Trial Outcomes & Findings for Blinded Safety & Efficacy Placebo Controlled Study of Icatibant for Angiotensin Converting Enzyme Inhibitor Induced Angioedema (NCT NCT01919801)

NCT ID: NCT01919801

Last Updated: 2021-06-08

Results Overview

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.

• Recruitment status: COMPLETED
• Study phase: PHASE3
• Target enrollment: 118 participants
• Primary outcome timeframe: Day 0 up to Day 5
• Results posted on: 2021-06-08

Participant Flow

The study was conducted at 59 sites in the United States, United Kingdom, Israel and Canada.

Overall 121 participants were randomized, of which 118 received the study medication, and 117 completed the study.

Participant milestones

Measure	Icatibant 30 mg Participants received a single dose of icatibant 30 milligram (mg) subcutaneous (SC) injection within 12 hours after the onset of the angiotensin-converting enzyme inhibitor (ACE-I) induced angioedema attack.	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.
Overall Study STARTED	61	60
Overall Study COMPLETED	60	57
Overall Study NOT COMPLETED	1	3

Reasons for withdrawal

Measure	Icatibant 30 mg Participants received a single dose of icatibant 30 milligram (mg) subcutaneous (SC) injection within 12 hours after the onset of the angiotensin-converting enzyme inhibitor (ACE-I) induced angioedema attack.	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.
Overall Study Withdrawal by Subject	1	0
Overall Study Physician Decision	0	1
Overall Study Lost to Follow-up	0	1
Overall Study Other	0	1

Baseline Characteristics

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

Baseline characteristics by cohort

Measure	Icatibant 30 mg n=61 Participants Participants received a single dose of icatibant 30 mg SC injection within 12 hours after the onset of the ACE-I induced angioedema attack.	Placebo n=60 Participants 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.	Total n=121 Participants Total of all reporting groups
Age, Continuous	60.9 years STANDARD_DEVIATION 12.1 • n=5 Participants	61.8 years STANDARD_DEVIATION 13.4 • n=7 Participants	61.4 years STANDARD_DEVIATION 12.7 • n=5 Participants
Sex: Female, Male Female	27 Participants n=5 Participants	35 Participants n=7 Participants	62 Participants n=5 Participants
Sex: Female, Male Male	34 Participants n=5 Participants	25 Participants n=7 Participants	59 Participants n=5 Participants

PRIMARY outcome

Timeframe: Day 0 up to Day 5

Population: Intent-to-treat (ITT) population included all randomized participants.

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.

Outcome measures

Measure	Icatibant 30 mg n=61 Participants Participants received a single dose of icatibant 30 mg SC injection within 12 hours after the onset of the ACE-I induced angioedema attack.	Placebo n=60 Participants 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.
Time to Meeting Discharge Criteria (TMDC)	4.03 days Interval 2.03 to 6.0	4.00 days Interval 1.03 to 6.0

PRIMARY outcome

Timeframe: 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.

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.

Outcome measures

Measure	Icatibant 30 mg n=60 Participants Participants received a single dose of icatibant 30 mg SC injection within 12 hours after the onset of the ACE-I induced angioedema attack.	Placebo n=58 Participants 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.
Number of Participants With Treatment-emergent Adverse Events (TEAE) and Treatment-emergent Serious Adverse Events (TESAEs) Participants with TEAEs	27 participants	21 participants
Number of Participants With Treatment-emergent Adverse Events (TEAE) and Treatment-emergent Serious Adverse Events (TESAEs) Participants with TESAEs	2 participants	1 participants

PRIMARY outcome

Timeframe: Day 0 to Day 5

Population: Safety population.

Injection site reaction included erythema, swelling, cutaneous pain, burning sensation, itching and warm sensation

Outcome measures

Measure	Icatibant 30 mg n=60 Participants Participants received a single dose of icatibant 30 mg SC injection within 12 hours after the onset of the ACE-I induced angioedema attack.	Placebo n=58 Participants 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.
Number of Participants With Treatment Emergent Injection Site Reaction Swelling	17 participants	13 participants
Number of Participants With Treatment Emergent Injection Site Reaction Erythema	31 participants	13 participants
Number of Participants With Treatment Emergent Injection Site Reaction Cutaneous pain	10 participants	7 participants
Number of Participants With Treatment Emergent Injection Site Reaction Burning sensation	15 participants	7 participants
Number of Participants With Treatment Emergent Injection Site Reaction Itching	13 participants	6 participants
Number of Participants With Treatment Emergent Injection Site Reaction Warm sensation	16 participants	8 participants

PRIMARY outcome

Timeframe: Day 0 to Day 5

Population: Safety population.

