A Study of Eliglustat Tartrate (Genz-112638) in Patients With Gaucher Disease (ENGAGE)

NCT00891202 | Completed Phase 3 Results DMC

• 3 other identifiers: GZGD025072008-005222-37EFC12813
• Study Type: interventional
• Target: 40
• Locations: 12 countries
• Sites: 18

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.

Conditions

Gaucher Disease, Type 1

Keywords

Gaucher,; beta-glucosidase,; acid ß-glucosidase,; glucocerebrosidase,; glucosylceramide,; D-glucosyl-N-acylsphingosine glucohydrolase,; substrate reduction therapy

Outcome Measures

Primary Outcomes (1)

• 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

  Percent change in spleen volume = (\[spleen volume at Week 39 minus spleen volume at baseline\] divided by \[spleen volume at baseline\]) multiplied by 100, where all volumes are in MN.

  PAP Baseline (Day 1), Week 39

Secondary Outcomes (8)

• PAP: Hemoglobin Level

  PAP Baseline (Day 1)

• PAP: Absolute Change From Baseline in Hemoglobin Level at Week 39

  PAP Baseline (Day 1), Week 39

• PAP: Percent Change From Baseline in Liver Volume (in MN) at Week 39

  PAP Baseline (Day 1), Week 39

• PAP: Percent Change From Baseline in Platelet Counts at Week 39

  PAP Baseline (Day 1), Week 39

• LTTP: Percent Change From Baseline in Spleen Volume (in MN) at Week 234

  PAP Baseline for Eliglustat (Originally on Eliglustat) arm, LTTP Baseline for Eliglustat (Originally on Placebo) arm, Week 234

Study Arms (2)

Active

EXPERIMENTAL

Eliglustat

Drug: Eliglustat tartrate

Placebo

PLACEBO COMPARATOR

Placebo

Drug: Placebo

Interventions

Eliglustat tartrate DRUG

PAP: Eliglustat tartrate (ET) capsule 50 mg orally on Day 1 followed by ET 50 mg capsule twice daily (BID) from Day 2 to Week 4, then either ET 50 mg capsule BID (participants with Genz-99067 \[active moiety of ET in plasma\] trough plasma concentration \>=5 ng/mL) or ET 100 mg capsule BID (participants with Genz-99067 trough plasma concentration \<5 ng/mL), up to Week 39. PK assessment at Week 2 used for dose adjustment after Week 4. LTTP: Participants of the eliglustat arm in PAP who completed PAP were included in LTTP and received ET capsule 50 mg BID orally from Day 1 (post Week 39) until Week 43 followed by ET 50 mg or 100 mg capsule BID up to Week 47, then ET 50 mg or 100 mg or 150 mg capsule BID up to Week 312. Dose adjustments at Week 43 and Week 47 were based on Genz-99067 trough plasma concentrations (if trough plasma concentration \<5 ng/mL: next higher dose administered; if \>=5 ng/mL: same dose continued) at Week 41 \& Week 45, respectively.

Also known as: Genz-112638

Active

Placebo DRUG

PAP: Matching placebo capsule once daily on Day 1 followed by matching placebo capsule BID from Day 2 through Week 39. LTTP: Participants of the placebo arm in PAP who completed PAP were included in LTTP and received eliglustat tartrate from Day 1 (post Week 39) up to Week 312. Day 1 (post Week 39) was considered as baseline for LTTP. On Day 1, participants received eliglustat tartrate capsule 50 mg BID orally until Week 43 followed by eliglustat tartrate 50 mg or 100 mg capsule BID up to Week 47, then eliglustat tartrate 50 mg or 100 mg or 150 mg capsule BID up to Week 312. Dose adjustments at Week 43 and Week 47 were based on Genz-99067 trough plasma concentrations (if trough plasma concentration \<5 ng/mL: next higher dose administered; if \>=5 ng/mL: same dose continued) at Week 41 \& Week 45, respectively.

Placebo

Eligibility Criteria

• Age: 16 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• Genzyme, a Sanofi Company: lead

Study Sites (18)

UCSF MS Center

San Francisco, California, 94143, United States

Location

Yale University School of Medicine

New Haven, Connecticut, 06510, United States

Location

Emory University Medical Genetics

Decatur, Georgia, 30033, United States

Location

University of Kansas Medical Center, Division of Hematology/Oncology, Dept. of Medicine

Westwood, Kansas, 66160, United States

Location

New York University School of Medicine, Neurology Department

New York, New York, 10016, United States

Location

Mount Sinai School of Medicine

New York, New York, 10029, United States

Location

University hospital "Alexandrovska" Sofia

Sofia, 1431, Bulgaria

Location

Sir Mortimer B. Davis - Jewish General Hospital

Montreal, Quebec, H3T 1E2, Canada

Location

Mount Sinai Hospital and the Samuel Lunenfeld Research Institute

Toronto Ontario, M5G 1X5, Canada

Location

Hospital de San Jose

Bogotá, Colombia

Location

Christian Medical College Hospital

Vellore, 632004, India

Location

Rabin Medical Center, Beilinson Hospital

Petach Tikvah, 49100, Israel

Location

Hôtel-Dieu de France University Hospital

Beirut, Lebanon

Location

OCA Hospital

Monterrey, Nuevo Leon, Mexico

Location

Hematology Research Center of Ministry of Healthcare of the Russian Federation

Moscow, 125167, Russia

Location

Institut za endokrinologiju

Belgrade, 11000, Serbia

Location

Hopital La-Rabta

Tunis, TN, 1007, Tunisia

Location

Royal Free Hospital

London, NW3 2QG, United Kingdom

Location

Related Publications (9)

• 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.

  PMID: 20439622 BACKGROUND

• 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.

  PMID: 20713962 BACKGROUND

• 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. doi: 10.1016/j.ymgme.2007.04.001. Epub 2007 May 16.

  PMID: 17509920 BACKGROUND

• 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.

  PMID: 20864621 BACKGROUND

• 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.

  PMID: 24816856 BACKGROUND

• 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.

  PMID: 24835462 BACKGROUND

• 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.

  PMID: 25688781 RESULT

• Peterschmitt MJ, Foster MC, Ji AJ, Zajdel MB, Cox GF. Plasma glucosylsphingosine correlations with baseline disease burden and response to eliglustat in two clinical trials of previously untreated adults with Gaucher disease type 1. Mol Genet Metab. 2023 Mar;138(3):107527. doi: 10.1016/j.ymgme.2023.107527. Epub 2023 Jan 25.

  PMID: 36739645 DERIVED

• 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.

  PMID: 34161616 DERIVED

MeSH Terms

Conditions

Gaucher Disease

Interventions

eliglustat

Condition Hierarchy (Ancestors)

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; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Lipidoses; Lipid Metabolism, Inborn Errors; Lysosomal Storage Diseases; Metabolic Diseases; Nutritional and Metabolic Diseases; Lipid Metabolism Disorders

Results Point of Contact

• Title: Trial Transparency Team
• Organization: Sanofi

Contact-us@sanofi.com

Study Officials

• Medical Monitor

  Genzyme, a Sanofi Company

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: April 30, 2009
• First Posted: May 1, 2009
• Study Start: November 1, 2009
• Primary Completion: July 1, 2012
• Study Completion: January 1, 2016
• Last Updated: March 3, 2017
• Results First Posted: September 3, 2014

Record last verified: 2017-01

Locations

ME (1); BU (1); IL (1); US (6); RU (1); GB (1); LE (1); CA (2); SE (1); CO (1); TU (1); IN (1)