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Simvastatin Therapy in Smith-Lemli-Opitz Syndrome

Primary Purpose

Smith-Lemli-Opitz Syndrome

Status
Completed
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
Simvastatin Susp.
OraPlus
Sponsored by
Forbes Porter, M.D.
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Smith-Lemli-Opitz Syndrome focused on measuring Cholesterol, SLOS, HMG-COA Reductase Inhibitor, Malformation Syndrome, Mental Retardation, Smith-Lemli-Opitz Syndrome

Eligibility Criteria

4 Years - 18 Years (Child, Adult)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

  • National Institutes of Health Clinical Center, 9000 Rockville Pike

Arms of the Study

Arm 1

Arm 2

Arm Type

Placebo Comparator

Active Comparator

Arm Label

OraPlus

Simvastatin Susp

Arm Description

Outcomes

Primary Outcome Measures

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).

Secondary Outcome Measures

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

Full Information

First Posted
July 11, 2003
Last Updated
June 4, 2014
Sponsor
Forbes Porter, M.D.
Collaborators
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
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1. Study Identification

Unique Protocol Identification Number
NCT00064792
Brief Title
Simvastatin Therapy in Smith-Lemli-Opitz Syndrome
Official Title
Investigation of Simvastatin Therapy in Smith-Lemli-Opitz Syndrome
Study Type
Interventional

2. Study Status

Record Verification Date
June 2014
Overall Recruitment Status
Completed
Study Start Date
July 2003 (undefined)
Primary Completion Date
December 2010 (Actual)
Study Completion Date
December 2010 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor-Investigator
Name of the Sponsor
Forbes Porter, M.D.
Collaborators
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

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.
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Smith-Lemli-Opitz Syndrome
Keywords
Cholesterol, SLOS, HMG-COA Reductase Inhibitor, Malformation Syndrome, Mental Retardation, Smith-Lemli-Opitz Syndrome

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Crossover Assignment
Masking
ParticipantCare ProviderInvestigator
Allocation
Randomized
Enrollment
23 (Actual)

8. Arms, Groups, and Interventions

Arm Title
OraPlus
Arm Type
Placebo Comparator
Arm Title
Simvastatin Susp
Arm Type
Active Comparator
Intervention Type
Drug
Intervention Name(s)
Simvastatin Susp.
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.
Intervention Type
Drug
Intervention Name(s)
OraPlus
Intervention Description
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
Primary Outcome Measure Information:
Title
Serum Cholesterol to Total Sterol Ratio
Description
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).
Time Frame
1 year after therapy.
Secondary Outcome Measure Information:
Title
Cerebral Spinal Fluid Dehydrocholesterol to Total Sterol Ratio
Description
Percent of 7-dehydrocholesterol + 8-dehydrocholesterol as a fraction of the total sterols (cholesterol + 7-dehydrocholesterol + 8-dehydrocholesterol measured in cerebral spinal fluid
Time Frame
12 months

10. Eligibility

Sex
All
Minimum Age & Unit of Time
4 Years
Maximum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
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.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Forbes D Porter, M.D.
Organizational Affiliation
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Official's Role
Principal Investigator
Facility Information:
Facility Name
National Institutes of Health Clinical Center, 9000 Rockville Pike
City
Bethesda
State/Province
Maryland
ZIP/Postal Code
20892
Country
United States

12. IPD Sharing Statement

Citations:
PubMed Identifier
11001807
Citation
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.
Results Reference
background
PubMed Identifier
10807690
Citation
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.
Results Reference
background
PubMed Identifier
9024554
Citation
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.
Results Reference
background
PubMed Identifier
27053961
Citation
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.
Results Reference
derived
Links:
URL
http://clinicalstudies.info.nih.gov/cgi/detail.cgi?B_2003-CH-0225.html
Description
NIH Clinical Center Detailed Web Page

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Simvastatin Therapy in Smith-Lemli-Opitz Syndrome

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