Phytosterols, Ezetimibe, and Cholesterol Metabolism

Study Overview
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Brief Summary
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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
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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.

Official Title
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Regulation of Cholesterol Absorption: LDL Cholesterol Response to a Combination of Phytosterols and Ezetimibe (Phyto-3)

Conditions
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Hypercholesterolemia, Coronary Heart Disease

Intervention / Treatment
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* Drug: Ezetimibe
* Other: Phytosterols + ezetimibe
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Crossover Assignment
Interventional Model Description: This is a randomized, crossover design. There are three periods of 21 days separated by two 7 day washouts. All subjects eat a controlled low-phytosterol diet for each of the three periods. During period B placebo phytosterols and placebo ezetimibe are given. During period C phytosterol placebo and active ezetimibe are given. During period A active phytosterols and active ezetimibe are given. Periods are assigned in random order as described in Arms below.
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Crossover order ABC<br>The order of treatments is A (phytosterols + ezetimibe), B (double placebo), and C (active ezetimibe and phytosterol placebo). | Drug: Ezetimibe<br>* Subjects will undergo three diet periods of 21 days each separated by 7 day washouts. Food will be supplied by a metabolic kitchen and will consist of a phytosterol-deficient baseline diet. During each period subjects will receive either phytosterol esters or placebo and ezetimibe or placebo.<br>* Other names: C;Other: Phytosterols + ezetimibe<br>* Subjects will undergo three diet periods of 21 days each separated by 7 day washouts. Food will be supplied by a metabolic kitchen and will consist of a phytosterol-deficient baseline diet. During each period subjects will receive either phytosterol esters or placebo and ezetimibe or placebo.<br>* Other names: A;Other: Placebo<br> <br> * Other names: B;|
| Experimental: Crossover order BCA<br>The order of treatments is B (double placebo), C (active ezetimibe and phytosterol placebo), and A (phytosterols + ezetimibe). | Drug: Ezetimibe<br>* Subjects will undergo three diet periods of 21 days each separated by 7 day washouts. Food will be supplied by a metabolic kitchen and will consist of a phytosterol-deficient baseline diet. During each period subjects will receive either phytosterol esters or placebo and ezetimibe or placebo.<br>* Other names: C;Other: Phytosterols + ezetimibe<br>* Subjects will undergo three diet periods of 21 days each separated by 7 day washouts. Food will be supplied by a metabolic kitchen and will consist of a phytosterol-deficient baseline diet. During each period subjects will receive either phytosterol esters or placebo and ezetimibe or placebo.<br>* Other names: A;Other: Placebo<br> <br> * Other names: B;|
| Experimental: Crossover order BAC<br>The order of treatments is B (double placebo), A (phytosterols + ezetimibe), and C (active ezetimibe and phytosterol placebo) | Drug: Ezetimibe<br>* Subjects will undergo three diet periods of 21 days each separated by 7 day washouts. Food will be supplied by a metabolic kitchen and will consist of a phytosterol-deficient baseline diet. During each period subjects will receive either phytosterol esters or placebo and ezetimibe or placebo.<br>* Other names: C;Other: Phytosterols + ezetimibe<br>* Subjects will undergo three diet periods of 21 days each separated by 7 day washouts. Food will be supplied by a metabolic kitchen and will consist of a phytosterol-deficient baseline diet. During each period subjects will receive either phytosterol esters or placebo and ezetimibe or placebo.<br>* Other names: A;Other: Placebo<br> <br> * Other names: B;|
| Experimental: Crossover order ACB<br>The order of treatments is A (phytosterols + ezetimibe), C (active ezetimibe and placebo phytosterols, and B (double placebo). | Drug: Ezetimibe<br>* Subjects will undergo three diet periods of 21 days each separated by 7 day washouts. Food will be supplied by a metabolic kitchen and will consist of a phytosterol-deficient baseline diet. During each period subjects will receive either phytosterol esters or placebo and ezetimibe or placebo.<br>* Other names: C;Other: Phytosterols + ezetimibe<br>* Subjects will undergo three diet periods of 21 days each separated by 7 day washouts. Food will be supplied by a metabolic kitchen and will consist of a phytosterol-deficient baseline diet. During each period subjects will receive either phytosterol esters or placebo and ezetimibe or placebo.<br>* Other names: A;Other: Placebo<br> <br> * Other names: B;|
| Experimental: Crossover order CAB<br>The order of treatments is C (active ezetimibe and placebo phytosterols), A (phytosterols + ezetimibe), and B (double placebo). | Drug: Ezetimibe<br>* Subjects will undergo three diet periods of 21 days each separated by 7 day washouts. Food will be supplied by a metabolic kitchen and will consist of a phytosterol-deficient baseline diet. During each period subjects will receive either phytosterol esters or placebo and ezetimibe or placebo.<br>* Other names: C;Other: Phytosterols + ezetimibe<br>* Subjects will undergo three diet periods of 21 days each separated by 7 day washouts. Food will be supplied by a metabolic kitchen and will consist of a phytosterol-deficient baseline diet. During each period subjects will receive either phytosterol esters or placebo and ezetimibe or placebo.<br>* Other names: A;Other: Placebo<br> <br> * Other names: B;|
| Experimental: Crossover order CBA<br>The order of treatments is C (active ezetimibe and placebo phytosterols), B (double placebo), and A (phytosterols and ezetimibe). | Drug: Ezetimibe<br>* Subjects will undergo three diet periods of 21 days each separated by 7 day washouts. Food will be supplied by a metabolic kitchen and will consist of a phytosterol-deficient baseline diet. During each period subjects will receive either phytosterol esters or placebo and ezetimibe or placebo.<br>* Other names: C;Other: Phytosterols + ezetimibe<br>* Subjects will undergo three diet periods of 21 days each separated by 7 day washouts. Food will be supplied by a metabolic kitchen and will consist of a phytosterol-deficient baseline diet. During each period subjects will receive either phytosterol esters or placebo and ezetimibe or placebo.<br>* Other names: A;Other: Placebo<br> <br> * Other names: B;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cholesterol Excretion | Milligrams of fecal cholesterol and cholesterol metabolites excreted per day | At the end of week 3 on each diet | 
| Percent Cholesterol Absorption | 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. | Determined on the final 5 days of each dietary period | 
| LDL Cholesterol |  | At the end of week 3 on each diet | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Phytosterols, Ezetimibe, Cholesterol Excretion, Cholesterol Absorption, Diet, Mass Spectrometry, Deuterium