A Study of Eliglustat Tartrate (Genz-112638) in Patients With Gaucher Disease to Evaluate Once Daily Versus Twice Daily Dosing (EDGE)

Study Overview
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Brief Summary
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The primary objective of this study was to evaluate the efficacy and safety of once daily (QD) versus twice daily (BID) dosing of eliglustat tartrate (Genz-112638) in participants with Gaucher disease type 1 who had demonstrated clinical stability on BID dosing of eliglustat tartrate (Genz-112638). The secondary objective was to evaluate the pharmacokinetics (PK) of Genz-99067 when eliglustat tartrate (Genz-112638) was administered QD and BID in participants with Gaucher disease type 1 who had demonstrated clinical stability on BID dosing of eliglustat tartrate (Genz-112638).

Detailed Description
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NOTE: Other Phase 3 studies being conducted with eliglustat tartrate (Genz-112638) are GZGD02507 (ENGAGE): NCT00891202 and GZGD02607 (ENCORE): NCT00943111

Official Title
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A Phase 3, Randomized, Multi-Center, Multi-National, Double-Blind Study to Evaluate the Efficacy, Safety and Pharmacokinetics of Once Daily Versus Twice Daily Dosing of Genz-112638 in Patients With Gaucher Disease Type 1 Who Have Demonstrated Clinical Stability on a Twice Daily Dose of Genz-112638

Conditions
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Gaucher Disease

Intervention / Treatment
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* Drug: Eliglustat tartrate


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: The participant who was willing and provided signed informed consent prior to any study-related procedures. The participant was ≥18 years of age. The participant diagnosed with GD 1 confirmed by a documented deficiency of acid β-glucosidase activity by enzyme assay. Female participants of childbearing potential had a documented negative pregnancy test prior to administration of the first dose of eliglustat tartrate (Genz-112638) in this study. In addition, all female participants of childbearing potential used a medically accepted form of contraception throughout the study, i.e., either a barrier method or hormonal contraceptive with norethindrone and ethinyl estradiol or similar active components The participant met all of the following criteria at the time of screening: hemoglobin level ≥9 g/dL (mean of 2 measurements); platelet count ≥70,000/mm^3 (mean of 2 measurements); spleen volume ≤25 multiples of normal (MN); liver volume ≤2.0 MN. The participant consented to provide a blood sample for genotyping for Gaucher disease and for CYP2D6 to categorize the participant's predicted rate of metabolism, if these genotyping results were not already available for the participant. The participant was willing to abstain from consumption of grapefruit, grapefruit juice, or grapefruit products for 72 hours prior to administration of the first dose of Genz-112638 and throughout the duration of the study. Exclusion Criteria: The participant was participating in GZGD02607 study, A Phase 3, Randomized, Multi-Center, Multi-National, Open-Label, Active Comparator Study to Evaluate the Efficacy and Safety of Genz-112638 in Participants with GD1 who have been Stabilized with Cerezyme ® , or was eligible for inclusion in GZGD02607 (while enrollment was ongoing) and had access to a physician participating in GZGD02607, or the participant was participating in GZGD02507 study, A Phase 3, Randomized, Double-Blind, Placebo-Controlled, Multi-Center Study Confirming the Efficacy and Safety of Genz-112638 in Participants with GD1, or was eligible for inclusion in GZGD02507 (while enrollment was ongoing) and had access to a physician participating in GZGD02507. The participant received miglustat within 6 months prior to administration of the first dose of Genz-112638 in this study. The participant had a partial or total splenectomy within 3 years prior to randomization. The participant received pharmacological chaperones or miglustat within 6 months prior to administration of the first dose of eliglustat tartrate (Genz-112638) in this study. The participant had any evidence of neurologic disorder (e.g., peripheral neuropathy, tremor, seizures, Parkinsonism or cognitive impairment) or pulmonary involvement (e.g., pulmonary hypertension) as related to Gaucher disease. The participant was transfusion-dependent. The participant had a documented deficiency of iron, vitamin B-12, or folate that requires treatment not yet initiated or, if initiated, the participant had not been stable under treatment for at least 3 months prior to administration of the first dose of Genz-112638 in this study. The participant had documented prior esophageal varices or clinically significant liver infarction or current liver enzymes (alanine transaminase [ALT]/aspartate aminotransferase [AST]) or total bilirubin >2 times the upper limit of normal (ULN), unless the participant had a diagnosis of Gilbert Syndrome. The participant had any clinically significant disease, other than Gaucher disease, including cardiovascular, renal, hepatic, gastrointestinal, pulmonary, neurologic, endocrine, metabolic (including hypokalaemia or hypomagnesemia), or psychiatric disease, other medical conditions, or serious intercurrent illnesses that, in the opinion of the Investigator, precluded participation in the study. The participant was known to have any of the following: Clinically significant coronary artery disease including history of myocardial infarction [MI] or ongoing signs or symptoms consistent with cardiac ischemia or heart failure; or clinically significant arrhythmias or conduction defect such as 2nd or 3rd degree AV block, complete bundle branch block, prolonged QTc interval, or sustained ventricular tachycardia (VT). The participant who tested positive for the human immunodeficiency virus (HIV) antibody, Hepatitis C antibody, or Hepatitis B surface antigen. The participant received an investigational product (other than eliglustat tartrate (Genz-112638)) within 30 days prior to administration of the first dose of eliglustat tartrate (Genz-112638) in this study. The participant was scheduled for in-participant hospitalization, including elective surgery, during the study. The participant had a history of cancer, with the exception of basal cell carcinoma, within 5 years prior to administration of the first dose of Genz-112638 in this study. The participant was pregnant or lactating. The participant had received any medication that may cause QTc interval prolongation within 30 days prior to the first dose of Genz-112638. Exception: Diphenhydramine (Benadryl) or other medications used as premedication for ERT infusions were allowed up to 7 days prior to the first dose of Genz-112638. The participant had received for the first time (i.e., the participant was not already chronically using) any of the following medications within 30 days prior to the first dose of Genz-112638: Strong inhibitors of CYP2D6 or CYP3A4; Inducers of CYP3A4. Exception: Premedications for ERT infusions were allowed up to 7 days prior to the first dose of Genz-112638. The participant was a CYP2D6 non-poor metabolizer or an indeterminate metabolizer with one allele identified as active who was chronically receiving both a strong competitive inhibitor of CYP2D6 and a strong competitive inhibitor of CYP3A4 and for whom no reasonable alternative medication exists. or The participant was a CYP2D6 poor metabolizer or an indeterminate metabolizer with neither allele known to be active who was chronically receiving a strong competitive inhibitor of CYP3A4 and for whom no reasonable alternative medication exists. Exception for both cases: Premedications for ERT infusions were allowed up to 7 days prior to the first dose of Genz-112638.

