Blinded Safety & Efficacy Placebo Controlled Study of Icatibant for Angiotensin Converting Enzyme Inhibitor Induced Angioedema
|Angiotensin Converting Enzyme Inhibitor Induced Angioedema||Drug: Icatibant Drug: Placebo||Phase 3|
|Study Design:||Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Participant, Outcomes Assessor
Primary Purpose: Treatment
|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|
- Time to Meeting Discharge Criteria (TMDC) [ Time Frame: Day 0 up to Day 5 ]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.
- Number of Participants With Treatment-emergent Adverse Events (TEAE) and Treatment-emergent Serious Adverse Events (TESAEs) [ Time Frame: From start of study drug administration (Day 0) up to follow-up (Day 5) ]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.
- Number of Participants With Treatment Emergent Injection Site Reaction [ Time Frame: Day 0 to Day 5 ]Injection site reaction included erythema, swelling, cutaneous pain, burning sensation, itching and warm sensation
- Number of Participants With Clinically Significant Changes in Laboratory Evaluation, Vital Signs, Electrocardiogram (ECG) and Physical Examination [ Time Frame: Day 0 to Day 5 ]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.
- Time to Onset of Symptom Relief (TOSR) [ Time Frame: Day 0 up to Day 5 ]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.
- Number of Participants Experienced Airway Intervention Due to ACE-I-induced Angioedema [ Time Frame: Day 0 up to Day 5 ]Airway Intervention included intubation, tracheotomy, cricothyrotomy.
- Number of Participants Admitted to Hospital or Intensive Care Unit (ICU) [ Time Frame: Day 0 up to Day 5 ]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.
- Number of Participants Experienced ACE-I-induced Angioedema Attack Following Study Drug Administration [ Time Frame: Day 0 up to Day 5 ]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.
- Percentage of Participants With Time to Meeting Discharge Criteria (TMDC) at Specified Time Points [ Time Frame: 4, 6, and 8 hours post treatment ]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.
- Area Under the Plasma Concentration Versus Time Curve (AUC) of Icatibant and Its Metabolites (M1 and M2) [ Time Frame: 0.75 and 2 hours post-dose ]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.
|Study Start Date:||December 2013|
|Study Completion Date:||August 2015|
|Primary Completion Date:||August 2015 (Final data collection date for primary outcome measure)|
Icatibant at a dose of 30 mg will be administered as a single subcutaneous injection
Single dose of 30 mg icatibant administered within 12 hours of the onset of an acute attack of ACE-I-induced angioedema
Other Name: Firazyr
Placebo Comparator: Placebo
Placebo will be administered as a single subcutaneous injection
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.
Please refer to this study by its ClinicalTrials.gov identifier: NCT01919801
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|Study Director:||Vipin Aggarwal, MD, MPH||Shire|