Fabry Disease
Conditions
Keywords
alpha-galactosidase A, a-GAL, r-haGAL, Fabry, GL-3, 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. Fabrazyme (agalsidase beta) is a drug that helps to break down and removes certain types of fatty substances called glycolipids. These glycolipids are normally present within the body in most cells. In Fabry disease, glycolipids build up in various tissues such as the liver, kidney, skin, and blood vessels because a-galactosidase A is not present, or is present in small quantities. The build up of glycolipid (globatriaosylceramide or GL-3) levels in these tissues in particular is thought to cause the clinical symptoms that are common to Fabry disease. This study analyzed the safety and efficacy of Fabrazyme in the treatment of patients with Fabry disease that previously participated in the AGAL-008-00 (NCT0074984) study.
Interventions
BIOLOGICALagalsidase beta
1.0 mg/kg every 2 weeks
Sponsors
Genzyme, a Sanofi Company
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
16 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Patients must have successfully completed the previous double-blind study AGAL-008-00 (NCT00074984) * Patients must provide written informed consent prior to study participation * Female patients of childbearing potential must have a negative pregnancy test prior to each dosing and all female patients must use a medically accepted form of contraception throughout the study
Exclusion criteria
* The patient was unable to complete AGAL-008-00 (NCT00074984) * The patient has undergone kidney transplantation or is currently on dialysis * The patient has diabetes mellitus or presence of confounding renal disease * The patient has a clinically significant organic disease or an unstable condition that precludes participation * The patient is unwilling to comply with the protocol requirements
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Difference in Inverse Serum Creatinine Within Patients' Slopes Between the Placebo AGAL-008-00 (NCT00074984) and Fabrazyme AGAL02503 (NCT00081497) Periods | Placebo period AGAL-008-00 (up to 35 months) through Fabrazyme period AGAL02503 (18 months) | The primary efficacy analysis was the summary of change in slope of inverse serum creatinine for Placebo/Fabrazyme patients in the Intent to Treat (ITT) Population. It compared the placebo period slope with the Fabrazyme period slope. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Serum Creatinine at Pre-Fabrazyme and 6, 12, and 18 Months | Pre-Fabrazyme, 6, 12, and 18 months | Pre-Fabrazyme=baseline visit of AGAL-008-00 (NCT00074984) for Fabrazyme patients; assessment prior to open-label for placebo patients who transitioned to Fabrazyme in AGAL-008-00 (NCT00074984); assessment prior to first Fabrazyme infusion in AGAL02503 (NCT00081497) for placebo patients who did not transition to Fabrazyme in AGAL-008-00 (NCT00074984). |
| Estimated Glomerular Filtration Rate (eGFR) at Pre-Fabrazyme and 6, 12, and 18 Months | Pre-Fabrazyme, 6, 12, and 18 months | Pre-Fabrazyme=baseline visit of AGAL-00-800 (NCT00074984) for Fabrazyme patients; assessment prior to open-label for placebo patients who transitioned to Fabrazyme in AGAL-008-00 (NCT00074984); assessment prior to first Fabrazyme infusion in AGAL02503 (NCT00081497) for placebo patients who did not transition to Fabrazyme in AGAL-008-00 (NCT00074984). |
| Plasma Globotriaosylceramide (GL-3) (Normal Plasma GL-3 Level is ≤ 7.03 µg/mL) at Pre-Fabrazyme and 6, 12, and 18 Months | Pre-Fabrazyme and 6, 12, and 18 months | Pre-Fabrazyme=baseline visit of AGAL00800 for Fabrazyme patients; assessment prior to open-label for placebo patients who transitioned to Fabrazyme in AGAL00800; assessment prior to first Fabrazyme infusion in AGAL02503 for placebo patients who did not transition to Fabrazyme in AGAL00800. |
| Proteinuria at Pre-Fabrazyme and 6, 12, and 18 Months | Pre-Fabrazyme and 6, 12, and 18 months | Pre-Fabrazyme=baseline visit of AGAL-008-00 (NCT00074984) for Fabrazyme patients; assessment prior to open-label for placebo patients who transitioned to Fabrazyme in AGAL-008-00 (NCT00074984); assessment prior to first Fabrazyme infusion in AGAL02503 (NCT00081497) for placebo patients who did not transition to Fabrazyme in AGAL-008-00 (NCT00074984). |
Countries
Canada, Czechia, Hungary, Poland, United Kingdom, United States
Participant flow
Recruitment details
Only those patients who successfully completed the AGAL-008-00 (NCT00074984) trial were eligible for participation in the AGAL02503 (NCT00081497) extension study.
