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Sponsored by: |
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) |
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Information provided by: | National Institutes of Health Clinical Center (CC) |
ClinicalTrials.gov Identifier: | NCT00064792 |
This study will evaluate the safety and effectiveness of simvastatin in treating children with Smith-Lemli-Opitz syndrome (SLOS). Patients with this inherited disease are deficient in an enzyme that converts a substance called 7-dehydrocholesterol (7-DHC) to cholesterol. Cholesterol synthesis is impaired, causing birth defects and mental retardation. This study will examine whether simvastatin can increase the amount of the deficient enzyme, thereby lowering 7-DHC and increasing cholesterol. It will examine the safety of simvastatin in affected children and its effects on their behavioral problems.
Children between 4 and 18 years of age with mild to typical SLOS may be eligible for this study. Participants will be evaluated at the NIH Clinical Center in Bethesda, MD, and at the Kennedy Krieger Institute in Baltimore, MD, upon admission to the study and again at 6, 12, 20, and 26 months. The visits will last 3 to 4 days, and will include a medical history and physical examination, photographs to document medical findings, and other procedures detailed below. In addition, blood samples will be collected at 1, 3, 9, 14, 15, 17, and 23 months. Parents will complete several questionnaires during the study. Procedures include the following:
Condition | Intervention | Phase |
---|---|---|
Smith-Lemli-Opitz Syndrome |
Drug: Simvastatin Susp. Drug: OraPlus |
Phase II |
Study Type: | Interventional |
Study Design: | Treatment |
Official Title: | Investigation of Simvastatin Therapy in Smith-Lemli-Opitz Syndrome |
Estimated Enrollment: | 25 |
Study Start Date: | July 2003 |
Smith-Lemli-Opitz syndrome (SLOS, RSH, OMIM #270400) is an autosomal recessive, multiple malformation, mental retardation syndrome due to an inborn error of cholesterol biosynthesis. Specifically, these patients have a deficiency of 3 beta-hydroxysterol Delta 7-reductase activity due to mutation of the 3 beta-hydroxysterol delta 7-reductase gene (DHCR7). This enzymatic deficiency impairs the conversion of 7-dehydrocholesterol (7-DHC) to cholesterol in the last step of cholesterol biosynthesis via the Kandutch-Russel biosynthetic pathway. The clinical manifestations of SLOS are extremely variable and the phenotypic spectrum is broad. At the severe end of the spectrum SLOS is a lethal disorder with multiple major congenital anomalies, and in mild cases SLOS combines minor physical stigmata with behavioral and learning disabilities. Based on clinical studies, the incidence of SLOS is on the order of 1/10,000 to 1/60,000. Molecular studies have shown a carrier frequency of about 1% for the most common SLOS mutant allele in North American populations. Currently therapy is based on dietary cholesterol supplementation. Although clinical improvement has been noted, serum cholesterol levels are rarely normalized and elevated serum 7-DHC levels persist. Because elevated 7-DHC levels may have toxic effects, treatment of SLOS patients with an HMG-CoA reductase inhibitor has been proposed. Two small (two-patient) open trials of simvastatin therapy in SLOS have been reported. One of these trials showed improved clinical status, decreased 7-DHC levels and increased cholesterol levels. The second trial showed decreased 7-DHC levels; however, treatment had to be discontinued in one patient with preexisting liver disease. The goal of this clinical research protocol will be to test the clinical efficacy and safety of simvastatin therapy in mild to classical SLOS patients using a double blinded, crossover design.
Ages Eligible for Study: | 4 Years to 18 Years |
Genders Eligible for Study: | Both |
Accepts Healthy Volunteers: | No |
All patients with biochemically proven SLOS will be considered for this study.
EXCLUSION CRITERIA:
Patients will be excluded if they cannot travel to the NIH because of their medical condition.
Age less than 4 and older than 18.
Pregnancy.
Weight less than 10 kg.
Developmental delay too severe to obtain adequate behavioral evaluation.
Severe behavioral problems that preclude proper physical and laboratory medicine evaluation.
SLOS severity score greater than 30.
No biochemical diagnosis of SLOS.
No molecular conformation of SLOS.
Residual fibroblasts enzymatic activity less than 10% of control value (cholesterol synthesis as a fraction of total sterol synthesis).
Dehydrocholesterol/cholesterol ratio greater than 1.0.
Renal insufficiency.
Contraindications for simvastatin use:
History of hypersensitivity to simvastatin or other "statins."
Acute liver disease.
Persistent elevations of serum transaminase levels or persistent elevations of CPK.
Concomitant therapy with tetralol-class calcium channel blockers (such as mibefradil).
Pregnancy or lactation.
History of rhabdomyolysis or myopathy.
Concomitant therapy with other drugs associated with myopathy (such as gemfibrazil or other fibrates, niacin) or metabolism by the P450 isoform 3A4 system (such as cyclosporin, itraconzaole, ketoconazole, macrolide antibiotics, or nefazodone (Serzone)).
Warfarin-type anticoagulant therapy.
Severe cataracts.
Contact: Patient Recruitment and Public Liaison Office | (800) 411-1222 | prpl@mail.cc.nih.gov |
Contact: TTY | 1-866-411-1010 |
United States, Maryland | |
National Institutes of Health Clinical Center, 9000 Rockville Pike | Recruiting |
Bethesda, Maryland, United States, 20892 |
Responsible Party: | National Institutes of Health ( Forbes D. Porter, M.D./National Institute of Child Health and Human Development ) |
Study ID Numbers: | 030225, 03-CH-0225 |
Study First Received: | July 11, 2003 |
Last Updated: | September 16, 2008 |
ClinicalTrials.gov Identifier: | NCT00064792 |
Health Authority: | United States: Federal Government |
Cholesterol SLOS HMG-COA Reductase Inhibitor Malformation Syndrome |
Mental Retardation Smith-Lemli-Opitz Syndrome SLOS Mental Retardation |
Lipid Metabolism, Inborn Errors Opitz syndrome Metabolic Diseases Simvastatin Smith-Lemli-Opitz Syndrome Mental Retardation Metabolism, Inborn Errors |
Genetic Diseases, Inborn Abnormalities, Multiple Congenital Abnormalities Metabolic disorder Dyslipidemias Lipid Metabolism Disorders |
Antimetabolites Pathologic Processes Disease Molecular Mechanisms of Pharmacological Action Therapeutic Uses Antilipemic Agents |
Syndrome Enzyme Inhibitors Anticholesteremic Agents Hydroxymethylglutaryl-CoA Reductase Inhibitors Steroid Metabolism, Inborn Errors Pharmacologic Actions |