Effect of Bradykinin Receptor Antagonism on ACE Inhibitor-associated Angioedema

• Sponsor: Vanderbilt University Medical Center (Other)
• Overall Status: Terminated
• CT.gov ID: NCT01574248
• Collaborator: Shire (Industry)
• Enrollment: 33
• Locations: 2
• Arms: 2
• Duration (Months): 54
• Patients Per Site: 16.5
• Patients Per Site Per Month: 0.3

Study Details

Study Description

Brief Summary

Individuals with heart disease or high blood pressure are often prescribed angiotensin converting enzyme (ACE) inhibitors to treat their disease. However, the use of ACE inhibitors can be associated with angioedema, a rare but life-threatening condition that causes swelling of the face and other body parts. This study will evaluate the effectiveness of the drug HOE-140 at decreasing symptoms of angioedema in people taking ACE inhibitors who develop the condition.

Condition or Disease	Intervention/Treatment	Phase
ACE Inhibitor-associated Angioedema	Drug: icatibant; Other: Placebo	Phase 4

Detailed Description

People who take ACE inhibitors may develop angioedema, a condition that causes itchy and painful swelling beneath the skin around the eyes, lips, tongue, throat, hands, or feet. In severe cases, the throat may swell, obstructing the airway and leading to breathing difficulty. ACE inhibitors prevent the breakdown of a natural chemical in the body called bradykinin. Increased levels of bradykinin, which can cause swelling, may contribute to the development of angioedema. Blocking bradykinin receptor cells prevents bradykinin from initiating swelling and may lead to a possible decrease in angioedema symptoms. The purpose of this study is to evaluate the effectiveness of HOE-140, a bradykinin receptor blocker, at reducing symptoms in people with ACE inhibitor-associated angioedema.

This study will enroll people admitted to the emergency room or hospital who have a severe case of ACE inhibitor-associated angioedema. Participants will be randomly assigned to receive an injection of either HOE-140 or placebo. Initially, participants will undergo an electrocardiogram to measure the electrical activity of the heart. Then blood pressure measurements, blood collection, a physical exam to determine the extent and duration of swelling, and photographs of the swelling will occur at 2, 4, 8, 16, and 24 hours following the start of treatment. Questionnaires will be completed by study staff and participants to assess changes in angioedema symptoms and the extent of swelling. Participants will remain in the hospital for 24 to 48 hours, depending on the severity of their symptoms. Blood will be collected at a follow-up visit that will occur 7 days after the resolution of angioedema symptoms.

Study Design

• Study Type: Interventional
• Actual Enrollment: 33 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Effect of Bradykinin Receptor Antagonism on ACE Inhibitor-associated Angioedema - a Mulitcenter Trial
• Study Start Date: Aug 1, 2011
• Actual Primary Completion Date: Sep 1, 2015
• Actual Study Completion Date: Feb 1, 2016

Arms and Interventions

Arm	Intervention/Treatment
Experimental: icatibant 30 mg icatibant will be administered subcutaneously 0 and 6 hours after randomization	Drug: icatibant; Subcutaneous at time 0 and 6 hours; Other Names: Firazyr HOE140
Placebo Comparator: Placebo Subcutaneous at time 0 and 6 hours	Other: Placebo; Subcutaneous at time 0 and 6 hours

Outcome Measures

Primary Outcome Measures

1. Time to Resolution of Angioedema [48 hours]

   Time interval between initiation of treatment and when there is no symptom, by visual analog scale <1 cm. Data provided are for worst symptom.

Secondary Outcome Measures

1. Number of Participants With Admission to Intensive Care Unit [T0 to T48 hours]

2. Number of Participants With Requirement for Intubation [T0 to T48 hours]

3. Number of Participants Given Steroids [T0 to T48 hours]

4. Number of Participants Given Histamine Receptor Type 1 (H1) and Type 2 (H2) Blockers [T0 to T48 hours]

5. Number of Participants Given Epinephrine [T0 to T48 hours]

6. Systolic Blood Pressure [T0 to T48 hours]

   Average of blood pressure measurements from zero to forty-eight hours provided.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 80 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• The subject has ongoing angioedema while taking an ACE inhibitor.

• The subject is between 18 and 80 years of age.

Exclusion Criteria:

• The subject has had angioedema while not taking an ACE inhibitor.

• The subject's angioedema only involves the bowel.

• The subject is known to be pregnant or has a positive urine pregnancy test.

