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

Phase 3

Completed

Conditions: Gaucher Disease

Interventions: Drug: Eliglustat tartrate

Registration Number: NCT01074944

Lead Sponsor: Genzyme, a Sanofi Company

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

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 170

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.

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Twice Daily (BID) Dose Regimen	Eliglustat tartrate	Patients will receive either 50 mg BID or 100 mg BID
Once Daily (QD) Dose Regimen	Eliglustat tartrate	Patients will receive either 100 mg QD or 200 mg QD

Primary Outcome Measures

Name	Time	Method
PAP: Percentage of Participants Who Remained Stable for 52 Weeks During the PAP	PAP Baseline up to the end of PAP (Week 52)	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.

Secondary Outcome Measures

Name	Time	Method
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 Macrophage Inflammatory Protein-1 Beta (MIP1-beta) Value at Baseline, Weeks 26, 52	Baseline, Week 26, Week 52	MIP1-beta biomarker was assayed from plasma.
PAP: Mean Biomarker (GL-1 on DBS) Value at Baseline, Week 26 and Week 52	Baseline, Week 26 and week 52	GL-1 on DBS biomarker was assayed from dried blood spot (DBS).
PAP: Mean Biomarker (Chitotriosidase) Value at Baseline, Weeks 26 and Week 52	Baseline, Week 26, Week 52	Chitotriosidase biomarker was assayed from plasma.
PAP: Total T-Scores for BMD at Baseline and Week 52	Baseline, 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).
PAP: Total Z-scores for BMD at Baseline and Week 52	Baseline, 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).
PAP: Bone Mineral Density (BMD) at Baseline and Week 52	Baseline, Week 52	BMD measurements of the spine and bilateral femur were acquired by dual-energy x-ray absorptiometry (DXA) scan.
PAP: Number of Participants With Mobility Status Asessments (MS) at Baseline, Weeks 26, and 52.	Baseline, Week 26 and Week 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.
PAP: Number of Participants With Bone Crises at Baseline, Weeks 26 and 52	Baseline, Week 26, and Week 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.
PAP: Number of Participants With Bone Pain Levels During the Past 4 Weeks at Baseline, Weeks 26 and 52	Baseline, Week 26, and Week 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.
PAP: Total Bone Marrow Burden Score (BMB) at Baseline and Week 52	Baseline, 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.
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	Baseline, Week 26, Week 52 and Week 78	Chitotriosidase biomarker was assayed from plasma.
LIP: Mean Biomarker (GL-1 on DBS) Value at Baseline, Week 26, Week 52, and Week 78	Baseline, Week 26, Week 52 and Week 78	GL-1 on DBS biomarker was assayed from dried blood spot.
LIP: Mean Biomarker (MIP1-beta) Value at Baseline, Week 78	Baseline and Week 78	MIP1-beta biomarker was assayed from plasma.
LIP: Number of Participants With Mobility Status (MS) at Baseline, Weeks 26, 52 and 78	Baseline, Week 26, Week 52, Week 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.
LIP: Number of Participants With Bone Crises Assessment at Baseline, Weeks 26, 52 and 78	Baseline, Week 26, Week 52, Week 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.
LIP: Number of Participants With Bone Pain Levels During the Past 4 Weeks at Baseline, Weeks 26, 52 and 78	Baseline, Week 26, Week 52, Week 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.
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	1 Year, 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.
LTTP: Number of Participants With Mobility Status (MS) at Baseline, 1 Year and 2 Years	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.
LTTP: Number of Participants With Bone Crises Assessment at Baseline, 1 Year and 2 Years	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.
LTTP: Number of Participants With Bone Pain Levels During the Past 4 Weeks at Baseline, 1 Year, and 2 Years	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.
LTTP: Bone Mineral Density (BMD) at Baseline, 1 Year, and 2 Years	Baseline, 1 year, and 2 years	BMD measurements of the spine and bilateral femur were acquired by DXA scan.
LTTP: Total T-Scores for BMD at Baseline, 1 Year, and 2 Years	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).
LTTP: Total Z-scores for BMD at Baseline, 1 Year, and 2 Years	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).
LTTP: Total Bone Marrow Burden Score (BMB) at Baseline, 1 Year, and 2 Years	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.
LTTP: Mean Biomarker (Chitotriosidase) Value at Baseline, 1 Year, and 2 Years	Baseline, 1 year, and 2 years	Chitotriosidase biomarker was assayed from plasma.
LTTP: Mean Biomarker (GL-1 on DBS) Value at Baseline, 1 Year, and 2 Years	Baseline, 1 year, and 2 years	GL-1 on DBS biomarker was assayed from dried blood spot.
LTTP: Mean Biomarker (MIP1-beta) Value at Baseline, 1 Year, and 2 Years	Baseline, 1 year, and 2 years	MIP1-beta biomarker was assayed from plasma.

