Effect of oral eliglustat on splenomegaly in patients with Gaucher disease type 1: The ENGAGE randomized clinical trial

Pramod K. Mistry, Elena Lukina, Hadhami Ben Turkia, Dominick Amato, Hagit Baris, Majed Dasouki, Marwan Ghosn, Atul Mehta, Seymour Packman, Gregory Pastores, Milan Petakov, Sarit Assouline, Manisha Balwani, Sumita Danda, Evgueniy Hadjiev, Andres Ortega, Suma Shankar, Maria Helena Solano, Leorah Ross, Jennifer AngellM. Judith Peterschmitt

Research output: Contribution to journalArticle

70 Citations (Scopus)

Abstract

Importance: Gaucher disease type 1 is characterized by hepatosplenomegaly, anemia, thrombocytopenia, and skeletal disease. A safe, effective oral therapy is needed. Objective: To determine whether eliglustat, a novel oral substrate reduction therapy, safely reverses clinical manifestations in untreated adults with Gaucher disease type 1. Design, Setting, and Participants: Phase 3, randomized, double-blind, placebo-controlled trial conducted at 18 sites in 12 countries from November 2009 to July 2012 among eligible patients with splenomegaly plus thrombocytopenia and/or anemia. Of 72 patients screened, 40 were enrolled. Interventions: Patients were stratified by spleen volume and randomized 1:1 to receive eliglustat (50 or 100mg twice daily; n = 20) or placebo (n = 20) for 9 months. Main Outcomes and Measures: The primary efficacy end pointwas percentage change in spleen volume in multiples of normal from baseline to 9 months; secondary efficacy end points were change in hemoglobin level and percentage changes in liver volume and platelet count. Results: All patients had baseline splenomegaly and thrombocytopenia (mostly moderate or severe), most had mild or moderate hepatomegaly, and 20% had mild anemia. Least-square mean spleen volume decreased by 27.77% (95% CI, -32.57% to -22.97%) in the eliglustat group (from 13.89 to 10.17 multiples of normal) vs an increase of 2.26% (95% CI, -2.54% to 7.06%) in the placebo group (from 12.50 to 12.84 multiples of normal) for an absolute treatment difference of -30.03% (95% CI, -36.82% to -23.24%; P < .001). For the secondary end points, the least-square mean absolute differences between groups all favored eliglustat, with a 1.22-g/dL increase in hemoglobin level (95% CI, 0.57-1.88 g/dL; P < .001), 6.64% decrease in liver volume (95% CI, -11.37% to -1.91%; P = .007), and 41.06% increase in platelet count (95% CI, 23.95%-58.17%; P < .001). No serious adverse events occurred. One patient in the eliglustat group withdrew (non-treatment related); 39 of the 40 patients transitioned to an open-label extension study. Conclusions and Relevance: Among previously untreated adults with Gaucher disease type 1, treatment with eliglustat compared with placebo for 9 months resulted in significant improvements in spleen volume, hemoglobin level, liver volume, and platelet count. The clinical significance of these findings is uncertain, and more definitive conclusions about clinical efficacy and utility will require comparison with the standard treatment of enzyme replacement therapy as well as longer-term follow-up. Trial Registration: clinicaltrials.gov Identifier: NCT00891202.

Original languageEnglish (US)
Pages (from-to)695-706
Number of pages12
JournalJAMA - Journal of the American Medical Association
Volume313
Issue number7
DOIs
StatePublished - Jan 1 2015
Externally publishedYes

Fingerprint

Gaucher Disease
Splenomegaly
Randomized Controlled Trials
Spleen
Platelet Count
Placebos
Thrombocytopenia
Anemia
Hemoglobins
Least-Squares Analysis
Liver
Enzyme Replacement Therapy
Therapeutics
Hepatomegaly
eliglustat
Outcome Assessment (Health Care)

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Effect of oral eliglustat on splenomegaly in patients with Gaucher disease type 1 : The ENGAGE randomized clinical trial. / Mistry, Pramod K.; Lukina, Elena; Turkia, Hadhami Ben; Amato, Dominick; Baris, Hagit; Dasouki, Majed; Ghosn, Marwan; Mehta, Atul; Packman, Seymour; Pastores, Gregory; Petakov, Milan; Assouline, Sarit; Balwani, Manisha; Danda, Sumita; Hadjiev, Evgueniy; Ortega, Andres; Shankar, Suma; Solano, Maria Helena; Ross, Leorah; Angell, Jennifer; Peterschmitt, M. Judith.

