Angiotensin Converting Enzyme Inhibitor Induced Angioedema
Conditions
Keywords
icatibant, Firazyr, ACE-I
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.
Interventions
DRUGIcatibant
Single dose of 30 mg icatibant administered within 12 hours of the onset of an acute attack of ACE-I-induced angioedema
DRUGPlacebo
Sponsors
PPD Development, LP
Shire
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Clinically Significant Changes in Laboratory Evaluation, Vital Signs, Electrocardiogram (ECG) and Physical Examination | 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 Meeting Discharge Criteria (TMDC) | 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) | 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 | Day 0 to Day 5 | Injection site reaction included erythema, swelling, cutaneous pain, burning sensation, itching and warm sensation |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Experienced ACE-I-induced Angioedema Attack Following Study Drug Administration | 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 | 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. |
| Time to Onset of Symptom Relief (TOSR) | 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 | Day 0 up to Day 5 | Airway Intervention included intubation, tracheotomy, cricothyrotomy. |
| Number of Participants Admitted to Hospital or Intensive Care Unit (ICU) | 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. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Area Under the Plasma Concentration Versus Time Curve (AUC) of Icatibant and Its Metabolites (M1 and M2) | 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. |
Countries
Canada, Israel, United Kingdom, United States
Participant flow
Recruitment details
The study was conducted at 59 sites in the United States, United Kingdom, Israel and Canada.
Pre-assignment details
Overall 121 participants were randomized, of which 118 received the study medication, and 117 completed the study.
Participants by arm
| Arm | Count |
|---|---|
| Icatibant 30 mg Participants received a single dose of icatibant 30 mg SC injection within 12 hours after the onset of the ACE-I induced angioedema attack. | 61 |
| Placebo Participants received a single dose of placebo matched to icatibant SC injection within 12 hours after the onset of the ACE-I induced angioedema attack. | 60 |
| Total | 121 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Lost to Follow-up | 0 | 1 |
| Overall Study | Other | 0 | 1 |
| Overall Study | Physician Decision | 0 | 1 |
| Overall Study | Withdrawal by Subject | 1 | 0 |
Baseline characteristics
| Characteristic | Icatibant 30 mg | Placebo | Total |
|---|---|---|---|
| Age, Continuous | 60.9 years STANDARD_DEVIATION 12.1 | 61.8 years STANDARD_DEVIATION 13.4 | 61.4 years STANDARD_DEVIATION 12.7 |
| Sex: Female, Male Female | 27 Participants | 35 Participants | 62 Participants |
| Sex: Female, Male Male | 34 Participants | 25 Participants | 59 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 14 / 60 | 11 / 58 |
| serious Total, serious adverse events | 2 / 60 | 1 / 58 |
Outcome results
Primary
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.
Time frame: Day 0 to Day 5
Population: Safety population.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Icatibant 30 mg | Number of Participants With Clinically Significant Changes in Laboratory Evaluation, Vital Signs, Electrocardiogram (ECG) and Physical Examination | 0 participants |
| Placebo | Number of Participants With Clinically Significant Changes in Laboratory Evaluation, Vital Signs, Electrocardiogram (ECG) and Physical Examination | 0 participants |
Primary
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.
Time frame: From start of study drug administration (Day 0) up to follow-up (Day 5)
Population: Safety population included all participants who received the study drug.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Icatibant 30 mg | Number of Participants With Treatment-emergent Adverse Events (TEAE) and Treatment-emergent Serious Adverse Events (TESAEs) | Participants with TEAEs | 27 participants |
| Icatibant 30 mg | Number of Participants With Treatment-emergent Adverse Events (TEAE) and Treatment-emergent Serious Adverse Events (TESAEs) | Participants with TESAEs | 2 participants |
| Placebo | Number of Participants With Treatment-emergent Adverse Events (TEAE) and Treatment-emergent Serious Adverse Events (TESAEs) | Participants with TEAEs | 21 participants |
| Placebo | Number of Participants With Treatment-emergent Adverse Events (TEAE) and Treatment-emergent Serious Adverse Events (TESAEs) | Participants with TESAEs | 1 participants |
Primary
Number of Participants With Treatment Emergent Injection Site Reaction
Injection site reaction included erythema, swelling, cutaneous pain, burning sensation, itching and warm sensation
Time frame: Day 0 to Day 5
Population: Safety population.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Icatibant 30 mg | Number of Participants With Treatment Emergent Injection Site Reaction | Swelling | 17 participants |
| Icatibant 30 mg | Number of Participants With Treatment Emergent Injection Site Reaction | Burning sensation | 15 participants |
| Icatibant 30 mg | Number of Participants With Treatment Emergent Injection Site Reaction | Erythema | 31 participants |
| Icatibant 30 mg | Number of Participants With Treatment Emergent Injection Site Reaction | Itching | 13 participants |
| Icatibant 30 mg | Number of Participants With Treatment Emergent Injection Site Reaction | Cutaneous pain | 10 participants |
| Icatibant 30 mg | Number of Participants With Treatment Emergent Injection Site Reaction | Warm sensation | 16 participants |
| Placebo | Number of Participants With Treatment Emergent Injection Site Reaction | Cutaneous pain | 7 participants |
| Placebo | Number of Participants With Treatment Emergent Injection Site Reaction | Erythema | 13 participants |
| Placebo | Number of Participants With Treatment Emergent Injection Site Reaction | Swelling | 13 participants |
| Placebo | Number of Participants With Treatment Emergent Injection Site Reaction | Warm sensation | 8 participants |
| Placebo | Number of Participants With Treatment Emergent Injection Site Reaction | Burning sensation | 7 participants |
| Placebo | Number of Participants With Treatment Emergent Injection Site Reaction | Itching | 6 participants |
Primary
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.
