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

Gaucher Disease, Type 1 Clinical Trial

— 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)

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT00943111
• Other study ID #: GZGD02607
• Secondary ID: 2008-005223-28EF
• Status: Active, not recruiting
• Phase: Phase 3
• First received: July 20, 2009
• Last updated: August 22, 2014
• Start date: September 2009
• Est. completion date: May 2015

Study information

• Verified date: August 2014
• Source: Sanofi
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug AdministrationArgentina: Administracion Nacional de Medicamentos, Alimentos y Tecnologia MedicaAustralia: Therapeutic Goods Administration'Brazil: Ministry of HealthBrazil: Ministry of HealthCanada: Health CanadaEgypt: Ministry of Health and PopulationFrance: Ministry of HealthGermany: Ministry of HealthItaly: Ministry of HealthRussia: Ministry of Health of the Russian FederationSpain: Ministry of HealthUnited Kingdom: Medicines and Healthcare Products Regulatory Agency
• Study type: Interventional

Clinical Trial Summary

This Phase 3 study is designed to confirm the efficacy and safety of eliglustat tartrate (Genz-112638) in participants with Gaucher disease type 1 who have reached therapeutic goals with enzyme replacement therapy (ERT).

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 is designed to determine the efficacy, safety, and pharmacokinetics (PK) of eliglustat tartrate in adult participants with Gaucher disease type 1 who have been stabilized on ERT.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 160
• Est. completion date: May 2015
• Est. primary completion date: November 2012
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• The participant (and/or their parent/legal guardian) is willing and able to provide signed informed consent prior to any study-related procedures to be performed

• The participant is at least 18 years old at the time of randomization

• The participant has a confirmed diagnosis of Gaucher disease type 1

• The participant has received treatment with ERT for at least 3 years. Within the 9 months prior to randomization, the participant has received a total monthly dose of 30 to 130 Units/kilogram for at least 6 months

• The participant has reached Gaucher disease therapeutic goals prior to randomization

• Female participants of childbearing potential must have 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 has had a partial or total splenectomy within 3 years prior to randomization

• The participant has received substrate reduction therapies for Gaucher disease within 6 months prior to randomization

• The participant has Gaucher disease type 2 or 3 or is suspected of having Gaucher disease type 3

• The participant has 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 has tested positive for the human immunodeficiency virus (HIV) antibody, Hepatitis C antibody, or Hepatitis B surface antigen

• The participant has received an investigational product within 30 days prior to randomization

• The participant is pregnant or lactating

Study Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Gaucher Disease
• Gaucher Disease, Type 1

Intervention

Drug:
• Eliglustat tartrate
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. The 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] the next higher dose was administered whereas if the Genz-99067 trough plasma concentration was greater than or equal to [>=] 5 ng/mL the same dose was continued. The pharmacokinetic (PK) assessment at Week 2 and Week 6 were used for dose adjustment after Week 4 and Week 8, respectively.
• Imiglucerase
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.

Locations

Country	Name	City	State
Argentina	Hospital General de Agudos J.M Ramos Mejia	Buenos Aires
Argentina	Hospital General de Ninos Dr. Ricardo Gutierrez	Buenos Aires
Australia	Royal Perth Hospital	Perth, WA
Brazil	Hospital de Clinicas da Universidade Federal do Parana	Curitiba
Brazil	Instituto de Estadual de Hemarologia Arthur de Siqueria Cavalcanti	Rio de Janeiro
Brazil	IGEIM	São Paulo
Canada	Mount Sinai Hospital and the Samuel Lunenfeld Research Institute	Toronto Ontario
Egypt	Abou El Reesh Children's University Hospital (El Mounira), Faculty of Medicine (Kasr Al-Aini), Cairo University Hospitals, El Mounira, Cairo, Egypt	Cairo
France	Hôpital Beaujon	Clichy
Germany	Charité Universitätsmedizin Berlin	Berlin
Germany	Asklepios Klinik St. Georg	Hamburg
Germany	Katholische Kliniken Oberhausen gem. GmbH	Oberhausen
Italy	Azienda Ospedaliero Universitaria Careggi	Firenze
Italy	Azienda Ospedialiero-Universitaria S. Maria Della Misericordia	Udine
Russian Federation	Hematology Research Center of Ministry of Healthcare of the Russian Federation	Moscow
Spain	Hospital University Miguel Servet	Zaragoza
United Kingdom	Cambridge University Hosptials, Addenbrookes Hospital	Cambridge
United States	Albany Medical Center	Albany	New York
United States	University of Colorado Health Science Center - Aurora	Aurora	Colorado
United States	Tower Hematology Oncology Medical Group	Beverly Hills	California
United States	Children's Memorial Hospital	Chicago	Illinois
United States	Cincinnati Children's Hospital Medical Center	Cincinnati	Ohio
United States	Northwest Oncology Hematology Associates PA	Coral Springs	Florida
United States	Emory University Medical Genetics	Decatur	Georgia
United States	Duke University Medical Center	Durham	North Carolina
United States	University of Iowa Hospitals and Clinics	Iowa City	Iowa
United States	North Shore University Medical Center	Manhasset	New York
United States	Yale University School of Medicine	New Haven	Connecticut
United States	Mount Sinai School of Medicine	New York	New York
United States	New York University School of Medicine	New York	New York
United States	Children's Hospital of Philadelphia	Philadelphia	Pennsylvania
United States	University of Pittsburgh Medical Center	Pittsburgh	Pennsylvania
United States	UCSF MS Center	San Francisco	California
United States	O and O Alpan LLC	Springfield	Virginia

