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

March 26, 2009
June 19, 2013
September 2009
January 2012   (final data collection date for primary outcome measure)
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.

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 ]
Complete list of historical versions of study NCT00872599 on ClinicalTrials.gov Archive Site
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
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 ]
Not Provided
Not Provided
 
The Effect of a Peroxisome Proliferator-activated Receptor (PPAR) Alpha Agonist on Cytochrome P450 (CYP) Monooxygenase Activity in Humans
The Effect of a PPAR Alpha Agonist on CYP Monooxygenase Activity in Humans

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.

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.

Interventional
Phase 4
Allocation: Randomized
Endpoint Classification: Pharmacodynamics Study
Intervention Model: Crossover Assignment
Masking: Double Blind (Subject, Investigator)
Primary Purpose: Treatment
Hypertension
  • 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: Placebo, then fenofibrate
    Randomized study of fenofibrate versus placebo during high salt diet
    Interventions:
    • Drug: fenofibrate
    • Drug: Placebo
  • Placebo Comparator: Fenofibrate, then placebo
    Randomized study of fenofibrate versus placebo during high salt intake.
    Interventions:
    • Drug: fenofibrate
    • Drug: Placebo
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.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Completed
75
January 2012
January 2012   (final data collection date for primary outcome measure)

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
Both
18 Years to 70 Years
Yes
Contact information is only displayed when the study is recruiting subjects
United States
 
NCT00872599
PPAR Alpha Agonist, Grant# DK38226-21
Yes
Nancy J. Brown, Vanderbilt University
Vanderbilt University
National Institutes of Health (NIH)
Principal Investigator: Nancy J Brown, MD Vanderbilt University
Vanderbilt University
June 2013

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP