Clinical trial NCT00701727: Ezetimibe Reverse Cholesterol Transport (RCT) Pilot Study
Official title: Ezetimibe Reverse Cholesterol Transport (RCT) Pilot Study
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Hypercholesterolemia
Keywords: metabolic diseases
metabolic disorder
dyslipidemias
lipid metabolism disorders
Lead sponsor: Radiant Research
Sponsor class: OTHER
First posted: 2008-06-19
Enrollment: 31
Sex: ALL
Minimum age (years): 21
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: TREATMENT

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.

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

Primary outcomes:
measure: Fecal Excretion of Plasma-derived Cholesterol
timeFrame: 7 weeks
Secondary outcomes:
measure: Change From Baseline in Total Cholesterol, From Fasting Plasma Samples
timeFrame: 7 weeks
measure: de Novo Cholesterol Synthesis (DNC)
timeFrame: 7 weeks
measure: Cholesterol Efflux Rate (Ra Cholesterol)
timeFrame: 7 weeks
measure: Triglycerides (TG)
timeFrame: 7 weeks
measure: Low-density Lipoprotein (LDL);
timeFrame: 7 weeks
measure: High-density Lipoprotein (HDL)
timeFrame: 7 weeks
Other outcomes:
Locations:
city: Chicago
country: United States
facility: Radiant Research
state: Illinois
Study officials:
affiliation: Radiant Research
name: Michael H Davidson, Md. FACC
role: PRINCIPAL_INVESTIGATOR
References:
citation: Davidson MH, Voogt J, Luchoomun J, Decaris J, Killion S, Boban D, Glass A, Mohammad H, Lu Y, Villegas D, Neese R, Hellerstein M, Neff D, Musliner T, Tomassini JE, Turner S. Inhibition of intestinal cholesterol absorption with ezetimibe increases components of reverse cholesterol transport in humans. Atherosclerosis. 2013 Oct;230(2):322-9. doi: 10.1016/j.atherosclerosis.2013.08.006. Epub 2013 Aug 13.