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

This study has been completed.
Sponsor:
Collaborator:
Information provided by (Responsible Party):
Nancy J. Brown, Vanderbilt University
ClinicalTrials.gov Identifier:
NCT00872599
First received: March 26, 2009
Last updated: June 19, 2013
Last verified: June 2013
  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 4

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Pharmacodynamics 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:


Further study details as provided by Vanderbilt University:

Primary Outcome Measures:
  • Change in Blood Pressure During High Salt Intake and Fenofibrate Treatment Compared to High Salt Intake and Placebo Treatment [ Time Frame: pressure measured on day 6 of high salt fenofibrate minus pressure measured on day 6 of high salt placebo ] [ Designated as safety issue: No ]

    Difference in blood pressure (mean arterial pressure) measured on the last day of high salt intake and fenofibrate treatment minus blood pressure (mean arterial pressure) measured during high salt intake and placebo treatment in participants classified as being salt-sensitive versus salt-resistant.

    Participants were classified as salt-sensitive if the average study day mean arterial pressure (MAP) was at least 5 mmHg higher during the high salt placebo arm than during low salt intake.



Secondary Outcome Measures:
  • HDL-cholesterol Measured During High Salt Fenofibrate in Salt-resistant and Salt-sensitive Hypertension [ Time Frame: Measured on day 6 of high salt intake and fenofibrate treatment ] [ Designated as safety issue: No ]
    HDL-cholesterol concentration measured on the last day of fenofibrate treatment in salt-resistant and salt-sensitive hypertensive patients


Enrollment: 75
Study Start Date: September 2009
Study Completion Date: January 2012
Primary Completion Date: January 2012 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Placebo Comparator: Placebo, then fenofibrate
Randomized study of fenofibrate versus placebo 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
Drug: Placebo
Subjects will be randomized to receive placebo or fenofibrate for five days by mouth
Other Name: Placebo
Placebo Comparator: Fenofibrate, then placebo
Randomized study of fenofibrate versus placebo during high salt intake.
Drug: fenofibrate
Subjects will be randomized to receive either fenofibrate 160 mg/day or matching placebo for five days by mouth.
Other Name: Tricor
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-hydroxyeicosatetraenoic acid(HETE) and epoxyeicosatrienoic acids(EET)s, 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 systolic blood pressure(SBP) greater than 179 mmHg or a seated diastolic blood pressure(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 aminotransferase [AST] and or alanine aminotransferase [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
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Please refer to this study by its ClinicalTrials.gov identifier: NCT00872599

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

Publications:
Responsible Party: Nancy J. Brown, Professor of Medicine, 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
Results First Received: February 26, 2013
Last Updated: June 19, 2013
Health Authority: United States: Institutional Review Board

Keywords provided by Vanderbilt University:
Hypertension
Phenotyping
High Salt intake
frequently sampled IV glucose tolerance test(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 September 22, 2014