Gaucher Disease, Type 1
Conditions
Keywords
Gaucher,, beta-glucosidase,, acid ß-glucosidase,, glucocerebrosidase,, glucosylceramide,, D-glucosyl-N-acylsphingosine glucohydrolase,, substrate reduction therapy
Brief summary
This Phase 3 study was designed to confirm the efficacy and safety of eliglustat tartrate (Genz-112638) in participants with Gaucher disease Type 1.
Detailed description
Gaucher disease is characterized by lysosomal accumulation of glucosylceramide due to impaired glucosylceramide hydrolysis. Type 1 Gaucher disease, the most common form accounts for greater than (\>) 90% of cases and does not involve the central nervous system (CNS). Typical manifestations of Type 1 Gaucher disease include splenomegaly, hepatomegaly, thrombocytopenia, anemia, skeletal pathology and decreased quality of life. The disease manifestations are caused by the accumulations of glucosylceramide (storage material) in Gaucher cells which have infiltrated the spleen and liver as well as other tissue. Eliglustat tartrate is a small molecule developed as an oral therapy which acts to specifically inhibit production of this storage material in Gaucher cells. This study was designed to determine the efficacy, safety, and pharmacokinetics (PK) of eliglustat tartrate in adult participants (\>16 years) with Gaucher disease Type 1. The study consisted of 2 periods: The Double-Blind Primary Analysis Period (PAP \[Day 1 to Week 39\]) and the Long Term Treatment Period (LTTP/Open-Label Period (post-Week 39 \[Day 1 of the Open-Label Period\] through study completion).
Interventions
PAP: Eliglustat tartrate (ET) capsule 50 mg orally on Day 1 followed by ET 50 mg capsule twice daily (BID) from Day 2 to Week 4, then either ET 50 mg capsule BID (participants with Genz-99067 \[active moiety of ET in plasma\] trough plasma concentration \>=5 ng/mL) or ET 100 mg capsule BID (participants with Genz-99067 trough plasma concentration \<5 ng/mL), up to Week 39. PK assessment at Week 2 used for dose adjustment after Week 4. LTTP: Participants of the eliglustat arm in PAP who completed PAP were included in LTTP and received ET capsule 50 mg BID orally from Day 1 (post Week 39) until Week 43 followed by ET 50 mg or 100 mg capsule BID up to Week 47, then ET 50 mg or 100 mg or 150 mg capsule BID up to Week 312. Dose adjustments at Week 43 and Week 47 were based on Genz-99067 trough plasma concentrations (if trough plasma concentration \<5 ng/mL: next higher dose administered; if \>=5 ng/mL: same dose continued) at Week 41 & Week 45, respectively.
DRUGPlacebo
PAP: Matching placebo capsule once daily on Day 1 followed by matching placebo capsule BID from Day 2 through Week 39. LTTP: Participants of the placebo arm in PAP who completed PAP were included in LTTP and received eliglustat tartrate from Day 1 (post Week 39) up to Week 312. Day 1 (post Week 39) was considered as baseline for LTTP. On Day 1, participants received eliglustat tartrate capsule 50 mg BID orally until Week 43 followed by eliglustat tartrate 50 mg or 100 mg capsule BID up to Week 47, then eliglustat tartrate 50 mg or 100 mg or 150 mg capsule BID up to Week 312. Dose adjustments at Week 43 and Week 47 were based on Genz-99067 trough plasma concentrations (if trough plasma concentration \<5 ng/mL: next higher dose administered; if \>=5 ng/mL: same dose continued) at Week 41 & Week 45, respectively.
Sponsors
Genzyme, a Sanofi Company
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
16 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* The participant (and/or their parent/legal guardian) was willing and able to provide signed informed consent prior to any study-related procedures to be performed; * The participant was at least 16 years old at the time of randomization; * The participant had a confirmed diagnosis of Gaucher disease Type 1; * Female participants of childbearing potential must had a documented negative pregnancy test prior to dosing. In addition all female participants of childbearing potential must use a medically accepted form of contraception throughout the study.
