Ezetimibe Reverse Cholesterol Transport (RCT) Pilot Study

Study Overview
=================
Brief Summary
-----------------
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.

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.

Official Title
-----------------
Ezetimibe Reverse Cholesterol Transport (RCT) Pilot Study

Conditions
-----------------
Hypercholesterolemia

Intervention / Treatment
-----------------
* Drug: ezetimibe
* Drug: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
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

Ages Eligible for Study
-----------------
Minimum Age: 21 Years
Maximum Age: 75 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 1<br>ezetimibe (10mg/day)for 7 weeks | Drug: ezetimibe<br>* 1 tablet,10mg, once a day, for 7 weeks<br>|
| Placebo Comparator: 2<br>Placebo control | Drug: Placebo<br>* 1 tablet, once a day, for 7 weeks<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Fecal Excretion of Plasma-derived Cholesterol | (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. | 7 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Total Cholesterol, From Fasting Plasma Samples | plasma levels of total cholesterol | 7 weeks | 
| de Novo Cholesterol Synthesis (DNC) | Plasma DNC will be measured following the isotope infusion of deuterated water, expressed as %. | 7 weeks | 
| Cholesterol Efflux Rate (Ra Cholesterol) | 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. | 7 weeks | 
| Triglycerides (TG) | Change from baseline in plasma triglycerides, measured in fasting blood samples | 7 weeks | 
| Low-density Lipoprotein (LDL); | Change from baseline in plasma low-density lipoprotein(LDL), measured in fasting blood samples | 7 weeks | 
| High-density Lipoprotein (HDL) | Change from baseline in plasma HDL, measured in fasting blood samples | 7 weeks | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
metabolic diseases, metabolic disorder, dyslipidemias, lipid metabolism disorders