Gaucher Disease, Type 1
Conditions
Keywords
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 the deficiency of functional GCB, glucocerebroside accumulates within macrophages leading to cellular engorgement, organomegaly, and organ system dysfunction. The purpose of this non-inferiority study is to evaluate the efficacy and safety of GA-GCB (velaglucerase alfa) administered every other week in comparison to imiglucerase in treatment naive 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 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. GA-GCB (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 and safety of GA-GCB (velaglucerase alfa) in comparison to imiglucerase in men, women, and children with Type 1 Gaucher disease.
Interventions
BIOLOGICALvelaglucerase alfa
IV infusion, 60 U/kg every other week for 9 months
BIOLOGICALimiglucerase
IV infusion, 60 U/kg every other week for 9 months
Sponsors
Shire
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
2 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Includes: * The patient has a documented diagnosis and clinical manifestation of type 1 Gaucher disease * The patient is at least 2 years of age. * The patient has not received treatment for Gaucher disease (investigational products, miglustat, or imiglucerase) within 12 months prior to study entry, as documented in the patient's medical history. * Female patients of child-bearing potential must agree to use a medically acceptable method of contraception at all times during the study and must have negative results to a pregnancy test performed at the time of enrollment and as required throughout their participation in the study. Male patients must use a medically acceptable method of birth control throughout their participation in the study and must report their partner's pregnancy. * The patient, the patient's parent(s) or legal guardian(s) has provided written informed consent that has been approved by the Institutional Review Board/Independent Ethics Committee (IRB/IEC). * The patient must be sufficiently cooperative to participate in this clinical study as judged by the Investigator.
Exclusion criteria
Includes: * The patient has type 2 or 3 Gaucher disease or is suspected of having type 3 Gaucher disease. * The patient has received treatment with any non-Gaucher disease-related investigational drug or device within the 30 days prior to study entry; such use during the study is not permitted. * The patient is known to be positive for human immunodeficiency virus (HIV). * The patient is known to be positive for hepatitis B and/or C. * The 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. * The patient has a significant comorbidity(ies) that might affect study data or confound the study results (e.g., malignancies, primary biliary cirrhosis, autoimmune liver disease, etc.). * The patient is unable to comply with the protocol, e.g., has a clinically relevant medical condition making implementation of the protocol difficult, has an uncooperative attitude, is unable to return for safety evaluations, or is otherwise unlikely to complete the study, as determined by the Investigator.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Mean Change From Baseline to Month 9 in Hemoglobin (Hgb) Concentration for Each Treatment Group. | Baseline to Month 9 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline to Month 9 in Normalized Liver Volume (Percent (%) Body Weight) for Each Treatment Group. | Baseline to Month 9 | Values shown are observed change from Baseline to Month 9. Measured by Magnetic resonance imaging (MRI). Liver volume has been normalized for percent (%) body weight for each treatment arm. Liver size relative to body weight = (Liver volume \[cubic centimeter (cc)\]/Body weight \[kg\]\*1000. |
| Change From Baseline to Month 9 in Normalized Spleen Volume (Percent (%) Body Weight) for Each Treatment Group. | Baseline to Month 9 | Values shown are observed change from Baseline to month 9. Measured by Magnetic resonance imaging (MRI). Spleen volume was normalized for percent (%) of body weight for each treatment arm. Spleen size relative to body weight=(Spleen volume \[cc\]/Body weight \[kg\])\*100. |
| Change From Baseline to Month 9 in Plasma Chitotriosidase for Each Treatment Group. | Baseline to Month 9. | Values shown are observed change from Baseline to Month 9. Units of measure is defined as nanomole per milliliter per hour. |
| Change From Baseline to Month 9 in Platelet Counts for Each Treatment Group. | Baseline to Month 9 | Values shown are observed change from Baseline to Month 9. |
| Number of Participants Who Developed Antibody for Each Treatment Group. | Baseline to Month 9 | Measure type is actual number of participants who developed antibodies to treatment; GA-GCB or imiglucerase. Antibody detection was based upon serum samples collected at various time points throughout the study. Serum samples were screened using an enzyme-linked immunosorbent assay (ELISA) and positive antibody confirmation was determined using a radioimmunoprecipitation assay (RIP); positive samples were also tested for enzyme neutralizing activity. Participant samples were compared to internal assay controls (positive/negative), positive samples were determined based upon individual assay criteria. |
| Time to Response- Comparison of GA-GCB and Imiglucerase on the Earliest Time to Respond as Assessed Via Hemoglobin Concentration | Response rate at Month 9 compared to Baseline | Time to response was defined as a ≥ 1 g/dL improvement in hemoglobin levels relative to Baseline. Units (%) correlates to the percentage of participants who had a change of ≥ 1 g/dL improvement in hemoglobin levels relative to Baseline during their participation in the study. |
| Change From Baseline to Month 9 in Plasma Chemokine (C-C Motif) Ligand 18 (CCL18) for Each Treatment Group. | Baseline to Month 9 | Values shown are observed change from Baseline to Month 9. |
Countries
Argentina, India, Israel, Paraguay, Russia, Spain, Tunisia, United Kingdom, United States
Participant flow
Recruitment details
The study was conducted in multiple sites from 29 January 2008 (first participant first enrolled) to 05 May 2009 (last participant completed).
