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Pharmacogenetics of Ace Inhibitor-Associated Angioedema

This study is currently recruiting participants.
Verified August 2012 by Vanderbilt University
Sponsor:
Information provided by (Responsible Party):
Nancy J. Brown, Vanderbilt University
ClinicalTrials.gov Identifier:
NCT01413542
First received: August 8, 2011
Last updated: August 3, 2012
Last verified: August 2012
History of Changes
  Purpose

The investigators would like to find out if sitagliptin, a drug to treat diabetes, affects blood vessel relaxation in healthy people receiving enalapril, a blood pressure medicine. Understanding how these drugs interact in healthy people will help us learn their potential effects in people who have diabetes.


Condition Intervention
Hypertension
Diabetes Type 2
 Drug: BNP, GLP-1, sitagliptin/placebo
Drug: Substance P, BK, sitagliptin/placebo

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Double Blind (Subject, Investigator)
Primary Purpose: Treatment
Official Title: Pharmacogenetics of Ace Inhibitor-Associated Angioedema:Aim 1

Resource links provided by NLM:

U.S. FDA Resources

Further study details as provided by Vanderbilt University:

Primary Outcome Measures:
  • The effect of enalaprilat, sitagliptin, or the combination on the vasodilator response to substance P and Bradykinin (Forearm Blood Flow) [ Time Frame: 1 year ] [ Designated as safety issue: No ]

    Bradykinin is a substrate of both ACE and DPPIV.It is expected that ACE inhibition will increase bradykin concentrations and potentiate the vasodilator response to bradykin as observed in a previous study but we do not expect sitagliptin to alter this effect.

    Subtance P is a substrate of both ACE and DPPIV.It is hypothesized that DPPIV inhibition will increase substance P concentrations and the vasodilator response to substance P during intra-arterial enalaprilat


  • The effect of enalaprilat, sitagliptin or the combination on the vasodilator response to BNP and GLP-1 (Forearm Blood Flow) [ Time Frame: 1 year ] [ Designated as safety issue: No ]

    DPPIV inhibition increases circulating concentrations of its substrate GLP-1. Based on data from animal studies, it is hypothesized that GLP-1 will cause dilation of the human forearm vasculature. It is also hypothesized that DPPIV inhibition will increase venous GLP-1 concentrations and the vasodilator response to GLP-1. Because GLP-1 is not an ACE substrate, no additional effect of enalaprilat is expected.

    DPPIV cleaves BNP to BNP3-32. It is expected that sitagliptin will increase the vasodilator response to BNP but there will be no additional effect of concurrent ACE inhibition



Secondary Outcome Measures:
  • Assess Peptide concentrations, nitric oxide metabolites,tissue type plasminogen activator and glucose [ Time Frame: 1 year ] [ Designated as safety issue: No ]
    Following measurement of FBF, samples will be obtained to determine the effect of ACE inhibition and/or DPPIV inhibition on venous nitric oxide metabolite concentrations and cGMP, on BK concentrations and tissue-type plasminogen activator,on GLP-1 concentrations and forearm glucose uptake and on 1-32 BNP.


Estimated Enrollment: 64
Study Start Date: November 2011
Estimated Study Completion Date: May 2015
Estimated Primary Completion Date: May 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: Substance P ,BK ,sitagliptin/placebo
Compare the effect of enalaprilat, sitagliptin or the combination on the vasodilator response to Substance P and bradykinin
 Drug: Substance P, BK, sitagliptin/placebo

Sitagliptin 200 mg or matching placebo will be given one hour prior to intra-arterial infusions.

One-half hour following administration of study drug, subjects will be instrumented for intra-arterial infusions. One hour after study drug, FBF will be measured and one of the peptides will be administered via brachial artery catheter in 3 graded doses for 5 minutes each:

Bradykinin- 25,50 and 100 ng/min Substance P- 2,4,8 pmol/min

Enalaprilat 0.33ug/min per 100 ml forearm volume will be given one half hour after the infusion of second peptide.

Thirty minutes later baseline measurements will be repeated and the two peptides infused again with an intervening rest period. The protocol will be repeated one week later using the opposite drug

Other Name: Januvia
Active Comparator: BNP ,GLP-1, sitagliptin/placebo
Compare the effect of enalaprilat, sitagliptin, the combination on the vasodilator response to BNP and GLP-1
 Drug: BNP, GLP-1, sitagliptin/placebo

Sitagliptin 200 mg or matching placebo will be given one hour prior to intra-arterial infusions.