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: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Twice Daily (BID) Dose Regimen<br>Patients will receive either 50 mg BID or 100 mg BID | Drug: Eliglustat tartrate<br>* Oral Capsule in 50 mg or 100 mg dosages<br>* Other names: Genz-112638;|
| Experimental: Once Daily (QD) Dose Regimen<br>Patients will receive either 100 mg QD or 200 mg QD | Drug: Eliglustat tartrate<br>* Oral Capsule in 50 mg or 100 mg dosages<br>* Other names: Genz-112638;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| PAP: Percentage of Participants Who Remained Stable for 52 Weeks During the PAP | Participants were considered as stable if they met all of the following criteria: 1) no more than 2 bone crisis during PAP (with no more than 1 bone crisis during either the first 6 months or the later 6 months of the period), and were free of other clinically symptomatic bone disease during the entire 52-week PAP; 2) hemoglobin level not decreased >1.5 g/dL from Baseline for PAP; 3) platelet count not decreased >25% from Baseline for PAP; 4) spleen volume (in multiples of normal [MN]) did not increase >25% from Baseline for PAP; 5) liver volume (in MN) did not increase >20% from Baseline for PAP. Baseline for PAP was defined as the last assessment prior to randomization. | PAP Baseline up to the end of PAP (Week 52) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| PAP: Mean Hemoglobin (Hb) Level at Baseline, Weeks 26 and 52 |  | Baseline, Week 26, Week 52 | 
| PAP: Mean Platelet Count at Baseline, Weeks 26, 52 |  | Baseline, Week 26, Week 52 | 
| PAP: Mean Spleen Volume at Baseline, Weeks 26, 52 |  | Baseline, Week 26, Week 52 | 
| PAP: Mean Liver Volume at Baseline, Weeks 26, 52 |  | Baseline, Week 26 and Week 52 | 
| PAP: Mean Biomarker (Chitotriosidase) Value at Baseline, Weeks 26 and Week 52 | Chitotriosidase biomarker was assayed from plasma. | Baseline, Week 26, Week 52 | 
| PAP: Mean Biomarker (GL-1 on DBS) Value at Baseline, Week 26 and Week 52 | GL-1 on DBS biomarker was assayed from dried blood spot (DBS). | Baseline, Week 26 and week 52 | 
| PAP: Mean Biomarker Macrophage Inflammatory Protein-1 Beta (MIP1-beta) Value at Baseline, Weeks 26, 52 | MIP1-beta biomarker was assayed from plasma. | Baseline, Week 26, Week 52 | 
| PAP: Bone Mineral Density (BMD) at Baseline and Week 52 | BMD measurements of the spine and bilateral femur were acquired by dual-energy x-ray absorptiometry (DXA) scan. | Baseline, Week 52 | 
| PAP: Total T-Scores for BMD at Baseline and 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. The T-score bone density categories were: normal (score >-1), osteopenia (score -2.5 to <=-1), and osteoporosis (score <= -2.5). | Baseline, Week 52 | 
| PAP: Total Z-scores for BMD at Baseline and 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). | Baseline, Week 52 | 
| PAP: Number of Participants With Mobility Status Asessments (MS) at Baseline, Weeks 26, and 52. | Mobility, i.e., ability to walk was assessed as a part of Gaucher disease assessment in participants. In this outcome, number of participants with their different mobility status along with the use of mobility aids (unrestricted mobility, walks with difficulty, walks with orthopaedic aid, requires wheelchair, bedridden) at specified time points were reported. | Baseline, Week 26 and Week 52 | 
| PAP: Number of Participants With Bone Crises at Baseline, Weeks 26 and 52 | Bone crisis was assessed as a part of Gaucher disease assessment in participants. Acute, excruciating episodic bone pain is characteristic of Gaucher bone crisis, which typically causes debilitation lasting several days or longer and requires treatment with immobilization, hydration, and opioid analgesics. Participants were categorized as 0= no bone crisis, 1= 1 bone crisis, and 2= 2 bone crises during the assessment period. In this outcome, number of participants with different bone crises levels at specified time points were reported. | Baseline, Week 26, and Week 52 | 