In: JAMA - Journal of the American Medical Association, Vol. 313, No. 7, 01.01.2015, p. 695-706.

Research output: Contribution to journalArticle

Mistry, PK, Lukina, E, Turkia, HB, 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 2015, 'Effect of oral eliglustat on splenomegaly in patients with Gaucher disease type 1: The ENGAGE randomized clinical trial', JAMA - Journal of the American Medical Association, vol. 313, no. 7, pp. 695-706. https://doi.org/10.1001/jama.2015.459
Mistry, Pramod K. ; Lukina, Elena ; Turkia, Hadhami Ben ; Amato, Dominick ; Baris, Hagit ; Dasouki, Majed ; Ghosn, Marwan ; Mehta, Atul ; Packman, Seymour ; Pastores, Gregory ; Petakov, Milan ; Assouline, Sarit ; Balwani, Manisha ; Danda, Sumita ; Hadjiev, Evgueniy ; Ortega, Andres ; Shankar, Suma ; Solano, Maria Helena ; Ross, Leorah ; Angell, Jennifer ; Peterschmitt, M. Judith. / Effect of oral eliglustat on splenomegaly in patients with Gaucher disease type 1 : The ENGAGE randomized clinical trial. In: JAMA - Journal of the American Medical Association. 2015 ; Vol. 313, No. 7. pp. 695-706.
@article{ee55c3afbab24600b686dcc16a117b88,
title = "Effect of oral eliglustat on splenomegaly in patients with Gaucher disease type 1: The ENGAGE randomized clinical trial",
abstract = "Importance: Gaucher disease type 1 is characterized by hepatosplenomegaly, anemia, thrombocytopenia, and skeletal disease. A safe, effective oral therapy is needed. Objective: To determine whether eliglustat, a novel oral substrate reduction therapy, safely reverses clinical manifestations in untreated adults with Gaucher disease type 1. Design, Setting, and Participants: Phase 3, randomized, double-blind, placebo-controlled trial conducted at 18 sites in 12 countries from November 2009 to July 2012 among eligible patients with splenomegaly plus thrombocytopenia and/or anemia. Of 72 patients screened, 40 were enrolled. Interventions: Patients were stratified by spleen volume and randomized 1:1 to receive eliglustat (50 or 100mg twice daily; n = 20) or placebo (n = 20) for 9 months. Main Outcomes and Measures: The primary efficacy end pointwas percentage change in spleen volume in multiples of normal from baseline to 9 months; secondary efficacy end points were change in hemoglobin level and percentage changes in liver volume and platelet count. Results: All patients had baseline splenomegaly and thrombocytopenia (mostly moderate or severe), most had mild or moderate hepatomegaly, and 20{\%} had mild anemia. Least-square mean spleen volume decreased by 27.77{\%} (95{\%} CI, -32.57{\%} to -22.97{\%}) in the eliglustat group (from 13.89 to 10.17 multiples of normal) vs an increase of 2.26{\%} (95{\%} CI, -2.54{\%} to 7.06{\%}) in the placebo group (from 12.50 to 12.84 multiples of normal) for an absolute treatment difference of -30.03{\%} (95{\%} CI, -36.82{\%} to -23.24{\%}; P < .001). For the secondary end points, the least-square mean absolute differences between groups all favored eliglustat, with a 1.22-g/dL increase in hemoglobin level (95{\%} CI, 0.57-1.88 g/dL; P < .001), 6.64{\%} decrease in liver volume (95{\%} CI, -11.37{\%} to -1.91{\%}; P = .007), and 41.06{\%} increase in platelet count (95{\%} CI, 23.95{\%}-58.17{\%}; P < .001). No serious adverse events occurred. One patient in the eliglustat group withdrew (non-treatment related); 39 of the 40 patients transitioned to an open-label extension study. Conclusions and Relevance: Among previously untreated adults with Gaucher disease type 1, treatment with eliglustat compared with placebo for 9 months resulted in significant improvements in spleen volume, hemoglobin level, liver volume, and platelet count. The clinical significance of these findings is uncertain, and more definitive conclusions about clinical efficacy and utility will require comparison with the standard treatment of enzyme replacement therapy as well as longer-term follow-up. Trial Registration: clinicaltrials.gov Identifier: NCT00891202.",
author = "Mistry, {Pramod K.} and Elena Lukina and Turkia, {Hadhami Ben} and Dominick Amato and Hagit Baris and Majed Dasouki and Marwan Ghosn and Atul Mehta and Seymour Packman and Gregory Pastores and Milan Petakov and Sarit Assouline and Manisha Balwani and Sumita Danda and Evgueniy Hadjiev and Andres Ortega and Suma Shankar and Solano, {Maria Helena} and Leorah Ross and Jennifer Angell and Peterschmitt, {M. Judith}",
year = "2015",
month = "1",
day = "1",
doi = "10.1001/jama.2015.459",
language = "English (US)",
volume = "313",
pages = "695--706",
journal = "JAMA - Journal of the American Medical Association",
issn = "0002-9955",
publisher = "American Medical Association",
number = "7",

