Simvastatin Therapy in Smith-Lemli-Opitz Syndrome

NCT00064792 | Completed Phase 2 Results DMC

• 2 other identifiers: 03022503-CH-0225
• Study Type: interventional
• Target: 23
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Smith-Lemli-Opitz Syndrome

Keywords

Cholesterol; SLOS; HMG-COA Reductase Inhibitor; Malformation Syndrome; Mental Retardation; Smith-Lemli-Opitz Syndrome

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (1)

• Cerebral Spinal Fluid Dehydrocholesterol to Total Sterol Ratio

  12 months

Study Arms (2)

OraPlus

PLACEBO COMPARATOR

Drug: OraPlus

Simvastatin Susp

ACTIVE COMPARATOR

Drug: Simvastatin Susp.

Interventions

Simvastatin Susp. DRUG

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.

Simvastatin Susp

OraPlus DRUG

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

OraPlus

Eligibility Criteria

• Age: 4 Years - 18 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• All patients with biochemically proven SLOS will be considered for this study.

You may not qualify if:

• 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.

Sponsors & Collaborators

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

Study Sites (1)

National Institutes of Health Clinical Center, 9000 Rockville Pike

Bethesda, Maryland, 20892, United States

Location

Related Publications (4)

• 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.

  PMID: 11001807 BACKGROUND

• 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.

  PMID: 10807690 BACKGROUND

• 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.

  PMID: 9024554 BACKGROUND

• 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.

  PMID: 27053961 DERIVED

Related Links

• NIH Clinical Center Detailed Web Page

MeSH Terms

Conditions

Smith-Lemli-Opitz Syndrome; Intellectual Disability

Condition Hierarchy (Ancestors)

Abnormalities, Multiple; Congenital Abnormalities; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Lipid Metabolism, Inborn Errors; Metabolism, Inborn Errors; Genetic Diseases, Inborn; Steroid Metabolism, Inborn Errors; Dyslipidemias; Lipid Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Neurobehavioral Manifestations; Neurologic Manifestations; Nervous System Diseases; Signs and Symptoms; Pathological Conditions, Signs and Symptoms; Neurodevelopmental Disorders; Mental Disorders

Results Point of Contact

• Title: Dr. Forbes Porter, Clinical Director, NICHD
• Organization: NICHD, NIH

fdporter@mail.nih.gov

301-435-4432

Study Officials

• Forbes D Porter, M.D.

  Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: NIH
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Clinical Director, NICHD

Study Record Dates

• First Submitted: July 11, 2003
• First Posted: July 14, 2003
• Study Start: July 1, 2003
• Primary Completion: December 1, 2010
• Study Completion: December 1, 2010
• Last Updated: June 6, 2014
• Results First Posted: June 6, 2014

Record last verified: 2014-06

Locations

US (1)