Gaucher Disease
Conditions
Keywords
Acid beta-glucocerebrosidase, human, glucocerebrosidase, Gaucher disease, Enzyme Replacement Therapy, D-glucosyl-N-acylsphingosine glucohydrolase, glucosylceramidase, gene activation, beta-glucocerebrosidase
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 study is to evaluate the safety and efficacy of every other week dosing of GA-GCB (velaglucerase alfa) in participants with type 1 Gaucher disease who were previously treated with imiglucerase.
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 safety of GA-GCB in men, women, and children with Type 1 Gaucher disease who were previously treated with imiglucerase. Each participant's duration of treatment will be 12 months.
Interventions
BIOLOGICALGA-GCB (velaglucerase alfa)
15-60 U/kg, every other week via intravenous infusion
Sponsors
Shire
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
2 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Includes: * The participant 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 the participant/legal guardian is willing and able to provide written informed consent prior to initiating any study-related procedures * The participant has received consistent treatment with imiglucerase at a dose ≤ 60 U/kg and ≥ 15 U/kg every other week for a minimum of 30 consecutive months. Participants who are anti-imiglucerase antibody positive will be allowed to enter this study * The participant is at least 2 years of age * Female participants of child-bearing potential agree to use a medically acceptable method of contraception. Male participants must agree to use a medically acceptable method of birth control * Participant must be sufficiently co-operative to participate in the study as judged by the Investigator.
Exclusion criteria
Includes: * The participant has type 2 or 3 Gaucher disease or is suspected of having type 3 Gaucher disease * The participant has received treatment with any investigational drug or device within the 30 days prior to study entry; such use during the study is not permitted * Participant is HIV positive * Participant is hepatitis B/C positive * The participant presents with sustained iron, folic acid and/or vitamin B12 deficiency-related anemia during Screening * The participant, participant's parent(s), or participant's legal guardian(s) is/are unable to understand the nature, scope, and possible consequences of the study * The participant has a significant comorbidity that might affect study data or confound the study results * The participant is unable to comply with the protocol or is otherwise unlikely to complete the study, as determined by the Investigator * The participant has experienced an anaphylactic/anaphylactoid reaction during treatment with imiglucerase * The participant has received miglustat during the 6 months prior to study enrollment * The participant has an active, clinically significant spleen infarction * The participant has active, progressive bone necrosis * The participant is a pregnant and/or lactating female
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Participants Who Experienced at Least One Adverse Event | Week 53 | Safety was assessed throughout the study by assessments including adverse events, concomitant medication use, and vital signs. Additional safety assessments, including 12-lead ECGs, physical examinations, clinical laboratory tests and determination of the presence of anti-velaglucerase alfa antibodies. Refer to Adverse event section for further details. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline to Week 53 in Hemoglobin Concentration | Week 53 | — |
| Percent Change From Baseline to Week 53 in Platelet Count | Week 53 | — |
| Percent Change From Baseline to Week 51 in Normalized Liver Volume | Week 51 | Liver volume has been normalized for percentage (%) of body weight. Liver size relative to body weight= (Liver volume \[cc\]/Body weight \[kg\])\*100 |
| Percent Change From Baseline to Week 51 in Normalized Spleen Volume | Week 51 | Spleen volume has been normalized for percentage (%) of body weight. Spleen size relative to body weight= (Spleen volume \[cc\]/Body weight \[kg\])\*100 |
Countries
Israel, Poland, Spain, United Kingdom, United States
Participant flow
Recruitment details
The first participant was enrolled on 25 July 2007 and the last participant completed on 26 June 2009. Participants received the same dose of velaglucerase alfa (GA-GCB) as their previous dose of imiglucerase (range- \</= 60 Unit per kilogram (U/kg) - \>/=15 U/kg) every other week via intravenous infusion.
Pre-assignment details
Participant at least 2 years old with documented diagnosis of type 1 Gaucher disease.Consistent treatment(every other week at a dose ≤/= 60 U/kg and ≥/= 15 U/kg) with imiglucerase for a minimum of 30 consecutive months;same dose during the 6 months prior to study enrollment.Minor dosing interval variance was allowed per standard clinical practice.
Participants by arm
| Arm | Count |
|---|---|
| GA-GCB (Velaglucerase Alfa) 15-60 U/kg, every other week via intravenous infusion | 40 |
| Total | 40 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 1 |
| Overall Study | Withdrawal by Subject | 1 |
Baseline characteristics
| Characteristic | GA-GCB (Velaglucerase Alfa) |
|---|---|
| Age, Categorical <=18 years | 9 Participants |
| Age, Categorical >=65 years | 4 Participants |
| Age, Categorical Between 18 and 65 years | 27 Participants |
| Age, Continuous | 35.6 years STANDARD_DEVIATION 18.37 |
| Baseline hemoglobin concentration | 13.775 gram per deciliter (g/dL) |
| Baseline liver volume | 1.90 Percent (%) body weight |
| Baseline platelet count | 162.00 10^9 per liter (10^9/L) |
| Baseline spleen volume | 0.50 Percent (%) body weight |
| Region of Enrollment Israel | 9 Participants |
| Region of Enrollment Poland | 5 Participants |
| Region of Enrollment Spain | 1 Participants |
| Region of Enrollment United Kingdom | 3 Participants |
| Region of Enrollment United States | 22 Participants |
| Sex: Female, Male Female | 22 Participants |
| Sex: Female, Male Male | 18 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 31 / 40 |
| serious Total, serious adverse events | 4 / 40 |
Outcome results
Primary
Participants Who Experienced at Least One Adverse Event
Safety was assessed throughout the study by assessments including adverse events, concomitant medication use, and vital signs. Additional safety assessments, including 12-lead ECGs, physical examinations, clinical laboratory tests and determination of the presence of anti-velaglucerase alfa antibodies. Refer to Adverse event section for further details.
Time frame: Week 53
Population: Safety population included subjects who have received at least 1 full or partial dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| GA-GCB (Velaglucerase Alfa) | Participants Who Experienced at Least One Adverse Event | 34 participants |
Secondary
Change From Baseline to Week 53 in Hemoglobin Concentration
Time frame: Week 53
Population: ITT population.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| GA-GCB (Velaglucerase Alfa) | Change From Baseline to Week 53 in Hemoglobin Concentration | -0.101 g/dL |
Secondary
Percent Change From Baseline to Week 51 in Normalized Liver Volume
Liver volume has been normalized for percentage (%) of body weight. Liver size relative to body weight= (Liver volume \[cc\]/Body weight \[kg\])\*100
Time frame: Week 51
Population: ITT population.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| GA-GCB (Velaglucerase Alfa) | Percent Change From Baseline to Week 51 in Normalized Liver Volume | -0.03 Percent (%) change |
Secondary
Percent Change From Baseline to Week 51 in Normalized Spleen Volume
Spleen volume has been normalized for percentage (%) of body weight. Spleen size relative to body weight= (Spleen volume \[cc\]/Body weight \[kg\])\*100
Time frame: Week 51
Population: ITT population. Four splenectomized participants were excluded.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| GA-GCB (Velaglucerase Alfa) | Percent Change From Baseline to Week 51 in Normalized Spleen Volume | -5.56 Percent (%) change |
Secondary
Percent Change From Baseline to Week 53 in Platelet Count
Time frame: Week 53
Population: ITT population.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| GA-GCB (Velaglucerase Alfa) | Percent Change From Baseline to Week 53 in Platelet Count | 7.04 percent (%) change |