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

Gaucher Disease, Type 1 Clinical Trial

Official title:

A Phase 2, Open-Label, Multi-Center Study Evaluating the Efficacy, Safety and Pharmacokinetics of Genz-112638 in Gaucher Type 1 Patients

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT00358150
• Other study ID #: GZGD00304
• Secondary ID: 2005-004732-42
• Status: Active, not recruiting
• Phase: Phase 2
• First received: July 27, 2006
• Last updated: October 16, 2015
• Start date: June 2006
• Est. completion date: December 2015

Study information

• Verified date: October 2015
• Source: Sanofi
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug AdministrationRussia: Pharmacological Committee, Ministry of HealthIsrael: Israeli Health Ministry Pharmaceutical AdministrationArgentina: Administracion Nacional de Medicamentos, Alimentos y Tecnologia MedicaMexico: Federal Commission for Protection Against Health Risks
• Study type: Interventional

Clinical Trial Summary

Gaucher disease is a genetic disease that results in a deficiency of an enzyme acid beta-glucosidase, also known as glucocerebrosidase. This enzyme is needed to digest a substrate (lipid) called glucosylceramide and, to a lesser degree, glucosylsphingosine. In participants 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, administered as an oral dose of either 50 milligram (mg) twice daily (BID) or 100 mg BID, to men and women with Gaucher disease Type 1 for 52 weeks.

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 participant 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 (that is, participant withdrawal, the study is terminated, eliglustat tartrate becomes commercially available, or where applicable, specific regulatory requirements have been met).

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 26
• Est. completion date: December 2015
• Est. primary completion date: August 2009
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years to 65 Years

Eligibility

Inclusion Criteria:

• The participant 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 participant is 18 to 65 years old and weighs between 50 and 120 kilogram (kg) at enrollment

• The participant 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 gram per deciliter (g/dL) if female, 8 to 11 g/dL if male)

• Thrombocytopenia - indicated by platelet count measurements taken during the screening phase (60000 to 100000 per cubic millimeter)

• Splenomegaly, as indicated by magnetic resonance imaging (MRI) or spiral computed tomography (CT) (>= 10 multiples of normal)

• Female participants of child-bearing potential must have a documented negative serum pregnancy test prior to dosing. Female participants agree to use a reliable method of birth control throughout duration of trial

Exclusion Criteria:

• Participant has had a partial or total splenectomy or infarcted areas of the spleen

• Participant has documented prior bleeding varices or liver infarction

• Participant received miglustat within 12 months prior to study enrollment

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

• Participant has neurologic or pulmonary involvement

• Participant has new pathological bone involvement or bone crisis in the 12 months prior to enrollment

• Participant is transfusion-dependent

• Participant has a documented etiology of anemia due to causes other than Gaucher disease

• The participant has cardiac functional and/or anatomical abnormalities, a history of cancer or tested positive for human immunodeficiency virus (HIV) antibody or Hepatitis

• Participant 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

Study Design

Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Cerebroside Lipidosis Syndrome
• Deficiency Diseases
• Gaucher Disease
• Gaucher Disease, Non-Neuronopathic Form
• Gaucher Disease, Type 1
• Glucocerebrosidase Deficiency Disease
• Glucosylceramide Beta-Glucosidase Deficiency Disease

Intervention

Drug:
• Eliglustat tartrate
Eliglustat (Genz-112638) capsule as single 50 milligram (mg) dose on Day 1 then eliglustat 50 mg twice daily (BID) from Day 2 to Day 19, and then either eliglustat 50 mg BID (if Genz-99067 [active moiety of eliglustat in plasma] trough plasma concentration was greater than or equal to [>=] 5 nanogram per milliliter [ng/mL] on Day 10) or eliglustat 100 mg BID (if Genz-99067 trough plasma concentration was less than [<] 5 ng/mL), from day 20 to Month 48. After primary completion date (Week 52) participants underwent treatment interruption period of approximately 2 weeks before continuing the same treatment up to Month 48. Participant receiving 100 mg BID could be considered for a further dose increase to 150 mg BID at Week 24 if they met certain criteria (for example, had been on treatment for at least 24 months, had not reached therapeutic goals established for participants receiving Cerezyme), and if all other causes for lack of treatment effect had been evaluated and ruled out).