Sponsors (1)

Lead Sponsor	Collaborator
Genzyme, a Sanofi Company

Countries where clinical trial is conducted

United States,  Argentina,  Australia,  Brazil,  Canada,  Egypt,  France,  Germany,  Italy,  Russian Federation,  Spain,  United Kingdom, 

References & Publications (5)

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. — View 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. — View 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. Erratum in: Blood. 2011 May 19;117(20):5551. — View 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. — View 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. Epub 2007 May 16. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	No
Secondary	Total T-Scores for Bone Mineral Density	Images of the spine and bilateral femur were obtained by dual energy X-Ray absorptiometry (DXA) to determine T-score for each bone area and total bone mineral density. T-score compares participant's bone density with that of healthy young participant. The T-score bone density categories are: normal (score greater than [>]-1), osteopenia (score -2.5 to less than or equal to [<=] -1), and osteoporosis (score <= -2.5).	Baseline	No
Secondary	Absolute Change From Baseline in Total T-Scores for Bone Mineral Density at Week 52	Images of the spine and bilateral femur were obtained by dual energy X-Ray absorptiometry (DXA) to determine T-score for each bone area and total bone mineral density. T-score compares participant's bone density with that of healthy young participant. The T-score bone density categories are: normal (score greater than [>]-1), osteopenia (score -2.5 to less than or equal to [<=] -1), and osteoporosis (score <= -2.5). Absolute change = T-score at Week 52 minus T-score at baseline.	Baseline, Week 52	No
Secondary	Total Z-Scores for Bone Mineral Density	Images of the spine and bilateral femur were obtained by dual energy X-Ray absorptiometry (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	No
Secondary	Absolute Change From Baseline in Total Z-Scores for Bone Mineral Density at Week 52	Images of the spine and bilateral femur were obtained by dual energy X-Ray absorptiometry (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). Absolute change = Z-score at Week 52 minus Z-score at baseline.	Baseline, Week 52	No
Secondary	Hemoglobin Level		Baseline	No
Secondary	Absolute Change From Baseline in Hemoglobin Levels at Week 52	Absolute change = hemoglobin level at Week 52 minus hemoglobin level at baseline.	Baseline, Week 52	No
Secondary	Percent Change From Baseline in Platelet Counts at Week 52	Percent change in platelet counts = ([platelet count at Week 52 minus platelet count at baseline] divided by [platelet count at baseline]) multiplied by 100.	Baseline, Week 52	No
Secondary	Percent Change From Baseline in Spleen Volume (in Multiplies of Normal [MN]) at Week 52	Percent change in spleen volume = ([spleen volume at Week 52 minus spleen volume at baseline] divided by [spleen volume at baseline]) multiplied by 100, where all volumes are in MN.	Baseline, Week 52	No
Secondary	Percent Change From Baseline in Liver Volume (in MN) at Week 52	Percent change in liver volume = ([liver volume at Week 52 minus liver volume at baseline] divided by [liver volume at baseline]) multiplied by 100, where all volumes are in multiples of normal.	52 weeks	No

External Links

•   A phase 2 study of eliglustat tartrate (Genz-112638), an oral substrate reduction therapy for Gaucher disease type 1