One-half hour following administration of study drug, subjects will be instrumented for intra-arterial infusions. One hour after study drug, FBF will be measured and one of the peptides will be administered via brachial artery catheter in 3 graded doses for 5 minutes each:

GLP-1- 0.03, 0.06 and 0.12 pmol/min/100ml forearm volume

BNP- 32,48 and 96 pmol/min/100 ml forearm volume

Enalaprilat 0.33ug/min per 100 ml forearm volume will then be given one half hour after the infusion of second peptide.

Thirty minutes later baseline measurements will be repeated and the two peptides infused again with an intervening rest period. The protocol will be repeated one week later using the opposite drug.

Other Name: Januvia

Detailed Description:

To test the hypothesis that DPPIV inhibition potentiates the vasodilator response to substance P in the presence of ACE inhibition and to BNP and GLP-1 even in the presence of ACE inhibition. The aim promises to provide important new data regarding the mechanism of action of DPPIV inhibitors and interactive effects of these two drug classes used in a growing population of diabetic patients.

  Eligibility

Ages Eligible for Study:   18 Years to 65 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  • Age 18 to 65 inclusive
  • Men and women
  • Black and White Americans
  • BMI <25

For female subjects:

  • Postmenopausal status for at least 1 year
  • Status post surgical sterilization
  • If childbearing potential, utilization of a barrier method of birth control and willingness to undergo blood B-hcg testing prior to drug treatment and on every study day

Exclusion Criteria:

  • Smoking
  • Diabetes type 1 or 2, as defined by a fasting glucose of 126 mg/dl or greater or the use of anti-diabetic medication
  • Hypertension as defined by an untreated seated SBP greater than 140 mmHg an untreated DBP greater than 90 mmHg or the use of antihypertensives
  • History of reported or recorded hypoglycemia (plasma glucose less than 70 mg/dl)
  • Pregnancy
  • Breast-feeding
  • Use of hormone replacement therapy
  • The use of contraceptive therapy
  • Use of any medication other than multivitamin
  • Hematocrit <35%
  • Cardiovascular disease such as history of myocardial infarction, presence of angina pectoris, significant arrhythmia, congestive heart failure(LV hypertrophy acceptable), deep vein thrombosis, pulmonary embolism, second or third degree heart block, mitral valve stenosis, aortic stenosis or hypertrophic cardiomyopathy
  • Asthma
  • History of angioedema
  • History of cough or other side effect during ACE inhibitor use
  • Impaired renal function, as defined by an eGFR<60ml/min/1.73M2
  • Clinically significant gastrointestinal impairment that could interfere with drug absorption
  • Impaired hepatic function (aspartate amino transaminase[AST] and/or alanine amino transferase [ALT]>2 x upper limit of normal range
  • History of alcohol or drug abuse
  • Treatment with any investigational drug in the 1 month preceding the study
  • Mental conditions rendering the subject unable to understand the nature, scope and possible consequences of the study
  • Inability to comply with the protocol, e.g., uncooperative attitude, inability to return to follow-up visits, and the unlikelihood of completing the study
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT01413542

Contacts
Contact: Carol Meisch, BSN 615-343-0644 carol.meisch@vanderbilt.edu
Contact: Jessica Devin, MD 615-936-1653 jessica.devin@vanderbilt.edu

Locations
United States, Tennessee
Vanderbilt University- General Clinic Research Center Recruiting
Nashville, Tennessee, United States, 37232
Sponsors and Collaborators
Vanderbilt University
Investigators
Principal Investigator: Nancy J Brown, MD Vanderbilt University
  More Information

No publications provided

Responsible Party: Nancy J. Brown, Chair of Dept of Medicine, Vanderbilt University
ClinicalTrials.gov Identifier: NCT01413542     History of Changes
Other Study ID Numbers: HL079184
Study First Received: August 8, 2011
Last Updated: August 3, 2012
Health Authority: United States: Food and Drug Administration

Keywords provided by Vanderbilt University:
DPPIV inhibitors
ACE inhibitors
Bradykinin
glucagon-like peptide (GLP-1)
 BNP
diabetes
hypertension
Diabetes

Additional relevant MeSH terms:
Angioedema
Diabetes Mellitus
Diabetes Mellitus, Type 2
Hypertension
Vascular Diseases
Cardiovascular Diseases
Urticaria
Skin Diseases, Vascular
Skin Diseases
Hypersensitivity, Immediate
Hypersensitivity
Immune System Diseases
Glucose Metabolism Disorders
Metabolic Diseases
Endocrine System Diseases
 Angiotensin-Converting Enzyme Inhibitors
Enalaprilat
Bradykinin
Sitagliptin
Substance P
Protease Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Vasodilator Agents
Cardiovascular Agents
Therapeutic Uses
Antihypertensive Agents
Neurotransmitter Agents
Physiological Effects of Drugs

ClinicalTrials.gov processed this record on May 22, 2013