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 language | English (US) |
|---|---|
| Pages (from-to) | 695-706 |
| Number of pages | 12 |
| Journal | JAMA - Journal of the American Medical Association |
| Volume | 313 |
| Issue number | 7 |
| DOIs | |
| State | Published - Jan 1 2015 |
| Externally published | Yes |
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ASJC Scopus subject areas
- Medicine(all)
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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 journal › Article
}
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 -