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| Sponsored by: |
National Institute of Neurological Disorders and Stroke (NINDS) |
|---|---|
| Information provided by: | National Institutes of Health Clinical Center (CC) |
| ClinicalTrials.gov Identifier: | NCT00231036 |
Purpose
This study will determine the safety and effectiveness of the experimental drug AT1001 for treating people with Fabry disease, an inherited metabolic disorder. In this disease, an enzyme called alpha-galactosidase A, which normally breaks down a fatty substance called globotriaosylceramide (Gb3), is missing or does not function properly. The resulting accumulation of Gb3 causes problems with the kidneys, heart, nerves, and blood vessels. AT1001 attaches to the alpha-galactoside A enzyme and changes it so that it can be transported to where it should be working in the body. Thus, the drug may be able to raise the level of the enzyme and possibly stop or even reverse some of the buildup of fatty substances.
Males with Fabry disease who are between 18 and 55 years of age may be eligible for this two-part study. Part 1 lasts 18 weeks; part 2 lasts 36 weeks. At week 12 the patient and doctor decide whether the patient should continue with part 2. Candidates are screened with a medical history and blood and urine tests.
Participants undergo the following tests and procedures:
Drug treatment: Patients take AT1001 capsules twice a day for 12 weeks during part 1 of the study. They take the lowest dose for 2 weeks, a middle dose for 2 weeks, and then the highest dose through week 12. Patients who continue in the study for part 2 keep taking the drug twice a day either at the highest dose or possibly at one of the other doses. Patients may not eat anything for 2 hours before and 2 hours after taking the drug.
Study visits: Patients come to the clinic seven times during part 1of the study and three times during part 2 for some or all of the tests listed below.
Patients must fast for 9 hours before most clinic visits.
Patients who are taking enzyme replacement therapy stop treatment for at least 18 weeks (minimum nine missed infusions). Those who continue into the second part of the study stop treatment for another 36 weeks (for a total of 26 missed infusions). This is to allow accurate measurement of alpha-galactosidase A and GL-3 produced by the body while taking AT1001.
| Condition | Intervention | Phase |
|---|---|---|
|
Fabry Disease |
Drug: Amigal (AT1001) |
Phase II |
| Study Type: | Interventional |
| Study Design: | Treatment, Open Label, Single Group Assignment, Safety/Efficacy Study |
| Official Title: | A Phase 2, Open-Label, Multicenter, 12-Week Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of AT1001 in Patients With Fabry Disease |
| Estimated Enrollment: | 20 |
| Study Start Date: | September 2005 |
| Estimated Study Completion Date: | March 2008 |
AT1001 is a new experimental oral therapy for Fabry Disease, a lysosomal storage disorder. Fabry disease is an X-linked inborn error of glycosphingolipid metabolism caused by a deficiency in the lysosomal enzyme alpha-galactosidase A (alpha-Gal A) as a result of mutations in the alpha-Gal A gene. The enzyme deficiency leads to intracellular accumulation of the substrate, globotriaosylceramide (GL-3, also commonly known as Gb(3)).
AT1001 belongs to a class of molecules known as pharmacological chaperones. The mechanism of action involves rescue and stabilization of misfolded mutant enzyme in the endoplasmic reticulum, and subsequent transport of the enzyme to the lysosomes where it functions normally, reversing the disease phenotype.
This phase 2 trial is designed primarily to assess the safety and tolerability of multiple doses of AT1001 in Fabry disease patients. Twenty patients with a documented missense mutation, measurable levels of residual enzyme activity, and a positive result in an in vivo assay for enzyme enhancement will be enrolled at 5 clinical sites. Patients on enzyme replacement therapy (ERT) will be asked to suspend ERT for a minimum of 22 weeks (4 weeks before screening and the initial treatment phase) and up to 52 weeks if patients continue into the first treatment extension and a second optional extension up to 48 weeks for a total of 100 weeks.
