Clinical trial NCT00943111: A Study of Eliglustat Tartrate (Genz-112638) in Patients With Gaucher Disease Who Have Reached Therapeutic Goals With Enzyme Replacement Therapy (ENCORE)
Official title: 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)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Gaucher Disease, Type 1
Keywords: Gaucher disease,
Genz-112638,
beta-glucosidase,
acid ß-glucosidase,
glucocerebrosidase,
glucosylceramide,
D-glucosyl-N-acylsphingosine glucohydrolase,
substrate reduction therapy
Lead sponsor: Sanofi
Sponsor class: INDUSTRY
First posted: 2009-07-22
Enrollment: 160
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: 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: 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.

Eligibility criteria: 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

Primary outcomes:
measure: Percentage of Participants Who Remained Stable for 52 Weeks During the Primary Analysis Period
timeFrame: Baseline up to Week 52
measure: Percentage of Participants Who Remained Stable Annually for 4 Years During the LTTP
timeFrame: Week 52 up to week 208
Secondary outcomes:
measure: Total T-Scores for Bone Mineral Density
timeFrame: Baseline
measure: Absolute Change From Baseline in Total T-Scores for Bone Mineral Density at Week 52
timeFrame: Baseline, Week 52
measure: Total Z-Scores for Bone Mineral Density
timeFrame: Baseline
measure: Absolute Change From Baseline in Total Z-Scores for Bone Mineral Density at Week 52
timeFrame: Baseline, Week 52
measure: Hemoglobin Level
timeFrame: Baseline
measure: Absolute Change From Baseline in Hemoglobin Levels at Week 52
timeFrame: Baseline, Week 52
measure: Percent Change From Baseline in Platelet Counts at Week 52
timeFrame: Baseline, Week 52
measure: Percent Change From Baseline in Spleen Volume (MN) at Week 52
timeFrame: Baseline, Week 52
measure: Percent Change From Baseline in Liver Volume (in MN) at Week 52
timeFrame: Baseline, Week 52
measure: Absolute Change From Baseline in Total T-Scores for Bone Mineral Density at Week 208
timeFrame: Baseline, Week 208
measure: Absolute Change From Baseline in Total Z-Scores for Bone Mineral Density at Week 208
timeFrame: Baseline, Week 208
measure: Absolute Change From Baseline in Hemoglobin Levels at Week 208
timeFrame: Baseline, Week 208
measure: Percent Change From Baseline in Platelet Counts at Week 208
timeFrame: Baseline, Week 208
measure: Percent Change From Baseline in Spleen Volume (in MN) at Week 208
timeFrame: Baseline, Week 208
measure: Percent Change From Baseline in Liver Volume (in MN) at Week 208
timeFrame: Baseline, Week 208
Other outcomes:
Locations:
city: Beverly Hills
country: United States
facility: Tower Hematology Oncology Medical Group
state: California
city: San Francisco
country: United States
facility: UCSF MS Center
state: California
city: Aurora
country: United States
facility: University of Colorado Health Science Center - Aurora
state: Colorado
city: New Haven
country: United States
facility: Yale University School of Medicine
state: Connecticut
city: Coral Springs
country: United States
facility: Northwest Oncology Hematology Associates PA
state: Florida
city: Decatur
country: United States
facility: Emory University Medical Genetics
state: Georgia
city: Chicago
country: United States
facility: Children's Memorial Hospital
state: Illinois
city: Iowa City
country: United States
facility: University of Iowa Hospitals and Clinics
state: Iowa
city: Albany
country: United States
facility: Albany Medical Center
state: New York
city: Manhasset
country: United States
facility: North Shore University Medical Center
state: New York
city: New York
country: United States
facility: Mount Sinai School of Medicine
state: New York
city: New York
country: United States
facility: New York University School of Medicine
