Fabry Disease
Conditions
Keywords
a-Galactosidase A, aGAL, 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 a-galactosidase A enzyme. Fabrazyme (agalsidase beta) is a drug that helps to breakdown and remove 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 (globotriaosylceramide or GL-3) levels in these tissues in particular is thought to cause the clinical symptoms that are common to Fabry disease. This study will test the safety and efficacy of Fabrazyme in the treatment of patients with Fabry disease.
Interventions
BIOLOGICALFabrazyme (agalsidase beta)
1mg/kg Fabrazyme (agalsidase beta) every 2 weeks
BIOLOGICALPlacebo
1 mg/kg placebo intravenously every 2 weeks
Sponsors
Genzyme, a Sanofi Company
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
16 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Patients must provide written informed consent * Patients must be at least 16 years old * Patients must have a current diagnosis of Fabry disease and have a clinical presentation consistent of Fabry disease (decreased sweating, Fabry pain, angiokeratoma, etc.) * Patients may not have received enzyme replacement therapy as a treatment for Fabry disease * Patients must have a documented plasma a-galactosidase A (aGAL) activity of \< 1.5 nmol/hr/mL or a documented leukocyte aGAL activity of \< 4 nmol/hr/mg * Patients must have one or more of the following: a serum creatinine measurement of 1.2 to 3 mg/dL (106.1 to 265 umol/L) OR estimated creatinine clearance \< 80 mL/min only if the patient's serum creatinine measurement is \< 1.2 mg/dL * 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
Exclusion criteria
* Patient has undergone or is currently scheduled for kidney transplantation or is currently on dialysis * Patient has acute renal failure * Patient has participated in a study employing an investigational drug within 30 days of study entry * Patient has diabetes mellitus or presence of confounding renal disease * Patient has a history of transient ischemic attack (TIA) or ischemic stroke within 3 months of study entry documented by mild-to-moderate neurological deficit * Patient has critical coronary disease * Patient has congestive heart failure * Patient has severe residual neurological deficit that will confound the detection of new events as determined by an attending neurologist and/or Principal Investigator * Patient is unwilling to comply with the requirements of the protocol or the patient has a medical condition, serious intercurrent illness, or extenuating circumstances that would significantly decrease study compliance, including prescribed follow-up
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Experiencing a Clinically Significant Renal, Cardiac or Cerebrovascular Event and/or Death in Fabrazyme (Agalsidase Beta) Patients as Compared to Placebo Patients | up to 35 months | The primary efficacy endpoint was the time to the first occurrence of a clinically significant renal (33% increase in serum creatinine, dialysis or transplant), cardiac (myocardial infarction, significant change in cardiac status, i.e., angina, congestive heart failure or symptomatic arrhythmia requiring medication or surgery) or cerebrovascular (stroke or transient ischemic attack) event and/or death (due to any cause) in Fabrazyme (agalsidase beta) patients as compared to placebo patients. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Experiencing a Renal Event in Fabrazyme (Agalsidase Beta) Patients as Compared to Placebo Patients | up to 35 months | Time to a clinically significant renal event (33% increase in serum creatinine, dialysis or transplant) in Fabrazyme (agalsidase beta) patients as compared to placebo patients. |
| Slope of Estimated Glomerular Filtration Rate (eGFR) Comparing Placebo vs Fabrazyme (Agalsidase Beta) Patients | up to 35 months | Summary of slopes of eGFR by baseline eGFR subgroups (\>60 and \<=60 mL/min/1.73m\^2/year) comparing Placebo vs Fabrazyme (agalsidase beta) Patients. |
| Slope of Inverse Serum Creatinine Values Comparing Placebo vs Fabrazyme (Agalsidase Beta)Patients | up to 35 months | Summary of slopes of inverse serum creatinine by baseline serum creatinine subgroups (\> or \<= 1.5 mg/dL) comparing Placebo vs Fabrazyme (agalsidase beta) patients. |
| Neuropathic Pain as Assessed by Question 12 of the Brief Pain Inventory (BPI) Questionnaire (Pain at Its Worst) | at 24 months | Neuropathic pain was assessed by Question 12 of the Brief Pain Inventory (BPI) Questionnaire on a scale of 0 (no pain) to 10 (pain as bad as you can imagine) |
Countries
Canada, Czechia, Hungary, Poland, United Kingdom, United States
Participant flow
Recruitment details
A total of 252 patients were screened for entry into the study and of these, 82 patients were eligible to be enrolled.
