Trial record 1 of 28 for:    neuropeptide y
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Effect of DPP4 Inhibition on Vasoconstriction

This study is currently recruiting participants. (see Contacts and Locations)
Verified March 2016 by Vanderbilt University
Sponsor:
Information provided by (Responsible Party):
Nancy J. Brown, Vanderbilt University
ClinicalTrials.gov Identifier:
NCT02639637
First received: December 16, 2015
Last updated: March 23, 2016
Last verified: March 2016
  Purpose
The purpose of this study is to understand how dipeptidyl peptidase IV (DPP4) inhibition in diabetics affects hemodynamic parameters and sympathetic activation in the setting of increasing concentrations of neuropeptide Y, an endogenous peptide. The central hypothesis is that DPP4 inhibition decreases degradation of neuropeptide Y, resulting in increased vasoconstriction and sympathetic activation.

Condition Intervention Phase
Type 2 Diabetes Mellitus
Drug: Sitagliptin
Drug: Placebo
Drug: Neuropeptide Y
Drug: Enalaprilat
Phase 4

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Pharmacodynamics Study
Intervention Model: Crossover Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Basic Science
Official Title: Contribution of Neuropeptide Y (NPY) to Vasoconstriction and Sympathetic Activation in the Setting of Dipeptidyl Peptidase IV (DPP4) Inhibition

Resource links provided by NLM:


Further study details as provided by Vanderbilt University:

Primary Outcome Measures:
  • Change in Forearm Blood Flow [ Time Frame: Measured at Time 0, 10, 20, 30, 40, 160, 170, 180, 190, and 200 minutes of each study day. ] [ Designated as safety issue: No ]
    Change in Forearm blood flow in response to neuropeptide Y


Secondary Outcome Measures:
  • Arterial catecholamines [ Time Frame: Measured at Time 0, 10, 20, 30, 40, 160, 170, 180, 190, and 200 minutes of each study day. ] [ Designated as safety issue: No ]
  • Venous catecholamines [ Time Frame: Measured at Time 0, 10, 20, 30, 40, 160, 170, 180, 190, and 200 minutes of each study day. ] [ Designated as safety issue: No ]
  • NPY metabolites [ Time Frame: Measured at Time 0, 10, 20, 30, 40, 160, 170, 180, 190, and 200 minutes of each study day. ] [ Designated as safety issue: No ]
  • Substance P [ Time Frame: Measured at Time 0, 10, 20, 30, 40, 160, 170, 180, 190, and 200 minutes of each study day. ] [ Designated as safety issue: No ]
  • Insulin [ Time Frame: Measured at Time 0, 40, 160 and 200 minutes of each study day. ] [ Designated as safety issue: No ]
  • GLP-1 [ Time Frame: Measured at Time 0 and 160 minutes of each study day. ] [ Designated as safety issue: No ]
  • Glucose [ Time Frame: Measured at Time 0, 40, 160 and 200 minutes of each study day. ] [ Designated as safety issue: No ]
  • ACE activity [ Time Frame: Measured at Time 0 and 160 minutes of each study day. ] [ Designated as safety issue: No ]
  • DPP4 Activity [ Time Frame: Measured at Time 0 and 160 minutes of each study day. ] [ Designated as safety issue: No ]
  • Low Frequency Variability of Blood Pressure Activity [ Time Frame: Measured at Time 0, 40, 160 and 200 minutes of each study day. ] [ Designated as safety issue: No ]
  • Arterial tPA [ Time Frame: Measured at Time 0, 40, 160 and 200 minutes of each study day. ] [ Designated as safety issue: No ]
  • Venous tPA [ Time Frame: Measured at Time 0, 40, 160 and 200 minutes of each study day. ] [ Designated as safety issue: No ]
  • Mean arterial pressure [ Time Frame: Measured at Time 0, 10, 20, 30, 40, 160, 170, 180, 190, and 200 minutes of each study day. ] [ Designated as safety issue: No ]
  • Blood pressure [ Time Frame: Measured at Time 0, 10, 20, 30, 40, 160, 170, 180, 190, and 200 minutes of each study day. ] [ Designated as safety issue: No ]
  • Heart Rate [ Time Frame: Measured at Time 0, 10, 20, 30, 40, 160, 170, 180, 190, and 200 minutes of each study day. ] [ Designated as safety issue: No ]