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.

Outcome measures

Measure	Icatibant 30 mg n=60 Participants Participants received a single dose of icatibant 30 mg SC injection within 12 hours after the onset of the ACE-I induced angioedema attack.	Placebo n=58 Participants 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.
Number of Participants With Clinically Significant Changes in Laboratory Evaluation, Vital Signs, Electrocardiogram (ECG) and Physical Examination	0 participants	0 participants

SECONDARY outcome

Timeframe: Day 0 up to Day 5

Population: ITT population.

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.

Outcome measures

Measure	Icatibant 30 mg n=61 Participants Participants received a single dose of icatibant 30 mg SC injection within 12 hours after the onset of the ACE-I induced angioedema attack.	Placebo n=60 Participants 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.
Time to Onset of Symptom Relief (TOSR)	2.00 days Interval 0.58 to 3.08	1.55 days Interval 0.5 to 3.88

SECONDARY outcome

Timeframe: Day 0 up to Day 5

Population: Modified Intent to treat (mITT) population included all randomized participants who received the study drug.

Airway Intervention included intubation, tracheotomy, cricothyrotomy.

Outcome measures

Measure	Icatibant 30 mg n=60 Participants Participants received a single dose of icatibant 30 mg SC injection within 12 hours after the onset of the ACE-I induced angioedema attack.	Placebo n=58 Participants 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.
Number of Participants Experienced Airway Intervention Due to ACE-I-induced Angioedema	1 participants	0 participants

SECONDARY outcome

Timeframe: Day 0 up to Day 5

Population: mITT population.

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.

Outcome measures

Measure	Icatibant 30 mg n=60 Participants Participants received a single dose of icatibant 30 mg SC injection within 12 hours after the onset of the ACE-I induced angioedema attack.	Placebo n=58 Participants 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.
Number of Participants Admitted to Hospital or Intensive Care Unit (ICU)	22 participants	22 participants

SECONDARY outcome

Timeframe: Day 0 up to Day 5

Population: mITT population.

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.

Outcome measures

Measure	Icatibant 30 mg n=60 Participants Participants received a single dose of icatibant 30 mg SC injection within 12 hours after the onset of the ACE-I induced angioedema attack.	Placebo n=58 Participants 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.
Number of Participants Experienced ACE-I-induced Angioedema Attack Following Study Drug Administration	35 participants	35 participants

SECONDARY outcome

Timeframe: 4, 6, and 8 hours post treatment

Population: mITT population.

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.

Outcome measures

Measure	Icatibant 30 mg n=60 Participants Participants received a single dose of icatibant 30 mg SC injection within 12 hours after the onset of the ACE-I induced angioedema attack.	Placebo n=58 Participants 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.
Percentage of Participants With Time to Meeting Discharge Criteria (TMDC) at Specified Time Points At 4 hours post treatment	55.0 percentage of participants	60.3 percentage of participants
Percentage of Participants With Time to Meeting Discharge Criteria (TMDC) at Specified Time Points At 6 hours post treatment	78.3 percentage of participants	75.9 percentage of participants
Percentage of Participants With Time to Meeting Discharge Criteria (TMDC) at Specified Time Points At 8 hours post treatment	91.7 percentage of participants	91.4 percentage of participants

OTHER_PRE_SPECIFIED outcome

Timeframe: 0.75 and 2 hours post-dose

Population: PK analysis population.

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.

