Ignite Creation Date:
2024-05-05 @ 11:58 AM
Last Modification Date:
2024-10-26 @ 9:17 AM
Study NCT ID:
NCT00195637
Status:
COMPLETED
Last Update Posted:
2019-12-04
First Post:
2005-09-18
Brief Title:
Intravenous Immune Globulin to Treat Hereditary Inclusion Body Myopathy
Sponsor:
National Human Genome Research Institute NHGRI
Organization:
National Institutes of Health Clinical Center CC
Study Overview
Official Title:
Pilot Study of the Use of Intravenous Immune Globulin in Hereditary Inclusion Body Myopathy
Status:
COMPLETED
Status Verified Date:
2018-05-22
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 patients with Hereditary Inclusion Body Myopathy HIBM and examine the effects of immune globulin IG treatment on muscle and muscle function HIBM is a progressive neuromuscular disease that begins in early adulthood primarily affecting limb muscles It results from mutations of the gene that is responsible for producing sialic acid a sugar normally found on the surface of certain proteins including alpha-dystroglycan which is involved in muscle function Some patients with HIBM have decreased sialic acid on the alpha-dystroglycan protein which may be the cause of their muscle weakness IG is a protein in the blood that carries a large amount of sialic acid This study will administer IG to patients with HIBM and determine if the sialic acid in IG is taken up by muscle cells in these patients and if it can restore some of their muscle function
Four patients with HIBM will be admitted to this study at the NIH Clinical Center for evaluation and IG treatment The evaluation lasts about 1 month After completing baseline studies see below patients receive two intravenous doses of immune globulin on days 6 and 7 followed by measurement of muscle strength 2 days later day 9 They receive additional IG infusions on days 13 20 and 27 A final set of tests is performed on day 29 Patients may leave the hospital on pass when no studies are being done
A patients initial evaluation includes
History and physical examination neurological examination eye examination
24-hour urine collection
Blood tests on two separate days
Photographs showing the extent of muscle affected
Chest x-ray electrocardiogram EKG and echocardiogram
Two muscle biopsies one before and one after the IG treatments For this procedure a small sample of muscle tissue is surgically removed for examination under the microscope
Muscle strength and endurance testing including the following
The patient uses pulleys attached to machines that measure the strength of 24 different muscle groups
The patient walks for 6 minutes and performs exercises
To evaluate swallowing the patient swallows a thick substance called barium
The patients tongue strength is measured using a specialized instrument
-Magnetic resonance imaging MRI of the muscles of the thigh or calf MRI uses a magnetic field and radio waves to produce detailed pictures of organs and tissues During the scan the subject lies on a table in a narrow cylinder containing a magnetic field wearing ear plugs to muffle loud noises that occur with electrical switching of the magnetic fields He or she can speak with a staff member via an intercom system at all times during the procedure
The neurological and muscle strength and endurance evaluations are repeated on study days 9 and 29
Four patients with HIBM will be admitted to this study at the NIH Clinical Center for evaluation and IG treatment The evaluation lasts about 1 month After completing baseline studies see below patients receive two intravenous doses of immune globulin on days 6 and 7 followed by measurement of muscle strength 2 days later day 9 They receive additional IG infusions on days 13 20 and 27 A final set of tests is performed on day 29 Patients may leave the hospital on pass when no studies are being done
A patients initial evaluation includes
History and physical examination neurological examination eye examination
24-hour urine collection
Blood tests on two separate days
Photographs showing the extent of muscle affected
Chest x-ray electrocardiogram EKG and echocardiogram
Two muscle biopsies one before and one after the IG treatments For this procedure a small sample of muscle tissue is surgically removed for examination under the microscope
Muscle strength and endurance testing including the following
The patient uses pulleys attached to machines that measure the strength of 24 different muscle groups
The patient walks for 6 minutes and performs exercises
To evaluate swallowing the patient swallows a thick substance called barium
The patients tongue strength is measured using a specialized instrument
-Magnetic resonance imaging MRI of the muscles of the thigh or calf MRI uses a magnetic field and radio waves to produce detailed pictures of organs and tissues During the scan the subject lies on a table in a narrow cylinder containing a magnetic field wearing ear plugs to muffle loud noises that occur with electrical switching of the magnetic fields He or she can speak with a staff member via an intercom system at all times during the procedure
The neurological and muscle strength and endurance evaluations are repeated on study days 9 and 29
Detailed Description:
Hereditary Inclusion Body Myopathy HIBM is an autosomal recessive neuromuscular disorder with onset in early adulthood and progressive muscle weakness leading to death within 2-3 decades The causative gene GNE codes for the bifunctional enzyme UDP N-acetylglucosamine 2-epimeraseN-acetylmannosamine kinase mutations on both GNE alleles in either or both the epimerase and kinase domains can result in HIBM Members of an Iranian-Jewish isolate are homozygous for a specific kinase domain mutation The epimerase and kinase enzymes catalyze the first and second rate-limiting steps in the synthesis of sialic acid also called N-acetylneuraminic acid This charged sugar provides the terminal carbohydrate on a variety of N-linked and O-linked glycoproteins that mediate cell-cell and protein-protein interactions The cells of HIBM patients produce reduced amounts of free sialic acid as evidenced by decreased sialylation of glycoproteins including a critical muscle protein called alpha-dystroglycan alpha-DG This protein decorated with O-mannosyl glycans containing a terminal sialic acid is part of the dystrophin-glycoprotein complex responsible for linking the inside of muscle cells with the extracellular matrix In HIBM improper sialylation of alpha-DG due to decreased sialic acid synthesis is considered to impair the interactions of alpha-DG with its protein ligands resulting in gradual deterioration of muscle cells In this open-label pilot study we propose to provide free sialic acid to muscle cells of HIBM patients by intravenous infusions of immune globulin IvIg a glycoprotein that contains 8 microlitermoles of sialic acid per gram and that has a proven safety profile as an FDA-approved drug Four subjects will be treated - two homozygous for the Iranian Jewish kinase domain mutation and two with at least one epimerase domain mutation IvIg will be given as a loading dose of 1 gram per kilogram body weight on two consecutive days followed each of the next 3 weeks by maintenance doses of 400 milligram per kilogram body weight This should maintain the serum immune globulin level high enough to achieve continuous breakdown of large amounts of the glycoprotein providing free sialic acid to the blood scavenger cells and we hope muscle cells Muscle biopsies and strength testing will be performed before and after the infusions The primary clinical outcome parameter will be muscle strength gauged mechanically by Quantitative Muscle Testing and manually by physical examination performed by a neurologist Secondary outcome parameters will employ the 6-minute walk test grip strength tongue strength swallowing duration and the Human Activity Profile questionnaire Staining of muscle beta-DG for sialic acid on O-mannosyl glycans will provide a histological outcome parameter An improvement in muscle strength or alpha-DG sialylation will prompt a controlled trial of the efficacy of this treatment
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 |
|---|---|---|---|
| 05-HG-0236 | None | None | None |