A Study of the Safety and Efficacy of Fabrazyme in Patients With Fabry Disease

Study Overview
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Brief Summary
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People with Fabry disease have an alteration in their genetic material (DNA) which causes a deficiency of the alpha-galactosidase A enzyme. This enzyme helps to break down and remove certain types of fatty substances called glycolipids. These glycolipids are normally present within the body in most cells. In people with Fabry disease, glycolipids build up in various tissues such as the liver, kidney, skin, and blood vessels because alpha-galactosidase A is not present, or is present in small quantities. The build up of glycolipid levels (also referred to as globotriaosylceramide or GL-3) in these tissues is thought to cause the clinical symptoms that are common to Fabry disease. Symptoms commonly appear during childhood with pain in the hands and feet. This trial is designed to evaluate the efficacy of a lower dose of Fabrazyme in patients who initially received 1.0 mg/kg every 2 weeks of Fabrazyme by investigating if the achieved clearance of glycosphingolipid deposits in the vascular endothelium of the kidney can be maintained at a lower dose.

Official Title
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A Multicenter, Open-label Study of Low Dose Maintenance Treatment of Fabrazyme (Recombinant Human Alpha-Galactosidase A (R-h Alpha-GAL)) Replacement Therapy in Patients With Fabry Disease

Conditions
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Fabry Disease

Intervention / Treatment
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* Biological: Fabrazyme (agalsidase beta)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Have clinical manifestations of Fabry disease All patients have to have a plasma αGAL activity of < 1.5 nmol/hr/mL or a documented leukocyte αGAL activity of < 4 nmol/hr/mg Patient or patient's parent/guardian had to provide written informed consent prior to any study-related procedures being performed Patients had to be male and ≥ 16 years of age Exclusion Criteria: There is evidence of renal insufficiency, as defined by serum creatinine greater than or equal to 2.2 mg/dL (194.7 μmol/L) AND/OR has an estimated glomerular filtration rate (GFR) of <80 mL/min (using the equation derived from the Modification of Diet in Renal Disease Study (MDRD)) Has undergone kidney transplantation or is currently on dialysis Has a clinically significant organic disease or an unstable condition (with the exception of symptoms relating to Fabry disease) that in the opinion of the Investigator would preclude participation in the trial Has participated in a study employing an investigational drug within 30 days of the start of this trial Patients who received prior treatment with enzyme replacement therapy for Fabry disease Patient was unable to comply with the requirements of the protocol

Ages Eligible for Study
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Minimum Age: 16 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Fabrazyme<br>Open-label study. Patients received 1.0 mg/kg Fabrazyme every two weeks for approximately six months followed by 0.3 mg/kg Fabrazyme every two weeks for approximately 18 months. | Biological: Fabrazyme (agalsidase beta)<br>* 1.0 mg/kg Fabrazyme every two weeks for approximately six months followed by 0.3 mg/kg Fabrazyme every two weeks for approximately 18 months<br>* Other names: r-hαGAL;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Globotriaosylceramide (GL-3) Clearance in Kidney Interstitial Capillary Endothelium | Kidney biopsies were taken at Baseline, Week 24, and Week 96 and analyzed for cellular GL-3 accumulation (inclusions) by light microscopy. Each biopsy was evaluated by pathologists for the total number of vessels with GL-3 accumulation on an inclusion severity score of 0 (none/trace), 1 (mild), 2 (moderate), and 3 (severe). | Throughout study; 96 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Skin Globotriaosylceramide (GL-3) Clearance From Superficial Skin Capillary Endothelium | Skin biopsies were taken at Baseline, Week 24, Week 48, Week 72, and Week 96 and analyzed for cellular GL-3 accumulation (inclusions) by light microscopy. Each biopsy was evaluated by pathologists for the total number of vessels with GL-3 accumulation on an inclusion severity score of 0 (none/trace), 1 (mild), 2 (moderate), and 3 (severe). | Throughout study ; 96 weeks | 
| Estimated Glomerular Filtration Rate (eGFR) | Evaluated at Baseline, Week 24 and Week 96. eGFR is an estimation of the glomerular filtration rate of the kidneys (how much blood the kidneys are filtering). For this study, normal eGFR was defined as greater than 90 mL/min/1.73 m2 | Throughout study; 96 weeks | 
| Plasma Globotriaosylceramide (GL-3) | Evaluated at Baseline, Week 24, Week 48, Week 72 and Week 96. Plasma GL-3 is often elevated in the plasma of patients diagnosed with Fabry disease. This outcome measure evaluated the mean plasma GL-3 values for all patients to see if it decreased while on Fabrazyme. Normal plasma GL-3 level was <= 7.03 µg/mL. | Throughout study; 96 weeks | 
| Urine Globotriaosylceramide (GL-3) | Evaluated at Baseline, Week 24 and Week 96. Urine GL-3 is often elevated in the urine of patients diagnosed with Fabry disease. This outcome measure evaluated the mean urine GL-3 in first morning void urine for all patients to see if it decreased while on Fabrazyme. Normal Urine GL-3 threshold was < 8.8 μg/mg. | Throughout study, 96 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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alpha Galactosidase A, aGAL, rh aGAL, Fabry, GL3, Fabrazyme