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

This study has been completed.
Sponsor:
ClinicalTrials.gov Identifier:
NCT00358150
First Posted: July 31, 2006
Last Update Posted: February 15, 2017
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
Information provided by (Responsible Party):
Sanofi ( Genzyme, a Sanofi Company )
  Purpose

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.


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 2

Study Type: Interventional
Study Design: Intervention Model: Single Group Assignment
Masking: None (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:


Further study details as provided by Sanofi ( Genzyme, a Sanofi Company ):

Primary Outcome Measures:
  • Percentage of Participants Demonstrating A Meaningful Clinical Response [ Time Frame: Baseline, Year 1 ]
    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.


Secondary Outcome Measures:
  • Percent Change From Baseline in Spleen Volume at Year 1, Year 2, Year 3, Year 4, Year 5, Year 6, Year 7, Year 8, Year 9 and at End of Study [ Time Frame: Baseline, Year 1, Year 2, Year 3, Year 4, Year 5, Year 6, Year 7, Year 8, Year 9 and at End of Study (Up to Year 9) ]
    Percent change in spleen volume = ([spleen volume at specified time points minus spleen volume at baseline] divided by [spleen volume at baseline]) multiplied by 100, where all volumes are in multiples of normal.

  • Percent Change From Baseline in Liver Volume at Year 1, Year 2, Year 3, Year 4, Year 5, Year 6, Year 7, Year 8, Year 9 and at End of Study [ Time Frame: Baseline, Year 1, Year 2, Year 3, Year 4, Year 5, Year 6, Year 7, Year 8, Year 9 and at End of Study (Up to Year 9) ]
    Percent change in liver volume = ([liver volume at specified time points minus liver volume at baseline] divided by [liver volume at baseline]) multiplied by 100, where all volumes are in multiples of normal.

  • Absolute Change From Baseline in Hemoglobin at Year 1, Year 2, Year 3, Year 4, Year 5, Year 6, Year 7, Year 8, Year 9 and at End of Study [ Time Frame: Baseline, Year 1, Year 2, Year 3, Year 4, Year 5, Year 6, Year 7, Year 8, Year 9 and at End of Study (Up to Year 9) ]
    Absolute change = hemoglobin level at specified time points minus hemoglobin level at baseline.

  • Percent Change From Baseline in Platelet Count at Year 1, Year 2, Year 3, Year 4, Year 5, Year 6, Year 7, Year 8, Year 9 and at End of Study [ Time Frame: Baseline, Year 1, Year 2, Year 3, Year 4, Year 5, Year 6, Year 7, Year 8, Year 9 and at End of Study (Up to Year 9) ]
    Percent change in platelet count = ([platelet count at specified time points minus platelet count at baseline] divided by [platelet count at baseline]) multiplied by 100.

  • Percent Change From Baseline in Biomarker (Angiotensin Converting Enzyme) Level at Year 1, Year 2, Year 3, Year 4, Year 5, Year 6, Year 7, Year 8, Year 9 and at End of Study [ Time Frame: Baseline, Year 1, Year 2, Year 3, Year 4, Year 5, Year 6, Year 7, Year 8, Year 9 and End of Study (Up to Year 9) ]
  • Percent Change From Baseline in Biomarker (Tartrate-Resistant Acid Phosphatase [TRAP]) Level at Year 1 and Year 2 [ Time Frame: Baseline, Year 1, Year 2 ]
  • Percent Change From Baseline in Biomarker Chemokine Ligand 18 (CCL18) Level at Year 1, Year 2, Year 3, Year 4, Year 5, Year 6, Year 7, Year 8, Year 9 and End of Study [ Time Frame: Baseline, Year 1, Year 2, Year 3, Year 4, Year 5, Year 6, Year 7, Year 8, Year 9 and End of Study (Up to Year 9) ]
  • Percent Change From Baseline in Biomarker (Chitotriosidase) Level at Year 1, Year 2, Year 3, Year 4, Year 5, Year 6, Year 7, Year 8, Year 9 and at End of Study [ Time Frame: Baseline, Year 1, Year 2, Year 3, Year 4, Year 5, Year 6, Year 7, Year 8, Year 9 and at End of Study (Up to Year 9) ]
  • Change From Baseline in 36-Item Short Form (SF-36) Health Survey Scores at Baseline, Year 1, Year 2, Year 3, Year 4, Year 5, Year 6, Year 7, Year 8 and Year 9 at End of Study [ Time Frame: Baseline, Year 1, Year 2, Year 3, Year 4, Year 5, Year 6, Year 7, Year 8, Year 9 and at End of Study (Up to Year 9) ]
    The SF-36 questionnaire, version 2, investigates the participant's health-related quality of life (HRQL). It is a 36-item questionnaire measuring 8 domains (physical functioning, role-physical, bodily pain, general health, vitality, social functioning, role emotional, and mental health). Each domain score ranges from 0 (worst) to 100 (best), with higher scores reflecting best health-related quality of life. Two summary scale scores were computed from the 8 domain scores: the Physical Component Summary and the Mental Component Summary. Score range for both summary scale ranges from 0 (worst) to 100 (best), with higher scores reflecting best health-related quality of life.