state: New York
city: Durham
country: United States
facility: Duke University Medical Center
state: North Carolina
city: Cincinnati
country: United States
facility: Cincinnati Children's Hospital Medical Center
state: Ohio
city: Philadelphia
country: United States
facility: Children's Hospital of Philadelphia
state: Pennsylvania
city: Pittsburgh
country: United States
facility: University of Pittsburgh Medical Center
state: Pennsylvania
city: Springfield
country: United States
facility: O and O Alpan LLC
state: Virginia
city: Buenos Aires
country: Argentina
facility: Hospital General de Agudos J.M Ramos Mejia
city: Buenos Aires
country: Argentina
facility: Hospital General de Ninos Dr. Ricardo Gutierrez
city: Perth, WA
country: Australia
facility: Royal Perth Hospital
city: Curitiba
country: Brazil
facility: Hospital de Clinicas da Universidade Federal do Parana
city: Rio de Janeiro
country: Brazil
facility: Instituto de Estadual de Hematologia Arthur de Siqueria Cavalcanti
city: São Paulo
country: Brazil
facility: IGEIM
city: Toronto Ontario
country: Canada
facility: Mount Sinai Hospital and the Samuel Lunenfeld Research Institute
city: Cairo
country: Egypt
facility: Abou El Reesh Children's University Hospital (El Mounira), Faculty of Medicine (Kasr Al-Aini), Cairo University Hospitals, El Mounira, Cairo, Egypt
city: Clichy
country: France
facility: Hôpital Beaujon
city: Berlin
country: Germany
facility: Charité Universitätsmedizin Berlin
city: Hamburg
country: Germany
facility: Asklepios Klinik St. Georg
city: Oberhausen
country: Germany
facility: Katholische Kliniken Oberhausen gem. GmbH
city: Firenze
country: Italy
facility: Azienda Ospedaliero Universitaria Careggi
city: Udine
country: Italy
facility: Azienda Ospedialiero-Universitaria S. Maria Della Misericordia
city: Moscow
country: Russian Federation
facility: Hematology Research Center of Ministry of Healthcare of the Russian Federation
city: Zaragoza
country: Spain
facility: Hospital University Miguel Servet
city: Cambridge
country: United Kingdom
facility: Cambridge University Hosptials, Addenbrookes Hospital
Study officials:
affiliation: Genzyme, a Sanofi Company
name: Medical Monitor
role: STUDY_DIRECTOR
References:
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: 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: Kamath RS, Lukina E, Watman N, Dragosky M, Pastores GM, Arreguin EA, Rosenbaum H, Zimran A, Aguzzi R, Puga AC, Norfleet AM, Peterschmitt MJ, Rosenthal DI. Skeletal improvement in patients with Gaucher disease type 1: a phase 2 trial of oral eliglustat. Skeletal Radiol. 2014 Oct;43(10):1353-60. doi: 10.1007/s00256-014-1891-9. Epub 2014 May 10.
citation: Lukina E, Watman N, Dragosky M, Pastores GM, Arreguin EA, Rosenbaum H, Zimran A, Angell J, Ross L, Puga AC, Peterschmitt JM. Eliglustat, an investigational oral therapy for Gaucher disease type 1: Phase 2 trial results after 4 years of treatment. Blood Cells Mol Dis. 2014 Dec;53(4):274-6. doi: 10.1016/j.bcmd.2014.04.002. Epub 2014 May 15.
citation: Cox TM, Drelichman G, Cravo R, Balwani M, Burrow TA, Martins AM, Lukina E, Rosenbloom B, Goker-Alpan O, Watman N, El-Beshlawy A, Kishnani PS, Pedroso ML, Gaemers SJM, Tayag R, Peterschmitt MJ. Eliglustat maintains long-term clinical stability in patients with Gaucher disease type 1 stabilized on enzyme therapy. Blood. 2017 Apr 27;129(17):2375-2383. doi: 10.1182/blood-2016-12-758409. Epub 2017 Feb 6.
citation: Cox TM, Drelichman G, Cravo R, Balwani M, Burrow TA, Martins AM, Lukina E, Rosenbloom B, Ross L, Angell J, Puga AC. Eliglustat compared with imiglucerase in patients with Gaucher's disease type 1 stabilised on enzyme replacement therapy: a phase 3, randomised, open-label, non-inferiority trial. Lancet. 2015 Jun 13;385(9985):2355-62. doi: 10.1016/S0140-6736(14)61841-9. Epub 2015 Mar 26.