| PAP: Number of Participants With Bone Pain Levels During the Past 4 Weeks at Baseline, Weeks 26 and 52 | Bone pain was assessed as a part of Gaucher disease assessment in participants. Participants were categorized as none (no bone pain), very mild bone pain, mild bone pain, moderate bone pain, severe bone pain and extreme bone pain during the past 4 weeks. In this outcome, number of participants with different level of bone pain during the past 4 weeks at specified time points were reported. | Baseline, Week 26, and Week 52 | 
| PAP: Total Bone Marrow Burden Score (BMB) at Baseline and Week 52 | BMB Score was measured using magnetic resonance imaging (MRI), range from 0 (no abnormalities) to 8 points (severe disease) for the lumbar spine and from 0 (no abnormalities) to 8 points (severe disease) for the femurs. The total score was calculated as the sum of scores for femur and lumbar spine regions which ranged from 0 (no abnormalities) -16 (severe disease) points. A higher BMB score signified more severe bone marrow involvement. | Baseline, Week 52 | 
| LIP: Mean Hemoglobin (Hb) Level at Baseline, Weeks 26, 52 and 78 |  | Baseline, Week 26, Week, 52, and Week 78 | 
| LIP: Mean Platelet Count at Baseline, Weeks 26, 52 and 78 |  | Baseline, Week 26, Week 52, Week 78 | 
| LIP: Mean Liver Volume at Baseline, Weeks 26, 52 and 78 |  | Baseline, Week 26, Week 52, Week 78 | 
| LIP: Mean Spleen Volume at Baseline, Weeks 26, 52 and 78 |  | Baseline, Week 26, Week 52, Week 78 | 
| LIP: Mean Biomarker (Chitotriosidase) Value at Baseline, Weeks 26, 52, and 78 | Chitotriosidase biomarker was assayed from plasma. | Baseline, Week 26, Week 52 and Week 78 | 
| LIP: Mean Biomarker (GL-1 on DBS) Value at Baseline, Week 26, Week 52, and Week 78 | GL-1 on DBS biomarker was assayed from dried blood spot. | Baseline, Week 26, Week 52 and Week 78 | 
| LIP: Mean Biomarker (MIP1-beta) Value at Baseline, Week 78 | MIP1-beta biomarker was assayed from plasma. | Baseline and Week 78 | 
| LIP: Number of Participants With Mobility Status (MS) at Baseline, Weeks 26, 52 and 78 | Mobility, i.e., ability to walk was assessed as a part of Gaucher disease assessment in participants. In this outcome, number of participants with their different mobility status along with the use of mobility aids (unrestricted mobility, walks with difficulty, walks with orthopaedic aid, requires wheelchair, bedridden) at specified time points were reported. | Baseline, Week 26, Week 52, Week 78 | 
| LIP: Number of Participants With Bone Crises Assessment at Baseline, Weeks 26, 52 and 78 | Bone crises was assessed as a part of Gaucher disease assessment in participants. Acute, excruciating episodic bone pain is characteristic of Gaucher bone crises, which typically causes debilitation lasting several days or longer and requires treatment with immobilization, hydration, and opioid analgesics. Participants were categorized as 0= no bone crisis, 1= 1 bone crisis, 2= 2 bone crises, 6= 6 bone crises, and 24= 24 bone crises during the assessment period. In this outcome, number of participants with different bone crises levels at specified time points were reported. | Baseline, Week 26, Week 52, Week 78 | 
| LIP: Number of Participants With Bone Pain Levels During the Past 4 Weeks at Baseline, Weeks 26, 52 and 78 | Bone pain was assessed as a part of Gaucher disease assessment in participants. Participants were categorized as none (no bone pain), very mild bone pain, mild bone pain, moderate bone pain, severe bone pain and extreme bone pain. In this outcome, number of participants with different type of bone pain during the past 4 weeks at specified time points were reported. | Baseline, Week 26, Week 52, Week 78 | 