Participants by arm
| Arm | Count |
|---|---|
| Placebo Patients randomized to placebo are administered 1 mg/kg placebo intravenously every 2 weeks. | 31 |
| Fabrazyme (Agalsidase Beta) Patients randomized to Fabrazyme (agalsidase beta) are administered 1mg/kg Fabrazyme (agalsidase beta) every 2 weeks. | 51 |
| Total | 82 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 1 | 2 |
| Overall Study | Patient Withdrawn Per Protocol | 0 | 3 |
| Overall Study | Withdrawal by Subject | 2 | 3 |
Baseline characteristics
| Characteristic | Placebo | Fabrazyme (Agalsidase Beta) | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 2 Participants | 2 Participants |
| Age, Categorical Between 18 and 65 years | 31 Participants | 49 Participants | 80 Participants |
| Age, Continuous | 44.3 years STANDARD_DEVIATION 9.23 | 46.9 years STANDARD_DEVIATION 9.75 | 45.9 years STANDARD_DEVIATION 9.58 |
| Age, Customized <40 years | 8 participants | 11 participants | 19 participants |
| Age, Customized ≥40 years | 23 participants | 40 participants | 63 participants |
| Race/Ethnicity Asian | 1 participants | 1 participants | 2 participants |
| Race/Ethnicity Black | 0 participants | 1 participants | 1 participants |
| Race/Ethnicity Caucasian | 27 participants | 45 participants | 72 participants |
| Race/Ethnicity Hispanic | 2 participants | 3 participants | 5 participants |
| Race/Ethnicity Other | 1 participants | 1 participants | 2 participants |
| Sex: Female, Male Female | 4 Participants | 6 Participants | 10 Participants |
| Sex: Female, Male Male | 27 Participants | 45 Participants | 72 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 | 51 / 51 | 29 / 31 | 80 / 82 |
| serious Total, serious adverse events | 18 / 51 | 12 / 31 | 30 / 82 |
Outcome results
Primary
Number of Participants Experiencing a Clinically Significant Renal, Cardiac or Cerebrovascular Event and/or Death in Fabrazyme (Agalsidase Beta) Patients as Compared to Placebo Patients
The primary efficacy endpoint was the time to the first occurrence of a clinically significant renal (33% increase in serum creatinine, dialysis or transplant), cardiac (myocardial infarction, significant change in cardiac status, i.e., angina, congestive heart failure or symptomatic arrhythmia requiring medication or surgery) or cerebrovascular (stroke or transient ischemic attack) event and/or death (due to any cause) in Fabrazyme (agalsidase beta) patients as compared to placebo patients.
