ACE Inhibitor-associated AngioedemaPhase 4NCT01574248
Effect of Bradykinin Receptor Antagonism on ACE Inhibitor-associated Angioedema
A Phase 4 study testing icatibant in people with ACE Inhibitor-associated Angioedema, run by Vanderbilt University Medical Center at 2 sites in United States.
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. Read more about this study
- Who is it for?
- Ages 18 to 80 years
- Conditions the study is for
- ACE Inhibitor-associated Angioedema
- What is being tested?
- icatibant
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 33 participants
- Where
- 2 sitesUnited States
- Study dates
- Aug 2011to Feb 2016
- Phase
- Phase 4
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 80 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- The subject has ongoing angioedema while taking an ACE inhibitor.
- The subject is between 18 and 80 years of age.
Who cannot join
- 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.
Trial locations and contacts
2 sites in 1 country.
United States2 sites
Vanderbilt University Medical Center
Nashville, Tennessee, 37235
University of California, San Diego
San Diego, California, 92093
About this study
Official title: Effect of Bradykinin Receptor Antagonism on ACE Inhibitor-associated Angioedema - a Mulitcenter Trial
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.
Read the 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.
- Conditions
- ACE Inhibitor-associated Angioedema
- Being tested
- icatibant, Placebo
- Keywords
- ACE inhibitor, Angioedema, Bradykinin, Swelling
- Medical subject headings
- Angioedema
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
icatibantDrug
Also called Firazyr, HOE140
Subcutaneous at time 0 and 6 hours
PlaceboOther
Subcutaneous at time 0 and 6 hours
| Study group | Role | What they receive |
|---|---|---|
| icatibant | Experimental | 30 mg icatibant will be administered subcutaneously 0 and 6 hours after randomization Receives: Drug: icatibant |
| Placebo | Placebo comparator | Subcutaneous at time 0 and 6 hours Receives: Other: Placebo |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: 48 hours
Secondary outcomes (6)
Number of Participants With Admission to Intensive Care Unit
Measured: T0 to T48 hours
Number of Participants With Requirement for Intubation
Measured: T0 to T48 hours
Number of Participants Given Steroids
Measured: T0 to T48 hours
Number of Participants Given Histamine Receptor Type 1 (H1) and Type 2 (H2) Blockers
Measured: T0 to T48 hours
Number of Participants Given Epinephrine
Measured: T0 to T48 hours
Systolic Blood Pressure
Average of blood pressure measurements from zero to forty-eight hours provided.
Measured: T0 to T48 hours
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted10 Apr 2012 (estimated)
- Study startAug 2011
- Primary completionSep 2015
- Study completionFeb 2016
Why it stopped: DSMC recommended discontinuation for futility and feasibility
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (9)Papers the sponsor has linked to this study.
- Other trials for ACE Inhibitor-associated AngioedemaStudies of the same condition, open and under way.
- More trials run by Vanderbilt University Medical CenterThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 4
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 33 participants (actual)
Sponsor and investigators
- Lead sponsor
- Vanderbilt University Medical Center
- Sponsor type
- University, hospital or other
- Collaborators
- Shire
- Responsible party
- Principal investigator, Nancy J. Brown, Vanderbilt University Medical Center
- Investigators
- Nancy J. Brown, MD, Principal investigator, Vanderbilt University
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01574248
- Sponsor's protocol ID
- 000626
- Status last verified
- Dec 2016
- First submitted
- 14 Dec 2011
- Last updated
- 17 Feb 2017
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
Publications
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.
PubMed 17085287Brown 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.
PubMed 8689816Brown 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.
PubMed 19581505Gainer 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.
PubMed 9791144Zuraw BL. Clinical practice. Hereditary angioedema. N Engl J Med. 2008 Sep 4;359(10):1027-36. doi: 10.1056/NEJMcp0803977. No abstract available.
PubMed 18768946Verresen 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.
PubMed 8072263Krieter 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.
PubMed 9551414Bork 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.
PubMed 17418383Brown 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.
PubMed 9218671
Study at a glance
From the registry record, last updated by the sponsor on 17 Feb 2017. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Effect of Bradykinin Receptor Antagonism on ACE Inhibitor-associated Angioedema - a Mulitcenter Trial
- ClinicalTrials.gov ID
- NCT01574248
- Acronym / sponsor ID
- 000626
- Conditions
- ACE Inhibitor-associated Angioedema
- Keywords
- ACE inhibitor, Angioedema, Bradykinin, Swelling
- Phase
- Phase 4
- Study type
- Interventional
- Recruitment status
- TerminatedReason stopped: DSMC recommended discontinuation for futility and feasibility
- Enrolment
- 33 participants (actual)
- Lead sponsor
- Vanderbilt University Medical CenterUniversity, hospital or other
- Collaborators
- Shire
- Study start
- Aug 2011
- Primary completion
- Sep 2015 (actual)
- Study completion
- Feb 2016 (actual)
- First posted
- 10 Apr 2012 (estimated)
- Results
- Posted 17 Feb 2017
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| icatibant | Experimental | Drug: icatibant30 mg icatibant will be administered subcutaneously 0 and 6 hours after randomization |
| Placebo | Placebo comparator | Other: PlaceboSubcutaneous at time 0 and 6 hours |
Who may qualify
- Ages
- 18 to 80 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (2 listed)
- The subject has ongoing angioedema while taking an ACE inhibitor.
- The subject is between 18 and 80 years of age.
Key exclusion criteria (4 listed)
- 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.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| icatibantAlso: Firazyr, HOE140Subcutaneous at time 0 and 6 hours | Drug | icatibant |
| PlaceboSubcutaneous at time 0 and 6 hours | Other | Placebo |
Primary outcome
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.
6 secondary outcomes
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
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 17 Feb 2017.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Background: PubMed 17085287Byrd 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.
- Background: PubMed 8689816Brown 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.
- Background: PubMed 19581505Brown 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.
- Background: PubMed 9791144Gainer 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.
- Background: PubMed 18768946Zuraw BL. Clinical practice. Hereditary angioedema. N Engl J Med. 2008 Sep 4;359(10):1027-36. doi: 10.1056/NEJMcp0803977. No abstract available.
- Background: PubMed 8072263Verresen 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.
- Background: PubMed 9551414Krieter 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.
- Background: PubMed 17418383Bork 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.
- Background: PubMed 9218671Brown 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.
Related trials for ACE Inhibitor-associated Angioedema
RecruitingObservational study
Bradykinin-degradating Enzymes Activities in Angiotensin-Converting Enzyme Inhibitors-associated Angioedema
Angio-Oedema Caused by Angiotensin-Converting-Enzyme Inhibitor
Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Nancy J. Brown, MD principal investigator
Vanderbilt University
2 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 4 study testing icatibant in people with ACE Inhibitor-associated Angioedema, run by Vanderbilt University Medical Center at 2 sites in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 2 inclusion and 4 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: stopped early, as of the sponsor's last update on 17 Feb 2017. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 2 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 17 Feb 2017). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Time to Resolution of Angioedema (time frame: 48 hours). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT01574248, which also lists 9 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 17 Feb 2017.