Ezetimibe Reverse Cholesterol Transport (RCT) Pilot Study

Overview

This is a prospective, placebo-controlled, cross-over trial comparing the the effects of approximately 7 weeks of placebo treatment to 7 weeks of ezetimibe (10mg/day) treatment on several parameters of reverse cholesterol transport (RCT) in men and post-menopausal women diagnosed with hypercholesterolemia. The primary hypothesis is that the ezetimibe treatment will increase the excretion of endogenous (plasma-derived) cholesterol as fecal sterols, with secondary hypotheses that there will be a significant increase in de novo cholesterol synthesis, treatment will increase cholesterol efflux from tissues into the bloodstream, and increase global RCT.

Study Type

  • Study Type: Interventional
  • Study Design
    • Allocation: Randomized
    • Intervention Model: Crossover Assignment
    • Primary Purpose: Treatment
    • Masking: None (Open Label)
  • Study Primary Completion Date: March 2009

Detailed Description

The study will compare the effects of approximately 7 weeks of placebo treatment to 7 weeks of ezetimibe (10mg/day) on: 1) the efficiency of endogenous (plasma-derived) cholesterol excretion (%/day) 2) de novo cholesterol (DNC) synthesis ((%/day) 3) cholesterol efflux from tissues into blood (Ra), and 4) global RCT (efflux from tissues that is excreted as fecal sterols). Subjects will receive 7 weeks of either treatment or placebo, undergo RCT and DNC measurements, taking 10 days, then cross-over to the alternate placebo or treatment for an additional 7 weeks, followed by a second set of RCT and DNC measurements.

Interventions

  • Drug: ezetimibe
    • 1 tablet,10mg, once a day, for 7 weeks
  • Drug: Placebo
    • 1 tablet, once a day, for 7 weeks

Arms, Groups and Cohorts

  • Experimental: 1
    • ezetimibe (10mg/day)for 7 weeks
  • Placebo Comparator: 2
    • Placebo control

Clinical Trial Outcome Measures

Primary Measures

  • Fecal Excretion of Plasma-derived Cholesterol
    • Time Frame: 7 weeks
    • (Fecal excretion of plasma-derived cholesterol):The following measurements will be made following isotope infusion: The composition of fecal neutral and acidic sterols will be measured as % of total. The excretion rate of fecal neutral and acidic sterols will be measured as mg/day. The isotopic enrichment of both fecal neutral and acidic sterols will be measured as atomic percent excess (% APE). Fecal isotope excretion, or recovery, of plasma-derived cholesterol will be calculated as %/day.

Secondary Measures

  • Change From Baseline in Total Cholesterol, From Fasting Plasma Samples
    • Time Frame: 7 weeks
    • plasma levels of total cholesterol
  • de Novo Cholesterol Synthesis (DNC)
    • Time Frame: 7 weeks
    • Plasma DNC will be measured following the isotope infusion of deuterated water, expressed as %.
  • Cholesterol Efflux Rate (Ra Cholesterol)
    • Time Frame: 7 weeks
    • The efflux, or mobilization, rate of cholesterol from peripheral tissues into the plasma will be measured as mg/kg/hr. An IV infusion of [13C2] cholesterol mixed in 10% Intralipid® and 10 % ethanol is given piggy-backed into normal saline over 20 hours (4pm – 12 noon). This is used to determine rate of appearance (Ra) cholesterol, which will be measured by dilution of infused [13C2] cholesterol during the plateau phase of plasma enrichment (approximately the last 4 hours of the infusion), as well as to provide the plasma cholesterol that will be traced into biliary sterols.
  • Triglycerides (TG)
    • Time Frame: 7 weeks
    • Change from baseline in plasma triglycerides, measured in fasting blood samples
  • Low-density Lipoprotein (LDL);
    • Time Frame: 7 weeks
    • Change from baseline in plasma low-density lipoprotein(LDL), measured in fasting blood samples
  • High-density Lipoprotein (HDL)
    • Time Frame: 7 weeks
    • Change from baseline in plasma HDL, measured in fasting blood samples

Participating in This Clinical Trial

Inclusion Criteria

  • male, non-smoker, 21-75 years of age – female, non-smoker, 40-75 years of age – post-menopausal women, as defined by lack of menses for at least 2 years and age >55, OR history of documented bilateral oophorectomy, confirmed with an elevated FSH at screening – low-density lipoprotein (LDL) concentration between 130-200 mg/dL. – triglyceride (TG) concentration <350 mg/dL, inclusive – high-density lipoprotein (HDL) between 30-60 mg/dL for men and 40 -70 mg/dL for women – ability to give informed consent Exclusion Criteria:

  • Subject has history of diabetes mellitus, active hepatitis, gall bladder disease, gastric or ileal bypass surgery, irritable bowel syndrome, and gastrointestinal disorder/condition associated with malabsorption, or clinically significant abnormalities on screening (prestudy) physical examination of laboratory tests. – Screening laboratory tests with hematocrit <30%, aspartate aminotransferase/alanine aminotransferase (AST/ALT) >2*upper limit of normal, abnormal thyroid-stimulating hormone (TSH), fasting glucose >=126mg/dL – renal impairment with creatinine clearance (CRCl)<80ml/min – treatment within the last 2 months with drugs known to alter lipid metabolism including beta blockers, thiazide diuretics, bile acid resins, statins, ezetimibe, niacin, fibrates, plant stanol esters (eg Benecol,phyto sterols) and fishoils – history of known coronary heart disease (CHD), stroke or prior revascularization procedure or peripheral vascular disease – history of allergy to egg or soy products – current or recent (past 12 months) of drug abuse or alcohol abuse. Alcohol use must be limited to no more than 2 drinks/day (1 drink=12 oz beer, 5 oz wine, or 1.5 oz hard liquor). Subject must be willing to avoid large day-to-day fluctuations in alcohol intake. – participation in another clinical trial or exposure to any investigational agent within 30 days prior to Visit 1 – Individual has a condition the Principal Investigator believes would interfere with his/her ability to provide informed consent, comply with study instructions, or which might confound the interpretation of the study results, or put the subject at undue risk

Gender Eligibility: All

Minimum Age: 21 Years

Maximum Age: 75 Years

Are Healthy Volunteers Accepted: Accepts Healthy Volunteers

Investigator Details

  • Lead Sponsor
    • Radiant Research
  • Provider of Information About this Clinical Study
    • Michael H. Davidson, MD, FACC, Radiant Research
  • Overall Official(s)
    • Michael H Davidson, Md. FACC, Principal Investigator, Radiant Research

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