Alternative Dosing and Regimen of Replagal to Treat Fabry Disease
Alternative Dosing and Regimen of Replagal to Treat Fabry Disease
The main goal of this study is to assess the pharmacodynamic effects of different or more
 frequent doses of Replagal compared to the standard dosing regimen. Replagal is a genetically
 engineered form of alpha-Galactosidase A, an enzyme that normally breaks down a fatty
 substance called globotriaosylceramide (Gb(3)). In patients with Fabry disease, GB(3) does
 not function properly and therefore builds up causing problems with the kidneys, heart,
 nerves, and blood vessels.

 Male patients 18 years of age or older with Fabry disease who are not on dialysis and have
 not received a kidney transplant may be eligible for this study.

 Participants are randomly assigned to receive one of the following five regimens of Replagal
 infusions, given through a vein over 20 to 80 minutes:

 0.1 mg/kg body weight every week

 0.2 mg/kg body weight every week

 0.2 mg/kg body weight every other week

 0.4 mg/kg body weight every week

 0.4 mg/kg body wieght every other week

 In the US, the infusions are given at the NIH Clinical Center. Vital signs are measured
 before, immediately after, and 1 hour after each infusion.

 Baseline evaluations are done on an inpatient or outpatient basis. Baseline tests include a
 check of vital signs (temperature, respiratory rate, pulse rate, and blood pressure);
 physical examination; laboratory tests; and review of treatment side effects. Evaluations are
 also done at every infusion visit, and 1 week and 1 month after the last infusion.

 Safety evaluations are done periodically and include vital sign measurements, physical
 examination, blood and urine tests, review of drug side effects, electrocardiogram (ECG),
 Holder monitor (2 hour ECG), and QSART (NIH only). The QSART (quantitative sudomotor axon
 reflex test) measures the amount of sweat in a particular area of skin, mostly the forearm.
 For this test, a cup partly filled with a liquid is strapped on the arm. A weak electric
 current is turned on, stimulating the sweat glands, and the amount of sweat produced is
 measured. There is a tingling sensation when the current is turned on.

 Patients who complete the study will be offered the opportunity of receiving Replagal for 6
 months in an extension study.
OBJECTIVES: The goal of this study is to assess the pharmacodynamic effects of alternative
 weekly and every two week dosing regimens of Replagal (agalsidase alfa) in comparison to the
 current standard Replagal treatment regimen of 0.2 mg/kg given intravenously every two weeks.

 STUDY POPULATION: Hemizygous males with Fabry disease who are 18 years of age or older.

 DESIGN: This is a randomized, open-label study that will assess the pharmacodynamics and
 pharmacokinetics of five different dosing regimens of enzyme replacement therapy with
 Replagal. The effects of dose as well as dosing frequency will be evaluated and compared to
 the standard Replagal regimen.

 OUTCOME MEASURES: The pharmacodynamic parameter to be assessed is plasma
 globotriaosylceramide (Gb3). The hypothesis to be tested is the role that frequency (weekly)
 and/or dose (0.1 to 0.4 mg/kg) of Replagal will play in pharmacodynamics as measured by
 reductions in plasma Gb3 compared to the current dose and frequency of 0.2 mg/kg given every
 two weeks. Clinical parameters including sweating, heart rate variability, proteinuria,
 severity of neuropathic pain, pain and anti-diarrheal medication usage, frequency and
 severity of abdominal pain, and frequency of diarrhea also will be assessed.
INCLUSION CRITERIA:

 Subject is a male hemizygote, age 18 years or older, with confirmed diagnosis of Fabry
 Disease. Diagnosis of Fabry disease may be confirmed by proof of a mutation of the
 alpha-Galactosidase A gene compatible with Fabry Disease and/or a deficiency of
 alpha-Galactosidase A (less than 4.0 nmol/mL/hour in plasma or serum or less than 8% of
 average mean normal in leukocytes).

 Subject must have one or more clinical manifestations of Fabry disease including
 neuropathic pain, angiokeratoma, corneal verticillata, cardiomyopathy, hypo- or anhydrosis,
 abdominal pain and/or diarrhea, serum creatinine greater than 1.0 mg/dl or proteinuria
 greater than 300 mg/24 hours.

 Subject must have voluntarily signed an Institutional Review Board (IRB) approved informed
 consent form after all relevant aspects of the study have been explained and discussed with
 the subject.

 EXCLUSION CRITERIA:

 Subject has been previously treated with Replagal or any other enzyme replacement therapy
 for Fabry Disease. If the patient has previously been treated with Replagal or another
 enzyme replacement therapy then they must have been off the therapy for at least 30 days
 and must have a Day-14 antibody blood sample drawn and that test must be negative for
 anti-agalsidase alfa IgG and IgE antibodies and not experienced a prior severe infusion
 reactions with prior enzyme replacement therapy.

 Subject has been enrolled in another clinical investigative study in the past 30 days.

 Subject is unable to give informed consent or is deemed unable to comply with all aspects
 of the clinical trial.

 Subject has plasma Gb(3) drawn on Day -14 less than 4.0 nmol/mL.

 Subject is undergoing dialysis or who has received a renal transplant.

 Subjects who cannot tolerate the study procedures or who are unable or unwilling to travel
 to the study center as required by this protocol.

 Subjects with an inter-current medical condition that would render them unsuitable for the
 study (e.g. HIV, diabetes) by confounding an assessment of the effects of the experimental
 therapy and its adverse events.

 Subjects who in the opinion of the investigator (for whatever reason) are thought to be
 unsuitable for the study.