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
The purpose of this study is to evaluate the long-term safety of every other week dosing of Gene-Activated® human glucocerebrosidase (GA-GCB, velaglucerase alfa) intravenously in 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 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 long-term safety of GA-GCB in men, women, and children with Type 1 Gaucher disease.
Interventions
BIOLOGICALVPRIV®
Intravenous infusion, every other week (EOW)
Sponsors
Shire
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
2 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. The patient has completed study TKT032 or TKT034, or study HGT-GCB-039. 2. 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. 3. Male patients must agree to use a medically acceptable method of contraception at all times during the study and report a partner's pregnancy to the investigator. 4. 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). 5. The patient must be sufficiently cooperative to participate in this clinical study as judged by the Investigator
Exclusion criteria
1. 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. 2. The patient is pregnant or lactating. 3. 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. 4. 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.). 5. 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 | Description |
|---|---|---|
| Overall Summary of Treatment Emergent Adverse Events | Baseline to termination of study | Safety was evaluated by an analysis of adverse events (AEs), concomitant medication use, clinical laboratory tests, vital signs during the infusion of study drug, physical examination, and the development of anti-velaglucerase alfa. No formal comparisons or statistical tests were applied for the safety analyses, including for differences between the groups. |
Secondary
| Measure | Time frame |
|---|---|
| Change From Baseline to 24 Months in Hemoglobin Concentration for Each Treatment Group | Baseline to 24 months |
| Change From Baseline to 24 Months in Platelet Counts for Each Treatment Group | Baseline to 24 months |
| Change From Baseline to 24 Months in Normalized Liver Volume for Each Treatment Group | Baseline to 24 months |
| Percentage Change From Baseline to 24 Months in Normalized Spleen Volume for Each Treatment Group | Baseline to 24 months |
Countries
Argentina, India, Israel, Paraguay, Poland, Russia, South Korea, Spain, Tunisia, United Kingdom, United States
Participant flow
Recruitment details
The first participant was enrolled in the study on 13 March 2008 and the last participant completed study procedures on 28 December 2012.
Pre-assignment details
2 participants who did not have type 1 Gaucher disease were withdrawn from the intent-to-treat (ITT) set as per the statistical analysis plan and removed from the long-term efficacy analyses in this study, needed to support the interpretation of the long-term efficacy results. Hence, 93 of 95 participants were included in the HGT-GCB-044 ITT set.
Participants by arm
| Arm | Count |
|---|---|
| VPRIV 60 U/kg (Parent Study VPRIV (45 U/kg)-TKT032) VPRIV 45 U/kg, IV, EOW for 51 weeks in parent study TKT032 (NCT00430625) and switched to 60 U/kg in HGT-GCB-044. | 12 |
| VPRIV 60 U/kg (Parent Study VPRIV (60 U/kg)-TKT032) VPRIV 60 U/kg, IV, EOW for 51 weeks in parent study TKT032 (NCT00430625). | 11 |
| VPRIV 60 U/kg (Parent Study VPRIV (60U/kg) HGT-GCB-039) VPRIV 60 U/kg, IV, EOW for 39 weeks in parent study HGT-GCB-039 (NCT00553631). | 16 |
| VPRIV 60 U/kg (Parent Study-imiglucerase (60 U/kg) HGT-GCB-039 Imiglucerase 60 U/kg, IV, EOW for 39 weeks in parent study HGT-GCB-039 (NCT00553631) and switched 60 U/kg VPRIV in HGT-GCB-044 | 16 |