  • Change From Baseline in Fatigue Severity Scale (FSS) Scores at Baseline, Year 1, Year 2, Year 3, Year 4, Year 5, Year 6, Year 7, Year 8, Year 9 and at End of Study [ Time Frame: Baseline, Year 1, Year 2, Year 3, Year 4, Year 5, Year 6, Year 7, Year 8, Year 9 and at End of Study (Up to Year 9) ]
    The FSS is an instrument consisting of 9 self-administered questions that measures the impact of severity of fatigue symptoms on everyday functioning, based on the recall over the past week. Score range for each question ranges from 1 (minimum) to 7 (maximum), where higher score indicates greater severity. FSS total score was calculated by averaging the results of all questions. Total FSS score ranges from 9 (minimum) to 63 (maximum), where higher scores indicates greater severity.

  • Number of Participants With Bone Pain Levels During the Past 4 Weeks at Baseline, Year 1, Year 2, Year 3, Year 4, Year 5, Year 6, Year 7, Year 8, Year 9 and at End of Study [ Time Frame: Baseline, Year 1, Year 2, Year 3, Year 4, Year 5, Year 6, Year 7, Year 8, Year 9 and at End of Study (Up to Year 9) ]
    Bone pain was assessed as a part of Gaucher disease assessment in participants. Participants were categorized as none (no bone pain), very mild bone pain, mild bone pain and moderate bone pain. In this outcome, number of participants with different levels of bone pain at specified time points were reported.

  • Number of Participants With Mobility Status (MS) at Baseline, Year 1, Year 2, Year 3, Year 4, Year 5, Year 6, Year 7, Year 8, Year 9 and at End of Study [ Time Frame: Baseline, Year 1, Year 2, Year 3, Year 4, Year 5, Year 6, Year 7, Year 8, Year 9 and at End of Study (Up to Year 9) ]
    Mobillity, i.e. ability to walk was assessed as a part of Gaucher disease assessment in participants.In this outcome, number of participants with their different mobility status (unrestricted mobility, walks with difficulty) at specified time points were reported.

  • Number of Participants With No Bone Crisis at Baseline, Year 1, Year 2, Year 3, Year 4, Year 5, Year 6, Year 7, Year 8, Year 9 and at End of Study [ Time Frame: Baseline, Year 1, Year 2, Year 3, Year 4, Year 5, Year 6, Year 7, Year 8, Year 9 and at End of Study (Up to Year 9) ]
    Bone crisis was assessed as a part of Gaucher disease assessment in participants. Acute, excruciating episodic bone pain is characteristic of Gaucher bone crisis, which typically causes debilitation lasting several days or longer and requires treatment with immobilization, hydration, and opioid analgesics. Participants were categorized as 0= no bone crisis, 1= 1 bone crisis, and 2= 2 bone crises during the assessment period. In this outcome, number of participants with 0= no bone crises levels at specified time points were reported.

  • Bone Marrow Infiltration: Number of Participants With Improvement From Baseline in Dark Marrow at Year 1, Year 2, Year 3, Year 4, Year 5, Year 6, Year 7, Year 8 and at End of Study (EOS) [ Time Frame: Baseline, Year 1, Year 2, Year 3, Year 4, Year 5, Year 6, Year 7, Year 8 and at End of Study (up to Year 9) ]
    Bone marrow infiltration assessments were designed to evaluate improvements in dark marrow using MRI. Each MRI assessment was performed for both femurs and consisted of reviewing 6 different zones (the femoral head, greater trochanter, intertrochanteric region, shaft, distal metaphysis, and condyles). MRI images recorded dark marrow for each zone as either present or not present at baseline. In this outcome, number of participants (for whom dark marrow was present at baseline) with improvement from baseline in dark marrow at each specified time point were reported.

  • Lumbar Spine and Femur T-Scores for Bone Mineral Density (BMD) at Baseline, Year 1, Year 2, Year 3, Year 4, Year 5, Year 6, Year 7, Year 8, Year 9 and at End of Study [ Time Frame: Baseline, Year 1, Year 2, Year 3, Year 4, Year 5, Year 6, Year 7, Year 8, Year 9 and at End of Study (up to Year 9) ]
    Images of the lumbar spine and femur were obtained by dual energy X-ray absorptiometry (DXA) to determine T-score for each bone area and total bone mineral density. T-scores compares participant's bone density with that of healthy young participant of same gender. The T-score bone density categories were: normal (score >-1), osteopenia (score -2.5 to <=-1), and osteoporosis (score <= -2.5).

