A Study of the Efficacy and Safety of Eliglustat Tartrate (Genz-112638) in Type 1 Gaucher Patients - Full Text View

Sponsor:	Genzyme
Information provided by (Responsible Party):	Genzyme
ClinicalTrials.gov Identifier:	NCT00358150

Purpose

Gaucher disease is a genetic disease that results in a deficiency of an enzyme acid β-glucosidase, also known as glucocerebrosidase. This enzyme is needed to digest a substrate (lipid) called glucosylceramide and, to a lesser degree, glucosphingosine. In patients with Gaucher disease, the liver, spleen, bone marrow and brain show increases in lipid concentration, specifically in cells derived from the monocyte/macrophage system.

Eliglustat tartrate (Genz-112638) is an oral drug that may regulate the Gaucher disease process by decreasing the synthesis of glucosylceramide. The primary objective of this study is to evaluate the efficacy, safety and pharmacokinetics (PK) of eliglustat tartrate (Genz-112638), administered as an oral dose of either 50mg twice daily (BID) or 100mg BID, to men and women with Gaucher disease Type 1 for 52 weeks.

Condition	Intervention	Phase
Gaucher Disease, Type 1 Cerebroside Lipidosis Syndrome Glucocerebrosidase Deficiency Disease Glucosylceramide Beta-Glucosidase Deficiency Disease Gaucher Disease, Non-Neuronopathic Form	Drug: eliglustat tartrate	Phase II

Study Type:	Interventional
Study Design:	Endpoint Classification: Safety/Efficacy Study Intervention Model: Single Group Assignment Masking: Open Label Primary Purpose: Treatment
Official Title:	A Phase 2, Open-Label, Multi-Center Study Evaluating the Efficacy, Safety and Pharmacokinetics of Genz-112638 in Gaucher Type 1 Patients

Resource links provided by NLM:

Genetics Home Reference related topics: argininosuccinic aciduria ataxia neuropathy spectrum carbamoyl phosphate synthetase I deficiency Chanarin-Dorfman syndrome childhood myocerebrohepatopathy spectrum cholesteryl ester storage disease citrullinemia deoxyguanosine kinase deficiency Farber lipogranulomatosis Gaucher disease mitochondrial neurogastrointestinal encephalopathy disease myoclonic epilepsy myopathy sensory ataxia N-acetylglutamate synthase deficiency ornithine translocase deficiency Schindler disease succinic semialdehyde dehydrogenase deficiency

MedlinePlus related topics: Gaucher's Disease

U.S. FDA Resources

Further study details as provided by Genzyme:

Primary Outcome Measures:

Proportion of patients demonstrating a meaningful clinical response [ Time Frame: Baseline to Week 52 ] [ Designated as safety issue: No ]
A meaningful clinical response is defined as an improvement in at least 2 of the 3 main efficacy parameters what were abnormal at study entry (hemoglobin, platelets, and/or spleen volume). Within each patient, only those parameters that were abnormal at Baseline will be used in the evaluation of meaningful clinical response. Responses are defined as:
- an increase in hemoglobin of ≥ 0.5 g/dL
- an increase in platelets of ≥ 15%
- reduction of ≥ 15% in total spleen volume
Incidence of reported Adverse Events (AEs) and Serious Adverse Events (SAEs) [ Time Frame: Up to Week 52 ] [ Designated as safety issue: Yes ]
Pharmacokinetics as measured by terminal elimination rate constant (λ), [ Time Frame: Up to Week 52 ] [ Designated as safety issue: No ]
Pharmacokinetics as measured by minimum concentration (Cmin) [ Time Frame: Up to Week 52 ] [ Designated as safety issue: No ]
Pharmacokinetics as measured by maximum concentration (Cmax) [ Time Frame: Up to Week 52 ] [ Designated as safety issue: No ]
Pharmacokinetics as measured by time to maximum observed concentration (tmax) [ Time Frame: Up to Week 52 ] [ Designated as safety issue: No ]
Pharmacokinetics as measured by area under the concentration time curve (AUC) [ Time Frame: Up to Week 52 ] [ Designated as safety issue: No ]
Pharmacokinetics as measured by volume of distribution during the terminal elimination phase (Vz/F) [ Time Frame: Up to Week 52 ] [ Designated as safety issue: No ]
Pharmacokinetics as measured by apparent oral clearance (CL/F) [ Time Frame: Up to Week 52 ] [ Designated as safety issue: No ]
Pharmacokinetics as measured by half-life (t1/2) [ Time Frame: Up to Week 52 ] [ Designated as safety issue: No ]

