Gaucher Disease Type 1
Conditions
Keywords
enzyme replacement therapy, Type 1 Gaucher Disease, miglustat
Brief summary
Although miglustat has been approved as a treatment for mild to moderate type 1 Gaucher disease in patients who are unsuitable for enzyme replacement therapy (ERT), more data are required to establish the long term efficacy, safety and tolerability of miglustat in maintaining diseases stability after a switch from ERT.
Interventions
DRUGMiglustat
Oral capsules containing miglustat 100 mg, administered three times daily (t.i.d.)
Sponsors
Actelion
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Males or females aged 18 years or older 2. Type 1 Gaucher disease, diagnosed by glucocerebrosidase assay or molecular analysis of the glucocerebrosidase gene. 3. Treatment with ERT for at least 3 years, with a stable dose regimen for at least the last 6 months. 4. Clinically and biologically stable disease for the previous 2 years, with at least 2 time points assessments (including baseline as one potential time point), defined as: * Stable organomegaly (assessed by magnetic resonance imaging (MRI) or computed tomography (CT)): * Liver volume within 10% of the mean. * Spleen volume within 10% of the mean. * Free of progressive symptomatic documented bone disease. * Hemoglobin levels \> 11g/dl * Mean platelet count \> 100x10\^9 /l. * Chitotriosidase activity within 20% of the mean. * If chitotriosidase is not available (in the case of chitotriosidase deficiency, or if it was not determined), other relevant biomarkers (e.g., angiotensin converting enzyme (ACE), tartrate resistant acid phosphatase (TRAP) and ferritin) could be considered. 5. Written informed consent.
Exclusion criteria
1. History or evidence of oculomotor gaze palsy, ataxia or other clinical manifestations typically associated with neuronopathic type 3 Gaucher disease. 2. Not ambulant patients, or with progressive symptomatic documented bone disease. 3. Splenectomy before 18 years of age for splenomegaly and/or thrombocytopenia. 4. Peripheral polyneuropathy (not mononeuropathy) documented with both clinical signs and symptoms, and electrodiagnostic (EDX). 5. Patients (males and females) who do not agree to use reliable contraception throughout the study and for 3 months after cessation of miglustat treatment. 6. Female patients who are pregnant or breast feeding, or without pregnancy test prior to Day 1. 7. History of significant lactose intolerance. 8. Clinically significant diarrhea (\>3 liquid stools per day for \>7 days) without definable cause within 6 months prior to Day 1, or a history of clinically relevant gastrointestinal disorders. 9. History of cataracts or known increased risk of cataract formation. 10. Severe renal impairment i.e., with a creatinine clearance \<30 ml/min/1.73m\^2 11. Concomitant active medical condition such as human immunodeficiency virus (HIV) or hepatitis B/C that would render patients unsuitable for study. 12. Previous treatment with miglustat.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Liver Volume at Baseline and at End of Treatment | Baseline and end of treatment (Month 24) | Liver volume was assessed at baseline and end of treatment by magnetic resonance imaging. Imputation methods for patients with missing values at Month 24 were applied as follows: if a patient had at least 640 days of treatment with the study drug, the last observation that was not more than 2 days after the end of treatment was carried forward. If a patient had discontinued study drug before Day 640, the 'worst' within-patient value not more than 2 days after the end of treatment was used to impute the missing value. |
| Mean Within-patient Percent Change From Baseline in Liver Volume | End of treatment (Month 24) | Liver volume was assessed at baseline and end of treatment by magnetic resonance imaging. Imputation methods for patients with missing values at Month 24 were applied as follows: if a patient had at least 640 days of treatment with the study drug, the last observation that was not more than 2 days after the end of treatment was carried forward. If a patient had discontinued study drug before Day 640, the 'worst' within-patient value not more than 2 days after the end of treatment was used to impute the missing value. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Spleen Volume at Baseline and End of Treatment | Baseline and end of treatment (Month 24) | Spleen volume was assessed at baseline and end of treatment by magnetic resonance imaging. Imputation methods for patients with missing values at Month 24 were applied as follows: if a patient had at least 640 days of treatment with the study drug, the last observation that was not more than 2 days after the end of treatment was carried forward. If a patient had discontinued study drug before Day 640, the 'worst' within-patient value not more than 2 days after the end of treatment was used to impute the missing value. |
| Mean Percent Change From Baseline in Spleen Volume | End of treatment (Month 24) | Spleen volume was assessed at baseline and end of treatment by magnetic resonance imaging. Imputation methods for patients with missing values at Month 24 were applied as follows: if a patient had at least 640 days of treatment with the study drug, the last observation that was not more than 2 days after the end of treatment was carried forward. If a patient had discontinued study drug before Day 640, the 'worst' within-patient value not more than 2 days after the end of treatment was used to impute the missing value. |
Participant flow
Recruitment details
Patients were enrolled at 16 centers in 10 countries (Australia, Brazil, Canada, Czech Republic, France, Netherlands , Spain, Taiwan, UK, and USA. The first patient, first visit was 21 February 2006 and the last patient, last visit was 22 June 2010.