• The subject has started on an oral contraceptive within the last 6 months.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of California, San Diego	San Diego	California	United States	92093
2	Vanderbilt University Medical Center	Nashville	Tennessee	United States	37235

Sponsors and Collaborators

• Vanderbilt University Medical Center
• Shire

Investigators

• Principal Investigator: Nancy J. Brown, MD, Vanderbilt University

Study Documents (Full-Text)

None provided.

More Information

Publications

• Bork K, Frank J, Grundt B, Schlattmann P, Nussberger J, Kreuz W. Treatment of acute edema attacks in hereditary angioedema with a bradykinin receptor-2 antagonist (Icatibant). J Allergy Clin Immunol. 2007 Jun;119(6):1497-503. Epub 2007 Apr 5.
• Brown NJ, Byiers S, Carr D, Maldonado M, Warner BA. Dipeptidyl peptidase-IV inhibitor use associated with increased risk of ACE inhibitor-associated angioedema. Hypertension. 2009 Sep;54(3):516-23. doi: 10.1161/HYPERTENSIONAHA.109.134197. Epub 2009 Jul 6.
• Brown NJ, Ray WA, Snowden M, Griffin MR. Black Americans have an increased rate of angiotensin converting enzyme inhibitor-associated angioedema. Clin Pharmacol Ther. 1996 Jul;60(1):8-13.
• Brown NJ, Snowden M, Griffin MR. Recurrent angiotensin-converting enzyme inhibitor--associated angioedema. JAMA. 1997 Jul 16;278(3):232-3.
• Byrd JB, Adam A, Brown NJ. Angiotensin-converting enzyme inhibitor-associated angioedema. Immunol Allergy Clin North Am. 2006 Nov;26(4):725-37. Review.
• Gainer JV, Morrow JD, Loveland A, King DJ, Brown NJ. Effect of bradykinin-receptor blockade on the response to angiotensin-converting-enzyme inhibitor in normotensive and hypertensive subjects. N Engl J Med. 1998 Oct 29;339(18):1285-92.
• Krieter DH, Grude M, Lemke HD, Fink E, Bönner G, Schölkens BA, Schulz E, Müller GA. Anaphylactoid reactions during hemodialysis in sheep are ACE inhibitor dose-dependent and mediated by bradykinin. Kidney Int. 1998 Apr;53(4):1026-35.
• Verresen L, Fink E, Lemke HD, Vanrenterghem Y. Bradykinin is a mediator of anaphylactoid reactions during hemodialysis with AN69 membranes. Kidney Int. 1994 May;45(5):1497-503.
• Zuraw BL. Clinical practice. Hereditary angioedema. N Engl J Med. 2008 Sep 4;359(10):1027-36. doi: 10.1056/NEJMcp0803977. Review.

• Responsible Party: Nancy J. Brown, Chair Department of Medicine, Vanderbilt University Medical Center
• ClinicalTrials.gov Identifier: NCT01574248
• Other Study ID Numbers: 000626
• First Posted: Apr 10, 2012
• Last Update Posted: Feb 17, 2017
• Last Verified: Dec 1, 2016

• Keywords provided by Nancy J. Brown, Chair Department of Medicine, Vanderbilt University Medical Center: ACE inhibitor; Angioedema; Bradykinin; Swelling
• Additional relevant MeSH terms: Angioedema; Icatibant

Study Results

Participant Flow

Arm/Group Title	Icatibant	Placebo
Arm/Group Description	30 mg icatibant will be administered subcutaneously 0 and 6 hours after randomization icatibant: Subcutaneous at time 0 and 6 hours	Subcutaneous at time 0 and 6 hours Placebo: Subcutaneous at time 0 and 6 hours
Period Title: Overall Study
STARTED	15	18
COMPLETED	12	18
NOT COMPLETED	3	0

Baseline Characteristics

Arm/Group Title	Icatibant	Placebo	Total
Arm/Group Description	30 mg icatibant will be administered subcutaneously 0 and 6 hours after randomization icatibant: Subcutaneous at time 0 and 6 hours	Subcutaneous at time 0 and 6 hours Placebo: Subcutaneous at time 0 and 6 hours	Total of all reporting groups
Overall Participants	12	18	30
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	56.3 (13.4)	60.7 (10.8)	58.9 (11.8)
Gender (Count of Participants)
Female	7 58.3%	12 66.7%	19 63.3%
Male	5 41.7%	6 33.3%	11 36.7%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	9 75%	11 61.1%	20 66.7%
White	3 25%	7 38.9%	10 33.3%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%
Region of Enrollment (Count of Participants)
United States	12 100%	18 100%	30 100%

