Simvastatin Therapy in Smith-Lemli-Opitz Syndrome
Condition: Smith-Lemli-Opitz Syndrome
MeSH terms: Cleft Palate; Hypertelorism; Hypospadias; Genetic Diseases, X-Linked; Smith-Lemli-Opitz Syndrome; Syndrome
Intervention: Simvastatin Susp.; OraPlus
Intervention description: 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.; 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
Intervention MeSH terms: Simvastatin
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Enrollment: 23.0
Sex: All
Minimum age: 4 Years
Maximum age: 18 Years
Healthy volunteers: No
Keywords: Cholesterol; SLOS; HMG-COA Reductase Inhibitor; Malformation Syndrome; Mental Retardation; Smith-Lemli-Opitz Syndrome

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.
    

Eligibility criteria:

        -  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.