| VPRIV 15-60 U/kg (Parent Study VPRIV (15-60 U/kg) TKT034) VPRIV 15- 60 U/kg, IV, EOW for 51 weeks in parent study TKT034 (NCT00478647). Participants continued to receive VPRIV at a dose of 15-60 U/kg throughout participation in HGT-GCB-044 | 38 |
| Total | 93 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 |
|---|---|---|---|---|---|---|
| Overall Study | Death | 0 | 0 | 0 | 1 | 0 |
| Overall Study | Refusal Of Required DiagnosticEvaluation | 0 | 0 | 1 | 0 | 0 |
| Overall Study | Termination Of Study By Sponsor | 12 | 6 | 10 | 6 | 6 |
| Overall Study | Withdrawal Of Consent | 0 | 0 | 0 | 2 | 2 |
Baseline characteristics
| Characteristic | VPRIV 60 U/kg (Parent Study VPRIV (45 U/kg)-TKT032) | VPRIV 60 U/kg (Parent Study VPRIV (60 U/kg)-TKT032) | VPRIV 60 U/kg (Parent Study VPRIV (60U/kg) HGT-GCB-039) | VPRIV 60 U/kg (Parent Study-imiglucerase (60 U/kg) HGT-GCB-039 | VPRIV 15-60 U/kg (Parent Study VPRIV (15-60 U/kg) TKT034) | Total |
|---|---|---|---|---|---|---|
| Age, Continuous | 32.5 Years STANDARD_DEVIATION 16.75 | 22 Years STANDARD_DEVIATION 11.08 | 32.9 Years STANDARD_DEVIATION 16.14 | 25 Years STANDARD_DEVIATION 17.33 | 34.3 Years STANDARD_DEVIATION 17.94 | 31.4 Years STANDARD_DEVIATION 17.15 |
| Age, Customized At least 18 years | 2 Participants | 3 Participants | 3 Participants | 5 Participants | 9 Participants | 22 Participants |
| Age, Customized Between 18 and 65 years | 10 Participants | 8 Participants | 13 Participants | 11 Participants | 26 Participants | 68 Participants |
| Age, Customized Greater than or equal to 65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 3 Participants | 3 Participants |
| Baseline hemoglobin concentration per treatment group | 10.68 gram per deciliter | 10.68 gram per deciliter | 11.56 gram per deciliter | 10.58 gram per deciliter | 13.82 gram per deciliter | 12.09 gram per deciliter |
| Baseline liver volume per treatment group | 1.64 Percent (%) body weight | 1.63 Percent (%) body weight | 1.59 Percent (%) body weight | 1.68 Percent (%) body weight | 0.82 Percent (%) body weight | 1.302 Percent (%) body weight |
| Baseline platelet counts per treatment group | 69.3 x10^9/L | 79.4 x10^9/L | 160.1 x10^9/L | 186.3 x10^9/L | 165.4 x10^9/L | 144.81 x10^9/L |
| Baseline Spleen volume per treatment group | 23.08 Multiple of Normal | 18.48 Multiple of Normal | 12.69 Multiple of Normal | 23.52 Multiple of Normal | 4.1 Multiple of Normal | 13.07 Multiple of Normal |
| Sex: Female, Male Female | 7 Participants | 6 Participants | 8 Participants | 7 Participants | 18 Participants | 46 Participants |
| Sex: Female, Male Male | 5 Participants | 5 Participants | 8 Participants | 9 Participants | 20 Participants | 47 Participants |
| Splenectomy status No | 12 Participants | 11 Participants | 7 Participants | 6 Participants | 35 Participants | 71 Participants |
| Splenectomy status Yes | 0 Participants | 0 Participants | 9 Participants | 10 Participants | 3 Participants | 22 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 | 35 / 38 | 35 / 41 | 15 / 16 |
| serious Total, serious adverse events | 6 / 38 | 6 / 41 | 4 / 16 |
Outcome results
Primary
Overall Summary of Treatment Emergent Adverse Events
Safety was evaluated by an analysis of adverse events (AEs), concomitant medication use, clinical laboratory tests, vital signs during the infusion of study drug, physical examination, and the development of anti-velaglucerase alfa. No formal comparisons or statistical tests were applied for the safety analyses, including for differences between the groups.
