Clinical trial NCT01074944: A Study of Eliglustat Tartrate (Genz-112638) in Patients With Gaucher Disease to Evaluate Once Daily Versus Twice Daily Dosing (EDGE)
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Gaucher Disease
Keywords: Gaucher disease
Genz-112638
beta-glucosidase
acid β-glucosidase
glucocerebrosidase
glucosylceramide
D-glucosyl-N-acylsphingosine glucohydrolase
substrate reduction therapy
Lead sponsor: Sanofi
Sponsor class: INDUSTRY
First posted: 2010-02-24
Enrollment: 170
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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

Eligibility criteria: 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.

Primary outcomes:
measure: PAP: Percentage of Participants Who Remained Stable for 52 Weeks During the PAP
timeFrame: PAP Baseline up to the end of PAP (Week 52)
Secondary outcomes:
measure: PAP: Mean Hemoglobin (Hb) Level at Baseline, Weeks 26 and 52
timeFrame: Baseline, Week 26, Week 52
measure: PAP: Mean Platelet Count at Baseline, Weeks 26, 52
timeFrame: Baseline, Week 26, Week 52
measure: PAP: Mean Spleen Volume at Baseline, Weeks 26, 52
timeFrame: Baseline, Week 26, Week 52
measure: PAP: Mean Liver Volume at Baseline, Weeks 26, 52
timeFrame: Baseline, Week 26 and Week 52
measure: PAP: Mean Biomarker (Chitotriosidase) Value at Baseline, Weeks 26 and Week 52
timeFrame: Baseline, Week 26, Week 52
measure: PAP: Mean Biomarker (GL-1 on DBS) Value at Baseline, Week 26 and Week 52
timeFrame: Baseline, Week 26 and week 52
measure: PAP: Mean Biomarker Macrophage Inflammatory Protein-1 Beta (MIP1-beta) Value at Baseline, Weeks 26, 52
timeFrame: Baseline, Week 26, Week 52
measure: PAP: Bone Mineral Density (BMD) at Baseline and Week 52
timeFrame: Baseline, Week 52
measure: PAP: Total T-Scores for BMD at Baseline and Week 52
timeFrame: Baseline, Week 52
measure: PAP: Total Z-scores for BMD at Baseline and Week 52
timeFrame: Baseline, Week 52
measure: PAP: Number of Participants With Mobility Status Asessments (MS) at Baseline, Weeks 26, and 52.
timeFrame: Baseline, Week 26 and Week 52
measure: PAP: Number of Participants With Bone Crises at Baseline, Weeks 26 and 52
timeFrame: Baseline, Week 26, and Week 52
measure: PAP: Number of Participants With Bone Pain Levels During the Past 4 Weeks at Baseline, Weeks 26 and 52
timeFrame: Baseline, Week 26, and Week 52
measure: PAP: Total Bone Marrow Burden Score (BMB) at Baseline and Week 52
timeFrame: Baseline, Week 52
measure: LIP: Mean Hemoglobin (Hb) Level at Baseline, Weeks 26, 52 and 78
timeFrame: Baseline, Week 26, Week, 52, and Week 78
measure: LIP: Mean Platelet Count at Baseline, Weeks 26, 52 and 78
timeFrame: Baseline, Week 26, Week 52, Week 78
measure: LIP: Mean Liver Volume at Baseline, Weeks 26, 52 and 78
timeFrame: Baseline, Week 26, Week 52, Week 78
measure: LIP: Mean Spleen Volume at Baseline, Weeks 26, 52 and 78
timeFrame: Baseline, Week 26, Week 52, Week 78
measure: LIP: Mean Biomarker (Chitotriosidase) Value at Baseline, Weeks 26, 52, and 78
timeFrame: Baseline, Week 26, Week 52 and Week 78
measure: LIP: Mean Biomarker (GL-1 on DBS) Value at Baseline, Week 26, Week 52, and Week 78
timeFrame: Baseline, Week 26, Week 52 and Week 78
measure: LIP: Mean Biomarker (MIP1-beta) Value at Baseline, Week 78
timeFrame: Baseline and Week 78
measure: LIP: Number of Participants With Mobility Status (MS) at Baseline, Weeks 26, 52 and 78
timeFrame: Baseline, Week 26, Week 52, Week 78
measure: LIP: Number of Participants With Bone Crises Assessment at Baseline, Weeks 26, 52 and 78
