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

NCT00943111 | Completed Phase 3 Results DMC

• 3 other identifiers: GZGD026072008-005223-28EFC12812
• Study Type: interventional
• Target: 160
• Locations: 12 countries
• Sites: 34

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).

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

Outcome Measures

Primary Outcomes (2)

• 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 Outcomes (15)

• Total T-Scores for Bone Mineral Density

  Baseline

• Absolute Change From Baseline in Total T-Scores for Bone Mineral Density at Week 52

  Baseline, Week 52

• Total Z-Scores for Bone Mineral Density

  Baseline

• Absolute Change From Baseline in Total Z-Scores for Bone Mineral Density at Week 52

  Baseline, Week 52

• Hemoglobin Level

  Baseline

Study Arms (2)

Investigational

EXPERIMENTAL

Eliglustat tartrate

Drug: Eliglustat tartrate

Imiglucerase

ACTIVE COMPARATOR

Drug: Imiglucerase

Interventions

Eliglustat tartrate DRUG

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.

Also known as: Genz-112638

Investigational

Imiglucerase DRUG

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.

Also known as: Cerezyme®

Imiglucerase

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Genzyme, a Sanofi Company: lead

Study Sites (34)

Tower Hematology Oncology Medical Group

Beverly Hills, California, United States

Location

UCSF MS Center

San Francisco, California, United States

Location

University of Colorado Health Science Center - Aurora

Aurora, Colorado, United States

Location

Yale University School of Medicine

New Haven, Connecticut, United States

Location

Northwest Oncology Hematology Associates PA

Coral Springs, Florida, United States

Location

Emory University Medical Genetics

Decatur, Georgia, United States

Location

Children's Memorial Hospital

Chicago, Illinois, United States

Location

University of Iowa Hospitals and Clinics

Iowa City, Iowa, United States

Location

Albany Medical Center

Albany, New York, United States

Location

North Shore University Medical Center

Manhasset, New York, 11030, United States

Location

Mount Sinai School of Medicine

New York, New York, United States

Location

New York University School of Medicine

New York, New York, United States

Location

Duke University Medical Center

Durham, North Carolina, United States

Location

Cincinnati Children's Hospital Medical Center

Cincinnati, Ohio, United States

Location

Children's Hospital of Philadelphia

Philadelphia, Pennsylvania, United States

Location

University of Pittsburgh Medical Center

Pittsburgh, Pennsylvania, United States

Location

O and O Alpan LLC

Springfield, Virginia, United States

Location

Hospital General de Agudos J.M Ramos Mejia

Buenos Aires, Argentina

Location

Hospital General de Ninos Dr. Ricardo Gutierrez

Buenos Aires, Argentina

Location

Royal Perth Hospital

Perth, WA, Australia

Location

Hospital de Clinicas da Universidade Federal do Parana

Curitiba, Brazil

Location

Instituto de Estadual de Hematologia Arthur de Siqueria Cavalcanti

Rio de Janeiro, Brazil

Location

IGEIM

São Paulo, Brazil

Location

Mount Sinai Hospital and the Samuel Lunenfeld Research Institute

Toronto Ontario, Canada

Location

Abou El Reesh Children's University Hospital (El Mounira), Faculty of Medicine (Kasr Al-Aini), Cairo University Hospitals, El Mounira, Cairo, Egypt

Cairo, Egypt

Location

Hôpital Beaujon

Clichy, France

Location

Charité Universitätsmedizin Berlin

Berlin, Germany

Location

Asklepios Klinik St. Georg

Hamburg, Germany

Location

Katholische Kliniken Oberhausen gem. GmbH

Oberhausen, Germany

Location

Azienda Ospedaliero Universitaria Careggi

Florence, Italy

Location

Azienda Ospedialiero-Universitaria S. Maria Della Misericordia

Udine, Italy

Location

Hematology Research Center of Ministry of Healthcare of the Russian Federation

Moscow, Russia

Location

Hospital University Miguel Servet

Zaragoza, Spain

Location

Cambridge University Hosptials, Addenbrookes Hospital

Cambridge, United Kingdom

Location

Related Publications (7)

• 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.

  PMID: 20439622 BACKGROUND

• 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.

  PMID: 20713962 BACKGROUND

• 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.

  PMID: 17509920 BACKGROUND

• 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.

  PMID: 24816856 BACKGROUND

• 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.

  PMID: 24835462 BACKGROUND

• 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.

  PMID: 28167660 DERIVED

• 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.

  PMID: 25819691 DERIVED

MeSH Terms

Conditions

Gaucher Disease

Interventions

eliglustat; imiglucerase

Condition Hierarchy (Ancestors)

Sphingolipidoses; Lysosomal Storage Diseases, Nervous System; Brain Diseases, Metabolic, Inborn; Brain Diseases, Metabolic; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Metabolism, Inborn Errors; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Lipidoses; Lipid Metabolism, Inborn Errors; Lysosomal Storage Diseases; Metabolic Diseases; Nutritional and Metabolic Diseases; Lipid Metabolism Disorders

Results Point of Contact

• Title: Trial Transparency Team
• Organization: Sanofi

Contact-us@sanofi.com

Study Officials

• Medical Monitor

  Genzyme, a Sanofi Company

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: July 20, 2009
• First Posted: July 22, 2009
• Study Start: September 1, 2009
• Primary Completion: November 1, 2012
• Study Completion: June 1, 2015
• Last Updated: November 25, 2016
• Results First Posted: September 4, 2014

Record last verified: 2016-10

Locations

AU (1); GB (1); AR (2); BR (3); ES (1); US (17); CA (1); FR (1); DE (3); IT (2); EG (1); RU (1)