Pre-assignment details
Participants at least 2 years of age with type 1 Gaucher disease.Gaucher-disease-related anemia and at least 1 of the following: moderate splenomegaly, Gaucher-disease-related thrombocytopenia, readily palpable enlarged liver. Participants had not received treatment for Gaucher disease within 12 months prior to study entry.
Participants by arm
| Arm | Count |
|---|---|
| Gene-Activated Human Glucocerebrosidase (GA-GCB) Velaglucerase alfa 60 U/kg administered IV every other week for 39 weeks. | 17 |
| Imiglucerase Imiglucerase 60 U/kg administered IV every other week for 39 weeks. | 17 |
| Total | 34 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Lost to Follow-up | 1 | 0 |
| Overall Study | Withdrawal by Subject | 0 | 1 |
Baseline characteristics
| Characteristic | Gene-Activated Human Glucocerebrosidase (GA-GCB) | Imiglucerase | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 4 Participants | 5 Participants | 9 Participants |
| Age, Categorical >=65 years | 0 Participants | 1 Participants | 1 Participants |
| Age, Categorical Between 18 and 65 years | 13 Participants | 11 Participants | 24 Participants |
| Age, Continuous | 36 years | 27 years | 30.5 years |
| Region of Enrollment Argentina | 2 Participants | 1 Participants | 3 Participants |
| Region of Enrollment India | 4 Participants | 4 Participants | 8 Participants |
| Region of Enrollment Israel | 1 Participants | 2 Participants | 3 Participants |
| Region of Enrollment Paraguay | 3 Participants | 2 Participants | 5 Participants |
| Region of Enrollment Russian Federation | 2 Participants | 2 Participants | 4 Participants |
| Region of Enrollment Spain | 1 Participants | 2 Participants | 3 Participants |
| Region of Enrollment Tunisia | 4 Participants | 2 Participants | 6 Participants |
| Region of Enrollment United Kingdom | 0 Participants | 1 Participants | 1 Participants |
| Region of Enrollment United States | 0 Participants | 1 Participants | 1 Participants |
| Sex: Female, Male Female | 9 Participants | 9 Participants | 18 Participants |
| Sex: Female, Male Male | 8 Participants | 8 Participants | 16 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 16 / 17 | 16 / 17 |
| serious Total, serious adverse events | 3 / 17 | 0 / 17 |
Outcome results
Primary
Mean Change From Baseline to Month 9 in Hemoglobin (Hgb) Concentration for Each Treatment Group.
Time frame: Baseline to Month 9
Population: Intent-to-treat (ITT) population comprised of all randomized participants who received at least 1 full or partial dose of study drug.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Gene-Activated Human Glucocerebrosidase (GA-GCB) | Mean Change From Baseline to Month 9 in Hemoglobin (Hgb) Concentration for Each Treatment Group. | 1.624 gram per deciliter (g/dl) | Standard Error 0.223 |
| Imiglucerase | Mean Change From Baseline to Month 9 in Hemoglobin (Hgb) Concentration for Each Treatment Group. | 1.488 gram per deciliter (g/dl) | Standard Error 0.281 |
Secondary
Change From Baseline to Month 9 in Normalized Liver Volume (Percent (%) Body Weight) for Each Treatment Group.
Values shown are observed change from Baseline to Month 9. Measured by Magnetic resonance imaging (MRI). Liver volume has been normalized for percent (%) body weight for each treatment arm. Liver size relative to body weight = (Liver volume \[cubic centimeter (cc)\]/Body weight \[kg\]\*1000.
Time frame: Baseline to Month 9
Population: ITT population.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Gene-Activated Human Glucocerebrosidase (GA-GCB) | Change From Baseline to Month 9 in Normalized Liver Volume (Percent (%) Body Weight) for Each Treatment Group. | -1.31 cubic centimeter (cm^3) | Standard Error 0.347 |
| Imiglucerase | Change From Baseline to Month 9 in Normalized Liver Volume (Percent (%) Body Weight) for Each Treatment Group. | -1.10 cubic centimeter (cm^3) | Standard Error 0.182 |
Secondary
Change From Baseline to Month 9 in Normalized Spleen Volume (Percent (%) Body Weight) for Each Treatment Group.