Exclusion criteria
* The participant has had a partial or total splenectomy; * The participant had received pharmacological chaperones or miglustat within 6 months prior to randomization; * The participant had received enzyme replacement therapy within 9 months prior to randomization; * The participant had Type 2 or 3 Gaucher disease or was suspected of having Type 3 Gaucher disease; * The participant had any clinically significant disease, other than Gaucher disease, including cardiovascular, renal, hepatic, gastrointestinal (GI), pulmonary, neurologic, endocrine, metabolic, (for example, hypokalemia, hypomagnesemia), or psychiatric disease, other medical conditions, or serious intercurrent illness that might confound the study results, or, on the opinion of the investigator, might preclude participation in the study; * The participant had tested positive for the human immunodeficiency virus (HIV) antibody, Hepatitis C antibody, or Hepatitis B surface antigen; * The participant had received an investigational product within 30 days prior to randomization; * The participant was pregnant or lactating.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| PAP: Percent Change From Baseline in Spleen Volume (in Multiples of Normal [MN]) at Week 39 of the Primary Analysis Period With Eliglustat Tartrate Treatment as Compared to Placebo | PAP Baseline (Day 1), Week 39 | Percent change in spleen volume = (\[spleen volume at Week 39 minus spleen volume at baseline\] divided by \[spleen volume at baseline\]) multiplied by 100, where all volumes are in MN. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| PAP: Hemoglobin Level | PAP Baseline (Day 1) | — |
| PAP: Absolute Change From Baseline in Hemoglobin Level at Week 39 | PAP Baseline (Day 1), Week 39 | Absolute change = hemoglobin level at Week 39 minus hemoglobin level at baseline. |
| PAP: Percent Change From Baseline in Liver Volume (in MN) at Week 39 | PAP Baseline (Day 1), Week 39 | Percent change in liver volume = (\[liver volume at Week 39 minus liver volume at baseline\] divided by \[liver volume at baseline\]) multiplied by 100, where all volumes are in MN. |
| PAP: Percent Change From Baseline in Platelet Counts at Week 39 | PAP Baseline (Day 1), Week 39 | Percent change in platelet count = (\[platelet count at Week 39 minus platelet count at baseline\] divided by \[platelet count at baseline\]) multiplied by 100. |
| LTTP: Percent Change From Baseline in Spleen Volume (in MN) at Week 234 | PAP Baseline for Eliglustat (Originally on Eliglustat) arm, LTTP Baseline for Eliglustat (Originally on Placebo) arm, Week 234 | Percent change in spleen volume = (\[spleen volume at Week 234 minus spleen volume at baseline\] divided by \[spleen volume at baseline\]) multiplied by 100, where all volumes are in MN. Baseline values for the original placebo participants refer to Day 1 of LTTP and baseline values for the original eliglustat participants refer to the Day 1 of PAP. |
| LTTP: Absolute Change From Baseline in Hemoglobin Level at Week 234 | PAP Baseline for Eliglustat (Originally on Eliglustat) arm, LTTP Baseline for Eliglustat (Originally on Placebo) arm, Week 234 | Baseline values for the original placebo participants refer to Day 1 of LTTP and baseline values for the original eliglustat participants refer to the Day 1 of PAP. |
| LTTP: Percent Change From Baseline in Liver Volume (in MN) at Week 234 | PAP Baseline for Eliglustat (Originally on Eliglustat) arm, LTTP Baseline for Eliglustat (Originally on Placebo) arm, Week 234 | Percent change in liver volume = (\[liver volume at Week 234 minus liver volume at baseline\] divided by \[liver volume at baseline\]) multiplied by 100, where all volumes are in MN. Baseline values for the original placebo participants refer to Day 1 of LTTP and baseline values for the original eliglustat participants refer to the Day 1 of PAP. |
| LTTP: Percent Change From Baseline in Platelet Counts at Week 234 | PAP Baseline for Eliglustat (Originally on Eliglustat) arm, LTTP Baseline for Eliglustat (Originally on Placebo) arm, Week 234 | Percent change in platelet count = (\[platelet count at Week 234 minus platelet count at baseline\] divided by \[platelet count at baseline\]) multiplied by 100. Baseline values for the original placebo participants refer to Day 1 of LTTP and baseline values for the original eliglustat participants refer to the Day 1 of PAP. |
Countries
Bulgaria, Canada, Colombia, India, Israel, Lebanon, Mexico, Russia, Serbia, Tunisia, United Kingdom, United States
Participant flow
Recruitment details
A total of 72 participants were screened between 5 November 2009 and 29 July 2011, of which 32 participants were screen failure. Overall 40 participants were enrolled and the study was conducted across 18 centers in 12 countries.