| LTTP: Percentage of Participants Who Maintained a Stable Bone Criterion ,Hemoglobin Level, Platelet Count, Liver Volume and Spleen Volume at 1 Year and 2 Years | Participant were considered as stable if they met the following criteria: hemoglobin level did not decrease >1.5 g/dL from baseline for PAP, platelet count does not decrease >25% below Baseline for PAP, liver volume does not increase >20% above Baseline for PAP, spleen volume does not increase >25% above Baseline for PAP. Baseline for PAP was defined as last available assessment prior to randomization. | 1 Year, 2 Years | 
| LTTP: Number of Participants With Mobility Status (MS) at Baseline, 1 Year and 2 Years | Mobility, i.e., ability to walk was assessed as a part of Gaucher disease assessment in participants. In this outcome, number of participants with their different mobility status along with the use of mobility aids (unrestricted mobility, walks with difficulty, walks with orthopaedic aid, requires wheelchair, bedridden) at specified time points were reported. | Baseline, 1 year, and 2 years | 
| LTTP: Number of Participants With Bone Crises Assessment at Baseline, 1 Year and 2 Years | Bone crises was assessed as a part of Gaucher disease assessment in participants. Acute, excruciating episodic bone pain is characteristic of Gaucher bone crises, which typically causes debilitation lasting several days or longer and requires treatment with immobilization, hydration, and opioid analgesics. Participants were categorized as 0= no bone crises, 1= 1 bone crisis during the assessment period. In this outcome, number of participants with different bone crises levels at specified time points were reported. | Baseline, 1 year and 2 years | 
| LTTP: Number of Participants With Bone Pain Levels During the Past 4 Weeks at Baseline, 1 Year, and 2 Years | Bone pain was assessed as a part of Gaucher disease assessment in participants. Participants were categorized as none (no bone pain), very mild bone pain, mild bone pain, moderate bone pain, severe bone pain and extreme bone pain. In this outcome, number of participants with different level of bone pain during the past 4 weeks at specified time points were reported. | Baseline, 1 year and 2 years | 
| LTTP: Bone Mineral Density (BMD) at Baseline, 1 Year, and 2 Years | BMD measurements of the spine and bilateral femur were acquired by DXA scan. | Baseline, 1 year, and 2 years | 
| LTTP: Total T-Scores for BMD at Baseline, 1 Year, and 2 Years | Images of the spine and bilateral femur were obtained by DXA to determine T-score for each bone area and total bone mineral density. The T-score bone density categories were: normal (score >-1), osteopenia (score -2.5 to <=-1), and osteoporosis (score <= -2.5). | Baseline, 1 year, and 2 years | 
| LTTP: Total Z-scores for BMD at Baseline, 1 Year, and 2 Years | 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, 1 year, and 2 years | 
| LTTP: Total Bone Marrow Burden Score (BMB) at Baseline, 1 Year, and 2 Years | BMB Score was measured using MRI, range from 0 (no abnormalities) to 8 points (severe disease) for the lumbar spine and from 0 (no abnormalities) to 8 points (severe disease) for the femurs. The total score was calculated as the sum of scores for femur and lumbar spine regions which ranged from 0 (no abnormalities) -16 (severe disease) points. A higher BMB score signified more severe bone marrow involvement. | Baseline, 1 year, and 2 years | 
| LTTP: Mean Biomarker (Chitotriosidase) Value at Baseline, 1 Year, and 2 Years | Chitotriosidase biomarker was assayed from plasma. | Baseline, 1 year, and 2 years | 
| LTTP: Mean Biomarker (GL-1 on DBS) Value at Baseline, 1 Year, and 2 Years | GL-1 on DBS biomarker was assayed from dried blood spot. | Baseline, 1 year, and 2 years | 
| LTTP: Mean Biomarker (MIP1-beta) Value at Baseline, 1 Year, and 2 Years | MIP1-beta biomarker was assayed from plasma. | Baseline, 1 year, and 2 years | 

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