Values shown are observed change from Baseline to month 9. Measured by Magnetic resonance imaging (MRI). Spleen volume was 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: Baseline to Month 9
Population: ITT population. Number of participants analyzed signifies participants evaluable for this outcome. Ten participants in each treatment group underwent splenectomy, and therefore, were excluded from the analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Gene-Activated Human Glucocerebrosidase (GA-GCB) | Change From Baseline to Month 9 in Normalized Spleen Volume (Percent (%) Body Weight) for Each Treatment Group. | -1.34 cm^3 | Standard Error 0.424 |
| Imiglucerase | Change From Baseline to Month 9 in Normalized Spleen Volume (Percent (%) Body Weight) for Each Treatment Group. | -2.46 cm^3 | Standard Error 0.966 |
Secondary
Change From Baseline to Month 9 in Plasma Chemokine (C-C Motif) Ligand 18 (CCL18) for Each Treatment Group.
Values shown are observed change from Baseline to Month 9.
Time frame: Baseline to Month 9
Population: ITT population.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Gene-Activated Human Glucocerebrosidase (GA-GCB) | Change From Baseline to Month 9 in Plasma Chemokine (C-C Motif) Ligand 18 (CCL18) for Each Treatment Group. | -926.2 nanogram per milliliter (ng/mL) | Standard Error 113.29 |
| Imiglucerase | Change From Baseline to Month 9 in Plasma Chemokine (C-C Motif) Ligand 18 (CCL18) for Each Treatment Group. | -1153.4 nanogram per milliliter (ng/mL) | Standard Error 269.63 |
Secondary
Change From Baseline to Month 9 in Plasma Chitotriosidase for Each Treatment Group.
Values shown are observed change from Baseline to Month 9. Units of measure is defined as nanomole per milliliter per hour.
Time frame: Baseline to Month 9.
Population: ITT population. Number of participants analyzed signifies participants evaluable for this outcome. Chitotriosidase levels were measured in 10 participants in the velaglucerase alfa group and 11 participants in the imiglucerase group.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Gene-Activated Human Glucocerebrosidase (GA-GCB) | Change From Baseline to Month 9 in Plasma Chitotriosidase for Each Treatment Group. | -34711.9 nanomole/milliliter/hour (nmol/mL/h) | Standard Error 6887.77 |
| Imiglucerase | Change From Baseline to Month 9 in Plasma Chitotriosidase for Each Treatment Group. | -35109.5 nanomole/milliliter/hour (nmol/mL/h) | Standard Error 7310.22 |
Secondary
Change From Baseline to Month 9 in Platelet Counts for Each Treatment Group.
Values shown are observed change from Baseline to Month 9.
Time frame: Baseline to Month 9
Population: ITT population.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Gene-Activated Human Glucocerebrosidase (GA-GCB) | Change From Baseline to Month 9 in Platelet Counts for Each Treatment Group. | 110.41 10^9 per liter (10^9/L) | Standard Error 17.159 |
| Imiglucerase | Change From Baseline to Month 9 in Platelet Counts for Each Treatment Group. | 144.38 10^9 per liter (10^9/L) | Standard Error 22.76 |
Secondary
Number of Participants Who Developed Antibody for Each Treatment Group.
Measure type is actual number of participants who developed antibodies to treatment; GA-GCB or imiglucerase. Antibody detection was based upon serum samples collected at various time points throughout the study. Serum samples were screened using an enzyme-linked immunosorbent assay (ELISA) and positive antibody confirmation was determined using a radioimmunoprecipitation assay (RIP); positive samples were also tested for enzyme neutralizing activity. Participant samples were compared to internal assay controls (positive/negative), positive samples were determined based upon individual assay criteria.
Time frame: Baseline to Month 9
Population: Safety population comprised of all randomized participants who received at least 1 full or partial dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Gene-Activated Human Glucocerebrosidase (GA-GCB) | Number of Participants Who Developed Antibody for Each Treatment Group. | 0 participants |
| Imiglucerase | Number of Participants Who Developed Antibody for Each Treatment Group. | 4 participants |
Secondary
Time to Response- Comparison of GA-GCB and Imiglucerase on the Earliest Time to Respond as Assessed Via Hemoglobin Concentration
Time to response was defined as a ≥ 1 g/dL improvement in hemoglobin levels relative to Baseline. Units (%) correlates to the percentage of participants who had a change of ≥ 1 g/dL improvement in hemoglobin levels relative to Baseline during their participation in the study.
Time frame: Response rate at Month 9 compared to Baseline
Population: ITT population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Gene-Activated Human Glucocerebrosidase (GA-GCB) | Time to Response- Comparison of GA-GCB and Imiglucerase on the Earliest Time to Respond as Assessed Via Hemoglobin Concentration | 92.9 Percentage of participants |
| Imiglucerase | Time to Response- Comparison of GA-GCB and Imiglucerase on the Earliest Time to Respond as Assessed Via Hemoglobin Concentration | 100 Percentage of participants |