Pre-assignment details
The 40 participants who met inclusion criteria received placebo or Genz-112638 (eliglustat tartrate) during 39 weeks primary analysis period (PAP). After Week 39 of the PAP, all participants who remained in the study received eliglustat tartrate in the long-term treatment period (LTTP) for up to Week 312.
Participants by arm
| Arm | Count |
|---|---|
| PAP: Eliglustat Eliglustat tartrate 50 mg capsule BID orally from Day 1 to Week 4, followed by eliglustat tartrate 50 mg or 100 mg capsule BID orally up to Week 39. | 20 |
| PAP: Placebo Matching placebo capsule once daily on Day 1 followed by matching placebo capsule BID from Day 2 through Week 39. | 20 |
| Total | 40 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| LTTP (Post-Week 39 up to Week 312) | Pregnancy | 0 | 0 | 1 | 0 |
| LTTP (Post-Week 39 up to Week 312) | Transitioned to commercial eliglustat | 0 | 0 | 2 | 5 |
| LTTP (Post-Week 39 up to Week 312) | Withdrawal by Subject | 0 | 0 | 4 | 0 |
| PAP (Up To Week 39) | Withdrawal by Subject | 1 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | PAP: Eliglustat | PAP: Placebo | Total |
|---|---|---|---|
| Age, Continuous | 31.6 years STANDARD_DEVIATION 11.55 | 32.1 years STANDARD_DEVIATION 11.26 | 31.8 years STANDARD_DEVIATION 11.26 |
| Body Mass Index (BMI) | 23.3 kilogram per square meter (kg/m^2) STANDARD_DEVIATION 2.74 | 23.4 kilogram per square meter (kg/m^2) STANDARD_DEVIATION 3.54 | 23.4 kilogram per square meter (kg/m^2) STANDARD_DEVIATION 3.13 |
| Gender Female | 12 Participants | 8 Participants | 20 Participants |
| Gender Male | 8 Participants | 12 Participants | 20 Participants |
| Height | 166.2 centimeter (cm) STANDARD_DEVIATION 9.91 | 170.0 centimeter (cm) STANDARD_DEVIATION 12.02 | 168.1 centimeter (cm) STANDARD_DEVIATION 11.05 |
| Race/Ethnicity, Customized Ethnicity: Hispanic or Latino | 2 participants | 0 participants | 2 participants |
| Race/Ethnicity, Customized Ethnicity: Not Hispanic or Latino | 18 participants | 20 participants | 38 participants |
| Race/Ethnicity, Customized Race: Asian | 1 participants | 0 participants | 1 participants |
| Race/Ethnicity, Customized Race: White | 19 participants | 20 participants | 39 participants |
| Weight | 64.8 kilogram (kg) STANDARD_DEVIATION 11.74 | 68.6 kilogram (kg) STANDARD_DEVIATION 17.17 | 66.7 kilogram (kg) STANDARD_DEVIATION 14.65 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 17 / 20 | 14 / 20 |
| serious Total, serious adverse events | 2 / 20 | 3 / 20 |
Outcome results
Primary
PAP: Percent Change From Baseline in Spleen Volume (in Multiples of Normal [MN]) at Week 39 of the Primary Analysis Period With Eliglustat Tartrate Treatment as Compared to Placebo
Percent change in spleen volume = (\[spleen volume at Week 39 minus spleen volume at baseline\] divided by \[spleen volume at baseline\]) multiplied by 100, where all volumes are in MN.