Participants by arm
| Arm | Count |
|---|---|
| Placebo/Fabrazyme Patients who had been randomized to placebo during AGAL-008-00 (NCT00074984) and were then transitioned to open-label Fabrazyme (1.0 mg/kg every 2 weeks) prior to or at entry to AGAL02503 (NCT00081497). | 28 |
| Fabrazyme/Fabrazyme Patients who had been randomized to Fabrazyme in AGAL-008-00 (NCT00074984) and were then transitioned to open-label Fabrazyme (1.0 mg/kg every 2 weeks) prior to or at entry into AGAL02503 (NCT00081497). | 39 |
| Total | 67 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 2 | 0 |
| Overall Study | Death | 0 | 1 |
| Overall Study | Non-compliance | 0 | 1 |
| Overall Study | Withdrawal by Subject | 1 | 0 |
Baseline characteristics
| Characteristic | Total | Fabrazyme/Fabrazyme | Placebo/Fabrazyme |
|---|---|---|---|
| Age, Continuous | 45.3 years STANDARD_DEVIATION 9.6 | 46.6 years STANDARD_DEVIATION 9.72 | 43.5 years STANDARD_DEVIATION 9.31 |
| Age, Customized <40 years | 15 participants | 7 participants | 8 participants |
| Age, Customized ≥40 years | 52 participants | 32 participants | 20 participants |
| Race/Ethnicity Asian | 2 participants | 1 participants | 1 participants |
| Race/Ethnicity Black | 0 participants | 0 participants | 0 participants |
| Race/Ethnicity Caucasian | 59 participants | 35 participants | 24 participants |
| Race/Ethnicity Hispanic | 5 participants | 3 participants | 2 participants |
| Race/Ethnicity Other | 1 participants | 0 participants | 1 participants |
| Sex: Female, Male Female | 9 Participants | 5 Participants | 4 Participants |
| Sex: Female, Male Male | 58 Participants | 34 Participants | 24 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 | 39 / 39 | 27 / 28 | 66 / 67 |
| serious Total, serious adverse events | 19 / 39 | 12 / 28 | 31 / 67 |
Outcome results
Primary
Difference in Inverse Serum Creatinine Within Patients' Slopes Between the Placebo AGAL-008-00 (NCT00074984) and Fabrazyme AGAL02503 (NCT00081497) Periods
The primary efficacy analysis was the summary of change in slope of inverse serum creatinine for Placebo/Fabrazyme patients in the Intent to Treat (ITT) Population. It compared the placebo period slope with the Fabrazyme period slope.