Outcome Measures

1. Primary Outcome

Title	Time to Resolution of Angioedema
Description	Time interval between initiation of treatment and when there is no symptom, by visual analog scale <1 cm. Data provided are for worst symptom.
Time Frame	48 hours

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Icatibant	Placebo
Arm/Group Description	30 mg icatibant will be administered subcutaneously 0 and 6 hours after randomization icatibant: Subcutaneous at time 0 and 6 hours	Subcutaneous at time 0 and 6 hours Placebo: Subcutaneous at time 0 and 6 hours
Measure Participants	12	18
Median (95% Confidence Interval) [hours]	36	24

2. Secondary Outcome

Title	Number of Participants With Admission to Intensive Care Unit
Time Frame	T0 to T48 hours

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Icatibant	Placebo
Arm/Group Description	30 mg icatibant will be administered subcutaneously 0 and 6 hours after randomization icatibant: Subcutaneous at time 0 and 6 hours	Subcutaneous at time 0 and 6 hours Placebo: Subcutaneous at time 0 and 6 hours
Measure Participants	12	18
Count of Participants [Participants]	6 50%	6 33.3%

3. Secondary Outcome

Title	Number of Participants With Requirement for Intubation
Time Frame	T0 to T48 hours

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Icatibant	Placebo
Arm/Group Description	30 mg icatibant will be administered subcutaneously 0 and 6 hours after randomization icatibant: Subcutaneous at time 0 and 6 hours	Subcutaneous at time 0 and 6 hours Placebo: Subcutaneous at time 0 and 6 hours
Measure Participants	12	18
Count of Participants [Participants]	2 16.7%	1 5.6%

4. Secondary Outcome

Title	Number of Participants Given Steroids
Time Frame	T0 to T48 hours

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Icatibant	Placebo
Arm/Group Description	30 mg icatibant will be administered subcutaneously 0 and 6 hours after randomization icatibant: Subcutaneous at time 0 and 6 hours	Subcutaneous at time 0 and 6 hours Placebo: Subcutaneous at time 0 and 6 hours
Measure Participants	12	18
Count of Participants [Participants]	11 91.7%	16 88.9%

5. Secondary Outcome

Title	Number of Participants Given Histamine Receptor Type 1 (H1) and Type 2 (H2) Blockers
Time Frame	T0 to T48 hours

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Icatibant	Placebo
Arm/Group Description	30 mg icatibant will be administered subcutaneously 0 and 6 hours after randomization icatibant: Subcutaneous at time 0 and 6 hours	Subcutaneous at time 0 and 6 hours Placebo: Subcutaneous at time 0 and 6 hours
Measure Participants	12	18
Count of Participants [Participants]	11 91.7%	16 88.9%

6. Secondary Outcome

Title	Number of Participants Given Epinephrine
Time Frame	T0 to T48 hours

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Icatibant	Placebo
Arm/Group Description	30 mg icatibant will be administered subcutaneously 0 and 6 hours after randomization icatibant: Subcutaneous at time 0 and 6 hours	Subcutaneous at time 0 and 6 hours Placebo: Subcutaneous at time 0 and 6 hours
Measure Participants	12	18
Count of Participants [Participants]	0 0%	3 16.7%

7. Secondary Outcome

Title	Systolic Blood Pressure
Description	Average of blood pressure measurements from zero to forty-eight hours provided.
Time Frame	T0 to T48 hours

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Icatibant	Placebo
Arm/Group Description	30 mg icatibant will be administered subcutaneously 0 and 6 hours after randomization icatibant: Subcutaneous at time 0 and 6 hours	Subcutaneous at time 0 and 6 hours Placebo: Subcutaneous at time 0 and 6 hours
Measure Participants	12	18
Mean (Standard Deviation) [mmHg]	134 (13)	133 (17)

Adverse Events

Arm/Group Title	Icatibant		Placebo
Arm/Group Description	30 mg icatibant will be administered subcutaneously 0 and 6 hours after randomization icatibant: Subcutaneous at time 0 and 6 hours		Subcutaneous at time 0 and 6 hours Placebo: Subcutaneous at time 0 and 6 hours
All Cause Mortality
	Icatibant		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Icatibant		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/12 (0%)		0/18 (0%)
Other (Not Including Serious) Adverse Events
	Icatibant		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/12 (8.3%)		2/18 (11.1%)
Cardiac disorders
elevated troponin	0/12 (0%)	0	1/18 (5.6%)	1
Immune system disorders
leukocytosis	1/12 (8.3%)	1	0/18 (0%)	0
Reproductive system and breast disorders
low sperm count	0/12 (0%)	0	1/18 (5.6%)	1

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.