Phytosterols, Ezetimibe, and Cholesterol Metabolism

Early Phase 1

Completed

Conditions: Hypercholesterolemia
Coronary Heart Disease

Interventions: Drug: Ezetimibe
Other: Phytosterols + ezetimibe
Other: Placebo

Registration Number: NCT00863265

Lead Sponsor: Washington University School of Medicine

Brief Summary: Phytosterols and ezetimibe each reduce intestinal cholesterol absorption by 30-55% but appear to have different mechanisms of action. The investigators' hypothesis is that phytosterols and ezetimibe given together will block cholesterol absorption in an additive fashion. In a randomized, placebo-controlled crossover trial the effects of placebo, ezetimibe treatment and ezetimibe plus phytosterol treatment will be measured.

Detailed Description: The investigators will perform a randomized, placebo-controlled crossover feeding study in 25 subjects with greater than ideal levels of LDL cholesterol who do not require anti-cholesterol drug treatment. Subjects will consume a baseline diet provided by a feeding center that is deficient in phytosterols for three periods of 21 days separated by 7-day washout periods. Treatments will be given in random order During period B placebo phytosterols and placebo ezetimibe will be given; during period C placebo phytosterols and active ezetimibe will be given; during period A active phytosterols and active ezetimibe will be given. Study endpoints are fecal cholesterol excretion and percent cholesterol absorption determined by gas chromatography/mass spectrometry and circulating LDL cholesterol.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 22

Inclusion Criteria

Male or female of any race or ethnicity between 18 to 80 years of age;
Body mass index between 20 - 35 kg/m2;
LDL-cholesterol between 130 - 189 mg/dL based on the average of duplicate screening measures. If the two LDL-C levels differ by more than 30 mg/dL, a third test will be scheduled with all three results averaged;
Free of chronic disease;
Willing to eat only the foods that are provided by the Center during the diet periods;
Willing to abstain from the consumption of alcohol for 48-hours prior to blood draw days;
Willing to drink no more than 5 cups of caffeine-containing beverages a day.

Exclusion Criteria

Age < 18 or > 80 years;
Based on duplicate screening laboratory values: 1)LDL-C >=190 mg/dL; 2)TG >=250 mg/dL;3)blood pressure >= 160 mm Hg systolic or 95 mm Hg diastolic;
Documented presence of atherosclerotic disease;
Diabetes mellitus;
Renal, hepatic, endocrine, gastrointestinal, hematological or other systemic disease;
Body mass index > 35;
For women, pregnancy, breast feeding or postpartum < 6 months;
For women, peri-menopausal;
For women, sexually active but not practicing effective birth control methods;
History of drug or alcohol abuse;
History of depression or mental illness requiring treatment or medication within the last 6 months;
multiple food allergies or significant food preferences or restrictions that would interfere with diet adherence;
Chronic use of over-the-counter medication which would interfere with study endpoints including laxatives and antacids;
Lifestyle or schedule incompatible with the study protocol;
Planned continued use of dietary supplements through the study trial;
Taking any lipid-lowering, or other medications known to affect blood cholesterol.

Study & Design

Study Type: INTERVENTIONAL

Study Design: CROSSOVER

Arm && Interventions

Group	Intervention	Description
Crossover order BAC	Placebo	The order of treatments is B (double placebo), A (phytosterols + ezetimibe), and C (active ezetimibe and phytosterol placebo)
Crossover order ABC	Phytosterols + ezetimibe	The order of treatments is A (phytosterols + ezetimibe), B (double placebo), and C (active ezetimibe and phytosterol placebo).
Crossover order ACB	Phytosterols + ezetimibe	The order of treatments is A (phytosterols + ezetimibe), C (active ezetimibe and placebo phytosterols, and B (double placebo).
Crossover order ABC	Placebo	The order of treatments is A (phytosterols + ezetimibe), B (double placebo), and C (active ezetimibe and phytosterol placebo).
Crossover order BCA	Phytosterols + ezetimibe	The order of treatments is B (double placebo), C (active ezetimibe and phytosterol placebo), and A (phytosterols + ezetimibe).
Crossover order BAC	Phytosterols + ezetimibe	The order of treatments is B (double placebo), A (phytosterols + ezetimibe), and C (active ezetimibe and phytosterol placebo)
Crossover order CBA	Phytosterols + ezetimibe	The order of treatments is C (active ezetimibe and placebo phytosterols), B (double placebo), and A (phytosterols and ezetimibe).
Crossover order BCA	Placebo	The order of treatments is B (double placebo), C (active ezetimibe and phytosterol placebo), and A (phytosterols + ezetimibe).
Crossover order ACB	Placebo	The order of treatments is A (phytosterols + ezetimibe), C (active ezetimibe and placebo phytosterols, and B (double placebo).
Crossover order CAB	Phytosterols + ezetimibe	The order of treatments is C (active ezetimibe and placebo phytosterols), A (phytosterols + ezetimibe), and B (double placebo).
Crossover order CAB	Placebo	The order of treatments is C (active ezetimibe and placebo phytosterols), A (phytosterols + ezetimibe), and B (double placebo).
Crossover order CBA	Placebo	The order of treatments is C (active ezetimibe and placebo phytosterols), B (double placebo), and A (phytosterols and ezetimibe).
Crossover order ABC	Ezetimibe	The order of treatments is A (phytosterols + ezetimibe), B (double placebo), and C (active ezetimibe and phytosterol placebo).
Crossover order BCA	Ezetimibe	The order of treatments is B (double placebo), C (active ezetimibe and phytosterol placebo), and A (phytosterols + ezetimibe).
Crossover order BAC	Ezetimibe	The order of treatments is B (double placebo), A (phytosterols + ezetimibe), and C (active ezetimibe and phytosterol placebo)
Crossover order ACB	Ezetimibe	The order of treatments is A (phytosterols + ezetimibe), C (active ezetimibe and placebo phytosterols, and B (double placebo).
Crossover order CAB	Ezetimibe	The order of treatments is C (active ezetimibe and placebo phytosterols), A (phytosterols + ezetimibe), and B (double placebo).
Crossover order CBA	Ezetimibe	The order of treatments is C (active ezetimibe and placebo phytosterols), B (double placebo), and A (phytosterols and ezetimibe).

Primary Outcome Measures

Name	Time	Method
Cholesterol Excretion	At the end of week 3 on each diet	Milligrams of fecal cholesterol and cholesterol metabolites excreted per day
Percent Cholesterol Absorption	Determined on the final 5 days of each dietary period	Percent of intestinal cholesterol absorbed. Intestinal cholesterol is comprised of dietary cholesterol intake and endogenous cholesterol secreted into the intestinal lumen. Cholesterol absorption is the percent of intestinal cholesterol that is taken back up into the body and excluded from fecal excretion. It is also referred to as the efficiency of intestinal cholesterol absorption.
LDL Cholesterol	At the end of week 3 on each diet

Secondary Outcome Measures