Time frame: Placebo period AGAL-008-00 (up to 35 months) through Fabrazyme period AGAL02503 (18 months)
Population: ITT Population - Analysis compares results during the placebo period with those during the Fabrazyme period and includes only the 28 patients who were randomized to placebo in the AGAL-008-00 (NCT00074984) study; as such no formal sample size calculations were performed.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo Period - AGAL-008-00 (NCT00074984) | Difference in Inverse Serum Creatinine Within Patients' Slopes Between the Placebo AGAL-008-00 (NCT00074984) and Fabrazyme AGAL02503 (NCT00081497) Periods | -0.044 dL/mg/year | Standard Error 0.012 |
| Fabrazyme Period - AGAL02503 (NCT00081497) | Difference in Inverse Serum Creatinine Within Patients' Slopes Between the Placebo AGAL-008-00 (NCT00074984) and Fabrazyme AGAL02503 (NCT00081497) Periods | -0.073 dL/mg/year | Standard Error 0.011 |
Comparison: The statistical analysis represents the primary outcome measure results.p-value: 0.01395% CI: [-0.051, -0.007]Mixed Models Analysis
Secondary
Estimated Glomerular Filtration Rate (eGFR) at Pre-Fabrazyme and 6, 12, and 18 Months
Pre-Fabrazyme=baseline visit of AGAL-00-800 (NCT00074984) for Fabrazyme patients; assessment prior to open-label for placebo patients who transitioned to Fabrazyme in AGAL-008-00 (NCT00074984); assessment prior to first Fabrazyme infusion in AGAL02503 (NCT00081497) for placebo patients who did not transition to Fabrazyme in AGAL-008-00 (NCT00074984).
Time frame: Pre-Fabrazyme, 6, 12, and 18 months
Population: ITT population-67 patients had assessments at 6 and 12 months while 65 patients had assessments at 18 months in the open-label extension study.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo Period - AGAL-008-00 (NCT00074984) | Estimated Glomerular Filtration Rate (eGFR) at Pre-Fabrazyme and 6, 12, and 18 Months | eGFR at Pre-Fabrazyme | 53.1 ml/min/1.73m^2 | Standard Deviation 19.62 |
| Placebo Period - AGAL-008-00 (NCT00074984) | Estimated Glomerular Filtration Rate (eGFR) at Pre-Fabrazyme and 6, 12, and 18 Months | eGFR at 6 months post-treatment | 52.6 ml/min/1.73m^2 | Standard Deviation 23.24 |
| Placebo Period - AGAL-008-00 (NCT00074984) | Estimated Glomerular Filtration Rate (eGFR) at Pre-Fabrazyme and 6, 12, and 18 Months | eGFR at 12 months post-treatment | 50.4 ml/min/1.73m^2 | Standard Deviation 22.73 |
| Placebo Period - AGAL-008-00 (NCT00074984) | Estimated Glomerular Filtration Rate (eGFR) at Pre-Fabrazyme and 6, 12, and 18 Months | eGFR at 18 months post-treatment | 47.8 ml/min/1.73m^2 | Standard Deviation 23.62 |
Secondary
Plasma Globotriaosylceramide (GL-3) (Normal Plasma GL-3 Level is ≤ 7.03 µg/mL) at Pre-Fabrazyme and 6, 12, and 18 Months
Pre-Fabrazyme=baseline visit of AGAL00800 for Fabrazyme patients; assessment prior to open-label for placebo patients who transitioned to Fabrazyme in AGAL00800; assessment prior to first Fabrazyme infusion in AGAL02503 for placebo patients who did not transition to Fabrazyme in AGAL00800.