timeFrame: Baseline, Week 26, Week 52, Week 78
measure: LIP: Number of Participants With Bone Pain Levels During the Past 4 Weeks at Baseline, Weeks 26, 52 and 78
timeFrame: Baseline, Week 26, Week 52, Week 78
measure: 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
timeFrame: 1 Year, 2 Years
measure: LTTP: Number of Participants With Mobility Status (MS) at Baseline, 1 Year and 2 Years
timeFrame: Baseline, 1 year, and 2 years
measure: LTTP: Number of Participants With Bone Crises Assessment at Baseline, 1 Year and 2 Years
timeFrame: Baseline, 1 year and 2 years
measure: LTTP: Number of Participants With Bone Pain Levels During the Past 4 Weeks at Baseline, 1 Year, and 2 Years
timeFrame: Baseline, 1 year and 2 years
measure: LTTP: Bone Mineral Density (BMD) at Baseline, 1 Year, and 2 Years
timeFrame: Baseline, 1 year, and 2 years
measure: LTTP: Total T-Scores for BMD at Baseline, 1 Year, and 2 Years
timeFrame: Baseline, 1 year, and 2 years
measure: LTTP: Total Z-scores for BMD at Baseline, 1 Year, and 2 Years
timeFrame: Baseline, 1 year, and 2 years
measure: LTTP: Total Bone Marrow Burden Score (BMB) at Baseline, 1 Year, and 2 Years
timeFrame: Baseline, 1 year, and 2 years
measure: LTTP: Mean Biomarker (Chitotriosidase) Value at Baseline, 1 Year, and 2 Years
timeFrame: Baseline, 1 year, and 2 years
measure: LTTP: Mean Biomarker (GL-1 on DBS) Value at Baseline, 1 Year, and 2 Years
timeFrame: Baseline, 1 year, and 2 years
measure: LTTP: Mean Biomarker (MIP1-beta) Value at Baseline, 1 Year, and 2 Years
timeFrame: Baseline, 1 year, and 2 years
Other outcomes:
Locations:
city: San Diego
country: United States
facility: University of California, San Diego Medical Center
state: California
city: New Haven
country: United States
facility: Yale University School of Medicine
state: Connecticut
city: Decatur
country: United States
facility: Emory University Medical Center
state: Georgia
city: Chicago
country: United States
facility: Children's Memorial Hospital
state: Illinois
city: New York
country: United States
facility: Mount Sinai Medical Center
state: New York
city: New York
country: United States
facility: New York University School of Medicine
state: New York
city: Philadelphia
country: United States
facility: Children's Hospital of Philadelphia
state: Pennsylvania
city: Pittsburgh
country: United States
facility: Children's Hospital of Pittsburgh
state: Pennsylvania
city: Salt Lake City
country: United States
facility: University of Utah
state: Utah
city: Springfield
country: United States
facility: O and O Alpan LLC
state: Virginia
city: Camperdown
country: Australia
facility: Royal Prince Alfred Hospital
city: Clayton, VIC
country: Australia
facility: Monash Medical Centre
city: Perth, WA
country: Australia
facility: Royal Perth Hospital
city: Vienna
country: Austria
facility: Medical University Vienna
city: Belo Horizonte
country: Brazil
facility: Hospital das Clinicas da UFMG
city: Brasília
country: Brazil
facility: Cettro - Centro de Tratamento de Oncologia e Hematologia
city: Campinas
country: Brazil
facility: Hemocentro - UNICAMP
city: Cuiaba
country: Brazil
facility: Instituto Tropical de Medicina Reprodutiva e Menopausa - INTRO
city: Fortaleza
country: Brazil
facility: Hospital Universitario Walter Cantidio - HUWC
city: Franca
country: Brazil
facility: Hemocentro de Ribeirão Preto Núcleo de Hemoterapia de Franca
city: Rio de Janeiro
country: Brazil
facility: Hemorio
city: Sao Paulo
country: Brazil
facility: Hospital de Clínicas da Universidade Federal do Parana
city: Sao Paulo
country: Brazil
