Effect of Bradykinin Receptor Antagonism on ACE Inhibitor-associated Angioedema

ACE Inhibitor-associated Angioedema Clinical Trial

Official title:

Effect of Bradykinin Receptor Antagonism on ACE Inhibitor-associated Angioedema - a Mulitcenter Trial

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT01574248
• Other study ID #: 000626
• Status: Terminated
• Phase: Phase 0
• First received: December 14, 2011
• Last updated: April 4, 2016
• Start date: August 2011
• Est. completion date: February 2016

Study information

• Verified date: April 2016
• Source: Vanderbilt University
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 21
• Est. completion date: February 2016
• Est. primary completion date: September 2015
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years to 80 Years

Eligibility

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.

Study Design

Allocation: Randomized, Endpoint Classification: Pharmacodynamics Study, Intervention Model: Single Group Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Treatment

Related Conditions & MeSH terms

• ACE Inhibitor-associated Angioedema
• Angioedema

Intervention

Drug:
• icatibant
Subcutaneous at time 0 and 6 hours

Other:
• Placebo
Subcutaneous at time 0 and 6 hours

Locations

Country	Name	City	State
United States	Vanderbilt University Medical Center	Nashville	Tennessee
United States	University of California, San Diego	San Diego	California

Sponsors (1)

Lead Sponsor	Collaborator
Vanderbilt University

Country where clinical trial is conducted

United States, 

References & Publications (9)

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. — View Citation

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. — View Citation

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. — View Citation

Brown NJ, Snowden M, Griffin MR. Recurrent angiotensin-converting enzyme inhibitor--associated angioedema. JAMA. 1997 Jul 16;278(3):232-3. — View Citation

Byrd JB, Adam A, Brown NJ. Angiotensin-converting enzyme inhibitor-associated angioedema. Immunol Allergy Clin North Am. 2006 Nov;26(4):725-37. Review. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

Zuraw BL. Clinical practice. Hereditary angioedema. N Engl J Med. 2008 Sep 4;359(10):1027-36. doi: 10.1056/NEJMcp0803977. Review. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Time to resolution of angioedema	Time interval between when participant first noted the onset of symptom and when there is no symptom, by visual analog scale. Will also measure AUC for VAS versus time for each symptom	48 hours	No
Secondary	Length of hospital stay		T0 to T48 hours	No
Secondary	Admission to intensive care unit		T0 to T48 hours	No
Secondary	Requirement for intubation		T0 to T48 hours	No
Secondary	Duration of intubation		T0 to T48 hours	No
Secondary	Use of steroids		T0 to T48 hours	No
Secondary	Use of histamine receptor type 1 (H1) and type 2 (H2) blockers		T0 to T48 hours	No
Secondary	Use of epinephrine		T0 to T48 hours	No
Secondary	Blood pressure levels		T0 to T48 hours	No