}

TY - JOUR

T1 - Effect of oral eliglustat on splenomegaly in patients with Gaucher disease type 1

T2 - The ENGAGE randomized clinical trial

AU - Mistry, Pramod K.

AU - Lukina, Elena

AU - Turkia, Hadhami Ben

AU - Amato, Dominick

AU - Baris, Hagit

AU - Dasouki, Majed

AU - Ghosn, Marwan

AU - Mehta, Atul

AU - Packman, Seymour

AU - Pastores, Gregory

AU - Petakov, Milan

AU - Assouline, Sarit

AU - Balwani, Manisha

AU - Danda, Sumita

AU - Hadjiev, Evgueniy

AU - Ortega, Andres

AU - Shankar, Suma

AU - Solano, Maria Helena

AU - Ross, Leorah

AU - Angell, Jennifer

AU - Peterschmitt, M. Judith

PY - 2015/1/1

Y1 - 2015/1/1

N2 - Importance: Gaucher disease type 1 is characterized by hepatosplenomegaly, anemia, thrombocytopenia, and skeletal disease. A safe, effective oral therapy is needed. Objective: To determine whether eliglustat, a novel oral substrate reduction therapy, safely reverses clinical manifestations in untreated adults with Gaucher disease type 1. Design, Setting, and Participants: Phase 3, randomized, double-blind, placebo-controlled trial conducted at 18 sites in 12 countries from November 2009 to July 2012 among eligible patients with splenomegaly plus thrombocytopenia and/or anemia. Of 72 patients screened, 40 were enrolled. Interventions: Patients were stratified by spleen volume and randomized 1:1 to receive eliglustat (50 or 100mg twice daily; n = 20) or placebo (n = 20) for 9 months. Main Outcomes and Measures: The primary efficacy end pointwas percentage change in spleen volume in multiples of normal from baseline to 9 months; secondary efficacy end points were change in hemoglobin level and percentage changes in liver volume and platelet count. Results: All patients had baseline splenomegaly and thrombocytopenia (mostly moderate or severe), most had mild or moderate hepatomegaly, and 20% had mild anemia. Least-square mean spleen volume decreased by 27.77% (95% CI, -32.57% to -22.97%) in the eliglustat group (from 13.89 to 10.17 multiples of normal) vs an increase of 2.26% (95% CI, -2.54% to 7.06%) in the placebo group (from 12.50 to 12.84 multiples of normal) for an absolute treatment difference of -30.03% (95% CI, -36.82% to -23.24%; P < .001). For the secondary end points, the least-square mean absolute differences between groups all favored eliglustat, with a 1.22-g/dL increase in hemoglobin level (95% CI, 0.57-1.88 g/dL; P < .001), 6.64% decrease in liver volume (95% CI, -11.37% to -1.91%; P = .007), and 41.06% increase in platelet count (95% CI, 23.95%-58.17%; P < .001). No serious adverse events occurred. One patient in the eliglustat group withdrew (non-treatment related); 39 of the 40 patients transitioned to an open-label extension study. Conclusions and Relevance: Among previously untreated adults with Gaucher disease type 1, treatment with eliglustat compared with placebo for 9 months resulted in significant improvements in spleen volume, hemoglobin level, liver volume, and platelet count. The clinical significance of these findings is uncertain, and more definitive conclusions about clinical efficacy and utility will require comparison with the standard treatment of enzyme replacement therapy as well as longer-term follow-up. Trial Registration: clinicaltrials.gov Identifier: NCT00891202.

