A Study of Eliglustat Tartrate (Genz-112638) in Patients With Gaucher Disease Who Have Reached Therapeutic Goals With Enzyme Replacement Therapy (ENCORE)

Study Overview
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Brief Summary
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This Phase 3 study was designed to confirm the efficacy and safety of eliglustat tartrate (Genz-112638) in participants with Gaucher disease type 1 who had reached therapeutic goals with enzyme replacement therapy (ERT).

Detailed Description
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Gaucher disease is characterized by lysosomal accumulation of glucosylceramide due to impaired glucosylceramide hydrolysis. Gaucher disease type 1, which is the most common form, accounts for greater than (>) 90% of cases and does not involve the central nervous system (CNS). Typical manifestations of Gaucher disease type 1 include splenomegaly, hepatomegaly, thrombocytopenia, anemia, bone disease, and decreased quality of life. The disease manifestations are caused by the accumulation of glucosylceramide (storage material) in macrophages (called Gaucher cells) which have infiltrated the spleen and liver as well as other tissues. Eliglustat tartrate is a small molecule drug 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 PK of eliglustat tartrate in adult participants with Gaucher disease type 1 who had been stabilized on ERT.

Official Title
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A Phase 3, Randomized, Multi-Center, Multi-National, Open-Label, Active Comparator Study to Evaluate the Efficacy and Safety of Genz-112638 in Patients With Gaucher Disease Type 1 Who Have Reached Therapeutic Goals With Enzyme Replacement Therapy (ENCORE)

Conditions
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Gaucher Disease, Type 1

Intervention / Treatment
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* Drug: Eliglustat tartrate
* Drug: Imiglucerase


