Clinical trial NCT00891202: A Study of Eliglustat Tartrate (Genz-112638) in Patients With Gaucher Disease (ENGAGE)
Official title: A Phase 3, Randomized, Double-Blind, Placebo-Controlled, Multi-Center Study Confirming the Efficacy and Safety of Genz-112638 in Patients With Gaucher Disease Type 1 (ENGAGE)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Gaucher Disease, Type 1
Keywords: Gaucher,
beta-glucosidase,
acid ß-glucosidase,
glucocerebrosidase,
glucosylceramide,
D-glucosyl-N-acylsphingosine glucohydrolase,
substrate reduction therapy
Lead sponsor: Sanofi
Sponsor class: INDUSTRY
First posted: 2009-05-01
Enrollment: 40
Sex: ALL
Minimum age (years): 16
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This Phase 3 study was designed to confirm the efficacy and safety of eliglustat tartrate (Genz-112638) in participants with Gaucher disease Type 1.

Detailed description: Gaucher disease is characterized by lysosomal accumulation of glucosylceramide due to impaired glucosylceramide hydrolysis. Type 1 Gaucher disease, the most common form accounts for greater than (\>) 90% of cases and does not involve the central nervous system (CNS). Typical manifestations of Type 1 Gaucher disease include splenomegaly, hepatomegaly, thrombocytopenia, anemia, skeletal pathology and decreased quality of life. The disease manifestations are caused by the accumulations of glucosylceramide (storage material) in Gaucher cells which have infiltrated the spleen and liver as well as other tissue. Eliglustat tartrate is a small molecule 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 pharmacokinetics (PK) of eliglustat tartrate in adult participants (\>16 years) with Gaucher disease Type 1. The study consisted of 2 periods: The Double-Blind Primary Analysis Period (PAP \[Day 1 to Week 39\]) and the Long Term Treatment Period (LTTP/Open-Label Period (post-Week 39 \[Day 1 of the Open-Label Period\] through study completion).

Eligibility 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 16 years old at the time of randomization;
* The participant had a confirmed diagnosis of Gaucher disease Type 1;
* Female participants of childbearing potential must 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 has had a partial or total splenectomy;
* The participant had received pharmacological chaperones or miglustat within 6 months prior to randomization;
* The participant had received enzyme replacement therapy within 9 months prior to randomization;
* The participant had Type 2 or 3 Gaucher disease or was suspected of having Type 3 Gaucher disease;
* The participant had any clinically significant disease, other than Gaucher disease, including cardiovascular, renal, hepatic, gastrointestinal (GI), pulmonary, neurologic, endocrine, metabolic, (for example, hypokalemia, hypomagnesemia), or psychiatric disease, other medical conditions, or serious intercurrent illness that might confound the study results, or, on the opinion of the investigator, might 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.

Primary outcomes:
measure: PAP: Percent Change From Baseline in Spleen Volume (in Multiples of Normal [MN]) at Week 39 of the Primary Analysis Period With Eliglustat Tartrate Treatment as Compared to Placebo
timeFrame: PAP Baseline (Day 1), Week 39
Secondary outcomes:
measure: PAP: Hemoglobin Level
timeFrame: PAP Baseline (Day 1)
measure: PAP: Absolute Change From Baseline in Hemoglobin Level at Week 39
timeFrame: PAP Baseline (Day 1), Week 39
measure: PAP: Percent Change From Baseline in Liver Volume (in MN) at Week 39
timeFrame: PAP Baseline (Day 1), Week 39
measure: PAP: Percent Change From Baseline in Platelet Counts at Week 39
timeFrame: PAP Baseline (Day 1), Week 39
measure: LTTP: Percent Change From Baseline in Spleen Volume (in MN) at Week 234
timeFrame: PAP Baseline for Eliglustat (Originally on Eliglustat) arm, LTTP Baseline for Eliglustat (Originally on Placebo) arm, Week 234
measure: LTTP: Absolute Change From Baseline in Hemoglobin Level at Week 234
timeFrame: PAP Baseline for Eliglustat (Originally on Eliglustat) arm, LTTP Baseline for Eliglustat (Originally on Placebo) arm, Week 234
measure: LTTP: Percent Change From Baseline in Liver Volume (in MN) at Week 234
timeFrame: PAP Baseline for Eliglustat (Originally on Eliglustat) arm, LTTP Baseline for Eliglustat (Originally on Placebo) arm, Week 234
measure: LTTP: Percent Change From Baseline in Platelet Counts at Week 234
timeFrame: PAP Baseline for Eliglustat (Originally on Eliglustat) arm, LTTP Baseline for Eliglustat (Originally on Placebo) arm, Week 234
Other outcomes:
Locations:
city: San Francisco
country: United States
facility: UCSF MS Center
state: California
city: New Haven
country: United States
facility: Yale University School of Medicine
state: Connecticut
city: Decatur
country: United States
facility: Emory University Medical Genetics
state: Georgia
city: Westwood
country: United States
facility: University of Kansas Medical Center, Division of Hematology/Oncology, Dept. of Medicine
state: Kansas
city: New York
country: United States
facility: New York University School of Medicine, Neurology Department
state: New York
city: New York
country: United States
facility: Mount Sinai School of Medicine
state: New York
city: Sofia
country: Bulgaria
facility: University hospital "Alexandrovska" Sofia
city: Montreal, Quebec
country: Canada
facility: Sir Mortimer B. Davis - Jewish General Hospital
city: Toronto Ontario
country: Canada
facility: Mount Sinai Hospital and the Samuel Lunenfeld Research Institute
city: Bogota
country: Colombia
facility: Hospital de San Jose
city: Vellore
country: India
facility: Christian Medical College Hospital
city: Petach Tikvah
country: Israel
facility: Rabin Medical Center, Beilinson Hospital
city: Beirut
country: Lebanon
facility: Hôtel-Dieu de France University Hospital
city: Monterrey, Nuevo Leon
country: Mexico
facility: OCA Hospital
city: Moscow
country: Russian Federation
facility: Hematology Research Center of Ministry of Healthcare of the Russian Federation
city: Belgrade
country: Serbia
facility: Institut za endokrinologiju
city: Tunis
country: Tunisia
facility: Hopital La-Rabta
state: TN
city: London
country: United Kingdom
facility: Royal Free Hospital
Study officials:
affiliation: Genzyme, a Sanofi Company
name: Medical Monitor
role: STUDY_DIRECTOR
References:
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.
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.
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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.
citation: 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.
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.
citation: Mistry PK, Lukina E, Ben Turkia H, Amato D, Baris H, Dasouki M, Ghosn M, Mehta A, Packman S, Pastores G, Petakov M, Assouline S, Balwani M, Danda S, Hadjiev E, Ortega A, Shankar S, Solano MH, Ross L, Angell J, Peterschmitt MJ. Effect of oral eliglustat on splenomegaly in patients with Gaucher disease type 1: the ENGAGE randomized clinical trial. JAMA. 2015 Feb 17;313(7):695-706. doi: 10.1001/jama.2015.459.
citation: Mistry PK, Lukina E, Ben Turkia H, Shankar SP, Baris Feldman H, Ghosn M, Mehta A, Packman S, Lau H, Petakov M, Assouline S, Balwani M, Danda S, Hadjiev E, Ortega A, Foster MC, Gaemers SJM, Peterschmitt MJ. Clinical outcomes after 4.5 years of eliglustat therapy for Gaucher disease type 1: Phase 3 ENGAGE trial final results. Am J Hematol. 2021 Sep 1;96(9):1156-1165. doi: 10.1002/ajh.26276. Epub 2021 Jul 11.