AB - Importance: Gaucher disease type 1 is characterized by hepatosplenomegaly, anemia, thrombocytopenia, and skeletal disease. A safe, effective oral therapy is needed. Objective: To determine whether eliglustat, a novel oral substrate reduction therapy, safely reverses clinical manifestations in untreated adults with Gaucher disease type 1. Design, Setting, and Participants: Phase 3, randomized, double-blind, placebo-controlled trial conducted at 18 sites in 12 countries from November 2009 to July 2012 among eligible patients with splenomegaly plus thrombocytopenia and/or anemia. Of 72 patients screened, 40 were enrolled. Interventions: Patients were stratified by spleen volume and randomized 1:1 to receive eliglustat (50 or 100mg twice daily; n = 20) or placebo (n = 20) for 9 months. Main Outcomes and Measures: The primary efficacy end pointwas percentage change in spleen volume in multiples of normal from baseline to 9 months; secondary efficacy end points were change in hemoglobin level and percentage changes in liver volume and platelet count. Results: All patients had baseline splenomegaly and thrombocytopenia (mostly moderate or severe), most had mild or moderate hepatomegaly, and 20% had mild anemia. Least-square mean spleen volume decreased by 27.77% (95% CI, -32.57% to -22.97%) in the eliglustat group (from 13.89 to 10.17 multiples of normal) vs an increase of 2.26% (95% CI, -2.54% to 7.06%) in the placebo group (from 12.50 to 12.84 multiples of normal) for an absolute treatment difference of -30.03% (95% CI, -36.82% to -23.24%; P < .001). For the secondary end points, the least-square mean absolute differences between groups all favored eliglustat, with a 1.22-g/dL increase in hemoglobin level (95% CI, 0.57-1.88 g/dL; P < .001), 6.64% decrease in liver volume (95% CI, -11.37% to -1.91%; P = .007), and 41.06% increase in platelet count (95% CI, 23.95%-58.17%; P < .001). No serious adverse events occurred. One patient in the eliglustat group withdrew (non-treatment related); 39 of the 40 patients transitioned to an open-label extension study. Conclusions and Relevance: Among previously untreated adults with Gaucher disease type 1, treatment with eliglustat compared with placebo for 9 months resulted in significant improvements in spleen volume, hemoglobin level, liver volume, and platelet count. The clinical significance of these findings is uncertain, and more definitive conclusions about clinical efficacy and utility will require comparison with the standard treatment of enzyme replacement therapy as well as longer-term follow-up. Trial Registration: clinicaltrials.gov Identifier: NCT00891202.

UR - http://www.scopus.com/inward/record.url?scp=84923186347&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84923186347&partnerID=8YFLogxK

U2 - 10.1001/jama.2015.459

DO - 10.1001/jama.2015.459

M3 - Article

C2 - 25688781

AN - SCOPUS:84923186347

VL - 313

SP - 695

EP - 706

JO - JAMA - Journal of the American Medical Association

JF - JAMA - Journal of the American Medical Association

SN - 0002-9955

IS - 7

ER -