Pharmacogenetics of Ace Inhibitor-Associated Angioedema

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Nancy J. Brown, Vanderbilt University
ClinicalTrials.gov Identifier:
NCT01413542
First received: August 8, 2011
Last updated: October 5, 2015
Last verified: October 2015

August 8, 2011
October 5, 2015
November 2011
July 2013   (final data collection date for primary outcome measure)
The Effect of Enalaprilat (ACE Inhibition), Sitagliptin (DPP4 Inhibition), or the Combination on the Vasodilator Response (Forearm Blood Flow) to Substance P (SP) and Bradykinin (Group 1) or Glucagon Like Peptide-1 and Brain Naturetic Peptide (Group 2). [ Time Frame: 60 minutes post-placebo or sitagliptin (DPP4 inhibition) and over last 2 minutes of each 5 min infusion per peptide dose (30 min washout between peptides); sequence repeated with enalaprilat (ACE inhibition) or vehicle ] [ Designated as safety issue: No ]
Forearm blood flow (FBF) was measured by strain gauge plethysmography at the completion of each dose of intra-arterial peptide. A dose response curve was therefore constructed for each vasoactive peptide substrate. The effect of sitagliptin (DPP4 inhibition) vs. placebo and enalaprilat (ACE inhibition) vs. vehicle on the forearm blood flow response to each peptide could then be determined.
  • 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 Tissue Type Plasminogen Activator (tPA) Release [ Time Frame: Blood for analysis of tPA release was obtained 60 minutes after sitagliptin (DPP4 inhibition) vs. placebo and after each assessment of FBF (see primary outcome measure) ] [ Designated as safety issue: No ]
    Following measurement of FBF, samples will be obtained to determine the effect of ACE inhibition and/or DPP4 inhibition on tPA release in response to bradykinin and substance P (SP) (group 1)
  • Assess Effect of ACE and/or DPP4 Inhibition on Heart Rate Response to Substance P (SP) [ Time Frame: Heart rate was measured every 5 minutes throughout the study day (and thus during each dose of peptide infusion) ] [ Designated as safety issue: No ]
  • Effect of Treatment (ACE or DPP4 Inhibition, or Combined) on Norepinephrine (NE) Release (Arterial Venous Gradient) in Response to Substance P (SP) [ Time Frame: Blood for analysis of norepinephrine (NE) release was obtained 60 minutes after sitagliptin (DPP4 inhibition) vs. placebo and after each assessment of FBF (see primary outcome measure) ] [ Designated as safety issue: No ]
  • Effect of Treatment (DPP4 Inhibition vs. Placebo) on Venous GLP-1 Levels in Response to Arterial GLP-1 Infusion [ Time Frame: Blood for analysis of GLP-1 levels was obtained one hour after sitagliptin (DPP4 inhibition) vs. placebo administration and after each dose of GLP-1 ] [ Designated as safety issue: No ]
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 (dipeptidyl peptidase-4 or DPP4 inhibition), a drug to treat diabetes, affects blood vessel relaxation in healthy people receiving enalapril (angiotensin converting enzyme or ACE inhibition), 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 with sitagliptin potentiates the vasodilator response to substance P in the presence of ACE inhibition with enalaprilat 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 (DPP4 inhibitor)
    Sitagliptin 200 mg (DPP4 inhibitor) 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 (ACE inhibitor)
    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 (DPP4 inhibition) 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 (DPP4 inhibition).
    Interventions:
    • Drug: Sitagliptin (DPP4 inhibitor)
    • Drug: Substance P,
    • Drug: bradykinin
    • Drug: enalaprilat (ACE inhibitor)
  • Placebo Comparator: Sitagliptin (DPP4 inhibition) then placebo group 1
    The effect of vehicle and enalaprilat (ACE inhibition) on the forearm blood flow and t-PA responses to substance P and bradykinin are studied after administration of sitagliptin (DPP4 inhibition) or placebo
    Interventions:
    • Drug: Sitagliptin (DPP4 inhibitor)
    • Drug: Substance P,
    • Drug: bradykinin
    • Drug: enalaprilat (ACE inhibitor)
  • Placebo Comparator: Placebo then sitagliptin group 2
    The effect of vehicle and enalaprilat (ACE inhibition) 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 (DPP4 inhibition).
    Interventions:
    • Drug: Sitagliptin (DPP4 inhibitor)
    • Drug: Glucagon-like peptide 1
    • Drug: brain natriuretic peptide
  • Placebo Comparator: Sitagliptin (DPP4 inhibition) 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 (DPP4 inhibition).
    Interventions:
    • Drug: Sitagliptin (DPP4 inhibitor)
    • 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.
 
Completed
44
July 2014
July 2013   (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 information is only displayed when the study is recruiting subjects
United States
 
NCT01413542
HL079184
Yes
Not Provided
Not Provided
Nancy J. Brown, Vanderbilt University
Vanderbilt University
Not Provided
Principal Investigator: Nancy J Brown, MD Vanderbilt University
Vanderbilt University
October 2015

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