to Day 5
Number of Participants Experienced Airway Intervention Due to ACE-I-induced Angioedema	Airway Intervention included intubation, tracheotomy, cricothyrotomy.	Day 0 up to Day 5
Number of Participants Admitted to Hospital or Intensive Care Unit (ICU)	Number of participants 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.	Day 0 up to Day 5
Number of Participants Experienced ACE-I-induced Angioedema Attack Following Study Drug Administration	Number of participants 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.	Day 0 up to Day 5
Percentage of Participants With Time to Meeting Discharge Criteria (TMDC) at Specified Time Points	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.	4, 6, and 8 hours post treatment

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Area Under the Plasma Concentration Versus Time Curve (AUC) of Icatibant and Its Metabolites (M1 and M2)	Area under the plasma concentration-time curve of Icatibant and its metabolites (M1 and M2) were analyzed. A population pharmacokinetic analysis approach using sparse pharmacokinetic sampling obtained from a subset of subjects was used to evaluate exposure to icatibant.	0.75 and 2 hours post-dose

Collaborators and Investigators

• Sponsor: Shire
• Collaborators: PPD

Publications and helpful links

General Publications

• Sinert R, Levy P, Bernstein JA, Body R, Sivilotti MLA, Moellman J, Schranz J, Baptista J, Kimura A, Nothaft W; CAMEO study group. Randomized Trial of Icatibant for Angiotensin-Converting Enzyme Inhibitor-Induced Upper Airway Angioedema. J Allergy Clin Immunol Pract. 2017 Sep-Oct;5(5):1402-1409.e3. doi: 10.1016/j.jaip.2017.03.003. Epub 2017 May 25.

Study record dates

Study Major Dates

• Study Start (Actual): December 2, 2013
• Primary Completion (Actual): August 22, 2015
• Study Completion (Actual): August 22, 2015

Study Registration Dates

• First Submitted: July 25, 2013
• First Submitted That Met QC Criteria: August 6, 2013
• First Posted (Estimate): August 9, 2013

Study Record Updates

• Last Update Posted (Actual): June 8, 2021
• Last Update Submitted That Met QC Criteria: May 14, 2021
• Last Verified: May 1, 2021

More Information

Terms related to this study

• Keywords: Firazyr; icatibant; ACE-I
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Skin Diseases; Immune System Diseases; Hypersensitivity, Immediate; Skin Diseases, Vascular; Hypersensitivity; Urticaria; Angioedema; 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-096; 2014-001213-12 (EudraCT Number)