Time frame: Baseline to termination of study
Population: All participants who received at least 1 infusion (full or partial) of study drug were evaluated for safety (ie, were included in the safety population). There were 95 participants in the safety population.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| VPRIV 60 U/kg(Parent Study VPRIV(45 or 60 U/kg) TKT032,GCB039) | Overall Summary of Treatment Emergent Adverse Events | Experienced at least 1 drug-related AE | 9 Participants |
| VPRIV 60 U/kg(Parent Study VPRIV(45 or 60 U/kg) TKT032,GCB039) | Overall Summary of Treatment Emergent Adverse Events | Experienced at least 1 Life-threatening AE | 0 Participants |
| VPRIV 60 U/kg(Parent Study VPRIV(45 or 60 U/kg) TKT032,GCB039) | Overall Summary of Treatment Emergent Adverse Events | Experienced at least 1 drug-related Life-threateni | 0 Participants |
| VPRIV 60 U/kg(Parent Study VPRIV(45 or 60 U/kg) TKT032,GCB039) | Overall Summary of Treatment Emergent Adverse Events | Experienced at least 1 infusion-related AE | 5 Participants |
| VPRIV 60 U/kg(Parent Study VPRIV(45 or 60 U/kg) TKT032,GCB039) | Overall Summary of Treatment Emergent Adverse Events | Experienced at least 1 drug-related serious AE | 0 Participants |
| VPRIV 60 U/kg(Parent Study VPRIV(45 or 60 U/kg) TKT032,GCB039) | Overall Summary of Treatment Emergent Adverse Events | Experienced at least 1 drug-related severe AE | 0 Participants |
| VPRIV 60 U/kg(Parent Study VPRIV(45 or 60 U/kg) TKT032,GCB039) | Overall Summary of Treatment Emergent Adverse Events | Experienced at least 1 severe AE | 4 Participants |
| VPRIV 60 U/kg(Parent Study VPRIV(45 or 60 U/kg) TKT032,GCB039) | Overall Summary of Treatment Emergent Adverse Events | Deaths | 0 Participants |
| VPRIV 60 U/kg(Parent Study VPRIV(45 or 60 U/kg) TKT032,GCB039) | Overall Summary of Treatment Emergent Adverse Events | Experienced no AEs | 3 Participants |
| VPRIV 60 U/kg(Parent Study VPRIV(45 or 60 U/kg) TKT032,GCB039) | Overall Summary of Treatment Emergent Adverse Events | Discontinued due to an AE | 0 Participants |
| VPRIV 60 U/kg(Parent Study VPRIV(45 or 60 U/kg) TKT032,GCB039) | Overall Summary of Treatment Emergent Adverse Events | Experienced at least 1 serious AE | 6 Participants |
| VPRIV 60 U/kg(Parent Study VPRIV(45 or 60 U/kg) TKT032,GCB039) | Overall Summary of Treatment Emergent Adverse Events | Experienced at least 1 AE | 38 Participants |
| VPRIV 60 U/kg (Parent Study-imiglucerase (60 U/kg)HGT-GCB-039) | Overall Summary of Treatment Emergent Adverse Events | Experienced at least 1 AE | 15 Participants |
| VPRIV 60 U/kg (Parent Study-imiglucerase (60 U/kg)HGT-GCB-039) | Overall Summary of Treatment Emergent Adverse Events | Experienced at least 1 Life-threatening AE | 0 Participants |
| VPRIV 60 U/kg (Parent Study-imiglucerase (60 U/kg)HGT-GCB-039) | Overall Summary of Treatment Emergent Adverse Events | Discontinued due to an AE | 0 Participants |
| VPRIV 60 U/kg (Parent Study-imiglucerase (60 U/kg)HGT-GCB-039) | Overall Summary of Treatment Emergent Adverse Events | Deaths | 1 Participants |
