Ignite Creation Date:
2024-05-05 @ 11:30 AM
Last Modification Date:
2024-10-26 @ 9:09 AM
Study NCT ID:
NCT00064792
Status:
COMPLETED
Last Update Posted:
2014-06-06
First Post:
2003-07-11
Brief Title:
Simvastatin Therapy in Smith-Lemli-Opitz Syndrome
Sponsor:
Forbes Porter MD
Organization:
National Institutes of Health Clinical Center CC
Study Overview
Official Title:
Investigation of Simvastatin Therapy in Smith-Lemli-Opitz Syndrome
Status:
COMPLETED
Status Verified Date:
2014-06
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
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 05 mgkgday for 6 weeks and then 1 mgkgday 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 childs eyes to the dark an electrode is taped to the childs 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 childs brain
Activity monitoring An activity monitor which looks like and is worn like a watch is used to record the childs 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 childs arm or thigh to collect skin cells
Stool collection A small stool sample is collected from the childs diaper or for children who are toilet trained from a toilet hat like that used to collect urine
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 05 mgkgday for 6 weeks and then 1 mgkgday 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 childs eyes to the dark an electrode is taped to the childs 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 childs brain
Activity monitoring An activity monitor which looks like and is worn like a watch is used to record the childs 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 childs arm or thigh to collect skin cells
Stool collection A small stool sample is collected from the childs 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 110000 to 160000 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 Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None
Secondary IDs
| Secondary ID | Type | Domain | Link |
|---|---|---|---|
| 03-CH-0225 | None | None | None |