Secondary Outcome Measures:

Change in liver volume compared to baseline [ Time Frame: Baseline to Week 52 ] [ Designated as safety issue: No ]
Change from baseline in biomarkers (Angiotensin Converting Enzyme [ACE], Tartrate-Resistant Acid Phosphatase [TRAP], CCL18, chitotriosidase) and exploratory biomarkers (e.g., GL-1, GL-3, GM3, sphingomyelin, ceramide, and HbA1c) [ Time Frame: Baseline to Week 52 ] [ Designated as safety issue: No ]
Changes in patient-reported Quality of Life [ Time Frame: Baseline to Week 52 ] [ Designated as safety issue: No ]
Changes in mobility, bone pain, bone crisis [ Time Frame: Baseline to Week 52 ] [ Designated as safety issue: No ]
Changes in radiographic measures of bone disease [ Time Frame: Baseline to Week 52 ] [ Designated as safety issue: No ]
Percent change in spleen volume [ Time Frame: Baseline to study completion ] [ Designated as safety issue: No ]
Study completion refers to (i.e., patient withdrawal, the study is terminated, Genz-112638 becomes commercially available, or where applicable, specific regulatory requirements have been met)
Percent change in liver volume [ Time Frame: Baseline to study completion ] [ Designated as safety issue: No ]
Study completion refers to (i.e., patient withdrawal, the study is terminated, Genz-112638 becomes commercially available, or where applicable, specific regulatory requirements have been met)
Absolute changes in hemoglobin [ Time Frame: Baseline to study completion ] [ Designated as safety issue: No ]
Study completion refers to (i.e., patient withdrawal, the study is terminated, Genz-112638 becomes commercially available, or where applicable, specific regulatory requirements have been met)
Percent change in platelets [ Time Frame: Baseline to study completion ] [ Designated as safety issue: No ]
Study completion refers to (i.e., patient withdrawal, the study is terminated, Genz-112638 becomes commercially available, or where applicable, specific regulatory requirements have been met)
Incidence of reported AEs and SAEs [ Time Frame: Baseline to study completion ] [ Designated as safety issue: Yes ]
Study completion refers to (i.e., patient withdrawal, the study is terminated, Genz-112638 becomes commercially available, or where applicable, specific regulatory requirements have been met)

Enrollment:	26
Study Start Date:	June 2006
Estimated Study Completion Date:	December 2015
Primary Completion Date:	September 2008 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
Experimental: eliglustat tartrate (Genz-112638)	Drug: eliglustat tartrate 50mg, 100 mg or 150mg Capsules, BID (twice daily) Other Name: Genz-112638

Detailed Description:

This study consists of several phases: Screening (-28 to -1 days), dose adjustment/treatment (Day 1 [treatment baseline] to Day 30), initial steady-state treatment (post-Day 30 through Week 52 post-baseline), a treatment interruption period (Week 52 through approximately Week 54), long-term steady-state treatment (approximately Week 54 through study completion), and safety follow-up (30 to 37 days after a patient withdraws from or completes the study). The Primary Analysis Period is from baseline through Week 52. The Extension Period is from Week 52 through study completion (i.e., patient withdrawal, the study is terminated, Genz-112638 becomes commercially available, or where applicable, specific regulatory requirements have been met).