  • Lumbar Spine and Femur Z-Scores for BMD at Baseline, Year 1, Year 2, Year 3, Year 4, Year 5, Year 6, Year 7, Year 8, Year 9 and at End of Study [ Time Frame: Baseline, Year 1, Year 2, Year 3, Year 4, Year 5, Year 6, Year 7, Year 8, Year 9 and at End of Study (up to Year 9) ]
    Images of the lumbar spine and femur were obtained by 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).


Enrollment: 26
Study Start Date: June 2006
Study Completion Date: December 2015
Primary Completion Date: August 2009 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Eliglustat tartrate Drug: Eliglustat tartrate
Eliglustat (Genz-112638) capsule as single 50 mg dose on Day 1 then eliglustat 50 mg twice daily (BID) from Day 2 to Day 19, 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 Year 4. After primary completion date (Week 52) participants underwent treatment interruption period of approximately 2 weeks before continuing same treatment through study completion (Year 9). Participant receiving 100 mg BID could be considered for 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).
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 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).
  Eligibility

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Ages Eligible for Study:   18 Years to 65 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • The participant had a diagnosis of Gaucher Type I disease and a documented deficiency of glucocerebrosidase activity by enzyme assay and was willing and able to provide written informed consent prior to initiating any study-related procedures;
  • The participant was 18 to 65 years old and weighed between 50 and 120 kilogram (kg) at enrollment;
  • The participant had 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 had a documented negative serum pregnancy test prior to dosing. Female participants agreed to use a reliable method of birth control throughout duration of trial.

Exclusion Criteria:

  • Participant had a partial or total splenectomy or infarcted areas of the spleen;
  • Participant had documented prior bleeding varices or liver infarction;
  • Participant received miglustat within 12 months prior to study enrollment;
  • The participant had received an investigational product within 30 days prior to study enrollment;
  • Participant had neurologic or pulmonary involvement;
  • Participant had new pathological bone involvement or bone crisis in the 12 months prior to enrollment;
  • Participant was transfusion-dependent;
  • Participant had a documented etiology of anemia due to causes other than Gaucher disease;
  • The participant had cardiac functional and/or anatomical abnormalities, a history of cancer or tested positive for human immunodeficiency virus (HIV) antibody or Hepatitis;
  • Participant had 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, might preclude participation in the study.
  Contacts and Locations
Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00358150


Locations
United States, New York
New York University
New York, New York, United States
New York, New York, United States
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
Buenos Aires, Argentina
Hospital Ramos Mejia
Ciudad Autonoma de Buenos Aires, Argentina
Israel
Rambam Medical Center
Haifa, Israel
Haifa, Israel
Sha'are Zedek Medical Centre
Jerusalem, Israel
Jerusalem, Israel
Italy
Universita degli Studi di Milano
Milano, Italy
Mexico
Instituto Mexicano del Seguro Social
D.f., Mexico
Mexico City, Mexico
Russian Federation
Hematology Research Center of Ministry of Healthcare of the Russian Federation
Moscow, Russian Federation
Moscow, Russian Federation
Sponsors and Collaborators
Genzyme, a Sanofi Company
Investigators
Study Director: Medical Monitor Genzyme, a Sanofi Company
  More Information

Publications:

Responsible Party: Genzyme, a Sanofi Company
ClinicalTrials.gov Identifier: NCT00358150     History of Changes
Other Study ID Numbers: GZGD00304
2005-004732-42 ( EudraCT Number )
DRI12816 ( Other Identifier: Sanofi )
First Submitted: July 27, 2006
First Posted: July 31, 2006
Results First Submitted: August 22, 2014
Results First Posted: September 3, 2014
Last Update Posted: February 15, 2017
Last Verified: December 2016

Keywords provided by Sanofi ( Genzyme, a Sanofi Company ):
Type 1 Gaucher Disease
Glucocerebrosidase Deficiency Disease

Additional relevant MeSH terms:
Gaucher Disease
Deficiency Diseases
Lipidoses
Lysosomal Storage Diseases, Nervous System
Brain Diseases, Metabolic, Inborn
Brain Diseases, Metabolic
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Genetic Diseases, Inborn
Lipid Metabolism, Inborn Errors
Lysosomal Storage Diseases
Metabolic Diseases
Lipid Metabolism Disorders
Nutrition Disorders
Sphingolipidoses
Metabolism, Inborn Errors
Malnutrition
Eliglustat
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action