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

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Sanofi ( Genzyme, a Sanofi Company )
ClinicalTrials.gov Identifier:
NCT00943111
First received: July 20, 2009
Last updated: May 12, 2016
Last verified: May 2016
  Purpose
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).

Condition Intervention Phase
Gaucher Disease, Type 1
Drug: Eliglustat tartrate
Drug: Imiglucerase
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
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)

Resource links provided by NLM:


Further study details as provided by Sanofi:

Primary Outcome Measures:
  • Percentage of Participants Who Remained Stable for 52 Weeks During the Primary Analysis Period [ Time Frame: Baseline up to Week 52 ] [ Designated as safety issue: No ]
    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.

  • Percentage of Participants Who Remained Stable Annually for 4 Years During the LTTP [ Time Frame: Week 52 up to week 208 ] [ Designated as safety issue: No ]
    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.


Secondary Outcome Measures:
  • Total T-Scores for Bone Mineral Density [ Time Frame: Baseline ] [ Designated as safety issue: No ]
    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 From Baseline in Total T-Scores for Bone Mineral Density at Week 52 [ Time Frame: Baseline, Week 52 ] [ Designated as safety issue: No ]
    Images of the spine and bilateral femur were obtained by 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 >-1), osteopenia (score -2.5 to <=-1), and osteoporosis (score <= -2.5). Absolute change = T-score at Week 52 minus T-score at baseline.

  • Total Z-Scores for Bone Mineral Density [ Time Frame: Baseline ] [ Designated as safety issue: No ]
    Images of the spine and bilateral 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).

  • Absolute Change From Baseline in Total Z-Scores for Bone Mineral Density at Week 52 [ Time Frame: Baseline, Week 52 ] [ Designated as safety issue: No ]
    Images of the spine and bilateral 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). Absolute change = Z-score at Week 52 minus Z-score at baseline.

  • Hemoglobin Level [ Time Frame: Baseline ] [ Designated as safety issue: No ]
  • Absolute Change From Baseline in Hemoglobin Levels at Week 52 [ Time Frame: Baseline, Week 52 ] [ Designated as safety issue: No ]
    Absolute change = hemoglobin level at Week 52 minus hemoglobin level at baseline.

  • Percent Change From Baseline in Platelet Counts at Week 52 [ Time Frame: Baseline, Week 52 ] [ Designated as safety issue: No ]
    Percent change in platelet counts = ([platelet count at Week 52 minus platelet count at baseline] divided by [platelet count at baseline]) multiplied by 100.

  • Percent Change From Baseline in Spleen Volume (MN) at Week 52 [ Time Frame: Baseline, Week 52 ] [ Designated as safety issue: No ]
    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.

  • Percent Change From Baseline in Liver Volume (in MN) at Week 52 [ Time Frame: Baseline, Week 52 ] [ Designated as safety issue: No ]
    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.

  • Absolute Change From Baseline in Total T-Scores for Bone Mineral Density at Week 208 [ Time Frame: Baseline, Week 208 ] [ Designated as safety issue: No ]
    Images of the spine and bilateral femur were obtained by 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 >-1), osteopenia (score -2.5 to <=-1), and osteoporosis (score <= -2.5). Absolute change = T-score at Week 208 minus T-score at baseline.

  • Absolute Change From Baseline in Total Z-Scores for Bone Mineral Density at Week 208 [ Time Frame: Baseline, Week 208 ] [ Designated as safety issue: No ]
    Images of the spine and bilateral 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). Absolute change = Z-score at Week 208 minus Z-score at baseline.

  • Absolute Change From Baseline in Hemoglobin Levels at Week 208 [ Time Frame: Baseline, Week 208 ] [ Designated as safety issue: No ]
    Absolute change = hemoglobin level at Week 208 minus hemoglobin level at baseline.

  • Percent Change From Baseline in Platelet Counts at Week 208 [ Time Frame: Baseline, Week 208 ] [ Designated as safety issue: No ]
    Percent change in platelet counts = ([platelet count at Week 208 minus platelet count at baseline] divided by [platelet count at baseline]) multiplied by 100.

  • Percent Change From Baseline in Spleen Volume (in MN) at Week 208 [ Time Frame: Baseline, Week 208 ] [ Designated as safety issue: No ]
    Percent change in spleen volume = ([spleen volume at Week 208 minus spleen volume at baseline] divided by [spleen volume at baseline]) multiplied by 100, where all volumes are in MN.

  • Percent Change From Baseline in Liver Volume (in MN) at Week 208 [ Time Frame: Baseline, Week 208 ] [ Designated as safety issue: No ]
    Percent change in liver volume = ([liver volume at Week 208 minus liver volume at baseline] divided by [liver volume at baseline]) multiplied by 100, where all volumes are in multiples of normal.


Enrollment: 160
Study Start Date: September 2009
Study Completion Date: June 2015
Primary Completion Date: November 2012 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Investigational
Eliglustat tartrate
Drug: Eliglustat tartrate

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.

Other Name: Genz-112638
Active Comparator: Imiglucerase Drug: Imiglucerase

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.

Other Name: Cerezyme®

Detailed 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 was designed to determine the efficacy, safety, and PK of eliglustat tartrate in adult participants with Gaucher disease type 1 who had been stabilized on ERT.

  Eligibility

Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • 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

Exclusion Criteria:

  • 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
  Contacts and Locations
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, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00943111

  Show 34 Study Locations
Sponsors and Collaborators
Genzyme, a Sanofi Company
Investigators
Study Director: Medical Monitor Genzyme, a Sanofi Company
  More Information

Additional Information:
Publications:

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Genzyme, a Sanofi Company
ClinicalTrials.gov Identifier: NCT00943111     History of Changes
Other Study ID Numbers: GZGD02607  2008-005223-28  EFC12812 
Study First Received: July 20, 2009
Results First Received: August 22, 2014
Last Updated: May 12, 2016
Health Authority: United States: Food and Drug Administration
Argentina: Administracion Nacional de Medicamentos, Alimentos y Tecnologia Medica
Australia: Therapeutic Goods Administration'Brazil: Ministry of Health
Brazil: Ministry of Health
Canada: Health Canada
Egypt: Ministry of Health and Population
France: Ministry of Health
Germany: Ministry of Health
Italy: Ministry of Health
Russia: Ministry of Health of the Russian Federation
Spain: Ministry of Health
United Kingdom: Medicines and Healthcare Products Regulatory Agency

Keywords provided by Sanofi:
Gaucher disease,
Genz-112638,
beta-glucosidase,
acid ß-glucosidase,
glucocerebrosidase,
glucosylceramide,
D-glucosyl-N-acylsphingosine glucohydrolase,
substrate reduction therapy

Additional relevant MeSH terms:
Gaucher Disease
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
Lipidoses
Lipid Metabolism, Inborn Errors
Lysosomal Storage Diseases
Metabolic Diseases
Lipid Metabolism Disorders
Eliglustat
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action

ClinicalTrials.gov processed this record on July 28, 2016