The Effect of a Peroxisome Proliferator-activated Receptor (PPAR) Alpha Agonist on Cytochrome P450 (CYP) Monooxygenase Activity in Humans - Full Text View

Sponsor:	Vanderbilt University
Collaborator:	National Institutes of Health (NIH)
Information provided by:	Vanderbilt University
ClinicalTrials.gov Identifier:	NCT00872599

Purpose

The hypothesis is to test to see if the drug fenofibrate will increase important chemicals in the body and specifically in the kidney, help to rid the body of salt by the kidneys, decrease blood pressure and improve insulin sensitivity during high-salt intake in individuals with hypertension.

Condition	Intervention	Phase
Hypertension	Drug: fenofibrate Drug: Placebo	Phase I

Study Type:	Interventional
Study Design:	Allocation: Randomized Endpoint Classification: Pharmacokinetics Study Intervention Model: Crossover Assignment Masking: Double Blind (Subject, Investigator) Primary Purpose: Treatment
Official Title:	The Effect of a PPAR Alpha Agonist on CYP Monooxygenase Activity in Humans

Resource links provided by NLM:

MedlinePlus related topics: Diabetes Medicines Dietary Sodium High Blood Pressure

Drug Information available for: Procetofen

U.S. FDA Resources

Further study details as provided by Vanderbilt University:

Primary Outcome Measures:

Focus on the effects of fenofibrate during high-salt intake on blood pressure twenty-four hour 20-HETE, EET and DHET excretion, renal blood flow and net sodium excretion and Aldosterone to renin ratio. [ Time Frame: 18 months ] [ Designated as safety issue: No ]

Secondary Outcome Measures:

Focus on the effect of fenofibrate on insulin sensitivity, glucose effectiveness, beta cell function and HDL-cholesterol. [ Time Frame: 18 months ] [ Designated as safety issue: No ]

Estimated Enrollment:	56
Study Start Date:	September 2009
Estimated Study Completion Date:	December 2012
Estimated Primary Completion Date:	January 2012 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
Active Comparator: 1 Randomized study of fenofibrate during high salt diet	Drug: fenofibrate Subjects will be randomized to receive either fenofibrate 160 mg/day or matching placebo for five days by mouth. Other Name: Tricor
Placebo Comparator: 2 Placebo verses fenofibrate	Drug: Placebo Subjects will be randomized to receive placebo or fenofibrate for five days by mouth Other Name: Placebo

Detailed Description:

Hypertension affects 73 million people in the United States and a billion people worldwide and contributes to death due to stroke, myocardial infarction, end-stage kidney disease and congestive heart failure. Fifty to 60% of individuals with hypertension have "salt-sensitive" hypertension, characterized by an exaggerated blood pressure response to increased salt intake. Salt-sensitive hypertension is associated with increased mortality due to cardiovascular disease.

This study will test the hypothesis that administration of a PPARa agonist, an intervention increases renal tubular Cyp2c and 4a expression in rodents, will increase urinary excretion of 20-HETE and EETs, induce natriuresis, decrease blood pressure, and improve insulin sensitivity during high-salt intake in individuals with hypertension.

Metabolites of the P450 arachidonic acid monooxygenases play an important role in the regulation of blood pressure in rodent models.

Targeted disruption of murine Cyp4a genes provides insight into the roles of renal monooxygenases and epoxygenases in the regulation of salt excretion and blood pressure.

PPARa agonists induce the expression of renal tubular monoxygenases and epoxygenases and decrease blood pressure in both Ang II- dependent and salt-sensitive rodent models of hypertension.

PPARa agonists have been reported to reduce blood pressure in clinical trials in humans. The effect of PPARa agonist on renal vasodilation, sodium excretion and excretion of urinary epoxygenase or monooxygenase products in response to salt loading is not known.

The regulation of urinary 20-HETE excretion may be impaired in human hypertension.

Eligibility

Ages Eligible for Study:	18 Years to 70 Years
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	Yes

Criteria

Inclusion Criteria:

Ambulatory subjects, 18-70 years of age, inclusive
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 adequate birth control and willingness to undergo urine beta-hcg testing prior to drug treatment and on every study day

Exclusion Criteria:

Secondary causes of hypertension
Diabetes type 1 or type 2 as defined by a fasting glucose of 126 mg/dl or greater or the use of anti-diabetic medication
Use of hormone replacement therapy
Statin or fibrate therapy
A seated SBP greater than 179 mmHg or a seated DBP greater than 110 mmHg
Pregnancy
Breast-feeding
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
Treatment with anticoagulants
History of serious neurologic diseases such as cerebral hemorrhage,stroke, or transient ischemic attack
History or presence of immunological or hematological disorders
Diagnosis of asthma
Clinically significant gastrointestinal impairment that could interfere with drug absorption
Impaired hepatic function (aspartate amino transaminase [AST] and or alanine amino transaminate [ALT] > 2.0 x upper range
Known preexisting gallbladder disease
Impaired renal function (eGFR < 60 ml/min/1.73M2)
Hematocrit < 35%
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 a glucocorticoid therapy
Treatment with lithium salts
History of 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 for follow-up visits, and unlikelihood of completing the study

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT00872599

Contacts

Contact: Delia M Woods, BSN

615-322-3371

delia.woods@vanderbilt.edu

Locations

United States, Tennessee
Vanderbilt University	Recruiting
Nashville, Tennessee, United States, 37232
Contact: Carol Bowling, BSN 615-322-8837 carol.bowling@vanderbilt.edu
Principal Investigator: Nancy J Brown, MD
Sub-Investigator: Kimberly Gilbert, MD

Sponsors and Collaborators

Vanderbilt University

National Institutes of Health (NIH)

Investigators

Principal Investigator:

Nancy J Brown, MD

Vanderbilt University

More Information

No publications provided

Responsible Party:	Nancy J. Brown, MD, Vanderbilt University
ClinicalTrials.gov Identifier:	NCT00872599 History of Changes
Other Study ID Numbers:	PPAR Alpha Agonist, Grant# DK38226-21
Study First Received:	March 26, 2009
Last Updated:	July 25, 2011
Health Authority:	United States: Institutional Review Board

Keywords provided by Vanderbilt University:

Hypertension
Phenotyping
High Salt intake
FSIVGTT
fenofibrate

epoxyeicosatrienoic acids
hydroxyeicosatetraenoic acids
dihydroxyeicosatrienoic acid
PPAR Alpha Agonist
CYP Monooxygenase Activity

Additional relevant MeSH terms:

Hypertension
Vascular Diseases
Cardiovascular Diseases
Fenofibrate
Hypolipidemic Agents

Antimetabolites
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Lipid Regulating Agents
Therapeutic Uses

ClinicalTrials.gov processed this record on February 09, 2012