Eligibility

Ages Eligible for Study:	18 Years to 65 Years
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

Criteria

INCLUSION CRITERIA:

The patient has a diagnosis of Gaucher Type I disease and a documented deficiency of glucocerebrosidase activity by enzyme assay and is willing and able to provide written informed consent prior to initiating any study-related procedures.
The patient is 18 to 65 years old and weighs between 50 and 120 kg at enrollment
The patient has the following symptoms of Gaucher disease identified within 28 days of enrollment (at Screening):
- Anemia - indicated by hemoglobin measurements taken during the screening phase (8 to 10 g/dL if female, 8 to 11 g/dL if male)
- Thrombocytopenia - indicated by platelet count measurements taken during the screening phase (60,000 to 100,000 /mm3)
- Splenomegaly, as indicated by magnetic resonance imaging (MRI) or spiral computed tomography (CT) (>= 10 multiples of normal)
Female patients of child-bearing potential must have a documented negative serum pregnancy test prior to dosing. Male and female patients agree to use a reliable method of birth control throughout duration of trial.

EXCLUSION CRITERIA:

Patient has had a partial or total splenectomy or infarcted areas of the spleen.
Patient has documented prior bleeding varices or liver infarction.
Patient received miglustat within 12 months prior to study enrollment
The patient has received an investigational product within 30 days prior to study enrollment.
Patient has neurologic or pulmonary involvement.
Patient has new pathological bone involvement or bone crisis in the 12 months prior to enrollment.
Patient is transfusion-dependent.
Patient has a documented etiology of anemia due to causes other than Gaucher disease.
The patient has cardiac functional and/or anatomical abnormalities, a history of cancer or tested positive for human immunodeficiency virus (HIV) antibody or Hepatitis
Patient has a clinically significant disease, other than Gaucher disease, including cardiovascular, renal, hepatic, gastrointestinal, pulmonary, neurologic, endocrine, metabolic, or psychiatric disease, other medical conditions, or serious intercurrent illnesses that, in the opinion of the Investigator, may preclude participation in the study.

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT00358150

Locations

United States, New York

New York, New York, United States
Argentina

Buenos Aires, Argentina
Israel

Haifa, Israel

Jerusalem, Israel
Mexico

Mexico City, Mexico
Russian Federation

Moscow, Russian Federation

Sponsors and Collaborators

Genzyme

Investigators

Study Director:

Medical Monitor

Genzyme

More Information

Publications:

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. Epub 2010 May 3.

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. Epub 2010 Aug 16.

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.

Responsible Party:	Genzyme
ClinicalTrials.gov Identifier:	NCT00358150 History of Changes
Other Study ID Numbers:	GZGD00304
Study First Received:	July 27, 2006
Last Updated:	December 16, 2011
Health Authority:	United States: Food and Drug Administration; Russia: Pharmacological Committee, Ministry of Health; Israel: Israeli Health Ministry Pharmaceutical Administration; Argentina: Administracion Nacional de Medicamentos, Alimentos y Tecnologia Medica; Mexico: Federal Commission for Protection Against Health Risks

Keywords provided by Genzyme:

Type 1 Gaucher Disease
Glucocerebrosidase Deficiency Disease

Additional relevant MeSH terms:

Deficiency Diseases
Carbamoyl-Phosphate Synthase I Deficiency Disease
Gaucher Disease
Lipidoses
Malnutrition
Nutrition Disorders
Urea Cycle Disorders, Inborn
Brain Diseases, Metabolic, Inborn
Brain Diseases, Metabolic
Brain Diseases
Central Nervous System Diseases

Nervous System Diseases
Amino Acid Metabolism, Inborn Errors
Metabolism, Inborn Errors
Genetic Diseases, Inborn
Metabolic Diseases
Mitochondrial Diseases
Sphingolipidoses
Lysosomal Storage Diseases, Nervous System
Lipid Metabolism, Inborn Errors
Lysosomal Storage Diseases
Lipid Metabolism Disorders

ClinicalTrials.gov processed this record on February 09, 2012