Time frame: Pre-Fabrazyme and 6, 12, and 18 months
Population: ITT population-64 patients had assessments at 6 and 18 months while 65 patients had assessments at 12 months in the open-label extension study.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo Period - AGAL-008-00 (NCT00074984) | Plasma Globotriaosylceramide (GL-3) (Normal Plasma GL-3 Level is ≤ 7.03 µg/mL) at Pre-Fabrazyme and 6, 12, and 18 Months | Plasma GL-3 at Pre-Fabrazyme | 9.0 µg/mL | Standard Deviation 3.35 |
| Placebo Period - AGAL-008-00 (NCT00074984) | Plasma Globotriaosylceramide (GL-3) (Normal Plasma GL-3 Level is ≤ 7.03 µg/mL) at Pre-Fabrazyme and 6, 12, and 18 Months | Plasma GL-3 at 6 months post-treatment | 4.8 µg/mL | Standard Deviation 1.76 |
| Placebo Period - AGAL-008-00 (NCT00074984) | Plasma Globotriaosylceramide (GL-3) (Normal Plasma GL-3 Level is ≤ 7.03 µg/mL) at Pre-Fabrazyme and 6, 12, and 18 Months | Plasma GL-3 at 12 months post-treatment | 4.7 µg/mL | Standard Deviation 1.59 |
| Placebo Period - AGAL-008-00 (NCT00074984) | Plasma Globotriaosylceramide (GL-3) (Normal Plasma GL-3 Level is ≤ 7.03 µg/mL) at Pre-Fabrazyme and 6, 12, and 18 Months | Plasma GL-3 at 18 months post-treatment | 4.6 µg/mL | Standard Deviation 1.82 |
Secondary
Proteinuria at Pre-Fabrazyme and 6, 12, and 18 Months
Pre-Fabrazyme=baseline visit of AGAL-008-00 (NCT00074984) for Fabrazyme patients; assessment prior to open-label for placebo patients who transitioned to Fabrazyme in AGAL-008-00 (NCT00074984); assessment prior to first Fabrazyme infusion in AGAL02503 (NCT00081497) for placebo patients who did not transition to Fabrazyme in AGAL-008-00 (NCT00074984).
Time frame: Pre-Fabrazyme and 6, 12, and 18 months
Population: ITT population-62 patients had assessments at 6 months, 61 patients had assessments at 12 months, and 54 patients had assessments at 18 months in the open-label extension study.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo Period - AGAL-008-00 (NCT00074984) | Proteinuria at Pre-Fabrazyme and 6, 12, and 18 Months | Proteinuria at Pre-Fabrazyme | 1.3 urine protein(mg/dL) / creatinine(mg/dL) | Standard Deviation 1.46 |
| Placebo Period - AGAL-008-00 (NCT00074984) | Proteinuria at Pre-Fabrazyme and 6, 12, and 18 Months | Proteinuria at 6 months post-treatment | 1.1 urine protein(mg/dL) / creatinine(mg/dL) | Standard Deviation 1.19 |
| Placebo Period - AGAL-008-00 (NCT00074984) | Proteinuria at Pre-Fabrazyme and 6, 12, and 18 Months | Proteinuria at 12 months post-treatment | 1.3 urine protein(mg/dL) / creatinine(mg/dL) | Standard Deviation 1.77 |
| Placebo Period - AGAL-008-00 (NCT00074984) | Proteinuria at Pre-Fabrazyme and 6, 12, and 18 Months | Proteinuria at 18 months post-treatment | 1.3 urine protein(mg/dL) / creatinine(mg/dL) | Standard Deviation 1.55 |
Secondary
Serum Creatinine at Pre-Fabrazyme and 6, 12, and 18 Months
Pre-Fabrazyme=baseline visit of AGAL-008-00 (NCT00074984) for Fabrazyme patients; assessment prior to open-label for placebo patients who transitioned to Fabrazyme in AGAL-008-00 (NCT00074984); assessment prior to first Fabrazyme infusion in AGAL02503 (NCT00081497) for placebo patients who did not transition to Fabrazyme in AGAL-008-00 (NCT00074984).