facility: IGEIM - Institute of Genetic and Inborn Erros of Metabolism
city: Toronto
country: Canada
facility: Mount Sinai Hospital
city: Beijing
country: China
facility: Peking Union Medical College Hospital
city: Beijing
country: China
facility: Peking University People's Hospital
city: Shanghai
country: China
facility: Shanghai Xinhua Hospital Shanghai Xinhua Hospital
city: Tianjin
country: China
facility: Tianjin Hematonosis Hospital
city: Zagreb
country: Croatia
facility: University Hospital Centre Zagreb
city: Bordeaux
country: France
facility: Hôpital Haut Lévêque
city: Bron
country: France
facility: Hôpital Femme Mère Enfant Centre de référence des maladies Héréditaires du métabolisme
city: Athens
country: Greece
facility: General Hospital of Athens "G. Gennimatas"
city: Mumbai
country: India
facility: King Edward Memorial (KEM) Hospital
city: Hiroshima
country: Japan
facility: Hiroshima University Hospital
city: Tokyo
country: Japan
facility: Jikei University Hospital
city: Tokyo
country: Japan
facility: Juntendo University Hospital
city: Tsu, Mie
country: Japan
facility: Mie Chuou Medical Center
city: Amsterdam
country: Netherlands
facility: Academic Medical Center
city: Lisboa
country: Portugal
facility: Hospital de Santa Maria
city: Ponta Delgada - São Miguel - Açores
country: Portugal
facility: Hospital do Divíno Espírito Santo
city: Cluj-Napoca
country: Romania
facility: Spitaulu Clinic de Urgenta
city: Chelyabinsk
country: Russian Federation
facility: State Medical and Prophylactic Healthcare Institution; Chelyabinsk Regional Clinical Hospital
city: Moscow
country: Russian Federation
facility: Hematology Research Center of Russian Academy of Medical Sciences
city: St. Petersburg
country: Russian Federation
facility: St. Petersburg State Medical Pavlov University
city: Belgrade
country: Serbia
facility: Clinical Centre of Serbia
city: Lund
country: Sweden
facility: University Hospital Lund
Study officials:
affiliation: Genzyme, a Sanofi Company
name: Medical Monitor
role: STUDY_DIRECTOR
References:
citation: McEachern KA, Fung J, Komarnitsky S, Siegel CS, Chuang WL, Hutto E, Shayman JA, Grabowski GA, Aerts JM, Cheng SH, Copeland DP, Marshall J. A specific and potent inhibitor of glucosylceramide synthase for substrate inhibition therapy of Gaucher disease. Mol Genet Metab. 2007 Jul;91(3):259-67. doi: 10.1016/j.ymgme.2007.04.001. Epub 2007 May 16.
citation: Lukina E, Watman N, Arreguin EA, Banikazemi M, Dragosky M, Iastrebner M, Rosenbaum H, Phillips M, Pastores GM, Rosenthal DI, Kaper M, Singh T, Puga AC, Bonate PL, Peterschmitt MJ. A phase 2 study of eliglustat tartrate (Genz-112638), an oral substrate reduction therapy for Gaucher disease type 1. Blood. 2010 Aug 12;116(6):893-9. doi: 10.1182/blood-2010-03-273151. Epub 2010 May 3.
citation: Lukina E, Watman N, Arreguin EA, Dragosky M, Iastrebner M, Rosenbaum H, Phillips M, Pastores GM, Kamath RS, Rosenthal DI, Kaper M, Singh T, Puga AC, Peterschmitt MJ. Improvement in hematological, visceral, and skeletal manifestations of Gaucher disease type 1 with oral eliglustat tartrate (Genz-112638) treatment: 2-year results of a phase 2 study. Blood. 2010 Nov 18;116(20):4095-8. doi: 10.1182/blood-2010-06-293902. Epub 2010 Aug 16.
citation: Charrow J, Fraga C, Gu X, Ida H, Longo N, Lukina E, Nonino A, Gaemers SJM, Jouvin MH, Li J, Wu Y, Xue Y, Peterschmitt MJ. Once- versus twice-daily dosing of eliglustat in adults with Gaucher disease type 1: The Phase 3, randomized, double-blind EDGE trial. Mol Genet Metab. 2018 Mar;123(3):347-356. doi: 10.1016/j.ymgme.2017.12.001. Epub 2018 Jan 4.