Participants by arm
| Arm | Count |
|---|---|
| Miglustat Oral administration of miglustat 100 mg t.i.d. for a period of 2 years | 42 |
| Total | 42 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | administrative reason | 1 |
| Overall Study | withdrawal of subject's consent | 7 |
Baseline characteristics
| Characteristic | Miglustat |
|---|---|
| Age, Continuous | 45.1 years STANDARD_DEVIATION 12.7 |
| Age, Customized Between 22 and 70 years | 42 participants |
| Region of Enrollment Australia | 3 participants |
| Region of Enrollment Brazil | 1 participants |
| Region of Enrollment Canada | 5 participants |
| Region of Enrollment Czech Republic | 2 participants |
| Region of Enrollment France | 1 participants |
| Region of Enrollment Netherlands | 3 participants |
| Region of Enrollment Spain | 2 participants |
| Region of Enrollment Taiwan | 1 participants |
| Region of Enrollment United Kingdom | 6 participants |
| Region of Enrollment United States | 18 participants |
| Sex: Female, Male Female | 20 Participants |
| Sex: Female, Male Male | 22 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 40 / 42 |
| serious Total, serious adverse events | 5 / 42 |
Outcome results
Primary
Liver Volume at Baseline and at End of Treatment
Liver volume was assessed at baseline and end of treatment by magnetic resonance imaging. Imputation methods for patients with missing values at Month 24 were applied as follows: if a patient had at least 640 days of treatment with the study drug, the last observation that was not more than 2 days after the end of treatment was carried forward. If a patient had discontinued study drug before Day 640, the 'worst' within-patient value not more than 2 days after the end of treatment was used to impute the missing value.
Time frame: Baseline and end of treatment (Month 24)
Population: One patient was excluded from analysis as the baseline liver volume not available
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Miglustat | Liver Volume at Baseline and at End of Treatment | Baseline | 1774.6 cm^3 | Standard Deviation 484.07 |
| Miglustat | Liver Volume at Baseline and at End of Treatment | End of treatment | 1727.1 cm^3 | Standard Deviation 381.73 |
Primary
Mean Within-patient Percent Change From Baseline in Liver Volume
Liver volume was assessed at baseline and end of treatment by magnetic resonance imaging. Imputation methods for patients with missing values at Month 24 were applied as follows: if a patient had at least 640 days of treatment with the study drug, the last observation that was not more than 2 days after the end of treatment was carried forward. If a patient had discontinued study drug before Day 640, the 'worst' within-patient value not more than 2 days after the end of treatment was used to impute the missing value.
Time frame: End of treatment (Month 24)
Population: One patient was excluded from analysis as the baseline liver volume not available
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Miglustat | Mean Within-patient Percent Change From Baseline in Liver Volume | -1.1 Percentage change | Standard Deviation 13.75 |
Secondary
Mean Percent Change From Baseline in Spleen Volume
Spleen volume was assessed at baseline and end of treatment by magnetic resonance imaging. Imputation methods for patients with missing values at Month 24 were applied as follows: if a patient had at least 640 days of treatment with the study drug, the last observation that was not more than 2 days after the end of treatment was carried forward. If a patient had discontinued study drug before Day 640, the 'worst' within-patient value not more than 2 days after the end of treatment was used to impute the missing value.
Time frame: End of treatment (Month 24)
Population: The analysis was performed on those non-splenectomized patients who had a post-baseline assessment of spleen volume while on treatment with miglustat
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Miglustat | Mean Percent Change From Baseline in Spleen Volume | 21.1 Percentage change | Standard Deviation 25.37 |
Secondary
Spleen Volume at Baseline and End of Treatment
Spleen volume was assessed at baseline and end of treatment by magnetic resonance imaging. Imputation methods for patients with missing values at Month 24 were applied as follows: if a patient had at least 640 days of treatment with the study drug, the last observation that was not more than 2 days after the end of treatment was carried forward. If a patient had discontinued study drug before Day 640, the 'worst' within-patient value not more than 2 days after the end of treatment was used to impute the missing value.
Time frame: Baseline and end of treatment (Month 24)
Population: The analysis was performed on those non-splenectomized patients who had a post-baseline assessment of spleen volume while on treatment with miglustat
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Miglustat | Spleen Volume at Baseline and End of Treatment | Baseline | 509.8 cm^3 | Standard Deviation 371.77 |
| Miglustat | Spleen Volume at Baseline and End of Treatment | End of treatment | 611.9 cm^3 | Standard Deviation 442.44 |