Time frame: PAP Baseline (Day 1), Week 39
Population: FAS for PAP included all participants who signed informed consent and received at least one dose of study drug (placebo or eliglustat).
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| PAP: Eliglustat | PAP: Percent Change From Baseline in Spleen Volume (in Multiples of Normal [MN]) at Week 39 of the Primary Analysis Period With Eliglustat Tartrate Treatment as Compared to Placebo | -27.77 percent change | Standard Error 2.37 |
| PAP: Placebo | PAP: Percent Change From Baseline in Spleen Volume (in Multiples of Normal [MN]) at Week 39 of the Primary Analysis Period With Eliglustat Tartrate Treatment as Compared to Placebo | 2.26 percent change | Standard Error 2.37 |
Comparison: Analysis was performed using analysis of covariance (ANCOVA) model fitted with treatment and baseline spleen severity (low spleen severity: spleen volume less than or equal to \[\<=\] 20 multiples of normal spleen volume, high spleen severity: spleen volume greater than \[\>\] 20 multiples of normal spleen volume).p-value: <0.000195% CI: [-36.82, -23.24]ANCOVA
Secondary
LTTP: Absolute Change From Baseline in Hemoglobin Level at Week 234
Baseline values for the original placebo participants refer to Day 1 of LTTP and baseline values for the original eliglustat participants refer to the Day 1 of PAP.
Time frame: PAP Baseline for Eliglustat (Originally on Eliglustat) arm, LTTP Baseline for Eliglustat (Originally on Placebo) arm, Week 234
Population: ITT population for LTTP included all participants who received at least 1 dose of eliglustat in LTTP period. Number of participants analyzed=participants evaluable for this outcome measure and had available data for baseline and Week 234 hemoglobin level assessment.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| PAP: Eliglustat | LTTP: Absolute Change From Baseline in Hemoglobin Level at Week 234 | 1.1 g/dL | Standard Deviation 0.65 |
| PAP: Placebo | LTTP: Absolute Change From Baseline in Hemoglobin Level at Week 234 | 1.9 g/dL | Standard Deviation 1.88 |
Secondary
LTTP: Percent Change From Baseline in Liver Volume (in MN) at Week 234
Percent change in liver volume = (\[liver volume at Week 234 minus liver volume at baseline\] divided by \[liver volume at baseline\]) multiplied by 100, where all volumes are in MN. Baseline values for the original placebo participants refer to Day 1 of LTTP and baseline values for the original eliglustat participants refer to the Day 1 of PAP.
Time frame: PAP Baseline for Eliglustat (Originally on Eliglustat) arm, LTTP Baseline for Eliglustat (Originally on Placebo) arm, Week 234
Population: ITT population for LTTP included all participants who received at least 1 dose of eliglustat in LTTP period. Number of participants analyzed=participants evaluable for this outcome measure and had available data for baseline and Week 234 liver volume assessment.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| PAP: Eliglustat | LTTP: Percent Change From Baseline in Liver Volume (in MN) at Week 234 | -24.3 percent change | Standard Deviation 11.21 |
| PAP: Placebo | LTTP: Percent Change From Baseline in Liver Volume (in MN) at Week 234 | -22.4 percent change | Standard Deviation 10.77 |
Secondary
LTTP: Percent Change From Baseline in Platelet Counts at Week 234
Percent change in platelet count = (\[platelet count at Week 234 minus platelet count at baseline\] divided by \[platelet count at baseline\]) multiplied by 100. Baseline values for the original placebo participants refer to Day 1 of LTTP and baseline values for the original eliglustat participants refer to the Day 1 of PAP.
