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

August 8, 2011
June 16, 2013
November 2011
May 2014   (final data collection date for primary outcome measure)
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.

  • Compare 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

  • Compare 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

Complete list of historical versions of study NCT01413542 on ClinicalTrials.gov Archive Site
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.
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.
Not Provided
Not Provided
 
Pharmacogenetics of Ace Inhibitor-Associated Angioedema
Pharmacogenetics of Ace Inhibitor-Associated Angioedema:Aim 1

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.

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.

Interventional
Not Provided
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Double Blind (Subject, Investigator)
Primary Purpose: Treatment
  • Hypertension
  • Diabetes Type 2
  • 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
  • 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: 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.
    Interventions:
    • Drug: Sitagliptin
    • Drug: Substance P,
    • Drug: bradykinin
    • Drug: enalaprilat
  • 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
    Interventions:
    • Drug: Sitagliptin
    • Drug: Substance P,
    • Drug: bradykinin
    • Drug: enalaprilat
  • 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.
    Interventions:
    • Drug: Sitagliptin
    • Drug: enalaprilat
    • Drug: Glucagon-like peptide 1
    • Drug: brain natriuretic peptide
  • 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.
    Interventions:
    • Drug: Sitagliptin
    • Drug: enalaprilat
    • Drug: Glucagon-like peptide 1
    • Drug: brain natriuretic peptide

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruiting
64
May 2014
May 2014   (final data collection date for primary outcome measure)

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
Both
18 Years to 65 Years
Yes
Contact: Stacy Glibert, RN 615-322-2105 Stacy.gilbert@vanderbilt.edu
Contact: Jessica Devin, MD 615-936-1653 jessica.devin@vanderbilt.edu
United States
 
NCT01413542
HL079184
Yes
Nancy J. Brown, Vanderbilt University
Vanderbilt University
Not Provided
Principal Investigator: Nancy J Brown, MD Vanderbilt University
Vanderbilt University
June 2013

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP