Pharmacogenetics of Ace Inhibitor-Associated Angioedema

This study is currently recruiting participants. (see Contacts and Locations)
Verified June 2013 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: June 16, 2013
Last verified: June 2013
  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: Sitagliptin
Drug: Substance P,
Drug: bradykinin
Drug: enalaprilat
Drug: Glucagon-like peptide 1
Drug: brain natriuretic peptide

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:


Further study details as provided by Vanderbilt University:

Primary Outcome Measures:
  • The effect of enalaprilat, sitagliptin, or the combination on the vasodilator response (forearm blood flow) to substance P and bradykinin (Group 1) or glucagon like peptide-1 and brain naturetic peptide (Group 2). [ Time Frame: 1 year ] [ Designated as safety issue: No ]

    Group 1 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 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.

    Group 2 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.

    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, glucose, and catecholamines [ 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 2014
Estimated Primary Completion Date: May 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Placebo Comparator: Placebo then sitagliptin group 1
The effect of vehicle and enalaprilat on the forearm blood flow and t-PA responses to bradykinin and substance P are studied after administration of placebo or sitagliptin.
Drug: Sitagliptin
Sitagliptin 200 mg or matching placebo will be given one hour prior to intra-arterial infusions
Other Name: Januvia
Drug: Substance P,
Substance P intra-brachial artery (2,4,8 pmol/min)
Drug: bradykinin
bradykinin intra-brachial artery (23.6, 47.2, and 94.3 pmol/min)
Drug: enalaprilat
intra-brachial artery(0.33 µg/min per 100 mL forearm volume)
Other Name: vasotec
Placebo Comparator: Sitagliptin then placebo group 1
The effect of vehicle and enalaprilat on the forearm blood flow and t-PA responses to substance P and bradykinin are studied after administration of sitagliptin or placebo
Drug: Sitagliptin
Sitagliptin 200 mg or matching placebo will be given one hour prior to intra-arterial infusions
Other Name: Januvia
Drug: Substance P,
Substance P intra-brachial artery (2,4,8 pmol/min)
Drug: bradykinin
bradykinin intra-brachial artery (23.6, 47.2, and 94.3 pmol/min)
Drug: enalaprilat
intra-brachial artery(0.33 µg/min per 100 mL forearm volume)
Other Name: vasotec
Placebo Comparator: Placebo then sitagliptin group 2
The effect of vehicle and enalaprilat on the forearm blood flow and t-PA responses to glucagon-like peptide-1 and brain natriuretic pepdie are studied after administration of placebo or sitagliptin.
Drug: Sitagliptin
Sitagliptin 200 mg or matching placebo will be given one hour prior to intra-arterial infusions
Other Name: Januvia
Drug: enalaprilat
intra-brachial artery(0.33 µg/min per 100 mL forearm volume)
Other Name: vasotec
Drug: Glucagon-like peptide 1
intra-brachial artery (0.45-3.60 pmol/min)
Other Name: GLP-1
Drug: brain natriuretic peptide
Intra-brachial artery (0.90, 1.80 and 3.6 pmol/min)
Other Name: nesiritide
Placebo Comparator: Sitagliptin then comparator group 2
The effect of vehicle and enalaprilat on the forearm blood flow and t-PA responses to glucagon-like peptide and brain natriuretic peptide are studied after administration of placebo or sitagliptin.
Drug: Sitagliptin
Sitagliptin 200 mg or matching placebo will be given one hour prior to intra-arterial infusions
Other Name: Januvia
Drug: enalaprilat
intra-brachial artery(0.33 µg/min per 100 mL forearm volume)
Other Name: vasotec
Drug: Glucagon-like peptide 1
intra-brachial artery (0.45-3.60 pmol/min)
Other Name: GLP-1
Drug: brain natriuretic peptide
Intra-brachial artery (0.90, 1.80 and 3.6 pmol/min)
Other Name: nesiritide

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
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01413542

Contacts
Contact: Stacy Glibert, RN 615-322-2105 Stacy.gilbert@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 by Vanderbilt University

Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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: June 16, 2013
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, Type 2
Hypertension
Cardiovascular Diseases
Diabetes Mellitus
Endocrine System Diseases
Glucose Metabolism Disorders
Hypersensitivity
Hypersensitivity, Immediate
Immune System Diseases
Metabolic Diseases
Skin Diseases
Skin Diseases, Vascular
Urticaria
Vascular Diseases
Angiotensin-Converting Enzyme Inhibitors
Bradykinin
Enalapril
Enalaprilat
Glucagon
Glucagon-Like Peptide 1
Kininogens
Natriuretic Peptide, Brain
Sitagliptin
Substance P
Antihypertensive Agents
Cardiovascular Agents
Cysteine Proteinase Inhibitors
Dipeptidyl-Peptidase IV Inhibitors
Enzyme Inhibitors

ClinicalTrials.gov processed this record on October 20, 2014