Effect of Bradykinin Receptor Antagonism on ACE Inhibitor-associated Angioedema

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ClinicalTrials.gov Identifier: NCT01574248

Recruitment Status : Terminated (DSMC recommended discontinuation for futility and feasibility)

First Posted : April 10, 2012

Results First Posted : February 17, 2017

Last Update Posted : February 17, 2017

Sponsor:

Collaborator:

Shire

Information provided by (Responsible Party):

Nancy J. Brown, Vanderbilt University Medical Center

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

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Study Type :	Interventional (Clinical Trial)
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 :	August 2011
Actual Primary Completion Date :	September 2015
Actual Study Completion Date :	February 2016

Resource links provided by the National Library of Medicine

Drug Information available for: Icatibant Icatibant acetate

U.S. FDA Resources

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 :

Time to Resolution of Angioedema [ Time Frame: 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 :

Number of Participants With Admission to Intensive Care Unit [ Time Frame: T0 to T48 hours ]
Number of Participants With Requirement for Intubation [ Time Frame: T0 to T48 hours ]
Number of Participants Given Steroids [ Time Frame: T0 to T48 hours ]
Number of Participants Given Histamine Receptor Type 1 (H1) and Type 2 (H2) Blockers [ Time Frame: T0 to T48 hours ]
Number of Participants Given Epinephrine [ Time Frame: T0 to T48 hours ]
Systolic Blood Pressure [ Time Frame: T0 to T48 hours ]
Average of blood pressure measurements from zero to forty-eight hours provided.

Eligibility Criteria

Information from the National Library of Medicine

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Ages Eligible for Study:	18 Years to 80 Years (Adult, Older Adult)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

Criteria

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01574248

Locations

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United States, California
University of California, San Diego
San Diego, California, United States, 92093
United States, Tennessee
Vanderbilt University Medical Center
Nashville, Tennessee, United States, 37235

Sponsors and Collaborators

Vanderbilt University Medical Center

Shire

Investigators

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Principal Investigator:	Nancy J. Brown, MD	Vanderbilt University

More Information

Publications:

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

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, 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.

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.

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

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.

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.

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

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Responsible Party:	Nancy J. Brown, Chair Department of Medicine, Vanderbilt University Medical Center
ClinicalTrials.gov Identifier:	NCT01574248
Other Study ID Numbers:	000626
First Posted:	April 10, 2012 Key Record Dates
Results First Posted:	February 17, 2017
Last Update Posted:	February 17, 2017
Last Verified:	December 2016

Keywords provided by Nancy J. Brown, Vanderbilt University Medical Center:


ACE inhibitor Angioedema Bradykinin Swelling

Additional relevant MeSH terms:

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Angioedema Vascular Diseases Cardiovascular Diseases Urticaria Skin Diseases, Vascular Skin Diseases Hypersensitivity, Immediate Hypersensitivity Immune System Diseases Icatibant Bradykinin Angiotensin-Converting Enzyme Inhibitors Kininogens Protease Inhibitors Enzyme Inhibitors	Molecular Mechanisms of Pharmacological Action Anti-Inflammatory Agents, Non-Steroidal Analgesics, Non-Narcotic Analgesics Sensory System Agents Peripheral Nervous System Agents Physiological Effects of Drugs Anti-Inflammatory Agents Antirheumatic Agents Bradykinin B2 Receptor Antagonists Bradykinin Receptor Antagonists Complement Inactivating Agents Immunosuppressive Agents Immunologic Factors Vasodilator Agents

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