Time frame: up to 35 months
Population: The Intent-to-treat (ITT) population consists of all 82 patients who were randomized, enrolled, and received at least one infusion of study medication.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo | Number of Participants Experiencing a Clinically Significant Renal, Cardiac or Cerebrovascular Event and/or Death in Fabrazyme (Agalsidase Beta) Patients as Compared to Placebo Patients | Participants with a clinical event | 13 participants |
| Placebo | Number of Participants Experiencing a Clinically Significant Renal, Cardiac or Cerebrovascular Event and/or Death in Fabrazyme (Agalsidase Beta) Patients as Compared to Placebo Patients | Participants with no clinical event | 18 participants |
| Fabrazyme (Agalsidase Beta) | Number of Participants Experiencing a Clinically Significant Renal, Cardiac or Cerebrovascular Event and/or Death in Fabrazyme (Agalsidase Beta) Patients as Compared to Placebo Patients | Participants with a clinical event | 14 participants |
| Fabrazyme (Agalsidase Beta) | Number of Participants Experiencing a Clinically Significant Renal, Cardiac or Cerebrovascular Event and/or Death in Fabrazyme (Agalsidase Beta) Patients as Compared to Placebo Patients | Participants with no clinical event | 37 participants |
p-value: 0.144995% CI: [0.269, 1.222]Log Rank
Comparison: Time to First Primary Endpoint Adjusting for Baseline Proteinuria using Cox Proportional Hazards Modelp-value: 0.057795% CI: [0.211, 1.025]Wald Test
Secondary
Neuropathic Pain as Assessed by Question 12 of the Brief Pain Inventory (BPI) Questionnaire (Pain at Its Worst)
Neuropathic pain was assessed by Question 12 of the Brief Pain Inventory (BPI) Questionnaire on a scale of 0 (no pain) to 10 (pain as bad as you can imagine)
Time frame: at 24 months
Population: Intent-to-treat population
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Neuropathic Pain as Assessed by Question 12 of the Brief Pain Inventory (BPI) Questionnaire (Pain at Its Worst) | 2 years (n=7, n=18) | 4.4 units on a scale | Standard Deviation 3.6 |
| Placebo | Neuropathic Pain as Assessed by Question 12 of the Brief Pain Inventory (BPI) Questionnaire (Pain at Its Worst) | Baseline (n=30, n=48) | 2.2 units on a scale | Standard Deviation 3 |
| Placebo | Neuropathic Pain as Assessed by Question 12 of the Brief Pain Inventory (BPI) Questionnaire (Pain at Its Worst) | Change from baseline to 2 years (n=7, n=17) | 0.9 units on a scale | Standard Deviation 3 |
| Fabrazyme (Agalsidase Beta) | Neuropathic Pain as Assessed by Question 12 of the Brief Pain Inventory (BPI) Questionnaire (Pain at Its Worst) | Baseline (n=30, n=48) | 2.7 units on a scale | Standard Deviation 3.1 |
| Fabrazyme (Agalsidase Beta) | Neuropathic Pain as Assessed by Question 12 of the Brief Pain Inventory (BPI) Questionnaire (Pain at Its Worst) | 2 years (n=7, n=18) | 2.7 units on a scale | Standard Deviation 3.2 |
| Fabrazyme (Agalsidase Beta) | Neuropathic Pain as Assessed by Question 12 of the Brief Pain Inventory (BPI) Questionnaire (Pain at Its Worst) | Change from baseline to 2 years (n=7, n=17) | -0.8 units on a scale | Standard Deviation 3.2 |
Secondary
Number of Participants Experiencing a Renal Event in Fabrazyme (Agalsidase Beta) Patients as Compared to Placebo Patients
Time to a clinically significant renal event (33% increase in serum creatinine, dialysis or transplant) in Fabrazyme (agalsidase beta) patients as compared to placebo patients.
Time frame: up to 35 months
Population: The Intent-to-treat population consisted of all 82 patients who were randomized, enrolled, and received at least one infusion of study medication.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo | Number of Participants Experiencing a Renal Event in Fabrazyme (Agalsidase Beta) Patients as Compared to Placebo Patients | Participants with a Renal event | 7 participants |
| Placebo | Number of Participants Experiencing a Renal Event in Fabrazyme (Agalsidase Beta) Patients as Compared to Placebo Patients | Participants with no Renal event | 24 participants |
| Fabrazyme (Agalsidase Beta) | Number of Participants Experiencing a Renal Event in Fabrazyme (Agalsidase Beta) Patients as Compared to Placebo Patients | Participants with a Renal event | 10 participants |
| Fabrazyme (Agalsidase Beta) | Number of Participants Experiencing a Renal Event in Fabrazyme (Agalsidase Beta) Patients as Compared to Placebo Patients | Participants with no Renal event | 41 participants |
Comparison: Analysis of Time to First Renal Event for ITT population.p-value: 0.526195% CI: [0.278, 1.927]Log Rank
Secondary
Slope of Estimated Glomerular Filtration Rate (eGFR) Comparing Placebo vs Fabrazyme (Agalsidase Beta) Patients
Summary of slopes of eGFR by baseline eGFR subgroups (\>60 and \<=60 mL/min/1.73m\^2/year) comparing Placebo vs Fabrazyme (agalsidase beta) Patients.