Trial Locations

Locations (46): Hospital Universitario Walter Cantidio - HUWC
🇧🇷
Fortaleza, Brazil
Royal Perth Hospital
🇦🇺
Perth, WA, Australia
Peking Union Medical College Hospital
🇨🇳
Beijing, China
Hospital das Clinicas da UFMG
🇧🇷
Belo Horizonte, Brazil
Instituto Tropical de Medicina Reprodutiva e Menopausa - INTRO
🇧🇷
Cuiaba, Brazil
Academic Medical Center
🇳🇱
Amsterdam, Netherlands
Hemorio
🇧🇷
Rio de Janeiro, Brazil
Juntendo University Hospital
🇯🇵
Tokyo, Japan
Hôpital Femme Mère Enfant Centre de référence des maladies Héréditaires du métabolisme
🇫🇷
Bron, France
Hiroshima University Hospital
🇯🇵
Hiroshima, Japan
Mount Sinai Hospital
🇨🇦
Toronto, Canada
Mie Chuou Medical Center
🇯🇵
Tsu, Mie, Japan
O and O Alpan LLC
🇺🇸
Springfield, Virginia, United States
IGEIM - Institute of Genetic and Inborn Erros of Metabolism
🇧🇷
Sao Paulo, Brazil
Jikei University Hospital
🇯🇵
Tokyo, Japan
Monash Medical Centre
🇦🇺
Clayton, VIC, Australia
Cettro - Centro de Tratamento de Oncologia e Hematologia
🇧🇷
Brasília, Brazil
Hemocentro - UNICAMP
🇧🇷
Campinas, Brazil
University Hospital Centre Zagreb
🇭🇷
Zagreb, Croatia
Hôpital Haut Lévêque
🇫🇷
Bordeaux, France
Hospital de Clínicas da Universidade Federal do Parana
🇧🇷
Sao Paulo, Brazil
University Hospital Lund
🇸🇪
Lund, Sweden
Hematology Research Center of Russian Academy of Medical Sciences
🇷🇺
Moscow, Russian Federation
Royal Prince Alfred Hospital
🇦🇺
Camperdown, Australia
Shanghai Xinhua Hospital Shanghai Xinhua Hospital
🇨🇳
Shanghai, China
Peking University People's Hospital
🇨🇳
Beijing, China
Tianjin Hematonosis Hospital
🇨🇳
Tianjin, China
Emory University Medical Center
🇺🇸
Decatur, Georgia, United States
Children's Hospital of Philadelphia
🇺🇸
Philadelphia, Pennsylvania, United States
Children's Memorial Hospital
🇺🇸
Chicago, Illinois, United States
Children's Hospital of Pittsburgh
🇺🇸
Pittsburgh, Pennsylvania, United States
University of Utah
🇺🇸
Salt Lake City, Utah, United States
Clinical Centre of Serbia
🇷🇸
Belgrade, Serbia
Hospital de Santa Maria
🇵🇹
Lisboa, Portugal
Medical University Vienna
🇦🇹
Vienna, Austria
King Edward Memorial (KEM) Hospital
🇮🇳
Mumbai, India
General Hospital of Athens "G. Gennimatas"
🇬🇷
Athens, Greece
Hospital do Divíno Espírito Santo
🇵🇹
Ponta Delgada - São Miguel - Açores, Portugal
New York University School of Medicine
🇺🇸
New York, New York, United States
Yale University School of Medicine
🇺🇸
New Haven, Connecticut, United States
Mount Sinai Medical Center
🇺🇸
New York, New York, United States
University of California, San Diego Medical Center
🇺🇸
San Diego, California, United States
Hemocentro de Ribeirão Preto Núcleo de Hemoterapia de Franca
🇧🇷
Franca, Brazil
Spitaulu Clinic de Urgenta
🇷🇴
Cluj-Napoca, Romania
St. Petersburg State Medical Pavlov University
🇷🇺
St. Petersburg, Russian Federation
State Medical and Prophylactic Healthcare Institution; Chelyabinsk Regional Clinical Hospital
🇷🇺
Chelyabinsk, Russian Federation