| VPRIV 60 U/kg (Parent Study-imiglucerase (60 U/kg)HGT-GCB-039) | Overall Summary of Treatment Emergent Adverse Events | Experienced no AEs | 1 Participants |
| VPRIV 60 U/kg (Parent Study-imiglucerase (60 U/kg)HGT-GCB-039) | Overall Summary of Treatment Emergent Adverse Events | Experienced at least 1 drug-related AE | 7 Participants |
| VPRIV 60 U/kg (Parent Study-imiglucerase (60 U/kg)HGT-GCB-039) | Overall Summary of Treatment Emergent Adverse Events | Experienced at least 1 infusion-related AE | 1 Participants |
| VPRIV 60 U/kg (Parent Study-imiglucerase (60 U/kg)HGT-GCB-039) | Overall Summary of Treatment Emergent Adverse Events | Experienced at least 1 severe AE | 3 Participants |
| VPRIV 60 U/kg (Parent Study-imiglucerase (60 U/kg)HGT-GCB-039) | Overall Summary of Treatment Emergent Adverse Events | Experienced at least 1 drug-related severe AE | 0 Participants |
| VPRIV 60 U/kg (Parent Study-imiglucerase (60 U/kg)HGT-GCB-039) | Overall Summary of Treatment Emergent Adverse Events | Experienced at least 1 drug-related Life-threateni | 0 Participants |
| VPRIV 60 U/kg (Parent Study-imiglucerase (60 U/kg)HGT-GCB-039) | Overall Summary of Treatment Emergent Adverse Events | Experienced at least 1 serious AE | 4 Participants |
| VPRIV 60 U/kg (Parent Study-imiglucerase (60 U/kg)HGT-GCB-039) | Overall Summary of Treatment Emergent Adverse Events | Experienced at least 1 drug-related serious AE | 0 Participants |
| VPRIV 15-60 U/kg (Parent Study VPRIV (15-60 U/kg) TKT034) | Overall Summary of Treatment Emergent Adverse Events | Experienced at least 1 drug-related AE | 8 Participants |
| VPRIV 15-60 U/kg (Parent Study VPRIV (15-60 U/kg) TKT034) | Overall Summary of Treatment Emergent Adverse Events | Experienced at least 1 Life-threatening AE | 0 Participants |
| VPRIV 15-60 U/kg (Parent Study VPRIV (15-60 U/kg) TKT034) | Overall Summary of Treatment Emergent Adverse Events | Experienced at least 1 drug-related Life-threateni | 0 Participants |
| VPRIV 15-60 U/kg (Parent Study VPRIV (15-60 U/kg) TKT034) | Overall Summary of Treatment Emergent Adverse Events | Experienced no AEs | 3 Participants |
| VPRIV 15-60 U/kg (Parent Study VPRIV (15-60 U/kg) TKT034) | Overall Summary of Treatment Emergent Adverse Events | Experienced at least 1 AE | 35 Participants |
| VPRIV 15-60 U/kg (Parent Study VPRIV (15-60 U/kg) TKT034) | Overall Summary of Treatment Emergent Adverse Events | Experienced at least 1 serious AE | 6 Participants |
| VPRIV 15-60 U/kg (Parent Study VPRIV (15-60 U/kg) TKT034) | Overall Summary of Treatment Emergent Adverse Events | Discontinued due to an AE | 0 Participants |
| VPRIV 15-60 U/kg (Parent Study VPRIV (15-60 U/kg) TKT034) | Overall Summary of Treatment Emergent Adverse Events | Deaths | 0 Participants |
| VPRIV 15-60 U/kg (Parent Study VPRIV (15-60 U/kg) TKT034) | Overall Summary of Treatment Emergent Adverse Events | Experienced at least 1 severe AE | 4 Participants |
| VPRIV 15-60 U/kg (Parent Study VPRIV (15-60 U/kg) TKT034) | Overall Summary of Treatment Emergent Adverse Events | Experienced at least 1 infusion-related AE | 5 Participants |