Estimated Enrollment: 18
Study Start Date: December 2015
Estimated Study Completion Date: September 2017
Estimated Primary Completion Date: September 2016 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Sitagliptin then Placebo
Subjects in this arm will receive sitagliptin 100 mg daily. After one week of treatment, subjects will report for study day #1. During the study day subjects will be given intra-aterial neuropeptide Y and enalaprilat. A four week washout of medications will occur after the study day. Subjects will then receive placebo for one week followed by study day #2.
Drug: Sitagliptin
Subjects will receive sitagliptin 100 mg daily for 7 days prior to one of the study days.
Other Name: Januvia
Drug: Placebo
Subjects will receive a placebo capsule daily for 7 days prior to one of the study days.
Other Name: Microcrystalline cellulose
Drug: Neuropeptide Y
During the study days, neuropeptide Y will be infused through an intra-arterial line. There will be four doses of neuropeptide Y used (0.1, 0.3, 1.0, and 3.0 nmol/min) and each dose will be infused for 10 minutes.
Other Name: NPY
Drug: Enalaprilat
Ninety minutes after the last dose of neuropeptide Y, enalaprilat will be infused through the intra-arterial line at 0.33 µg/min/100mL of forearm volume. After 30 minutes, a second infusion of neuropeptide Y will begin. Similar to the previous neuropeptide infusion, four doses of neuropeptide Y will be used (0.1, 0.3, 1.0, and 3.0 nmol/min) and each dose will be infused for 10 minutes.
Other Name: Vasotec I.V.
Placebo then Sitagliptin
Subjects in this arm will receive placebo for one week. After this, subjects will report for study day #1. During the study day subjects will be given intra-aterial neuropeptide Y and enalaprilat. A four week washout of medications will occur after the study day. Subjects will then receive 100 mg of sitagliptin daily for one week followed by study day #2.
Drug: Sitagliptin
Subjects will receive sitagliptin 100 mg daily for 7 days prior to one of the study days.
Other Name: Januvia
Drug: Placebo
Subjects will receive a placebo capsule daily for 7 days prior to one of the study days.
Other Name: Microcrystalline cellulose
Drug: Neuropeptide Y
During the study days, neuropeptide Y will be infused through an intra-arterial line. There will be four doses of neuropeptide Y used (0.1, 0.3, 1.0, and 3.0 nmol/min) and each dose will be infused for 10 minutes.
Other Name: NPY
Drug: Enalaprilat
Ninety minutes after the last dose of neuropeptide Y, enalaprilat will be infused through the intra-arterial line at 0.33 µg/min/100mL of forearm volume. After 30 minutes, a second infusion of neuropeptide Y will begin. Similar to the previous neuropeptide infusion, four doses of neuropeptide Y will be used (0.1, 0.3, 1.0, and 3.0 nmol/min) and each dose will be infused for 10 minutes.
Other Name: Vasotec I.V.

Detailed Description:
Dipeptidyl peptidase IV (DPP4) inhibitors are routinely used for the treatment of type II diabetes mellitus (T2DM). Since the prevalence of hypertension is 1.5-3 times greater in diabetics compared to sex-aged matched controls, the use of antihypertensives such as ACE inhibitors is also common in diabetics. DPP4 is involved in the degradation of multiple vasoactive peptides, one of which is neuropeptide Y. This peptide is thought to play a role in blood pressure regulation and sympathetic nervous system activation. The aim of this study is to investigate how DPP4 inhibition affects vasoconstriction in response to increasing neuropeptide Y concentrations. Additionally, the investigators want to understand how the combination of DPP4 inhibition and ACE inhibition affects vasoconstriction and sympathetic activation. Understanding the hemodynamic and neurohumoral changes associated with DPP4 and ACE inhibitors has important implications for the millions of patients with T2DM who take these drugs concurrently.
  Eligibility

Ages Eligible for Study:   18 Years to 55 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

