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Effect of Bradykinin Receptor Antagonism on ACE Inhibitor-associated Angioedema

Primary Purpose

ACE Inhibitor-associated Angioedema

Status
Terminated
Phase
Phase 4
Locations
United States
Study Type
Interventional
Intervention
icatibant
Placebo
Sponsored by
Vanderbilt University Medical Center
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for ACE Inhibitor-associated Angioedema focused on measuring ACE inhibitor, Angioedema, Bradykinin, Swelling

Eligibility Criteria

18 Years - 80 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

  • University of California, San Diego
  • Vanderbilt University Medical Center

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Placebo Comparator

Arm Label

icatibant

Placebo

Arm Description

30 mg icatibant will be administered subcutaneously 0 and 6 hours after randomization

Subcutaneous at time 0 and 6 hours

Outcomes

Primary Outcome Measures

Time to Resolution of Angioedema
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
Number of Participants With Requirement for Intubation
Number of Participants Given Steroids
Number of Participants Given Histamine Receptor Type 1 (H1) and Type 2 (H2) Blockers
Number of Participants Given Epinephrine
Systolic Blood Pressure
Average of blood pressure measurements from zero to forty-eight hours provided.

Full Information

First Posted
December 14, 2011
Last Updated
December 22, 2016
Sponsor
Vanderbilt University Medical Center
Collaborators
Shire
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1. Study Identification

Unique Protocol Identification Number
NCT01574248
Brief Title
Effect of Bradykinin Receptor Antagonism on ACE Inhibitor-associated Angioedema
Official Title
Effect of Bradykinin Receptor Antagonism on ACE Inhibitor-associated Angioedema - a Mulitcenter Trial
Study Type
Interventional

2. Study Status

Record Verification Date
December 2016
Overall Recruitment Status
Terminated
Why Stopped
DSMC recommended discontinuation for futility and feasibility
Study Start Date
August 2011 (undefined)
Primary Completion Date
September 2015 (Actual)
Study Completion Date
February 2016 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Vanderbilt University Medical Center
Collaborators
Shire

4. Oversight

Data Monitoring Committee
Yes

5. 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.
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
ACE Inhibitor-associated Angioedema
Keywords
ACE inhibitor, Angioedema, Bradykinin, Swelling

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 4
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
33 (Actual)

8. Arms, Groups, and Interventions

Arm Title
icatibant
Arm Type
Experimental
Arm Description
30 mg icatibant will be administered subcutaneously 0 and 6 hours after randomization
Arm Title
Placebo
Arm Type
Placebo Comparator
Arm Description
Subcutaneous at time 0 and 6 hours
Intervention Type
Drug
Intervention Name(s)
icatibant
Other Intervention Name(s)
Firazyr, HOE140
Intervention Description
Subcutaneous at time 0 and 6 hours
Intervention Type
Other
Intervention Name(s)
Placebo
Intervention Description
Subcutaneous at time 0 and 6 hours
Primary Outcome Measure Information:
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
Secondary Outcome Measure Information:
Title
Number of Participants With Admission to Intensive Care Unit
Time Frame
T0 to T48 hours
Title
Number of Participants With Requirement for Intubation
Time Frame
T0 to T48 hours
Title
Number of Participants Given Steroids
Time Frame
T0 to T48 hours
Title
Number of Participants Given Histamine Receptor Type 1 (H1) and Type 2 (H2) Blockers
Time Frame
T0 to T48 hours
Title
Number of Participants Given Epinephrine
Time Frame
T0 to T48 hours
Title
Systolic Blood Pressure
Description
Average of blood pressure measurements from zero to forty-eight hours provided.
Time Frame
T0 to T48 hours

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
80 Years
Accepts Healthy Volunteers
No
Eligibility 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.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Nancy J. Brown, MD
Organizational Affiliation
Vanderbilt University
Official's Role
Principal Investigator
Facility Information:
Facility Name
University of California, San Diego
City
San Diego
State/Province
California
ZIP/Postal Code
92093
Country
United States
Facility Name
Vanderbilt University Medical Center
City
Nashville
State/Province
Tennessee
ZIP/Postal Code
37235
Country
United States

12. IPD Sharing Statement

Citations:
PubMed Identifier
17085287
Citation
Byrd JB, Adam A, Brown NJ. Angiotensin-converting enzyme inhibitor-associated angioedema. Immunol Allergy Clin North Am. 2006 Nov;26(4):725-37. doi: 10.1016/j.iac.2006.08.001.
Results Reference
background
PubMed Identifier
8689816
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. doi: 10.1016/S0009-9236(96)90161-7.
Results Reference
background
PubMed Identifier
19581505
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.
Results Reference
background
PubMed Identifier
9791144
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. doi: 10.1056/NEJM199810293391804.
Results Reference
background
PubMed Identifier
18768946
Citation
Zuraw BL. Clinical practice. Hereditary angioedema. N Engl J Med. 2008 Sep 4;359(10):1027-36. doi: 10.1056/NEJMcp0803977. No abstract available.
Results Reference
background
PubMed Identifier
8072263
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. doi: 10.1038/ki.1994.195.
Results Reference
background
PubMed Identifier
9551414
Citation
Krieter DH, Grude M, Lemke HD, Fink E, Bonner G, Scholkens BA, Schulz E, Muller GA. Anaphylactoid reactions during hemodialysis in sheep are ACE inhibitor dose-dependent and mediated by bradykinin. Kidney Int. 1998 Apr;53(4):1026-35. doi: 10.1111/j.1523-1755.1998.00837.x.
Results Reference
background
PubMed Identifier
17418383
Citation
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. doi: 10.1016/j.jaci.2007.02.012. Epub 2007 Apr 5.
Results Reference
background
PubMed Identifier
9218671
Citation
Brown NJ, Snowden M, Griffin MR. Recurrent angiotensin-converting enzyme inhibitor--associated angioedema. JAMA. 1997 Jul 16;278(3):232-3. doi: 10.1001/jama.278.3.232.
Results Reference
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Effect of Bradykinin Receptor Antagonism on ACE Inhibitor-associated Angioedema

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