| VPRIV 15-60 U/kg (Parent Study VPRIV (15-60 U/kg) TKT034) | Overall Summary of Treatment Emergent Adverse Events | Experienced at least 1 drug-related serious AE | 0 Participants |
| VPRIV 15-60 U/kg (Parent Study VPRIV (15-60 U/kg) TKT034) | Overall Summary of Treatment Emergent Adverse Events | Experienced at least 1 drug-related severe AE | 0 Participants |
Secondary
Change From Baseline to 24 Months in Hemoglobin Concentration for Each Treatment Group
Time frame: Baseline to 24 months
| Arm | Measure | Value (MEAN) |
|---|---|---|
| VPRIV 60 U/kg(Parent Study VPRIV(45 or 60 U/kg) TKT032,GCB039) | Change From Baseline to 24 Months in Hemoglobin Concentration for Each Treatment Group | 2.75 (g/dL) |
| VPRIV 60 U/kg (Parent Study-imiglucerase (60 U/kg)HGT-GCB-039) | Change From Baseline to 24 Months in Hemoglobin Concentration for Each Treatment Group | 2.00 (g/dL) |
| VPRIV 15-60 U/kg (Parent Study VPRIV (15-60 U/kg) TKT034) | Change From Baseline to 24 Months in Hemoglobin Concentration for Each Treatment Group | -0.05 (g/dL) |
Secondary
Change From Baseline to 24 Months in Normalized Liver Volume for Each Treatment Group
Time frame: Baseline to 24 months
| Arm | Measure | Value (MEAN) |
|---|---|---|
| VPRIV 60 U/kg(Parent Study VPRIV(45 or 60 U/kg) TKT032,GCB039) | Change From Baseline to 24 Months in Normalized Liver Volume for Each Treatment Group | -1.206 % Body weight |
| VPRIV 60 U/kg (Parent Study-imiglucerase (60 U/kg)HGT-GCB-039) | Change From Baseline to 24 Months in Normalized Liver Volume for Each Treatment Group | -1.688 % Body weight |
| VPRIV 15-60 U/kg (Parent Study VPRIV (15-60 U/kg) TKT034) | Change From Baseline to 24 Months in Normalized Liver Volume for Each Treatment Group | -0.026 % Body weight |
Secondary
Change From Baseline to 24 Months in Platelet Counts for Each Treatment Group
Time frame: Baseline to 24 months
| Arm | Measure | Value (MEAN) |
|---|---|---|
| VPRIV 60 U/kg(Parent Study VPRIV(45 or 60 U/kg) TKT032,GCB039) | Change From Baseline to 24 Months in Platelet Counts for Each Treatment Group | 87.85 (10^9/L) |
| VPRIV 60 U/kg (Parent Study-imiglucerase (60 U/kg)HGT-GCB-039) | Change From Baseline to 24 Months in Platelet Counts for Each Treatment Group | 160.94 (10^9/L) |
| VPRIV 15-60 U/kg (Parent Study VPRIV (15-60 U/kg) TKT034) | Change From Baseline to 24 Months in Platelet Counts for Each Treatment Group | 9.03 (10^9/L) |
Secondary
Percentage Change From Baseline to 24 Months in Normalized Spleen Volume for Each Treatment Group
Time frame: Baseline to 24 months
| Arm | Measure | Value (MEAN) |
|---|---|---|
| VPRIV 60 U/kg(Parent Study VPRIV(45 or 60 U/kg) TKT032,GCB039) | Percentage Change From Baseline to 24 Months in Normalized Spleen Volume for Each Treatment Group | -64.49 Precent (%) change |
| VPRIV 60 U/kg (Parent Study-imiglucerase (60 U/kg)HGT-GCB-039) | Percentage Change From Baseline to 24 Months in Normalized Spleen Volume for Each Treatment Group | -63.82 Precent (%) change |
| VPRIV 15-60 U/kg (Parent Study VPRIV (15-60 U/kg) TKT034) | Percentage Change From Baseline to 24 Months in Normalized Spleen Volume for Each Treatment Group | -8.04 Precent (%) change |