The study will consist of a 12-week treatment phase that may be extended an additional 36 weeks for the first treatment extension and an additional 48 weeks for a second treatment extension. The trial includes a run-in period of 2 weeks to allow for the performance of Screening and Baseline study assessments, including an in vivo run-in period to evaluate eligibility. The trial also includes a 2-week follow-up period for patients who are not continuing into the treatment extension period. Each patient will be scheduled for 7 clinic visits (9 if continuing into the extension) and 1 telephone visit.
Patients will undergo safety assessments including vital signs, clinical laboratory tests (serum chemistry, hematology, and urinalysis), electrocardiograms (ECGs), and physical examination.
Plasma and urine will be collected to measure pharmacokinetic parameters.
In addition, the following measures of pharmacodynamic parameters will be made: alpha-Gal A (leukocytes and skin), GL-3 (plasma, urine, skin, leukocytes), cardiac function (echocardiograms, cardiac MRIs), blood and urine renal function tests (serum creatinine, creatinine clearance, 24-hour protein excretion, urine protein electrophoresis, total protein, microalbumin, urine beta-2 microglobulin titers), and nerve conduction (Quantitative Sudomotor Axon Reflex Test [QSART, to be performed at certain sites only] and Quantitative Sensory Testing [CASE study, to be performed at certain sites only]).
Eligibility| Ages Eligible for Study: | 18 Years to 65 Years |
| Genders Eligible for Study: | Male |
| Accepts Healthy Volunteers: | No |
All patients considered for study participation must meet the following criteria:
Have enhanceable enzyme activity, as defined by meeting one of the following criteria at the end of the run-in period:
Note: All inclusion criteria, with the exception of #4 (enhanceable enzyme activity), must be met on Day -28 before the run-in period begins.
Inclusion criterion #4 must be met, and all other inclusion criteria must continue to be met, at the end of the screening period in order for the patient to be enrolled in the study. Subjects who fail to meet any inclusion criterion at the end of the screening period will be considered screening failures and will not be enrolled into the study.
EXCLUSION CRITERIA:
Patients will be excluded from the study if there is evidence of any of the following criteria:
Contacts and Locations| United States, California | |
| Cedars Sinai Medical Center | |
| Los Angeles, California, United States, 90048-1804 | |
| United States, Georgia | |
| Emory University | |
| Atlanta, Georgia, United States, 30322-1102 | |
| United States, New York | |
| New York University School of Medicine | |
| New York, New York, United States, 10016 | |
| United States, Texas | |
| Baylor College of Medicine | |
| Houston, Texas, United States, 77030 | |
More Information
| Study ID Numbers: | 050250, 05-N-0250 |
| Study First Received: | October 2, 2005 |
| Last Updated: | March 7, 2008 |
| ClinicalTrials.gov Identifier: | NCT00231036 History of Changes |
| Health Authority: | United States: Federal Government |
|
Therapy Glycolipid Cardiac Disease |
Lysosomal Storage Disorder Fabry Disease Fabry Disease |
|
Lipid Metabolism, Inborn Errors Sphingolipidoses Metabolic Diseases Heart Diseases Lysosomal Storage Diseases Sphingolipidosis Central Nervous System Diseases Brain Diseases Metabolism, Inborn Errors |
Genetic Diseases, Inborn Fabry Disease Genetic Diseases, X-Linked Ceramide Trihexosidosis Brain Diseases, Metabolic, Inborn Lipidoses Metabolic Disorder Lipid Metabolism Disorders Brain Diseases, Metabolic |
|
Lipid Metabolism, Inborn Errors Sphingolipidoses Metabolic Diseases Lysosomal Storage Diseases, Nervous System Lysosomal Storage Diseases Nervous System Diseases Central Nervous System Diseases Brain Diseases |
Metabolism, Inborn Errors Genetic Diseases, Inborn Fabry Disease Genetic Diseases, X-Linked Brain Diseases, Metabolic, Inborn Lipidoses Lipid Metabolism Disorders Brain Diseases, Metabolic |
