Fabry Disease
Conditions
Keywords
alpha Galactosidase A, aGAL, rh aGAL, Fabry, GL3, Fabrazyme
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.
Interventions
BIOLOGICALFabrazyme (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
Sponsors
Genzyme, a Sanofi Company
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
MALE
Age
16 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Globotriaosylceramide (GL-3) Clearance in Kidney Interstitial Capillary Endothelium | 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
| Measure | Time frame | Description |
|---|---|---|
| Skin Globotriaosylceramide (GL-3) Clearance From Superficial Skin Capillary Endothelium | 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). |
| Estimated Glomerular Filtration Rate (eGFR) | 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 |
| Plasma Globotriaosylceramide (GL-3) | 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. |
| Urine Globotriaosylceramide (GL-3) | 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. |
Countries
Czechia, Estonia, Poland, Slovakia
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| 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. | 21 |
| Total | 21 |
Baseline characteristics
| Characteristic | Fabrazyme |
|---|---|
| Age, Continuous | 34.0 years STANDARD_DEVIATION 10 |
| Race/Ethnicity, Customized Caucasian | 21 Participants |
| Sex: Female, Male Female | 0 Participants |
| Sex: Female, Male Male | 21 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 9 / 21 | 12 / 21 | 14 / 21 |
| serious Total, serious adverse events | 0 / 21 | 4 / 21 | 5 / 21 |
Outcome results
Primary
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).
Time frame: Throughout study; 96 weeks
Population: Intent-to-Treat (ITT) Population. One patient switched back to 1.0 mg/kg Fabrazyme treatment at Week 76 and therefore assessments at Week 76 and thereafter for this patient were excluded from the analysis.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Fabrazyme | Globotriaosylceramide (GL-3) Clearance in Kidney Interstitial Capillary Endothelium | Zero (0) Kidney GL-3 Score at Baseline | 3 Participants |
| Fabrazyme | Globotriaosylceramide (GL-3) Clearance in Kidney Interstitial Capillary Endothelium | Zero (0) Kidney GL-3 Score at Week 24 | 21 Participants |
| Fabrazyme | Globotriaosylceramide (GL-3) Clearance in Kidney Interstitial Capillary Endothelium | Zero (0) Kidney GL-3 Score at Week 96 | 18 Participants |
| Fabrazyme | Globotriaosylceramide (GL-3) Clearance in Kidney Interstitial Capillary Endothelium | Mild (1) Kidney GL-3 Score at Baseline | 17 Participants |
| Fabrazyme | Globotriaosylceramide (GL-3) Clearance in Kidney Interstitial Capillary Endothelium | Mild (1) Kidney GL-3 Score at Week 24 | 0 Participants |
| Fabrazyme | Globotriaosylceramide (GL-3) Clearance in Kidney Interstitial Capillary Endothelium | Mild (1) Kidney GL-3 Score at Week 96 | 2 Participants |
| Fabrazyme | Globotriaosylceramide (GL-3) Clearance in Kidney Interstitial Capillary Endothelium | Moderate (2) Kidney GL-3 Score at Baseline | 1 Participants |
| Fabrazyme | Globotriaosylceramide (GL-3) Clearance in Kidney Interstitial Capillary Endothelium | Moderate (2) Kidney GL-3 Score at Week 24 | 0 Participants |
| Fabrazyme | Globotriaosylceramide (GL-3) Clearance in Kidney Interstitial Capillary Endothelium | Moderate (2) Kidney GL-3 Score at Week 96 | 0 Participants |
| Fabrazyme | Globotriaosylceramide (GL-3) Clearance in Kidney Interstitial Capillary Endothelium | Severe (3) Kidney GL-3 Score at Baseline | 0 Participants |
| Fabrazyme | Globotriaosylceramide (GL-3) Clearance in Kidney Interstitial Capillary Endothelium | Severe (3) Kidney GL-3 Score at Week 24 | 0 Participants |
| Fabrazyme | Globotriaosylceramide (GL-3) Clearance in Kidney Interstitial Capillary Endothelium | Severe (3) Kidney GL-3 Score at Week 96 | 0 Participants |
Secondary
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
Time frame: Throughout study; 96 weeks
Population: ITT Population. One patient switched back to 1.0 mg/kg Fabrazyme treatment at Week 76 and therefore assessments at Week 76 and thereafter for this patient were excluded from the analysis.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Fabrazyme | Estimated Glomerular Filtration Rate (eGFR) | eGFR at Baseline | 92.5 ml/min/1.73 m2 | Standard Deviation 21.12 |
| Fabrazyme | Estimated Glomerular Filtration Rate (eGFR) | eGFR at Week 24 | 93.1 ml/min/1.73 m2 | Standard Deviation 24.1 |
| Fabrazyme | Estimated Glomerular Filtration Rate (eGFR) | eGFR at Week 96 | 92.8 ml/min/1.73 m2 | Standard Deviation 27.42 |
Secondary
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.
Time frame: Throughout study; 96 weeks
Population: ITT population. One patient switched back to 1.0 mg/kg Fabrazyme treatment at Week 76 and therefore assessments at Week 76 and thereafter for this patient were excluded from the analysis.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Fabrazyme | Plasma Globotriaosylceramide (GL-3) | Plasma GL-3 values at Baseline | 12.24 μg/mL | Standard Deviation 3.369 |
| Fabrazyme | Plasma Globotriaosylceramide (GL-3) | Plasma GL-3 values at Week 24 | 5.18 μg/mL | Standard Deviation 1.276 |
| Fabrazyme | Plasma Globotriaosylceramide (GL-3) | Plasma GL-3 values at Week 48 | 5.50 μg/mL | Standard Deviation 1.48 |
| Fabrazyme | Plasma Globotriaosylceramide (GL-3) | Plasma GL-3 values at Week 72 | 5.64 μg/mL | Standard Deviation 1.635 |
| Fabrazyme | Plasma Globotriaosylceramide (GL-3) | Plasma GL-3 values at Week 96 | 6.53 μg/mL | Standard Deviation 1.497 |
Secondary
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).