Outcome measures

Measure	Icatibant 30 mg n=21 Participants Participants received a single dose of icatibant 30 mg SC injection within 12 hours after the onset of the ACE-I induced angioedema attack.	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.
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	—
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	—
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	—

Adverse Events

Icatibant 30 mg

Serious events: 2 serious events

Other events: 14 other events

Deaths: 0 deaths

Placebo

Serious events: 1 serious events

Other events: 11 other events

Deaths: 0 deaths

Serious adverse events

Measure	Icatibant 30 mg n=60 participants at risk Participants received a single dose of icatibant 30 mg SC injection within 12 hours after the onset of the ACE-I induced angioedema attack.	Placebo n=58 participants at risk 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.
Respiratory, thoracic and mediastinal disorders Hypoxia	1.7% 1/60 • Number of events 1 • From start of study treatment up to Day 5 Injection site reactions were reported separately from general reports of adverse events as they were considered as adverse events of special interest.	0.00% 0/58 • From start of study treatment up to Day 5 Injection site reactions were reported separately from general reports of adverse events as they were considered as adverse events of special interest.
Respiratory, thoracic and mediastinal disorders Laryngeal oedema	1.7% 1/60 • Number of events 1 • From start of study treatment up to Day 5 Injection site reactions were reported separately from general reports of adverse events as they were considered as adverse events of special interest.	0.00% 0/58 • From start of study treatment up to Day 5 Injection site reactions were reported separately from general reports of adverse events as they were considered as adverse events of special interest.
Skin and subcutaneous tissue disorders Rash pruritic	0.00% 0/60 • From start of study treatment up to Day 5 Injection site reactions were reported separately from general reports of adverse events as they were considered as adverse events of special interest.	1.7% 1/58 • Number of events 1 • From start of study treatment up to Day 5 Injection site reactions were reported separately from general reports of adverse events as they were considered as adverse events of special interest.

Other adverse events

Measure	Icatibant 30 mg n=60 participants at risk Participants received a single dose of icatibant 30 mg SC injection within 12 hours after the onset of the ACE-I induced angioedema attack.	Placebo n=58 participants at risk 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.
Gastrointestinal disorders Nausea	0.00% 0/60 • From start of study treatment up to Day 5 Injection site reactions were reported separately from general reports of adverse events as they were considered as adverse events of special interest.	5.2% 3/58 • Number of events 3 • From start of study treatment up to Day 5 Injection site reactions were reported separately from general reports of adverse events as they were considered as adverse events of special interest.
Nervous system disorders Headache	11.7% 7/60 • Number of events 7 • From start of study treatment up to Day 5 Injection site reactions were reported separately from general reports of adverse events as they were considered as adverse events of special interest.	6.9% 4/58 • Number of events 4 • From start of study treatment up to Day 5 Injection site reactions were reported separately from general reports of adverse events as they were considered as adverse events of special interest.
Respiratory, thoracic and mediastinal disorders Dysphonia	5.0% 3/60 • Number of events 4 • From start of study treatment up to Day 5 Injection site reactions were reported separately from general reports of adverse events as they were considered as adverse events of special interest.	3.4% 2/58 • Number of events 2 • From start of study treatment up to Day 5 Injection site reactions were reported separately from general reports of adverse events as they were considered as adverse events of special interest.
Respiratory, thoracic and mediastinal disorders Dyspnoea	1.7% 1/60 • Number of events 1 • From start of study treatment up to Day 5 Injection site reactions were reported separately from general reports of adverse events as they were considered as adverse events of special interest.	5.2% 3/58 • Number of events 3 • From start of study treatment up to Day 5 Injection site reactions were reported separately from general reports of adverse events as they were considered as adverse events of special interest.
Skin and subcutaneous tissue disorders Angioedema	11.7% 7/60 • Number of events 9 • From start of study treatment up to Day 5 Injection site reactions were reported separately from general reports of adverse events as they were considered as adverse events of special interest.	3.4% 2/58 • Number of events 4 • From start of study treatment up to Day 5 Injection site reactions were reported separately from general reports of adverse events as they were considered as adverse events of special interest.

Additional Information

Study Director

Shire

Phone: +1 866 842 5335

Email: ClinicalTransparency@shire.com

Results disclosure agreements

• Principal investigator is a sponsor employee If a multicenter publication is not submitted within twelve (12) months after conclusion, abandonment or termination of the Study at all sites, or after Sponsor confirms there shall be no multicenter Study publication, the Institution and/or such Principal Investigator may publish the results from the Institution site individually.
• Publication restrictions are in place

Restriction type: OTHER