Simvastatin Therapy in Smith-Lemli-Opitz Syndrome

Investigation of Simvastatin Therapy in Smith-Lemli-Opitz Syndrome

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:

• Simvastatin and cholesterol supplementation therapy. Patients take cholesterol supplements (50 milligrams per kilogram per day) plus simvastatin (0.5 mg/kg/day for 6 weeks and then 1 mg/kg/day) for 12 months, and cholesterol supplements plus a placebo for 12 months.
• Blood draws to check liver, muscle, and kidney function, hormone levels, vitamin D levels, blood counts, cholesterol and 7-DHC levels, and lipoprotein levels. Some extra blood is drawn for research purposes.
• Urine collection. Urine is collected using a toilet hat. For children who are not toilet trained, urine is collected in a bag taped to the skin with an adhesive.
• Electroretinogram (ERG) to measure the function of the retina, the light-sensitive tissue at the back of the eye. ERG is done under sedation. After adapting the child's eyes to the dark, an electrode is taped to the child's forehead, the surface of one eye is numbed with eye drops, and a contact lens is placed on the eye. The child looks inside a globe that emits a series of light flashes. The contact lens senses electrical signals generated by the retina when the light flashes. After the ERG, the patient has a full eye exam, including pupil dilation and photographs of the eye.
• Lumbar puncture (spinal tap) to collect a sample of cerebral spinal fluid (CSF). This procedure, done while the patient is sedated for the ERG, shows whether simvastatin affects brain cholesterol and chemical levels. Under local anesthetic, a needle is inserted in the space between the bones in the lower back where the CSF circulates below the spinal cord. A small amount of fluid is collected through the needle.
• CRH stimulation test to detect hormone-related problems in cholesterol synthesis. The patient is given CRH, a hormone involved in cholesterol synthesis, through a plastic tube placed in a vein. Blood samples are collected through the same catheter to measure levels of other hormones involved in cholesterol production.
• Electroencephalogram (EEG) to look at the electrical activity (brain waves) of the child's brain.
• Activity monitoring. An activity monitor, which looks like and is worn like a watch, is used to record the child's level of activity for a 48-hour period.
• Urine pregnancy test at every visit for female patients over age 10.
• Skin swab for sterol (solid alcohol, such as cholesterol) analysis. An alcohol pad is rubbed lightly against the child's arm or thigh to collect skin cells.
• Stool collection. A small stool sample is collected from the child's diaper or, for children who are toilet trained, from a toilet "hat" like that used to collect urine.

Study Overview

• Status: Completed
• Conditions: Smith-Lemli-Opitz Syndrome
• Intervention / Treatment: Drug: OraPlus; Drug: Simvastatin Susp.

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 23
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Maryland
    • Bethesda, Maryland, United States, 20892
      • National Institutes of Health Clinical Center, 9000 Rockville Pike

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 4 years to 18 years (ADULT, CHILD)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

• INCLUSION CRITERIA:

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.

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 gemfibrozil or other fibrates, niacin) or metabolism by the P450 isoform 3A4 system (such as cyclosporin, itraconazole, ketoconazole, macrolide antibiotics, or nefazodone (Serzone)).

Warfarin-type anticoagulant therapy.

Severe cataracts.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: CROSSOVER
• Masking: TRIPLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
PLACEBO_COMPARATOR: OraPlus	Drug: OraPlus; During this trial and for two months prior, patients will be maintained on 150 mg/kg/day of dietary cholesterol (150 mg/ml in OraPlus) for the duration of the trial
ACTIVE_COMPARATOR: Simvastatin Susp	Drug: Simvastatin Susp.; During the simvastatin phase of the trial, therapy will be initiated at 0.5 mg/kg/day for six weeks and then increased to 1.0 mg/kg/day if adverse side effects are minimal or absent.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Serum Cholesterol to Total Sterol Ratio	Total serum cholesterol (mg/dL) divided by the sum of all sterols (cholesterol plus its precursors, 7-dehydrocholesterol - 7DHC, and 8-dehydrocholesterol- 8DHC - in mg/dL).	1 year after therapy.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cerebral Spinal Fluid Dehydrocholesterol to Total Sterol Ratio	Percent of 7-dehydrocholesterol + 8-dehydrocholesterol as a fraction of the total sterols (cholesterol + 7-dehydrocholesterol + 8-dehydrocholesterol measured in cerebral spinal fluid	12 months

Collaborators and Investigators

• Sponsor: Forbes Porter, M.D.
• Collaborators: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

Publications and helpful links

General Publications

• Porter FD. RSH/Smith-Lemli-Opitz syndrome: a multiple congenital anomaly/mental retardation syndrome due to an inborn error of cholesterol biosynthesis. Mol Genet Metab. 2000 Sep-Oct;71(1-2):163-74. doi: 10.1006/mgme.2000.3069.
• Kelley RI, Hennekam RC. The Smith-Lemli-Opitz syndrome. J Med Genet. 2000 May;37(5):321-35. doi: 10.1136/jmg.37.5.321.
• Kelley RI. A new face for an old syndrome. Am J Med Genet. 1997 Jan 31;68(3):251-6. doi: 10.1002/(sici)1096-8628(19970131)68:33.0.co;2-p. No abstract available.
• Thurm A, Tierney E, Farmer C, Albert P, Joseph L, Swedo S, Bianconi S, Bukelis I, Wheeler C, Sarphare G, Lanham D, Wassif CA, Porter FD. Development, behavior, and biomarker characterization of Smith-Lemli-Opitz syndrome: an update. J Neurodev Disord. 2016 Apr 5;8:12. doi: 10.1186/s11689-016-9145-x. eCollection 2016.

Helpful Links

• NIH Clinical Center Detailed Web Page

Study record dates

Study Major Dates

• Study Start: July 1, 2003
• Primary Completion (ACTUAL): December 1, 2010
• Study Completion (ACTUAL): December 1, 2010

Study Registration Dates

• First Submitted: July 11, 2003
• First Submitted That Met QC Criteria: July 11, 2003
• First Posted (ESTIMATE): July 14, 2003

Study Record Updates

• Last Update Posted (ESTIMATE): June 6, 2014
• Last Update Submitted That Met QC Criteria: June 4, 2014
• Last Verified: June 1, 2014

More Information

Terms related to this study

• Keywords: Cholesterol; Mental Retardation; SLOS; Smith-Lemli-Opitz Syndrome; HMG-COA Reductase Inhibitor; Malformation Syndrome
• Additional Relevant MeSH Terms: Pathologic Processes; Metabolic Diseases; Disease; Urogenital Abnormalities; Congenital Abnormalities; Genetic Diseases, Inborn; Musculoskeletal Diseases; Stomatognathic Diseases; Mouth Diseases; Bone Diseases; Metabolism, Inborn Errors; Lipid Metabolism Disorders; Dyslipidemias; Mouth Abnormalities; Stomatognathic System Abnormalities; Jaw Abnormalities; Jaw Diseases; Maxillofacial Abnormalities; Craniofacial Abnormalities; Musculoskeletal Abnormalities; Abnormalities, Multiple; Lipid Metabolism, Inborn Errors; Bone Diseases, Developmental; Steroid Metabolism, Inborn Errors; Penile Diseases; Craniofacial Dysostosis; Dysostoses; Syndrome; Cleft Palate; Hypospadias; Genetic Diseases, X-Linked; Smith-Lemli-Opitz Syndrome; Hypertelorism; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antimetabolites; Anticholesteremic Agents; Hypolipidemic Agents; Lipid Regulating Agents; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Simvastatin
• Other Study ID Numbers: 030225; 03-CH-0225