Gaucher Disease, Type 1
Conditions
Keywords
VPRIV®, Enzyme Replacement Therapy, Gaucher disease, glucocerebrosidase, beta-glucocerebrosidase, Acid beta-glucocerebrosidase, glucosylceramidase, D-glucosyl-N-acylsphingosine glucohydrolase, gene activation, human
Brief summary
Gaucher disease is a rare lysosomal storage disorder caused by the deficiency of the enzyme glucocerebrosidase (GCB). Due to this deficiency of functional GCB, glucocerebroside accumulates within macrophages leading to cellular engorgement, organomegaly, and organ system dysfunction. The purpose of this study is to evaluate the efficacy of every other week dosing of Gene-Activated® Human Glucocerebrosidase (GA-GCB, velaglucerase alfa) at doses of 45 and 60 U/kg in treatment-naïve patients with type 1 Gaucher disease.
Detailed description
Type 1 Gaucher disease, the most common form, accounts for more than 90% of all cases and does not involve the Central Nervous System (CNS). Typical manifestations of type 1 Gaucher disease include hepatomegaly, splenomegaly, thrombocytopenia, bleeding tendencies, anemia, hypermetabolism, skeletal pathology, growth retardation, pulmonary disease, and decreased quality of life. Gene-Activated® human glucocerebrosidase (GA-GCB; velaglucerase alfa) is produced in a continuous human cell line using proprietary gene-activation technology and has an identical amino acid sequence to the naturally occurring human enzyme. Velaglucerase alfa contains terminal mannose residues that target the enzyme to the macrophages-the primary target cells in Gaucher disease. This study was designed to determine the efficacy, safety and pharmacokinetics of GA-GCB in men, women, and children with Type 1 Gaucher disease. Each patients duration of treatment was 12 months.
Interventions
BIOLOGICALVPRIV ®,
Intravenous (IV) infusion, every other week via intravenous infusion for 12 months
Sponsors
Shire
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
2 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Patient has a documented diagnosis of type 1 Gaucher disease, as determined by deficient glucocerebrosidase (GCB) activity relative to normal as measured in leukocytes or by genotype analysis and is willing and able to provide written informed consent prior to initiating any study-related procedures * Patient is at least 2 years of age * Patient has Gaucher disease-related anemia and * Patient has at least moderate splenomegaly or * Patient has Gaucher disease-related thrombocytopenia or * Patient has a readily palpable enlarged liver * Patient has not received treatment for Gaucher disease within 30 months prior to study entry * Female patients of child-bearing potential agree to use a medically acceptable method of contraception. Male patients must agree to use a medically acceptable method of birth control. * Patient must be sufficiently cooperative to participate in the study as judged by the Investigator.
Exclusion criteria
Includes: * Patient has type 2 or 3 Gaucher disease or is suspected of having type 3 Gaucher disease * Patient is antibody-positive to imiglucerase during screening or has experienced an anaphylactic reaction to imiglucerase * Patient has received treatment with any investigational drug or device within the 30 days prior to study entry * Patient is Human immunodeficiency virus (HIV) positive * Patient is hepatitis positive * Patient presents with iron, folic acid and/or vitamin B12 deficiency sustained anemia during screening * Patient, patient's parent(s), or patient's legal guardian(s) is/are unable to understand the nature, scope, and possible consequences of the study * Patient has a significant comorbidity(ies)that might affect study data or confound the study results * Patient is a pregnant and/or lactating female * Patient is unable to comply with the protocol or is unlikely to complete the study, as determined by the Investigator
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline to 12 Months in Hemoglobin Concentration for the 60 U/kg Treatment Group. | Week 53 | Efficacy endpoint |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline to 12 Months in Hemoglobin Concentration in 45 U/kg Treatment Group | Week 53 | — |
| Change From Baseline to 12 Months in Normalized Liver Volume (Percent Body Weight) for Each Treatment Group (Measured by Magnetic Resonance Imaging (MRI) | Week 51 | Liver Volume has been normalized for percentage of body weight for each treatment arm. Liver size relative to body weight = (Liver volume \[cc\]/Body weight \[kg\])\*100 |
| Change From Baseline to 12 Months in Platelet Counts for Each Treatment Group. | Week 53 | intent to treat (ITT) Population |
| Percent Change From Baseline to 12 Months in Plasma Chitotriosidase for Each Treatment Group | Week 53 | Percent Change from Baseline to Weeks 53 by Randomized velaglucerase alfa Treatment Group - Subset of intent to treat (ITT) Population who were wild type homozygous for chitotriosidase. |
| Percent Change From Baseline to 12 Months in Chemokine (C-C Motif) Ligand 18 (CCL18) | Week 53 | — |
| Change From Baseline to 12 Months in Normalized Spleen Volume (Percent Body Weight) for Each Treatment Group (Measured by Magnetic Resonance Imaging (MRI)) | Week 51 | 12 patients in the 60 U/kg group and 13 patients in the 45 U/kg group were analyzed for efficacy in the intent to treat (ITT) population. Spleen Volume has been normalized for percent of body weight for each treatment arm. Spleen size relative to body weight = (Spleen volume \[cc\]/Body weight \[kg\])\*100 |
Countries
Argentina, Israel, Paraguay, Russia, Tunisia
Participant flow
Recruitment details
Type 1 Gaucher disease patients (pts) \>2 years. The first patient (pt) was enrolled in the study on 15 February 2007.
