title: Effect of oral eliglustat on splenomegaly in patients with Gaucher disease type 1: the ENGAGE randomized clinical trial.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  METHODS
  Patients were stratified by spleen volume and randomized 1:1 to receive eliglustat (50 or 100 mg twice daily; n = 20) or placebo (n = 20) for 9 months.
  
  
  METHODS
  The primary efficacy end point was 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
  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.
  
  
  BACKGROUND
  clinicaltrials.gov Identifier: NCT00891202.
authors: Yale University School of Medicine, New Haven, Connecticut.
authors: Pramod K
authors: PK
authors: Mistry
authors: Hematology Research Center, Moscow, Russia.
authors: Elena
authors: E
authors: Lukina
authors: Hôpital La Rabta, Tunis, Tunisia.
authors: Hadhami
authors: H
authors: Ben Turkia
authors: Mount Sinai Hospital, Toronto, Ontario, Canada.
authors: Dominick
authors: D
authors: Amato
authors: Rabin Medical Center, Petach Tikvah, and Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors: Hagit
authors: H
authors: Baris
authors: University of Kansas Medical Center, Kansas City.
authors: Majed
authors: M
authors: Dasouki
authors: Hôtel-Dieu de France University Hospital, Beirut, Lebanon.
authors: Marwan
authors: M
authors: Ghosn
authors: The Royal Free Hospital, London, England.
authors: Atul
authors: A
authors: Mehta
authors: University of California, San Francisco, School of Medicine, San Francisco.
authors: Seymour
authors: S
authors: Packman
authors: New York University School of Medicine, New York, New York.
authors: Gregory
authors: G
authors: Pastores
authors: Clinical Center of Serbia, University of Belgrade School of Medicine, Belgrade, Serbia.
authors: Milan
authors: M
authors: Petakov
authors: Jewish General Hospital, Montreal, Quebec, Canada.
authors: Sarit
authors: S
authors: Assouline
authors: Icahn School of Medicine at Mount Sinai Hospital, New York, New York.
authors: Manisha
authors: M
authors: Balwani
authors: Christian Medical College, Vellore, India.
authors: Sumita
authors: S
authors: Danda
authors: University Hospital Alexandrovska, Sofia, Bulgaria.
authors: Evgueniy
authors: E
authors: Hadjiev
authors: OCA Hospital, Monterrey, Mexico.
authors: Andres
authors: A
authors: Ortega
authors: Emory University, Atlanta, Georgia.
authors: Suma
authors: S
authors: Shankar
authors: Hospital de San Jose-Fundacion Universitaria de Ciencias de la Salud San Jose, Bogota, Colombia.
authors: Maria Helena
authors: MH
authors: Solano
authors: Genzyme, Cambridge, Massachusetts.
authors: Leorah
authors: L
authors: Ross
authors: Genzyme, Cambridge, Massachusetts.
authors: Jennifer
authors: J
authors: Angell
authors: Genzyme, Cambridge, Massachusetts.
authors: M Judith
authors: MJ
authors: Peterschmitt
mesh_terms: D000284:Administration, Oral; D000328:Adult; D004311:Double-Blind Method; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D005260:Female; D005776:Gaucher Disease / Q000150:complications / Q000188:drug therapy*; D005964:Glucosyltransferases / Q000037:antagonists & inhibitors*; D006801:Humans; D008297:Male; D009929:Organ Size / Q000187:drug effects; D011759:Pyrrolidines / Q000494:pharmacology / Q000627:therapeutic use*; D013154:Spleen / Q000473:pathology; D013163:Splenomegaly / Q000188:drug therapy* / Q000209:etiology; D055815:Young Adult
chemical_list: D004791:Enzyme Inhibitors; D011759:Pyrrolidines; C522917:eliglustat; D005964:Glucosyltransferases; C023246:ceramide glucosyltransferase