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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
  Purpose
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.

Condition Intervention
Hypertension
Diabetes Type 2
Drug: Sitagliptin (DPP4 inhibitor)
Drug: Substance P,
Drug: bradykinin
Drug: enalaprilat (ACE inhibitor)
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 (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.


Secondary Outcome Measures:
  • 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 ]

Enrollment: 44
Study Start Date: November 2011
Study Completion Date: July 2014
Primary Completion Date: July 2013 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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).
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
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
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
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).
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: 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 (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).
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: 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 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.
  Eligibility

Ages Eligible for Study:   18 Years to 65 Years   (Adult)
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

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

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
Obsolete Identifiers: NCT00139503
Other Study ID Numbers: HL079184 
Study First Received: August 8, 2011
Results First Received: November 7, 2014
Last Updated: October 5, 2015
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

Additional relevant MeSH terms:
Hypertension
Angioedema
Diabetes Mellitus, Type 2
Vascular Diseases
Cardiovascular Diseases
Urticaria
Skin Diseases, Vascular
Skin Diseases
Hypersensitivity, Immediate
Hypersensitivity
Immune System Diseases
Diabetes Mellitus
Glucose Metabolism Disorders
Metabolic Diseases
Endocrine System Diseases
Sitagliptin Phosphate
Glucagon-Like Peptide 1
Dipeptidyl-Peptidase IV Inhibitors
Kininogens
Enalaprilat
Enalapril
Glucagon
Angiotensin-Converting Enzyme Inhibitors
Bradykinin
Substance P
Neurokinin A
Natriuretic Peptide, Brain
Hypoglycemic Agents
Physiological Effects of Drugs
Incretins

ClinicalTrials.gov processed this record on September 27, 2016