Pre-assignment details
Gaucher disease-related anemia and at least 1 of the following: moderate splenomegaly, thrombocytopenia or palpable enlarged liver. Patients were not to have received any treatment for Gaucher disease within 30 months of study entry. Patients randomized to receive VPRIV®(45 or 60 U/kg)every other week by intravenous (IV) infusion.
Participants by arm
| Arm | Count |
|---|---|
| VPRIV® (45 U/kg, IV, Every Other Week) velaglucerase alfa, Gene Activated® human glucocerebrosidase, GA-GCB | 13 |
| VPRIV® (60 U/kg, IV, Every Other Week) velaglucerase alfa, Gene Activated® human glucocerebrosidase, GA-GCB | 12 |
| Total | 25 |
Baseline characteristics
| Characteristic | VPRIV® (45 U/kg, IV, Every Other Week) | VPRIV® (60 U/kg, IV, Every Other Week) | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 3 Participants | 4 Participants | 7 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 10 Participants | 8 Participants | 18 Participants |
| Age, Continuous | 30.0 years FULL_RANGE 16.75 | 23.5 years FULL_RANGE 11.77 | 25 years FULL_RANGE 15.28 |
| Baseline hemoglobin concentration per treatment group | 10.90 g/dL FULL_RANGE 1.278 | 10.83 g/dL FULL_RANGE 1.272 | 10.85 g/dL FULL_RANGE 1.248 |
| Baseline liver volume | 3.50 Percent of body weight | 3.65 Percent of body weight | 3.5 Percent of body weight |
| Baseline platelet counts per treatment group | 58.00 (x10^9/L) FULL_RANGE 59.56 | 66.75 (x10^9/L) FULL_RANGE 111.91 | 65.5 (x10^9/L) FULL_RANGE 86.71 |
| Baseline Spleen volume | 2.9 Percent of body weight | 2.8 Percent of body weight | 2.9 Percent of body weight |
| Region of Enrollment Argentina | 1 Participants | 0 Participants | 1 Participants |
| Region of Enrollment Israel | 1 Participants | 6 Participants | 7 Participants |
| Region of Enrollment Paraguay | 6 Participants | 5 Participants | 11 Participants |
| Region of Enrollment Russian Federation | 3 Participants | 0 Participants | 3 Participants |
| Region of Enrollment Tunisia | 2 Participants | 1 Participants | 3 Participants |
| Sex: Female, Male Female | 5 Participants | 5 Participants | 10 Participants |
| Sex: Female, Male Male | 8 Participants | 7 Participants | 15 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 9 / 13 | 6 / 12 |
| serious Total, serious adverse events | 0 / 13 | 1 / 12 |
Outcome results
Primary
Change From Baseline to 12 Months in Hemoglobin Concentration for the 60 U/kg Treatment Group.