Time frame: Pre-Fabrazyme, 6, 12, and 18 months
Population: ITT population-67 patients had assessments at 6 and 12 months while 65 patients had assessments at 18 months in the open-label extension study.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo Period - AGAL-008-00 (NCT00074984) | Serum Creatinine at Pre-Fabrazyme and 6, 12, and 18 Months | Serum Creatinine at Pre-Fabrazyme | 1.7 mg/dL | Standard Deviation 0.6 |
| Placebo Period - AGAL-008-00 (NCT00074984) | Serum Creatinine at Pre-Fabrazyme and 6, 12, and 18 Months | Serum Creatinine at 6 months post-treatment | 1.8 mg/dL | Standard Deviation 0.77 |
| Placebo Period - AGAL-008-00 (NCT00074984) | Serum Creatinine at Pre-Fabrazyme and 6, 12, and 18 Months | Serum Creatinine at 12 months post-treatment | 1.9 mg/dL | Standard Deviation 0.98 |
| Placebo Period - AGAL-008-00 (NCT00074984) | Serum Creatinine at Pre-Fabrazyme and 6, 12, and 18 Months | Serum Creatinine at 18 months post-treatment | 2.1 mg/dL | Standard Deviation 1.21 |
Post Hoc
Differences in Slopes of Estimated Glomerular Filtration Rate (eGFR) Comparing Randomized Placebo vs Fabrazyme Patients (Based on the Original Randomization in AGAL-008-00 (NCT00074984)) by Baseline eGFR Subgroups of >60 and ≤60 mL/Min/1.73 m^2.
Summary of differences in slopes of eGFR comparing randomized placebo vs Fabrazyme patients by baseline eGFR subgroups. Differences in slopes are the placebo slope minus the Fabrazyme slope. Therefore, a negative difference indicates a greater decline in the placebo patients relative to the Fabrazyme patients.
Time frame: Throughout study; 18 months
Population: ITT population. For subgroup Estimated Glomerular Filtration Rate (eGFR) \>60, there were 9 placebo patients and 15 Fabrazyme patients. For subgroup eGFR ≤60, there were 19 placebo patients and 24 Fabrazyme patients. For randomized Fabrazyme patients, both the double-blind and open-label data was used.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo Period - AGAL-008-00 (NCT00074984) | Differences in Slopes of Estimated Glomerular Filtration Rate (eGFR) Comparing Randomized Placebo vs Fabrazyme Patients (Based on the Original Randomization in AGAL-008-00 (NCT00074984)) by Baseline eGFR Subgroups of >60 and ≤60 mL/Min/1.73 m^2. | -7.685 mL/min/1.73m^2/year | Standard Error 1.836 |
| Fabrazyme Period - AGAL02503 (NCT00081497) | Differences in Slopes of Estimated Glomerular Filtration Rate (eGFR) Comparing Randomized Placebo vs Fabrazyme Patients (Based on the Original Randomization in AGAL-008-00 (NCT00074984)) by Baseline eGFR Subgroups of >60 and ≤60 mL/Min/1.73 m^2. | -0.898 mL/min/1.73m^2/year | Standard Error 1.129 |
| Placebo - AGAL-008-00 (NCT00074984) eGFR ≤60 | Differences in Slopes of Estimated Glomerular Filtration Rate (eGFR) Comparing Randomized Placebo vs Fabrazyme Patients (Based on the Original Randomization in AGAL-008-00 (NCT00074984)) by Baseline eGFR Subgroups of >60 and ≤60 mL/Min/1.73 m^2. | -2.575 mL/min/1.73m^2/year | Standard Error 1.188 |
| Fabrazyme - AGAL02503 (NCT00081497) eGFR ≤60 | Differences in Slopes of Estimated Glomerular Filtration Rate (eGFR) Comparing Randomized Placebo vs Fabrazyme Patients (Based on the Original Randomization in AGAL-008-00 (NCT00074984)) by Baseline eGFR Subgroups of >60 and ≤60 mL/Min/1.73 m^2. | -4.906 mL/min/1.73m^2/year | Standard Error 0.9 |
Comparison: Statistical Analysis 1 represents the post-hoc outcome results for difference in slope mean of eGFR subgroup \>60.p-value: 0.002795% CI: [-11.123, -2.45]Mixed Effects Model
Comparison: Statistical Analysis 2 represents the post-hoc outcome results for difference in slope mean of eGFR subgroup ≤ 60.p-value: 0.126895% CI: [-0.685, 5.345]Mixed Effects Model