Time frame: PAP Baseline for Eliglustat (Originally on Eliglustat) arm, LTTP Baseline for Eliglustat (Originally on Placebo) arm, Week 234
Population: ITT population for LTTP included all participants who received at least 1 dose of eliglustat in LTTP period. Number of participants analyzed=participants evaluable for this outcome measure and had available data for baseline and Week 234 platelet count assessment.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| PAP: Eliglustat | LTTP: Percent Change From Baseline in Platelet Counts at Week 234 | 77.3 percent change | Standard Deviation 28.17 |
| PAP: Placebo | LTTP: Percent Change From Baseline in Platelet Counts at Week 234 | 100.1 percent change | Standard Deviation 80.69 |
Secondary
LTTP: Percent Change From Baseline in Spleen Volume (in MN) at Week 234
Percent change in spleen volume = (\[spleen volume at Week 234 minus spleen volume at baseline\] divided by \[spleen volume at baseline\]) multiplied by 100, where all volumes are in MN. Baseline values for the original placebo participants refer to Day 1 of LTTP and baseline values for the original eliglustat participants refer to the Day 1 of PAP.
Time frame: PAP Baseline for Eliglustat (Originally on Eliglustat) arm, LTTP Baseline for Eliglustat (Originally on Placebo) arm, Week 234
Population: Intent-to-treat (ITT) population for LTTP included all participants who received at least 1 dose of eliglustat in LTTP period. Number of participants analyzed= participants evaluable for this outcome measure and had available data for baseline and Week 234 spleen volume assessment.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| PAP: Eliglustat | LTTP: Percent Change From Baseline in Spleen Volume (in MN) at Week 234 | -66.9 percent change | Standard Deviation 8.45 |
| PAP: Placebo | LTTP: Percent Change From Baseline in Spleen Volume (in MN) at Week 234 | -64.0 percent change | Standard Deviation 6.43 |
Secondary
PAP: Absolute Change From Baseline in Hemoglobin Level at Week 39
Absolute change = hemoglobin level at Week 39 minus hemoglobin level at baseline.
Time frame: PAP Baseline (Day 1), Week 39
Population: FAS for PAP included all participants who signed informed consent and received at least one dose of study drug (placebo or eliglustat).
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| PAP: Eliglustat | PAP: Absolute Change From Baseline in Hemoglobin Level at Week 39 | 0.69 g/dL | Standard Error 0.23 |
| PAP: Placebo | PAP: Absolute Change From Baseline in Hemoglobin Level at Week 39 | -0.54 g/dL | Standard Error 0.23 |
Secondary
PAP: Hemoglobin Level
Time frame: PAP Baseline (Day 1)
Population: FAS for PAP included all participants who signed informed consent and received at least one dose of study drug (placebo or eliglustat).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| PAP: Eliglustat | PAP: Hemoglobin Level | 12.05 gram per deciliter (g/dL) | Standard Deviation 1.816 |
| PAP: Placebo | PAP: Hemoglobin Level | 12.75 gram per deciliter (g/dL) | Standard Deviation 1.629 |
Secondary
PAP: Percent Change From Baseline in Liver Volume (in MN) at Week 39
Percent change in liver volume = (\[liver volume at Week 39 minus liver volume at baseline\] divided by \[liver volume at baseline\]) multiplied by 100, where all volumes are in MN.
Time frame: PAP Baseline (Day 1), Week 39
Population: FAS for PAP included all participants who signed informed consent and received at least one dose of study drug (placebo or eliglustat).
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| PAP: Eliglustat | PAP: Percent Change From Baseline in Liver Volume (in MN) at Week 39 | -5.20 percent change | Standard Error 1.64 |
| PAP: Placebo | PAP: Percent Change From Baseline in Liver Volume (in MN) at Week 39 | 1.44 percent change | Standard Error 1.64 |
Secondary
PAP: Percent Change From Baseline in Platelet Counts at Week 39
Percent change in platelet count = (\[platelet count at Week 39 minus platelet count at baseline\] divided by \[platelet count at baseline\]) multiplied by 100.
Time frame: PAP Baseline (Day 1), Week 39
Population: FAS for PAP included all participants who signed informed consent and received at least one dose of study drug (placebo or eliglustat).
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| PAP: Eliglustat | PAP: Percent Change From Baseline in Platelet Counts at Week 39 | 32.00 percent change | Standard Error 5.95 |
| PAP: Placebo | PAP: Percent Change From Baseline in Platelet Counts at Week 39 | -9.06 percent change | Standard Error 5.95 |