Efficacy endpoint
Time frame: Week 53
Population: 12 patients in the 60 U/kg group were analyzed for efficacy in the intent to treat (ITT) population.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| VPRIV® (60 U/kg, IV, Every Other Week) | Change From Baseline to 12 Months in Hemoglobin Concentration for the 60 U/kg Treatment Group. | 2.429 g/dL |
Comparison: Primary endpoint was based solely on the 60 U/kg treatment armp-value: <0.000195% CI: [1.717, 3.141]paired t-test
Secondary
Change From Baseline to 12 Months in Hemoglobin Concentration in 45 U/kg Treatment Group
Time frame: Week 53
Population: 13 patients in the 45 U/kg group were analyzed for efficacy in the intent to treat (ITT) population.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| VPRIV® (60 U/kg, IV, Every Other Week) | Change From Baseline to 12 Months in Hemoglobin Concentration in 45 U/kg Treatment Group | 2.438 (g/dL) |
Secondary
Change From Baseline to 12 Months in Normalized Liver Volume (Percent Body Weight) for Each Treatment Group (Measured by Magnetic Resonance Imaging (MRI)
Liver Volume has been normalized for percentage of body weight for each treatment arm. Liver size relative to body weight = (Liver volume \[cc\]/Body weight \[kg\])\*100
Time frame: Week 51
Population: 12 patients in the 60 U/kg group and 13 patients in the 45 U/kg group were analyzed for efficacy in the intent to treat (ITT) population.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| VPRIV® (60 U/kg, IV, Every Other Week) | Change From Baseline to 12 Months in Normalized Liver Volume (Percent Body Weight) for Each Treatment Group (Measured by Magnetic Resonance Imaging (MRI) | -0.30 Percent body weight |
| VPRIV® (60 U/kg, IV, Every Other Week) | Change From Baseline to 12 Months in Normalized Liver Volume (Percent Body Weight) for Each Treatment Group (Measured by Magnetic Resonance Imaging (MRI) | -0.84 Percent body weight |
Secondary
Change From Baseline to 12 Months in Normalized Spleen Volume (Percent Body Weight) for Each Treatment Group (Measured by Magnetic Resonance Imaging (MRI))
12 patients in the 60 U/kg group and 13 patients in the 45 U/kg group were analyzed for efficacy in the intent to treat (ITT) population. Spleen Volume has been normalized for percent of body weight for each treatment arm. Spleen size relative to body weight = (Spleen volume \[cc\]/Body weight \[kg\])\*100
Time frame: Week 51
Population: 12 patients in the 60 U/kg group and 13 patients in the 45 U/kg group were analyzed for efficacy in the intent to treat (ITT) population.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| VPRIV® (60 U/kg, IV, Every Other Week) | Change From Baseline to 12 Months in Normalized Spleen Volume (Percent Body Weight) for Each Treatment Group (Measured by Magnetic Resonance Imaging (MRI)) | -1.87 Percent body weight |
| VPRIV® (60 U/kg, IV, Every Other Week) | Change From Baseline to 12 Months in Normalized Spleen Volume (Percent Body Weight) for Each Treatment Group (Measured by Magnetic Resonance Imaging (MRI)) | -1.92 Percent body weight |
Secondary
Change From Baseline to 12 Months in Platelet Counts for Each Treatment Group.
intent to treat (ITT) Population
Time frame: Week 53
Population: 12 patients in the 60 U/kg group and 13 patients in the 45 U/kg group were analyzed for efficacy in the intent to treat (ITT) population.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| VPRIV® (60 U/kg, IV, Every Other Week) | Change From Baseline to 12 Months in Platelet Counts for Each Treatment Group. | 40.92 x10^9/L |
| VPRIV® (60 U/kg, IV, Every Other Week) | Change From Baseline to 12 Months in Platelet Counts for Each Treatment Group. | 50.88 x10^9/L |
Secondary
Percent Change From Baseline to 12 Months in Chemokine (C-C Motif) Ligand 18 (CCL18)
Time frame: Week 53
Population: 12 patients in the 60 U/kg group and 13 patients in the 45 U/kg group were analyzed.
| Arm | Measure | Value (NUMBER) | Dispersion |
|---|---|---|---|
| VPRIV® (60 U/kg, IV, Every Other Week) | Percent Change From Baseline to 12 Months in Chemokine (C-C Motif) Ligand 18 (CCL18) | -46.76 Percent | 7.623 |
| VPRIV® (60 U/kg, IV, Every Other Week) | Percent Change From Baseline to 12 Months in Chemokine (C-C Motif) Ligand 18 (CCL18) | -66.02 Percent | 5.358 |
Secondary
Percent Change From Baseline to 12 Months in Plasma Chitotriosidase for Each Treatment Group
Percent Change from Baseline to Weeks 53 by Randomized velaglucerase alfa Treatment Group - Subset of intent to treat (ITT) Population who were wild type homozygous for chitotriosidase.
Time frame: Week 53
Population: 2 patients in the 60 U/kg group and 7 patients in the 45 U/kg group who were wild type for the chitotriosidase mutation were analyzed; remaining patients were deficient in chitotriosidase activity.
| Arm | Measure | Value (NUMBER) | Dispersion |
|---|---|---|---|
| VPRIV® (60 U/kg, IV, Every Other Week) | Percent Change From Baseline to 12 Months in Plasma Chitotriosidase for Each Treatment Group | -61.16 Percent | 7.768 |
| VPRIV® (60 U/kg, IV, Every Other Week) | Percent Change From Baseline to 12 Months in Plasma Chitotriosidase for Each Treatment Group | -69.65 Percent | 17.65 |