Gaucher Disease
Conditions
Brief summary
Gaucher disease, the most prevalent lysosomal storage disorder, is caused by mutations in the human glucocerebrosidase gene (GCD) leading to reduced activity of the lysosomal enzyme glucocerebrosidase and thereby to the accumulation of substrate glucocerebroside (GlcCer) in the cells of the monocyte-macrophage system. This is the second trial to utilize a recombinant active form of lysosomal enzyme, glucocerebrosidase, (human prGCD) which is expressed and purified in a bioreactor system from transformed carrot plant root cell line.
Detailed description
This will be a multi-center, randomized, double-blind, parallel group, dose-ranging trial to assess the safety and efficacy of prGCD in 30 untreated patients with Gaucher disease. Patients will receive IV infusion of prGCD every two weeks at the selected medical center. The duration of the study will be nine months. At the end of the 9-month treatment period (20 visits, 38 weeks) eligible patients will be offered enrollment in an open-label extension study. There will be two treatment groups, 15 patients in each treatment group. Treatment Group I: 30 units/kg every 2 weeks. Treatment Group II: 60 units/kg every 2 weeks. All patients will have pharmacokinetic data collected over approximately 3 hours with frequent blood samples following the first and final doses of prGCD.
Interventions
Intravenous infusion every two weeks for 9 months
Sponsors
Pfizer
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Males and females, 18 years or older * Confirmed enzymatic diagnosis of Gaucher disease * Splenomegaly defined as greater than eight times the expected volume (measured volume divided by estimated volume (0.2% of body weight)\] as determined by MRI volumetric analysis * Female patients of child-bearing potential who agree to use a medically acceptable method of contraception * Thrombocytopenia (defined as platelet counts below the lower limit of normal) and/or anemia (defined by hemoglobin level at least 1 g/dL below normal range according to sex and age). * Patients who have not received ERT in the past or patients whoc have not received ERT in the past 12 months and have a negative anti-glucocerebrosidase antibody test. * Patients who have not received substrate reduction therapy (SRT) in the past 12 months. * Ability to provide a written informed consent.
Exclusion criteria
* Currently taking another experimental drug for any condition * Pregnant or nursing * Presence of HIV and/or, HBsAg and/or hepatitis C infections * Presence of severe neurological signs and symptoms, defined as complete ocular paralysis, overt myoclonus or history of seizures, characteristic of neuronopathic Gaucher disease. * Previous anaphylactoid reaction to Cerezyme® or Ceredase®. * History of allergy to carrots.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Spleen Volume Measured by MRI. | Baseline and 9 months | Calculated as percent change in spleen volume from Baseline to 9 months |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Liver Volume | Baseline and 9 months | Calculated as percent change in liver volume from Baseline to 9 months |
| Change in Hemoglobin | Baseline and Month 9 | Absolute change in Hemoglobin concentration from Baseline to Month 9 |
| Change in Platelet Count | Baseline and Month 9 | Change in Platelet count from Baseline to Month 9 |
Other
| Measure | Time frame | Description |
|---|---|---|
| Change in Chitotriosidase | Baseline and Month 9 | Change in Chitotriosidase from Baseline to Month 9 |
Countries
Canada, Chile, Israel, Italy, South Africa, Spain, United Kingdom, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| ELELYSO 30 Units/kg Taliglucerase alfa 30 Units/kg by intravenous infusion every two weeks | 16 |
| ELELYSO 60 Units/kg Taliglucerase alfa 60 Units/kg by intravenous infusion every two weeks | 16 |
| Total | 32 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 1 | 1 |
| Overall Study | Pregnancy | 1 | 0 |
Baseline characteristics
| Characteristic | ELELYSO 60 Units/kg | Total | ELELYSO 30 Units/kg |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 1 Participants | 1 Participants |
| Age, Categorical Between 18 and 65 years | 16 Participants | 31 Participants | 15 Participants |
| Age, Continuous | 36.0 years STANDARD_DEVIATION 12.2 | 36.2 years STANDARD_DEVIATION 11.8 | 36.3 years STANDARD_DEVIATION 11.8 |
| Chitotriosidase | 24702 nmol/ml/hr STANDARD_DEVIATION 17428 | 26000 nmol/ml/hr STANDARD_DEVIATION 14000 | 28158 nmol/ml/hr STANDARD_DEVIATION 11686 |
| Hemoglobin | 11.4 g/dL STANDARD_DEVIATION 2.6 | 12 g/dL STANDARD_DEVIATION 2 | 12.2 g/dL STANDARD_DEVIATION 1.7 |
| Liver Volume | 2481.31 mL STANDARD_DEVIATION 452.74 | 2600 mL STANDARD_DEVIATION 600 | 2880.60 mL STANDARD_DEVIATION 736.12 |
| Platelet Count | 65,038 count/mm^3 | 70,000 count/mm^3 | 75,320 count/mm^3 |
| Region of Enrollment Canada | 1 participants | 2 participants | 1 participants |
| Region of Enrollment Chile | 1 participants | 2 participants | 1 participants |
| Region of Enrollment Israel | 6 participants | 12 participants | 6 participants |
| Region of Enrollment Italy | 1 participants | 2 participants | 1 participants |
| Region of Enrollment Mexico | 2 participants | 6 participants | 4 participants |
| Region of Enrollment Serbia | 2 participants | 4 participants | 2 participants |
| Region of Enrollment South Africa | 1 participants | 2 participants | 1 participants |
| Region of Enrollment Spain | 1 participants | 1 participants | 0 participants |
| Region of Enrollment United Kingdom | 1 participants | 1 participants | 0 participants |
| Sex: Female, Male Female | 8 Participants | 16 Participants | 8 Participants |
| Sex: Female, Male Male | 8 Participants | 16 Participants | 8 Participants |
| Spleen Volume | 2117.38 mL STANDARD_DEVIATION 1356.17 | 2120 mL STANDARD_DEVIATION 1200 | 2130.94 mL STANDARD_DEVIATION 1154.72 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 6 / 16 | 4 / 16 |
| serious Total, serious adverse events | 0 / 16 | 0 / 16 |
Outcome results
Primary
Change From Baseline in Spleen Volume Measured by MRI.
