Clinical trial NCT01919801: Blinded Safety & Efficacy Placebo Controlled Study of Icatibant for Angiotensin Converting Enzyme Inhibitor Induced Angioedema
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Angiotensin Converting Enzyme Inhibitor Induced Angioedema
Keywords: icatibant
Firazyr
ACE-I
Lead sponsor: Takeda
Sponsor class: INDUSTRY
Collaborators: name: PPD Development, LP
First posted: 2013-08-09
Enrollment: 118
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.

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.

Eligibility criteria: 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.

Primary outcomes:
measure: Time to Meeting Discharge Criteria (TMDC)
timeFrame: Day 0 up to Day 5
measure: Number of Participants With Treatment-emergent Adverse Events (TEAE) and Treatment-emergent Serious Adverse Events (TESAEs)
timeFrame: From start of study drug administration (Day 0) up to follow-up (Day 5)
measure: Number of Participants With Treatment Emergent Injection Site Reaction
timeFrame: Day 0 to Day 5
measure: Number of Participants With Clinically Significant Changes in Laboratory Evaluation, Vital Signs, Electrocardiogram (ECG) and Physical Examination
timeFrame: Day 0 to Day 5
Secondary outcomes:
measure: Time to Onset of Symptom Relief (TOSR)
timeFrame: Day 0 up to Day 5
measure: Number of Participants Experienced Airway Intervention Due to ACE-I-induced Angioedema
timeFrame: Day 0 up to Day 5
measure: Number of Participants Admitted to Hospital or Intensive Care Unit (ICU)
timeFrame: Day 0 up to Day 5
measure: Number of Participants Experienced ACE-I-induced Angioedema Attack Following Study Drug Administration
timeFrame: Day 0 up to Day 5
measure: Percentage of Participants With Time to Meeting Discharge Criteria (TMDC) at Specified Time Points
timeFrame: 4, 6, and 8 hours post treatment
Other outcomes:
measure: Area Under the Plasma Concentration Versus Time Curve (AUC) of Icatibant and Its Metabolites (M1 and M2)
timeFrame: 0.75 and 2 hours post-dose
Locations:
city: La Jolla
country: United States
facility: University of California San Diego Medical Center
state: California
city: La Jolla
country: United States
facility: University of California San Diego
state: California
city: Washington
country: United States
facility: Washington Hospital Center
state: District of Columbia
city: Gainesville
country: United States
facility: UF Health Shands Hospital
state: Florida
city: Orlando
country: United States
facility: Orlando Health
state: Florida
city: Tampa
country: United States
facility: Tampa General Hospital
state: Florida
city: Chicago
country: United States
facility: Federal Health Care Center
state: Illinois
city: Chicago
country: United States
facility: Cook County Hospital
state: Illinois
city: Kansas City
country: United States
facility: University of Kansas Cancer Center
state: Kansas
city: New Orleans
country: United States
facility: Ochsner Medical Center
state: Louisiana
city: Baltimore
country: United States
facility: University of Maryland School of Medicine
state: Maryland
city: Boston
country: United States
facility: Massachusetts General Hospital
state: Massachusetts
city: Boston
country: United States
facility: Brigham and Womens Hospital
state: Massachusetts
city: Springfield
country: United States
facility: Baystate Medical Center
state: Massachusetts
city: Detroit
country: United States
facility: Detroit Receiving Hospital and University Health Center
state: Michigan
city: Detroit
country: United States
facility: Sinai Grace Hospital
state: Michigan
city: Detroit
country: United States
facility: Henry Ford Health System
state: Michigan
city: Royal Oak
country: United States
facility: William Beaumont Hospital
state: Michigan
city: Troy
country: United States
facility: William Beaumont Hospital
state: Michigan
city: Minneapolis
country: United States
facility: Hennepin County Medical Center
state: Minnesota
city: Saint Louis
country: United States
facility: Barnes Jewish Hospital
state: Missouri
city: Saint Louis
country: United States
facility: Washington University
state: Missouri
city: Vineland
country: United States
facility: Inspira Health Network
state: New Jersey
city: Albuquerque
country: United States
facility: University of New Mexico
state: New Mexico
city: Brooklyn
country: United States
facility: Kings County Hospital Center
state: New York
city: Brooklyn
country: United States
facility: SUNY Downstate Medical Center
state: New York
city: New York
country: United States
facility: Weill Medical College of Cornell University
state: New York
city: Greenville
country: United States
facility: East Carolina University
state: North Carolina
city: Cincinnati
country: United States
facility: University of Cincinnati
state: Ohio
city: Cleveland
country: United States
facility: Cleveland Clinic Foundation
state: Ohio
city: Gahanna
country: United States
facility: Ohio State University Hospital - East
state: Ohio
city: Chambersburg
country: United States
facility: Summit Health
state: Pennsylvania
city: Philadelphia
country: United States
facility: Hahnemann University Hospital
state: Pennsylvania
city: Philadelphia
country: United States
facility: Temple University Hospital
state: Pennsylvania
city: Philadelphia
country: United States
facility: Albert Einstein Medical Center
state: Pennsylvania
city: Pittsburgh
country: United States
facility: Allegheny General Hospital
state: Pennsylvania
city: Providence
country: United States
facility: Rhode Island Hospital
state: Rhode Island
city: Columbia
country: United States
facility: University of South Carolina School of Medicine
state: South Carolina
city: Dallas
country: United States
facility: Baylor University Medical Center
state: Texas
city: Fort Worth
country: United States
facility: John Peter Smith Hospital
state: Texas
city: Galveston
country: United States
facility: University of Texas Medical Branch
state: Texas
city: Houston
country: United States
facility: Baylor College of Medicine
state: Texas
city: Charlottesville
country: United States
facility: University of Virginia
state: Virginia
city: Halifax
country: Canada
facility: Queen Elizabeth II Health Sciences Center
state: Nova Scotia
city: Kingston
country: Canada
facility: Kingston General Hospital
state: Ontario
city: Kingston
country: Canada
facility: Hotel Dieu Hospital
state: Ontario
city: Beer Sheva
country: Israel
facility: Soroka University Medical Center
city: Haifa
country: Israel
facility: Bnai Zion Medical Center
city: Safed
country: Israel
facility: Ziv Medical Center
city: Tel Aviv
country: Israel
facility: Tel-Aviv Sourasky Medical Center
city: Brighton
country: United Kingdom
facility: Brighton and Sussex University Hospitals NHS Trust
city: Exeter
country: United Kingdom
facility: Royal Devon and Exeter Hospital NHS Trust
city: Liverpool
country: United Kingdom
facility: University Hospital Aintree
city: Manchester
country: United Kingdom
facility: Manchester Royal Infirmary
city: Nottingham
country: United Kingdom
facility: Queen's Medical Centre
Study officials:
affiliation: Takeda
name: Study Director
role: STUDY_DIRECTOR
References:
citation: 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.