Time frame: up to 35 months
Population: The Intent-to-treat population consisted of all 82 patients who were randomized, enrolled, and received at least one infusion of study medication
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Slope of Estimated Glomerular Filtration Rate (eGFR) Comparing Placebo vs Fabrazyme (Agalsidase Beta) Patients | eGFR Total | -3.62 mL/min/1.73m^2/year | Standard Deviation 3.38 |
| Placebo | Slope of Estimated Glomerular Filtration Rate (eGFR) Comparing Placebo vs Fabrazyme (Agalsidase Beta) Patients | Baseline eGFR >60 | -5.09 mL/min/1.73m^2/year | Standard Deviation 3.52 |
| Placebo | Slope of Estimated Glomerular Filtration Rate (eGFR) Comparing Placebo vs Fabrazyme (Agalsidase Beta) Patients | Baseline eGFR <= 60 | -3.02 mL/min/1.73m^2/year | Standard Deviation 3.21 |
| Fabrazyme (Agalsidase Beta) | Slope of Estimated Glomerular Filtration Rate (eGFR) Comparing Placebo vs Fabrazyme (Agalsidase Beta) Patients | eGFR Total | -3.25 mL/min/1.73m^2/year | Standard Deviation 2.92 |
| Fabrazyme (Agalsidase Beta) | Slope of Estimated Glomerular Filtration Rate (eGFR) Comparing Placebo vs Fabrazyme (Agalsidase Beta) Patients | Baseline eGFR >60 | -1.51 mL/min/1.73m^2/year | Standard Deviation 2.85 |
| Fabrazyme (Agalsidase Beta) | Slope of Estimated Glomerular Filtration Rate (eGFR) Comparing Placebo vs Fabrazyme (Agalsidase Beta) Patients | Baseline eGFR <= 60 | -4.20 mL/min/1.73m^2/year | Standard Deviation 2.52 |
Secondary
Slope of Inverse Serum Creatinine Values Comparing Placebo vs Fabrazyme (Agalsidase Beta)Patients
Summary of slopes of inverse serum creatinine by baseline serum creatinine subgroups (\> or \<= 1.5 mg/dL) comparing Placebo vs Fabrazyme (agalsidase beta) patients.
Time frame: up to 35 months
Population: The Intent-to-treat population consisted of all 82 patients who were randomized, enrolled, and received at least one infusion of study medication.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Slope of Inverse Serum Creatinine Values Comparing Placebo vs Fabrazyme (Agalsidase Beta)Patients | Total | -0.038 dL/mg/year | Standard Deviation 0.037 |
| Placebo | Slope of Inverse Serum Creatinine Values Comparing Placebo vs Fabrazyme (Agalsidase Beta)Patients | Baseline Serum Creatinine > 1.5 | -0.043 dL/mg/year | Standard Deviation 0.03 |
| Placebo | Slope of Inverse Serum Creatinine Values Comparing Placebo vs Fabrazyme (Agalsidase Beta)Patients | Baseline Serum Creatinine <= 1.5 | -0.033 dL/mg/year | Standard Deviation 0.043 |
| Fabrazyme (Agalsidase Beta) | Slope of Inverse Serum Creatinine Values Comparing Placebo vs Fabrazyme (Agalsidase Beta)Patients | Total | -0.036 dL/mg/year | Standard Deviation 0.035 |
| Fabrazyme (Agalsidase Beta) | Slope of Inverse Serum Creatinine Values Comparing Placebo vs Fabrazyme (Agalsidase Beta)Patients | Baseline Serum Creatinine > 1.5 | -0.050 dL/mg/year | Standard Deviation 0.028 |
| Fabrazyme (Agalsidase Beta) | Slope of Inverse Serum Creatinine Values Comparing Placebo vs Fabrazyme (Agalsidase Beta)Patients | Baseline Serum Creatinine <= 1.5 | -0.022 dL/mg/year | Standard Deviation 0.035 |