Higher-Dose Ezetimibe to Treat Homozygous Sitosterolemia

Heart Diseases Clinical Trial

Official title: A Study to Assess Adding Ezetimibe 30 mg to Ongoing Treatment With Ezetimibe 10 mg in Patients With Homozygous Sitosterolemia

Status Completed

Clinical Trial Summary

This study will test the safety and effectiveness of 40 mg of ezetimibe (Zetia ) daily in lowering blood levels of cholesterol and of the plant sterols sitosterol and campesterol in patients with homozygous sitosterolemia, an inherited disorder of sterol metabolism. (Sterols are alcohol substances found in animal and plant fats.) In this disorder, an excess of many plant sterols is absorbed and not enough excreted. Patients can develop atherosclerosis and coronary heart disease as early as childhood, as well as other problems including arthritis, arthralgia, and tendon xanthomas (lipid deposits). Current treatment consists of ezetimibe 10 mg, dietary restriction of plant and shellfish sterols, and bile salt binding resins. Ezetimibe is a cholesterol-lowering drug that inhibits intestinal absorption of cholesterol and structurally related plant sterols across the intestinal wall.

Patients with homozygous sitosterolemia who are between 18 and 85 years of age have completed NHLBI's 1-year study of ezetimibe at 10 mg a day may be eligible for this study.

All participants maintain their current stable diet and take a 10-mg pill of ezetimibe daily for 26 weeks. They are also randomly selected to take either an additional 30-mg pill of ezetimibe or a placebo (look-alike pill with no active ingredients). Patients fast for at least 12 hours before each of 6 visits scheduled during the course of the study. At these visits, patients undergo some or all of the following procedures for monitoring their health and evaluating their response to treatment:

• Medical history and review of medications

• Physical examination

• Measurement of vital signs (pulse rate, blood pressure, breathing rate and temperature)

• Review of dietary maintenance

• Measurements of height, weight, and waist circumference

• Measurement (with ruler) and photographs of non-Achilles xanthoma

• X-ray of Achilles tendon

• Blood draw and urine collection

• Pregnancy test for women of childbearing potential

Clinical Trial Description

Homozygous Sitosterolemia is an inherited, autosomal recessive disorder of sterol metabolism. Patients with homozygous sitosterolemia experience accelerated atherosclerosis with initial coronary heart disease (CHD) events occurring in childhood. Plasma concentrations of sitosterol and other dietary plant sterols are markedly elevated in homozygous sitosterolemic patients, and are characteristic of this disorder. Sitosterolemic individuals demonstrate a range of abnormalities in sterol absorption, metabolism, and excretion. Recent reports have shown that sitosterolemia can result from mutations in 1 of 2 ATP-binding cassette half-transporters (ABCG5 or ABCG8), which are responsible for regulation of non-cholesterol sterols in the body.

Current treatment of homozygous sitosterolemia consists of ezetimibe 10 mg, dietary restriction of plant and shellfish sterols, as well as the use of bile salt binding resins. Ezetimibe is the first member of a new class of cholesterol-lowering agents that inhibits the intestinal absorption of cholesterol and structurally-related noncholesterol sterols (plant sterols) across the intestinal wall. Importantly, ezetimibe is not an inhibitor or inducer of CYP450, reducing the potential for drug-drug interactions which renders ezetimibe a particularly appealing candidate with other drugs. Ezetimibe has proved to be generally safe and well-tolerated as monotherapy or when coadministered with statins, with an overall clinical adverse experience profile similar to placebo. In clinical studies with hypercholesterolemic patients, ezetemibe doses ranging from 0.25 to 40 mg daily for periods of 8 to 12 weeks were more effective than placebo in lowering plasma TC and LDL-C concentrations. There were no dose-related increase in adverse experiences or laboratory abnormalities in these studies. We will investigate whether a higher dose of ezetimibe is safe and efficacious in lowering plant sterols in patients with sitosterolemia. ;

Study Design

Endpoint Classification: Efficacy Study, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Heart Diseases
• Metabolism, Inborn Errors

• NCT number: NCT00099996
• Study type: Interventional
• Source: National Institutes of Health Clinical Center (CC)
• Status: Completed
• Phase: Phase 3
• Start date: December 2004
• Completion date: December 2005