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

• Sponsor: Genzyme, a Sanofi Company
• Information provided by: Sanofi

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Fabry Disease	Biological: Fabrazyme (agalsidase beta)	Phase 2

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 21 participants
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: 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
• Study Start Date: June 2003
• Actual Primary Completion Date: April 2006
• Actual Study Completion Date: March 2007

Arms and Interventions

Arm	Intervention/treatment
Experimental: Fabrazyme; 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); 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; Other Name: r-hαGAL

Outcome Measures

Primary Outcome Measures :

1. Globotriaosylceramide (GL-3) Clearance in Kidney Interstitial Capillary Endothelium [ Time Frame: Throughout study; 96 weeks ]
   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).

Secondary Outcome Measures :

1. Skin Globotriaosylceramide (GL-3) Clearance From Superficial Skin Capillary Endothelium [ Time Frame: Throughout study ; 96 weeks ]
   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).
2. Estimated Glomerular Filtration Rate (eGFR) [ Time Frame: Throughout study; 96 weeks ]
   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
3. Plasma Globotriaosylceramide (GL-3) [ Time Frame: Throughout study; 96 weeks ]
   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.
4. Urine Globotriaosylceramide (GL-3) [ Time Frame: Throughout study, 96 weeks ]
   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.

Eligibility Criteria

• Ages Eligible for Study: 16 Years and older (Child, Adult, Older Adult)
• Sexes Eligible for Study: Male
• Accepts Healthy Volunteers: No

Criteria

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

Contacts and Locations

Locations

Czech Republic

II. interní klinika 1. LF UK

Praha 2, Czech Republic, 128 02

Estonia

Tartu University Clinics, Department of Internal Medicine

Tartu, Estonia, 51014

Poland

Klinika Chorob Metabolicznych, Instytut "Pomnik-Centrum Zdrowia Dziecka"

Warsaw, Poland, 04-736

Slovakia

Detská fakultná nemocnica Kramáre I. Interná klinika

Bratislava 37, Slovakia, 833 40

Sponsors and Collaborators

Genzyme, a Sanofi Company

Investigators

• Study Director: Medical Monitor; Genzyme, a Sanofi Company

More Information

• Responsible Party: Medical Monitor, Genzyme Corporation
• ClinicalTrials.gov Identifier: NCT00196716 History of Changes
• Other Study ID Numbers: AGAL-017-01
• First Posted: September 20, 2005
• Results First Posted: April 2, 2009
• Last Update Posted: April 3, 2015
• Last Verified: March 2015

Keywords provided by Sanofi:

alpha Galactosidase A; aGAL; rh aGAL; Fabry; GL3; Fabrazyme

Additional relevant MeSH terms:

Fabry Disease; Sphingolipidoses; Lysosomal Storage Diseases, Nervous System; Brain Diseases, Metabolic, Inborn; Brain Diseases, Metabolic; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Cerebral Small Vessel Diseases; Cerebrovascular Disorders; Vascular Diseases; Cardiovascular Diseases; Genetic Diseases, X-Linked; Genetic Diseases, Inborn; Metabolism, Inborn Errors; Lipidoses; Lipid Metabolism, Inborn Errors; Lysosomal Storage Diseases; Metabolic Diseases; Lipid Metabolism Disorders