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

NCT ID: NCT00872599

Last Updated: 2013-06-28

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE4
• Total Enrollment: 75 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2009-09-30
• Study Completion Date: 2012-01-31

Brief Summary

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.

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.

Conditions

Hypertension

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: CROSSOVER
• Primary Study Purpose: TREATMENT
• Blinding Strategy: DOUBLE

Study Groups

Placebo, then fenofibrate

Randomized study of fenofibrate versus placebo during high salt diet

Group Type: PLACEBO_COMPARATOR

fenofibrate

Intervention Type: DRUG

Subjects will be randomized to receive either fenofibrate 160 mg/day or matching placebo for five days by mouth.

Placebo

Intervention Type: DRUG

Subjects will be randomized to receive placebo or fenofibrate for five days by mouth

Fenofibrate, then placebo

Randomized study of fenofibrate versus placebo during high salt intake.

Group Type: PLACEBO_COMPARATOR

fenofibrate

Intervention Type: DRUG

Subjects will be randomized to receive either fenofibrate 160 mg/day or matching placebo for five days by mouth.

Placebo

Intervention Type: DRUG

Subjects will be randomized to receive placebo or fenofibrate for five days by mouth

Interventions

fenofibrate

Subjects will be randomized to receive either fenofibrate 160 mg/day or matching placebo for five days by mouth.

Intervention Type: DRUG

Placebo

Subjects will be randomized to receive placebo or fenofibrate for five days by mouth

Intervention Type: DRUG

Other Intervention Names

Tricor

Eligibility 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

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 70 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: Yes

Sponsors

National Institutes of Health (NIH)

NIH

Sponsor Role: collaborator

Vanderbilt University

OTHER

Sponsor Role: lead

Responsible Party

Nancy J. Brown

Professor of Medicine

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Nancy J Brown, MD

Role: PRINCIPAL_INVESTIGATOR

Vanderbilt University Medical Center

Locations

Vanderbilt University

Nashville, Tennessee, United States

Countries

United States

References

Gilbert K, Nian H, Yu C, Luther JM, Brown NJ. Fenofibrate lowers blood pressure in salt-sensitive but not salt-resistant hypertension. J Hypertens. 2013 Apr;31(4):820-9. doi: 10.1097/HJH.0b013e32835e8227.

Reference Type: RESULT

PMID: 23385647 (View on PubMed)

Ramirez CE, Shuey MM, Milne GL, Gilbert K, Hui N, Yu C, Luther JM, Brown NJ. Arg287Gln variant of EPHX2 and epoxyeicosatrienoic acids are associated with insulin sensitivity in humans. Prostaglandins Other Lipid Mediat. 2014 Oct;113-115:38-44. doi: 10.1016/j.prostaglandins.2014.08.001. Epub 2014 Aug 28.

Reference Type: DERIVED

PMID: 25173047 (View on PubMed)

Other Identifiers

Grant# DK38226-21

Identifier Type: -

Identifier Source: secondary_id

PPAR Alpha Agonist

Identifier Type: -

Identifier Source: org_study_id