Participation Criteria
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Eligibility Criteria
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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 18 years old at the time of randomization The participant had a confirmed diagnosis of Gaucher disease type 1 The participant had received treatment with ERT for at least 3 years. Within the 9 months prior to randomization, the participant had received a total monthly dose of 30 to 130 Units/kilogram for at least 6 months The participant had reached Gaucher disease therapeutic goals prior to randomization Female participants of childbearing potential must have 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 had a partial or total splenectomy within 3 years prior to randomization The participant had received substrate reduction therapies for Gaucher disease within 6 months prior to randomization The participant had Gaucher disease type 2 or 3 or was suspected of having Gaucher disease type 3 The participant had any clinically significant disease, other than Gaucher disease, including cardiovascular, renal, hepatic, gastrointestinal (GI), pulmonary, neurologic, endocrine, metabolic (e.g. hypokalemia, hypomagnesemia), or psychiatric disease, other medical conditions, or serious intercurrent illnesses that may confound the study results or, in the opinion of the Investigator, may 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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Investigational<br>Eliglustat tartrate | Drug: Eliglustat tartrate<br>* Primary analysis period (PAP): Eliglustat tartrate capsule 50 milligram (mg) twice daily (BID) orally from Day 1 to Week 4 followed by eliglustat tartrate 50 mg or 100 mg capsule BID up to Week 8, and then eliglustat tartrate 50 mg or 100 mg or 150 mg capsule BID up to Week 52. Dose adjustments after Week 4 and Week 8 were based on Genz-99067 (active moiety of eliglustat tartrate in plasma) trough plasma concentrations. If Genz-99067 trough plasma concentration was less than (<) 5 nanogram per milliliter [ng/mL] next higher dose was administered whereas if Genz-99067 trough plasma concentration was greater than or equal to (>=) 5 ng/mL same dose was continued. Pharmacokinetic (PK) assessment at Week 2 and 6 were used for dose adjustment after Week 4 and Week 8, respectively. Long-term treatment period (LTTP): Participants originally randomized to eliglustat in PAP continued to receive eliglustat dose, based on their Genz 99067 plasma trough concentration at Week 6.<br>* Other names: Genz-112638;|
| Active Comparator: Imiglucerase<br> | Drug: Imiglucerase<br>* PAP: Imiglucerase intravenous infusion every other week (q2w) up to Week 52 in doses equivalent to participant's past ERT dose prior to any unanticipated treatment interruption, dose reduction, or regimen change. LTTP: Participants originally randomized to imiglucerase received eliglustat tartrate capsule 50 mg BID orally from Week 52+1 Day to Week 56 followed by eliglustat tartrate 50 mg or 100 mg capsule BID up to Week 60, and then eliglustat tartrate 50 mg or 100 mg or 150 mg capsule BID up to 5 years. The dose adjustments after Week 56 and Week 60 were based on Genz-99067 (active moiety of eliglustat tartrate in plasma) trough plasma concentrations. If Genz-99067 trough plasma concentration was <5 ng/mL the next higher dose was administered whereas if the Genz-99067 trough plasma concentration was >=5 ng/mL the same dose was continued. The PK assessment at Week 54 and Week 58 were used for dose adjustment after Week 56 and Week 60, respectively.<br>* Other names: Cerezyme®;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Who Remained Stable for 52 Weeks During the Primary Analysis Period | For a participant to be classified as stable, the participant must have remained stable in hematological parameters (hemoglobin levels and platelet counts) and organ volumes (spleen, when applicable, and liver volumes in multiples of normal [MN]). Stable hematological parameters were defined as hemoglobin level did not decrease more than (>) 1.5 gram per deciliter (g/dL) from baseline and platelet count did not decrease >25% from baseline. Stable organ volumes were defined as spleen volume (in MN) did not increase >25% from baseline, if applicable, and liver volume (in MN) did not increase >20% from baseline. | Baseline up to Week 52 | 
| Percentage of Participants Who Remained Stable Annually for 4 Years During the LTTP | For a participant to be classified as stable, the participant must have remained stable in hematological parameters (hemoglobin levels and platelet counts) and organ volumes (spleen, when applicable, and liver volumes in MN). Stable hematological parameters were defined as hemoglobin level did not decrease >1.5 g/dL from baseline and platelet count did not decrease >25% from baseline. Stable organ volumes were defined as spleen volume (in MN) did not increase >25% from baseline, if applicable, and liver volume did not increase >20% from baseline. | Week 52 up to week 208 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Total T-Scores for Bone Mineral Density | Images of the spine and bilateral femur were obtained by dual energy X-Ray absorptiometry (DXA) to determine T-score for each bone area and total bone mineral density. T-score compares participant's bone density with that of healthy young participant. The T-score bone density categories are: normal (score greater than [>]-1), osteopenia (score -2.5 to less than or equal to [<=] -1), and osteoporosis (score <= -2.5). | Baseline | 
| Absolute Change From Baseline in Total T-Scores for Bone Mineral Density at Week 52 | Images of the spine and bilateral femur were obtained by DXA to determine T-score for each bone area and total bone mineral density. T-score compares participant's bone density with that of healthy young participant. The T-score bone density categories are: normal (score >-1), osteopenia (score -2.5 to <=-1), and osteoporosis (score <= -2.5). Absolute change = T-score at Week 52 minus T-score at baseline. | Baseline, Week 52 | 
| Total Z-Scores for Bone Mineral Density | Images of the spine and bilateral femur were obtained by DXA to determine Z-score for each bone area and total bone mineral density. The Z-score bone density categories are: normal (score >-2) and below normal (score <=-2). | Baseline | 
| Absolute Change From Baseline in Total Z-Scores for Bone Mineral Density at Week 52 | Images of the spine and bilateral femur were obtained by DXA to determine Z-score for each bone area and total bone mineral density. The Z-score bone density categories are: normal (score >-2) and below normal (score <=-2). Absolute change = Z-score at Week 52 minus Z-score at baseline. | Baseline, Week 52 | 
| Hemoglobin Level |  | Baseline | 
| Absolute Change From Baseline in Hemoglobin Levels at Week 52 | Absolute change = hemoglobin level at Week 52 minus hemoglobin level at baseline. | Baseline, Week 52 | 
| Percent Change From Baseline in Platelet Counts at Week 52 | Percent change in platelet counts = ([platelet count at Week 52 minus platelet count at baseline] divided by [platelet count at baseline]) multiplied by 100. | Baseline, Week 52 | 
| Percent Change From Baseline in Spleen Volume (MN) at Week 52 | Percent change in spleen volume = ([spleen volume at Week 52 minus spleen volume at baseline] divided by [spleen volume at baseline]) multiplied by 100, where all volumes are in MN. | Baseline, Week 52 | 
| Percent Change From Baseline in Liver Volume (in MN) at Week 52 | Percent change in liver volume = ([liver volume at Week 52 minus liver volume at baseline] divided by [liver volume at baseline]) multiplied by 100, where all volumes are in multiples of normal. | Baseline, Week 52 | 
| Absolute Change From Baseline in Total T-Scores for Bone Mineral Density at Week 208 | Images of the spine and bilateral femur were obtained by DXA to determine T-score for each bone area and total bone mineral density. T-score compares participant's bone density with that of healthy young participant. The T-score bone density categories are: normal (score >-1), osteopenia (score -2.5 to <=-1), and osteoporosis (score <= -2.5). Absolute change = T-score at Week 208 minus T-score at baseline. | Baseline, Week 208 | 
| Absolute Change From Baseline in Total Z-Scores for Bone Mineral Density at Week 208 | Images of the spine and bilateral femur were obtained by DXA to determine Z-score for each bone area and total bone mineral density. The Z-score bone density categories are: normal (score >-2) and below normal (score <=-2). Absolute change = Z-score at Week 208 minus Z-score at baseline. | Baseline, Week 208 | 
| Absolute Change From Baseline in Hemoglobin Levels at Week 208 | Absolute change = hemoglobin level at Week 208 minus hemoglobin level at baseline. | Baseline, Week 208 | 
| Percent Change From Baseline in Platelet Counts at Week 208 | Percent change in platelet counts = ([platelet count at Week 208 minus platelet count at baseline] divided by [platelet count at baseline]) multiplied by 100. | Baseline, Week 208 | 
| Percent Change From Baseline in Spleen Volume (in MN) at Week 208 | Percent change in spleen volume = ([spleen volume at Week 208 minus spleen volume at baseline] divided by [spleen volume at baseline]) multiplied by 100, where all volumes are in MN. | Baseline, Week 208 | 
| Percent Change From Baseline in Liver Volume (in MN) at Week 208 | Percent change in liver volume = ([liver volume at Week 208 minus liver volume at baseline] divided by [liver volume at baseline]) multiplied by 100, where all volumes are in multiples of normal. | Baseline, Week 208 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Gaucher disease,, Genz-112638,, beta-glucosidase,, acid ß-glucosidase,, glucocerebrosidase,, glucosylceramide,, D-glucosyl-N-acylsphingosine glucohydrolase,, substrate reduction therapy