dosing study of replagal in patients with fabry disease

Conditions: Fabry Disease

Summary: this study will determine the safety and effectiveness of increasing replagal infusions in certain patients with fabry disease. replagal is a genetically engineered form of alpha-galactosidase a, an enzyme that normally breaks down a fatty substance called globotriaosylceramide (gb3). in patients with fabry disease, alpha-galactosidase a does not function properly and, therefore, gb3 builds up, causing problems with the kidneys, heart, nerves, and blood vessels. patients with fabry disease who are participating in nih protocol 00-n-0185 or 02-n-0220 may be eligible for this study. this includes patients who are currently taking replagal but whose kidney function continues to worsen, or patients who have certain test results that are much improved after replagal infusion. participants will receive replagal infusions (0.2 mg/kg body weight) through a vein once a week (as opposed to the previous dosage of once every 2 weeks) for up to 2 years. the first infusion, and some others, are given at the nih clinical center, but most are administered by the patient's local doctor. vital signs are measured before, immediately after, and 1 hour after each infusion. baseline evaluations are done on an inpatient basis at the nih clinical center over a 1-week period before and after the first replagal infusion and at 6-month intervals during the study. tests include a check of vital signs (temperature, respiratory rate, pulse rate, and blood pressure); weight measurement; physical and neurological examinations; routine blood and urine tests; 24-hour urine collection; electrocardiogram; and review of treatment side effects. in addition, the following tests are done: * quantitative sensory testing: this is a non-invasive test to measure the ability to sense warm, cold and vibration in the hand and foot. * qsart: this test measures the amount of sweat in a particular area of skin that did not sweat enough. a small amount of a medicine called acetylcholine is put on the skin and made to enter the skin using a very small electric current. * doppler skin blood flow: this test measures blood flow to the blood vessels of the skin. a machine takes pictures of blood flow in the skin of the forearm using a laser beam. pictures are taken before and during application of medicines that cause blood vessels to dilate. acetylcholine is used on one forearm and nitroprusside is used on the other. the medication is made to enter the skin using a small el...

objectives: the goal of this study is to determine whether higher frequency of dosing of enzyme replacement therapy (ert) can either significantly slow the decline of renal function or continuously sustain the normalization of other objective functions in patients with fabry disease who have been receiving intravenous infusions of replagal (agalsidase alfa) at a dose of 0.2 mg/kg of body weight administered every 2 weeks. study population: patients with fabry disease who are currently on clinical research protocols 00-n-0185/tkt011 or 02-n-0220/tkt015 and who have demonstrated progressive decline in calculated glomerular filtration rate (gfr) of at least 5 ml/min/year on ert or who consistently show transient improvement in objective functions (such as sweating) in the few days post-infusion. design: this is an open label study comparing one dosing regimen with a previous less intensive dosing regimen. patients will receive a dose of 0.2 mg/kg of body weight every week. outcome measures: the main outcome measure will be a change in the mean linear rate of decline of the estimated calculated gfr. the main hypothesis is that a more frequent administration of the previous dose of replagal will significantly reduce the mean slope of the decline of the calculated glomerular filtration rate gfr compared with the currently observed slope on a dose of 0.2 mg/kg administered every 2 weeks. at the 2-year time point, the dose will be increased to 0.4 mg/kg only in the patients whose gfr continues to significantly decline. secondary outcome measures will be globotriaosylceramide (gb(3)) in plasma and urinary sediment, quantitative sudomotor axon reflex test, quantitative sensory testing. study duration is 2 years with a possibility of additional one-year extensions.

Eligibility criteria:
* inclusion criteria: patients with fabry disease participating in 00-n-0185/tkt011 or 02-n-0220/tkt015 may be eligible. no other fabry patients will be eligible. patients losing gfr at a rate greater than 5 ml/min/year despite ert with agalsidase alfa for greater than or equal to 2.5 years in 00-n-0185/tkt/003/006/011 study or ert over greater than or equal to 1.0 years in 02-n-0220/tkt/010/015 study. patients who at least twice demonstrated significant improvement or normalization of sweat function (by qsart or thermoregulatory sweat test) or reduction in serum creatinine by at least 10% but return to the pre-infusion state before the subsequent biweekly enzyme infusion. patients who freely agree to participate in this study and understand the nature, risks and benefits of this study and give their written informed consent. exclusion criteria: patients with fabry disease, who are not already part of 00-n-0185/tkt011 or 02-n-0220/tkt015. patients on these protocols who have stable serum creatinine (or a lesser rise in serum creatinine than stipulated in the inclusion criteria), and do not show other objective evidence of incomplete clinical response between biweekly infusions (e.g. sweat function). patients who have begun dialysis or who have received a renal transplant. patients who cannot tolerate the study procedures or who are unable or unwilling to travel to the study center as required by this protocol. patients with an intercurrent medical condition that would render them unsuitable for mthe study e.g. hiv, diabetes. the reason is that the pathologies of these conditions will be significant confounders in assessing the effect of the experimental therapy and its adverse events. patients who in the opinion of the investigator (for whatever reason) are thought to be unsuitable for the study.

Keywords: lysosomal storage renal insufficiency stroke hypohidrosis peripheral neuropathy fabry disease