SCH-58235 (Ezetimibe) to Treat Homozygous Sitosterolemia
This study will test the safety and effectiveness of SCH-58235 (Ezetimibe) in lowering sitosterol, plant sterol and cholesterol blood levels in patients with homozygous sitosterolemia when added to the patients' current treatment regimen. Homozygous sitosterolemia is an inherited disorder of sterol metabolism in which an excess of many plant sterols, including sitosterol, is absorbed and not enough excreted. (Sterols are substances used to form hormones, vitamins and membranes found in animal and plant lipids.). Patients can develop atherosclerosis with coronary heart disease as early as childhood, as well as other problems including arthritis, arthralgia, and tendon xanthomas (lipid deposits). Current sitosterolemia treatments may include a low sterol diet, medications, intestinal surgery, or a combination of these. Ezetimibe is a member of a new class of drugs called "specific cholesterol absorption inhibitors" that may lower cholesterol, sitosterol and other plant sterol blood levels.
Patients with homozygous sitosterolemia 10 years of age and older may be eligible for this study. Participants will have a medical history and physical examination and will be randomly assigned to one of two treatment groups. One group, which will include about 80 percent of all study participants, will take 10 mg of Ezetimibe a day, and the second group (20 percent of participants) will take a placebo (an inactive look-a-like pill).
Patients will have 7 clinic visits during the 12-week study, when some or all of the following procedures and tests will be done:
- Measurement of vital signs (heart rate, blood pressure, breathing rate and temperature)
- Dietary maintenance - interview about how well that patient is adhering to the diet
- Medication review - interview about other medications the patient is taking
- Blood draw for tests
- Urine sample for tests
- Pregnancy test for women of childbearing potential
- Electrocardiogram (ECG) to measure the electrical activity of the heart
- Blood draw to determine sitosterol, other plant sterol levels, and lipid levels (cholesterol and other blood lipid concentrations)
- Xanthoma measurement (with a ruler and X-ray of the foot)
|Study Design:||Endpoint Classification: Safety/Efficacy Study
Primary Purpose: Treatment
|Official Title:||A Multicenter, Randomized, Double-Blind, Placebo-Controlled, Study to Evaluate SCH-58235 in Homozygous Sitosterolemia|
|Study Start Date:||March 2001|
|Estimated Study Completion Date:||April 2004|
Homozygous sitosterolemia is an autosomally inherited recessive disorder of sterol metabolism. Patients with homozygous sitosterolemia can present with accelerated atherosclerosis with initial CHD events occurring in childhood. In addition, these patients can have tendon xanthomas, hemolytic episodes, as well as arthritis and arthralgias. Plasma levels of sitosterol and other dietary sterols are markedly elevated in homozygous sitosterolemic patients, and are diagnostic of this disorder. A low sterol diet provides only limited reduction in sitosterol levels and currently available medical treatments, such as bile salt binding resins, are usually insufficiently effective or poorly tolerated.
SCH-58235 is a member of a new class of therapeutic agents, specific cholesterol absorption inhibitors, being developed to treat hypercholesterolemia. Preclinical animal studies and clinical studies in humans have demonstrated significant reductions in serum cholesterol levels with SCH-58235 treatment. In the current study, the efficacy and safety of SCH-58235 will be studied in patients with homozygous sitosterolemia, an inherited condition in which a wide range of plant sterols, including sitosterol, are excessively absorbed and inadequately excreted, leading to dramatic increases in tissue deposition. SCH-58235 may lower sitosterol levels by directly inhibiting sitosterol absorption (since plant sterols and cholesterol are structurally similar sterols) and/or by inhibiting cholesterol absorption and indirectly by increasing hepatic uptake of plasma LDL with increased cholesterol and sitosterol excretion. These mechanisms of action could lead to reductions in both plant sterol and LDL cholesterol levels in these patients, thereby providing important clinical benefits. The current study will determine if SCH-58235 will be safe and well tolerated and provide significant reductions in plant sterols (plasma sitosterol and campesterol) and low-density lipoprotein-cholesterol (LDL-C) concentrations in patients with homozygous sitosterolemia.
This is a multicenter, randomized, double-blind, placebo-controlled study lasting 12 weeks. Patients with a diagnosis of homozygous sitosterolemia who have an elevated plasma sitosterol level on their current regimen will be studied. Patients will be eligible to enroll in the study whether their current regimen is medication(s), surgical (prior ileal bypass), apheresis, a combination of treatments, or no active regimen. The primary objective of this study is to evaluate the efficacy and safety of 10 mg/day of SCH-58235 in patients with homozygous sitosterolemia who continue to have an elevated plasma sitosterol level.
|United States, Maryland|
|National Heart, Lung and Blood Institute (NHLBI)|
|Bethesda, Maryland, United States, 20892|