Calculated as percent change in spleen volume from Baseline to 9 months
Time frame: Baseline and 9 months
Population: Intent to treat
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| ELELYSO 30 Units/kg | Change From Baseline in Spleen Volume Measured by MRI. | -26.91 percentage of change | Standard Deviation 7.79 |
| ELELYSO 60 Units/kg | Change From Baseline in Spleen Volume Measured by MRI. | -38.01 percentage of change | Standard Deviation 9.38 |
Comparison: The primary efficacy analysis was based on two one-sample t-tests (one for each treatment group) to determine if the percent change in spleen volume is different than zero.~With 12 patients in each treatment group, there was greater than 95% power to detect a change of 20% or more using a one-sample t-test (alpha=0.025, 2-sided test to allow for each group to be tested separately) to evaluate the primary outcome of percent change in spleen volume after nine months.p-value: <0.0001one-sample t-test
Comparison: The primary efficacy analysis was based on two one-sample t-tests (one for each treatment group) to determine if the percent change in spleen volume is different than zero.~With 12 patients in each treatment group, there was greater than 95% power to detect a change of 20% or more using a one-sample t-test (alpha=0.025, 2-sided test to allow for each group to be tested separately) to evaluate the primary outcome of percent change in spleen volume after nine months.p-value: <0.0001one-sample t-test
Secondary
Change From Baseline in Liver Volume
Calculated as percent change in liver volume from Baseline to 9 months
Time frame: Baseline and 9 months
Population: Intent to treat
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| ELELYSO 30 Units/kg | Change From Baseline in Liver Volume | -10.48 percentage of change from baseline | Standard Deviation 11.27 |
| ELELYSO 60 Units/kg | Change From Baseline in Liver Volume | -11.11 percentage of change from baseline | Standard Deviation 6.68 |
Comparison: For each of the secondary endpoints, a one-sample t-test (% change in liver volume, mean change in hemoglobin and platelet count) was examined first for each dose using the step-down approach. Next, a mixed effects model that included dose and time, with subject as a random effect, was fit to examine whether there was a difference between dose groups, for those outcomes that were tested in the step-down approach.p-value: 0.0041One-sample t-test
Comparison: For each of the secondary endpoints, a one-sample t-test (% change in liver volume, mean change in hemoglobin and platelet count) was examined first for each dose using the step-down approach. Next, a mixed effects model that included dose and time, with subject as a random effect, was fit to examine whether there was a difference between dose groups, for those outcomes that were tested in the step-down approach.p-value: <0.0001One-sample t-test
Secondary
Change in Hemoglobin
Absolute change in Hemoglobin concentration from Baseline to Month 9
Time frame: Baseline and Month 9
Population: Intent to treat
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| ELELYSO 30 Units/kg | Change in Hemoglobin | 1.6 g/dL | Standard Deviation 1.4 |
| ELELYSO 60 Units/kg | Change in Hemoglobin | 2.2 g/dL | Standard Deviation 1.4 |
Comparison: For each of the secondary endpoints, a one-sample t-test (% change in liver volume, mean change in hemoglobin and platelet count) was examined first for each dose using the step-down approach. Next, a mixed effects model that included dose and time, with subject as a random effect, was fit to examine whether there was a difference between dose groups, for those outcomes that were tested in the step-down approach.p-value: 0.001One-sample t-test
Comparison: For each of the secondary endpoints, a one-sample t-test (% change in liver volume, mean change in hemoglobin and platelet count) was examined first for each dose using the step-down approach. Next, a mixed effects model that included dose and time, with subject as a random effect, was fit to examine whether there was a difference between dose groups, for those outcomes that were tested in the step-down approach.p-value: <0.0001One-sample t-test
Secondary
Change in Platelet Count
Change in Platelet count from Baseline to Month 9
Time frame: Baseline and Month 9
Population: Intent to treat
| Arm | Measure | Value (MEAN) |
|---|---|---|
| ELELYSO 30 Units/kg | Change in Platelet Count | 11,427 count/mm^3 |
| ELELYSO 60 Units/kg | Change in Platelet Count | 41,494 count/mm^3 |
Comparison: For each of the secondary endpoints, a one-sample t-test (% change in liver volume, mean change in hemoglobin and platelet count) was examined first for each dose using the step-down approach. Next, a mixed effects model that included dose and time, with subject as a random effect, was fit to examine whether there was a difference between dose groups, for those outcomes that were tested in the step-down approach.p-value: 0.046One-sample t-test
Comparison: For each of the secondary endpoints, a one-sample t-test (% change in liver volume, mean change in hemoglobin and platelet count) was examined first for each dose using the step-down approach. Next, a mixed effects model that included dose and time, with subject as a random effect, was fit to examine whether there was a difference between dose groups, for those outcomes that were tested in the step-down approach.p-value: 0.0031One-sample t-test
Other Pre-specified
Change in Chitotriosidase
Change in Chitotriosidase from Baseline to Month 9
Time frame: Baseline and Month 9
Population: Intent to treat
| Arm | Measure | Value (MEAN) |
|---|---|---|
| ELELYSO 30 Units/kg | Change in Chitotriosidase | -14,548 nmol/ml/hr |
| ELELYSO 60 Units/kg | Change in Chitotriosidase | -12,538 nmol/ml/hr |