Effects of Ezetimibe on the Absorption of Oxidized Cholesterol

A Randomized, Double-Blind, Placebo-Controlled, 2-Period, Crossover Study to Evaluate the Effects of Ezetimibe on the Plasma Appearance of 7-Ketocholesterol After an Oral Bolus in Patients With Primary Hypercholesterolemia

The purpose of this study is to test the effects of Zetia™ (ezetimibe) 10 milligrams (mg) on the absorption of oxysterol into the blood following a meal containing oxysterol.

Study Overview

• Status: Completed
• Conditions: Hypercholesterolemia
• Intervention / Treatment: Drug: placebo; Drug: ezetimibe

Detailed Description

There are a number of cholesterol-lowering drugs available that can lower blood cholesterol to a healthier level. Zetia™ (ezetimibe) 10 mg is available by prescription for the treatment of high cholesterol. While Zetia has been shown to inhibit the absorption of dietary cholesterol into the bloodstream, its effects on oxysterol absorption from the diet have not been completely evaluated.

• Study Type: Interventional
• Enrollment (Actual): 26
• Phase: Phase 4

Contacts and Locations

Study Locations

• United States
  • California
    • Berkeley, California, United States, 94705
      • Cholesterol Research Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 68 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Not currently pregnant or lactating and is highly unlikely to conceive
• Body Mass Index (BMI) between 20-30 kilograms per meter squared (kg/m2) inclusive.
• Body weight, as reported by patient, stable (±2 kg) for >6 weeks
• Plasma low density lipoprotein cholesterol (LDL-C) between 130 and 180 milligrams per deciliter (mg/dL) inclusive. Note: One retest allowed.
• Triglyceride (TG) concentrations ≤150 mg/dL. Note: One retest allowed.
• Fasting blood glucose <110 mg/dL and hemoglobin A1c (HbA1C) ≤ 6 percent at Visit 1. Note: One retest allowed.
• Liver transaminases (ALT, AST) ≤1.5 x upper limit of normal (ULN) and no active liver disease. Note: One retest allowed.
• Creatine Phosphokinase (CPK) ≤2x ULN. Note: One retest allowed.
• Willingness to maintain a stable diet for the duration of the study.
• Can understand and comply with study procedures and signs a written informed consent.
• Patient is ≥80 precent compliant with dosing during Placebo Run-In Period or, in the opinion of the investigator, is able to maintain ≥80 percent therapy compliance during the active treatment period of the study.

Exclusion Criteria:

• Lipid-lowering therapy and replacement of this therapy with study medication is considered inappropriate by the investigator.
• Consumes an average of more than 2 alcoholic drinks per day.
• Smokes.
• Currently engages in a vigorous exercise regimen or intensive exercise bouts >4x per month.
• Treated with any other investigational drug within 30 days of Visit 1.
• Hypersensitivity or intolerance to ezetimibe or any component of this medication.
• Any condition or situation which poses a risk to the patient or interfere with participation in the study.
• Congestive heart failure.
• Uncontrolled cardiac arrhythmias.
• History of myocardial infarction, stroke, or any other clinical manifestation of coronary, cerebral, or peripheral vascular disease.
• Uncontrolled hypertension
• Impaired renal function, nephrotic syndrome or other clinically significant renal disease at Visit 1.
• Active or chronic hepatobiliary or hepatic disease.
• History of irritable bowel syndrome, ileal bypass, gastric bypass or any gastrointestinal disorder/condition associated with malabsorption.
• Uncontrolled endocrine or metabolic disease known to influence serum lipids or lipoproteins.
• Type I or Type II diabetes mellitus.
• Disorders of the hematologic, digestive, or central nervous systems including cerebrovascular disease and degenerative disease that would limit study evaluation or participation.
• Human Immunodeficiency Virus (HIV) positive.
• History of cancer within the past 5 years (except for successfully treated basal and squamous cell carcinomas).
• History of uncontrolled psychiatric illness or drug/alcohol abuse within the past 5 years. Individuals with psychiatric illness adequately controlled and stable on pharmacotherapy may be enrolled at the discretion of the investigator.
• Lipid-lowering agents taken within 6 weeks and fibrates taken within 8 weeks prior to visit 3.
• Cardiovascular medications are acceptable provided the patient has been on a stable regimen for at least 6 weeks prior to Visit 3 and indicates a willingness to continue the stable regimen for the duration of the study.
• Supplementation with antioxidants beyond a standard multivitamin for the duration of the study.
• Psyllium, other fiber-based laxatives, and/or over the counter (OTC) therapies known to affect serum lipid levels taken within 6 weeks of Visit 3.
• Female patients receiving hormone replacement therapy, any estrogen antagonist/agonist or hormonal contraceptives.
• Treatment with cyclosporine except for ophthalmic indication
• Anti-obesity medications such as orlistat or sibutramine taken within 3 months prior to Visit 1.
• Therapeutic doses of systemic corticosteroids except inhaled steroid therapy (for example, Pulmicort®) maintained on a stable dosing regimen for at least 6 weeks prior to randomization (Visit 3) and throughout the duration of the study