Type 2 Diabetes Mellitus, as defined by one or more of the following,

  • Hgb A1C ≥6.5%, or
  • Fasting plasma glucose ≥126mg/dL, or
  • Two hour plasma glucose ≥200 mg/dL following 75gr oral glucose load

For female subjects the following conditions must be met:

  • Postmenopausal status for at least 1 year, or
  • Status post-surgical sterilization, or
  • If of childbearing potential, utilization of some form of birth control and willingness to undergo β-HCG testing prior to drug treatment and on every study day

Exclusion Criteria:

  • Type 1 diabetes.
  • Poorly controlled T2DM, defined as Hgb A1C>8.7%.
  • Use of anti-diabetic medications other than metformin.
  • Hypertension.
  • Subjects who have participated in a weight-reduction program during the last 6 months and whose weight has increased or decreased more than 5 kg over the preceding 6 months.
  • Pregnancy. Breast-feeding.
  • Treatment with any of the following drugs: cisapride, pimozide, terfenadine, astemizol
  • Clinically significant gastrointestinal impairment that could interfere with drug absorption
  • Cardiovascular disease that would pose risk for the subject to participate in the study, such as: myocardial infarction within 6 months prior to enrollment, presence of angina pectoris, significant arrhythmia, congestive heart failure (LV hypertrophy acceptable), deep vein thrombosis, pulmonary embolism, second- or third-degree AV block, mitral valve stenosis, or hypertrophic cardiomyopathy.
  • Impaired hepatic function (aspartate amino transaminase [AST] and/or alanine amino transaminase [ALT] >2 x upper limit of normal range)
  • Impaired renal function (eGFR< 60mL/min/1.73m2 as determined by the MDRD equation).
  • History or presence of immunological or hematological disorders.
  • History of pancreatitis or known pancreatic lesions.
  • History of angioedema or cough while taking an ACE inhibitor.
  • Hematocrit <35%.
  • Treatment with anticoagulants.
  • Growth hormone deficiency.
  • Diagnosis of asthma requiring use of an inhaled β-2 agonist more than 1 time per week.
  • Any underlying or acute disease requiring regular medication which could possibly pose a threat to the subject or make implementation of the protocol or interpretation of the study results difficult
  • Treatment with systemic glucocorticoids within the last 6 months.
  • Treatment with lithium salts
  • Ongoing tobacco use or recreational drug use.
  • Treatment with any investigational drug in the 1 month preceding the study
  • Mental conditions rendering the subject unable to understand the nature, scope, or possible consequences of the study
  • Inability to comply with the protocol, e.g., uncooperative attitude, inability to return for follow-up visits, and 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: NCT02639637

Contacts
Contact: Jessica R Wilson, MD jessica.r.wilson@vanderbilt.edu
Contact: Scott A Hubers, MD scott.hubers@vanderbilt.edu

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

Responsible Party: Nancy J. Brown, Professor, Vanderbilt University
ClinicalTrials.gov Identifier: NCT02639637     History of Changes
Other Study ID Numbers: 151133 
Study First Received: December 16, 2015
Last Updated: March 23, 2016
Health Authority: United States: Institutional Review Board
United States: Data and Safety Monitoring Board
United States: Food and Drug Administration

Keywords provided by Vanderbilt University:
Type 2 Diabetes Mellitus
Sitagliptin
Dipeptidyl Peptidase IV Inhibitors
Angiotensin Converting Enzyme Inhibitors
Enalaprilat
Neuropeptide Y

Additional relevant MeSH terms:
Diabetes Mellitus
Diabetes Mellitus, Type 2
Endocrine System Diseases
Glucose Metabolism Disorders
Metabolic Diseases
Angiotensin-Converting Enzyme Inhibitors
Dipeptidyl-Peptidase IV Inhibitors
Enalapril
Enalaprilat
Sitagliptin
Antihypertensive Agents
Cardiovascular Agents
Enzyme Inhibitors
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Hypoglycemic Agents
Incretins
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Physiological Effects of Drugs
Protease Inhibitors
Therapeutic Uses

ClinicalTrials.gov processed this record on May 04, 2016