Time frame: Day 0 up to Day 5
Population: Intent-to-treat (ITT) population included all randomized participants.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Icatibant 30 mg | Time to Meeting Discharge Criteria (TMDC) | 4.03 days |
| Placebo | Time to Meeting Discharge Criteria (TMDC) | 4.00 days |
Comparison: A total of 121 participants were analysed, however 3 participants did not receive the study medication and were censored at time 0.p-value: 0.633Adjusted Peto-Prentice
Secondary
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.
Time frame: Day 0 up to Day 5
Population: mITT population.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Icatibant 30 mg | Number of Participants Admitted to Hospital or Intensive Care Unit (ICU) | 22 participants |
| Placebo | Number of Participants Admitted to Hospital or Intensive Care Unit (ICU) | 22 participants |
Secondary
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.
Time frame: Day 0 up to Day 5
Population: mITT population.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Icatibant 30 mg | Number of Participants Experienced ACE-I-induced Angioedema Attack Following Study Drug Administration | 35 participants |
| Placebo | Number of Participants Experienced ACE-I-induced Angioedema Attack Following Study Drug Administration | 35 participants |
Secondary
Number of Participants Experienced Airway Intervention Due to ACE-I-induced Angioedema
Airway Intervention included intubation, tracheotomy, cricothyrotomy.
Time frame: Day 0 up to Day 5
Population: Modified Intent to treat (mITT) population included all randomized participants who received the study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Icatibant 30 mg | Number of Participants Experienced Airway Intervention Due to ACE-I-induced Angioedema | 1 participants |
| Placebo | Number of Participants Experienced Airway Intervention Due to ACE-I-induced Angioedema | 0 participants |
Secondary
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.
Time frame: 4, 6, and 8 hours post treatment
Population: mITT population.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Icatibant 30 mg | Percentage of Participants With Time to Meeting Discharge Criteria (TMDC) at Specified Time Points | At 4 hours post treatment | 55.0 percentage of participants |
| Icatibant 30 mg | Percentage of Participants With Time to Meeting Discharge Criteria (TMDC) at Specified Time Points | At 6 hours post treatment | 78.3 percentage of participants |
| Icatibant 30 mg | Percentage of Participants With Time to Meeting Discharge Criteria (TMDC) at Specified Time Points | At 8 hours post treatment | 91.7 percentage of participants |
| Placebo | Percentage of Participants With Time to Meeting Discharge Criteria (TMDC) at Specified Time Points | At 4 hours post treatment | 60.3 percentage of participants |
| Placebo | Percentage of Participants With Time to Meeting Discharge Criteria (TMDC) at Specified Time Points | At 6 hours post treatment | 75.9 percentage of participants |
| Placebo | Percentage of Participants With Time to Meeting Discharge Criteria (TMDC) at Specified Time Points | At 8 hours post treatment | 91.4 percentage of participants |
Secondary
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.
Time frame: Day 0 up to Day 5
Population: ITT population.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Icatibant 30 mg | Time to Onset of Symptom Relief (TOSR) | 2.00 days |
| Placebo | Time to Onset of Symptom Relief (TOSR) | 1.55 days |
Other Pre-specified
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.
Time frame: 0.75 and 2 hours post-dose
Population: PK analysis population.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Icatibant 30 mg | Area Under the Plasma Concentration Versus Time Curve (AUC) of Icatibant and Its Metabolites (M1 and M2) | Icatibant | 2530 hours*nanogram per milliliter (h*ng/mL) | Standard Deviation 786 |
| Icatibant 30 mg | Area Under the Plasma Concentration Versus Time Curve (AUC) of Icatibant and Its Metabolites (M1 and M2) | Metabolite M1 | 2890 hours*nanogram per milliliter (h*ng/mL) | Standard Deviation 813 |
| Icatibant 30 mg | Area Under the Plasma Concentration Versus Time Curve (AUC) of Icatibant and Its Metabolites (M1 and M2) | Metabolite M2 | 3180 hours*nanogram per milliliter (h*ng/mL) | Standard Deviation 931 |