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Sugar Pill; Placebo medication will be taken orally once daily in the morning on rising either during the first intervention period or the second intervention period. Single-blind ezetimibe placebo will be taken during the Run-In Period. Patients will be issued one bottle containing either active drug or placebo for each treatment period.	Drug: placebo; Blinded study medication (matched placebo) will be taken orally once daily in the morning on rising. Single-blind ezetimibe placebo will be taken during the Run-In Period. Patients will be issued one bottle containing either active drug or placebo for each treatment period.; Other Names: Sugar Pill
Experimental: ezetimibe; 10 mg medication will be taken orally once daily in the morning on rising either during the first intervention period or the second intervention period. Single-blind ezetimibe placebo will be taken during the Run-In Period. Patients will be issued one bottle containing either active drug or placebo for each treatment period.	Drug: ezetimibe; Blinded study medication (ezetimibe 10 mg in tablet form) will be taken orally once daily in the morning on rising. Single-blind ezetimibe placebo will be taken during the Run-In Period. Patients will be issued one bottle containing either active drug or placebo for each treatment period.; Other Names: Zetia

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Log[Area-under-the-plasma-concentration-curve(AUC) 0-8 Hours 7-ketocholesterol] After an Oral Bolus	Log of Area-under-the-plasma-concentration curve (AUC 0-8hrs) of 7-ketocholesterol after an oral bolus in patients with primary hypercholesterolemia after treatment with ezetimibe versus placebo	6 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Log(Maximal Plasma Concentration (Cmax) of 7-ketocholesterol) After an Oral Bolus	Log Cmax of 7 ketocholesterol after an oral bolus in patients with primary hypercholesterolemia.	6 weeks

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Log(Fasting Plasma Levels of Diet-derived Oxysterols (7-ketocholesterol))		6 weeks
Log (AUC of Plasma Total Cholesterol) After an Oral Bolus	Area under the curve (AUC) calculated over 8 hours	6 weeks
Log (AUC of Plasma Triglyceride) After an Oral Bolus	Area under the curve (AUC) calculated over 8 hours	6 weeks
Percent Change of Fasting Apolipoprotein B From Baseline	Change = [(Week 6 - baseline)/baseline value *100]	Baseline (placebo run-in) and 6 weeks
Percent Change of Fasting Low Density Lipoprotein Cholesterol From Baseline	Change = [(Week 6 - baseline)/baseline value *100]	Baseline (placebo run-in) and 6 weeks
Percent Change in Fasting High Density Lipoprotein Cholesterol	Change = [(Week 6 - baseline)/baseline value *100]	Baseline (placebo run-in) and 6 weeks
Percent Change of Fasting Non-high Density Lipoprotein Cholesterol From Baseline	Change = [(Week 6 - baseline)/baseline value *100]	Baseline (placebo run-in) and 6 weeks

Collaborators and Investigators

• Sponsor: UCSF Benioff Children's Hospital Oakland
• Collaborators: Merck Schering-Plough

Study record dates

Study Major Dates

• Study Start: June 1, 2006
• Primary Completion (Actual): February 1, 2008
• Study Completion (Actual): September 1, 2008

Study Registration Dates

• First Submitted: November 19, 2008
• First Submitted That Met QC Criteria: November 19, 2008
• First Posted (Estimate): November 20, 2008

Study Record Updates

• Last Update Posted (Actual): March 9, 2021
• Last Update Submitted That Met QC Criteria: February 12, 2021
• Last Verified: February 1, 2021

More Information

Terms related to this study

• Keywords: Hypercholesterolemia; Ezetimibe; Oxysterol; Zetia
• Additional Relevant MeSH Terms: Metabolic Diseases; Lipid Metabolism Disorders; Hyperlipidemias; Dyslipidemias; Hypercholesterolemia; Molecular Mechanisms of Pharmacological Action; Antimetabolites; Anticholesteremic Agents; Hypolipidemic Agents; Lipid Regulating Agents; Ezetimibe
• Other Study ID Numbers: MM6997