Time frame: Throughout study ; 96 weeks
Population: ITT Population. One patient switched back to 1.0 mg/kg Fabrazyme treatment at Week 76 and therefore assessments at Week 76 and thereafter for this patient were excluded from the analysis.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Fabrazyme | Skin Globotriaosylceramide (GL-3) Clearance From Superficial Skin Capillary Endothelium | Zero (0) Skin GL-3 Score at Baseline | 5 Participants |
| Fabrazyme | Skin Globotriaosylceramide (GL-3) Clearance From Superficial Skin Capillary Endothelium | Zero (0) Skin GL-3 Score at Week 24 | 20 Participants |
| Fabrazyme | Skin Globotriaosylceramide (GL-3) Clearance From Superficial Skin Capillary Endothelium | Zero (0) Skin GL-3 Score at Week 48 | 15 Participants |
| Fabrazyme | Skin Globotriaosylceramide (GL-3) Clearance From Superficial Skin Capillary Endothelium | Zero (0) Skin GL-3 Score at Week 72 | 17 Participants |
| Fabrazyme | Skin Globotriaosylceramide (GL-3) Clearance From Superficial Skin Capillary Endothelium | Zero (0) Skin GL-3 Score at Week 96 | 16 Participants |
| Fabrazyme | Skin Globotriaosylceramide (GL-3) Clearance From Superficial Skin Capillary Endothelium | Mild (1) Skin GL-3 Score at Baseline | 1 Participants |
| Fabrazyme | Skin Globotriaosylceramide (GL-3) Clearance From Superficial Skin Capillary Endothelium | Mild (1) Skin GL-3 Score at Week 24 | 1 Participants |
| Fabrazyme | Skin Globotriaosylceramide (GL-3) Clearance From Superficial Skin Capillary Endothelium | Mild (1) Skin GL-3 Score at Week 48 | 4 Participants |
| Fabrazyme | Skin Globotriaosylceramide (GL-3) Clearance From Superficial Skin Capillary Endothelium | Mild (1) Skin GL-3 Score at Week 72 | 3 Participants |
| Fabrazyme | Skin Globotriaosylceramide (GL-3) Clearance From Superficial Skin Capillary Endothelium | Mild (1) Skin GL-3 Score at Week 96 | 2 Participants |
| Fabrazyme | Skin Globotriaosylceramide (GL-3) Clearance From Superficial Skin Capillary Endothelium | Moderate (2) Skin GL-3 Score at Baseline | 11 Participants |
| Fabrazyme | Skin Globotriaosylceramide (GL-3) Clearance From Superficial Skin Capillary Endothelium | Moderate (2) Skin GL-3 Score at Week 24 | 0 Participants |
| Fabrazyme | Skin Globotriaosylceramide (GL-3) Clearance From Superficial Skin Capillary Endothelium | Moderate (2) Skin GL-3 Score at Week 48 | 2 Participants |
| Fabrazyme | Skin Globotriaosylceramide (GL-3) Clearance From Superficial Skin Capillary Endothelium | Moderate (2) Skin GL-3 Score at Week 72 | 1 Participants |
| Fabrazyme | Skin Globotriaosylceramide (GL-3) Clearance From Superficial Skin Capillary Endothelium | Moderate (2) Skin GL-3 Score at Week 96 | 2 Participants |
| Fabrazyme | Skin Globotriaosylceramide (GL-3) Clearance From Superficial Skin Capillary Endothelium | Severe (3) Skin GL-3 Score at Baseline | 4 Participants |
| Fabrazyme | Skin Globotriaosylceramide (GL-3) Clearance From Superficial Skin Capillary Endothelium | Severe (3) Skin GL-3 Score at Week 24 | 0 Participants |
| Fabrazyme | Skin Globotriaosylceramide (GL-3) Clearance From Superficial Skin Capillary Endothelium | Severe (3) Skin GL-3 Score at Week 48 | 0 Participants |
| Fabrazyme | Skin Globotriaosylceramide (GL-3) Clearance From Superficial Skin Capillary Endothelium | Severe (3) Skin GL-3 Score at Week 72 | 0 Participants |
| Fabrazyme | Skin Globotriaosylceramide (GL-3) Clearance From Superficial Skin Capillary Endothelium | Severe (3) Skin GL-3 Score at Week 96 | 0 Participants |
Secondary
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.
Time frame: Throughout study, 96 weeks
Population: ITT population. One patient switched back to 1.0 mg/kg Fabrazyme treatment at Week 76 and therefore assessments at Week 76 and thereafter for this patient were excluded from the analysis.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Fabrazyme | Urine Globotriaosylceramide (GL-3) | Urine GL-3 values at Week 96 | 122.5 μg/mg | Standard Deviation 181.06 |
| Fabrazyme | Urine Globotriaosylceramide (GL-3) | Urine GL-3 values at Baseline | 221.3 μg/mg | Standard Deviation 152 |
| Fabrazyme | Urine Globotriaosylceramide (GL-3) | Urine GL-3 values at Week 24 | 109.2 μg/mg | Standard Deviation 120 |