Locations

Country	Name	City	State
Argentina	Aprillus Asistencia e Investigación	Buenos Aires
Argentina	Hospital de Oncologia Maria Curie	Buenos Aires
Argentina	IMAI	Buenos Aires
Argentina	Instituto Argentino de Diagnostico y Tratamiento (IADT)	Buenos Aires
Argentina	Hospital Ramos Mejia	Ciudad Autonoma de Buenos Aires
Israel	Rambam Medical Center	Haifa
Israel	Sha'are Zedek Medical Centre	Jerusalem
Italy	Universita degli Studi di Milano	Milano
Mexico	Instituto Mexicano del Seguro Social	D.f.
Russian Federation	Hematology Research Center of Ministry of Healthcare of the Russian Federation	Moscow
United States	New York University	New York	New York

Sponsors (1)

Lead Sponsor	Collaborator
Genzyme, a Sanofi Company

Countries where clinical trial is conducted

United States,  Argentina,  Israel,  Italy,  Mexico,  Russian Federation, 

References & Publications (6)

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. Sk — 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 red — 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 ty — 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 Ce — 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

Peterschmitt MJ, Burke A, Blankstein L, Smith SE, Puga AC, Kramer WG, Harris JA, Mathews D, Bonate PL. Safety, tolerability, and pharmacokinetics of eliglustat tartrate (Genz-112638) after single doses, multiple doses, and food in healthy volunteers. J Clin Pharmacol. 2011 May;51(5):695-705. doi: 10.1177/0091270010372387. Epub 2010 Sep 23. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Change From Baseline in Biomarkers (Angiotensin Converting Enzyme [ACE], Tartrate-Resistant Acid Phosphatase [TRAP], Chemokine Ligand 18 [CCL18], Chitotriosidase) at Month 48		Baseline, Month 48	No
Other	Participant Reported Quality of Life: Change From Baseline in Medical Outcomes Study 36-Item Short Form (SF-36) Health Survey at Month 48		Baseline, Month 48	No
Other	Participant Reported Quality of Life: Fatigue Severity Scale Survey at Month 48		Baseline, Month 48	No
Other	Change From Baseline in Mobility, Bone Pain, and Bone Crisis at Month 48		Baseline, Month 48	No
Other	Change From Baseline in Radiographic Measures of Bone Disease at Month 48		Baseline, Month 48	No
Primary	Percentage of Participants Demonstrating A Meaningful Clinical Response	A meaningful clinical response was defined as an improvement in at least 2 of the 3 main efficacy parameters: a) an increase in hemoglobin of greater than or equal to (>=) 0.5 gram/deciliter from baseline, b) an increase in platelets of >=15 percent (%) from baseline, c) reduction in total spleen volume of >= 15% from baseline. As hemoglobin, platelets, total spleen volume were abnormal at baseline, within each participant, only those parameters were used in the evaluation of meaningful clinical response which were abnormal at baseline.	Baseline, Week 52	No
Secondary	Percent Change From Baseline in Spleen Volume at Month 48	Percent change in spleen volume = ([spleen volume at Month 48 minus spleen volume at baseline] divided by [spleen volume at baseline]) multiplied by 100, where all volumes are in multiples of normal.	Baseline, Month 48	No
Secondary	Percent Change From Baseline in Liver Volume at Month 48	Percent change in liver volume = ([liver volume at Month 48 minus liver volume at baseline] divided by [liver volume at baseline]) multiplied by 100, where all volumes are in multiples of normal.	Baseline, Month 48	No
Secondary	Absolute Change From Baseline in Hemoglobin at Month 48	Absolute change = hemoglobin level at Month 48 minus hemoglobin level at baseline.	Baseline, Month 48	No
Secondary	Percent Change From Baseline in Platelet Count at Month 48	Percent change in platelet count = ([platelet count at Month 48 minus platelet count at baseline] divided by [platelet count at baseline]) multiplied by 100.	Baseline, Month 48	No