title: Placebo-controlled phase 3 study of oral BG-12 or glatiramer in multiple sclerosis.
abstract: BACKGROUND
  BG-12 (dimethyl fumarate) is in development as an oral treatment for relapsing-remitting multiple sclerosis, which is commonly treated with parenteral agents (interferon or glatiramer acetate).
  
  
  METHODS
  In this phase 3, randomized study, we investigated the efficacy and safety of oral BG-12, at a dose of 240 mg two or three times daily, as compared with placebo in patients with relapsing-remitting multiple sclerosis. An active agent, glatiramer acetate, was also included as a reference comparator. The primary end point was the annualized relapse rate over a period of 2 years. The study was not designed to test the superiority or noninferiority of BG-12 versus glatiramer acetate.
  
  
  RESULTS
  At 2 years, the annualized relapse rate was significantly lower with twice-daily BG-12 (0.22), thrice-daily BG-12 (0.20), and glatiramer acetate (0.29) than with placebo (0.40) (relative reductions: twice-daily BG-12, 44%, P<0.001; thrice-daily BG-12, 51%, P<0.001; glatiramer acetate, 29%, P=0.01). Reductions in disability progression with twice-daily BG-12, thrice-daily BG-12, and glatiramer acetate versus placebo (21%, 24%, and 7%, respectively) were not significant. As compared with placebo, twice-daily BG-12, thrice-daily BG-12, and glatiramer acetate significantly reduced the numbers of new or enlarging T(2)-weighted hyperintense lesions (all P<0.001) and new T(1)-weighted hypointense lesions (P<0.001, P<0.001, and P=0.002, respectively). In post hoc comparisons of BG-12 versus glatiramer acetate, differences were not significant except for the annualized relapse rate (thrice-daily BG-12), new or enlarging T(2)-weighted hyperintense lesions (both BG-12 doses), and new T(1)-weighted hypointense lesions (thrice-daily BG-12) (nominal P<0.05 for each comparison). Adverse events occurring at a higher incidence with an active treatment than with placebo included flushing and gastrointestinal events (with BG-12) and injection-related events (with glatiramer acetate). There were no malignant neoplasms or opportunistic infections reported with BG-12. Lymphocyte counts decreased with BG-12.
  
  
  CONCLUSIONS
  In patients with relapsing-remitting multiple sclerosis, BG-12 (at both doses) and glatiramer acetate significantly reduced relapse rates and improved neuroradiologic outcomes relative to placebo. (Funded by Biogen Idec; CONFIRM ClinicalTrials.gov number, NCT00451451.).
authors.affiliation: Mellen Center for Multiple Sclerosis Treatment and Research, Cleveland Clinic, Cleveland, OH 44195, USA. foxr@ccf.org
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Fox
authors.forename: David H
authors.initials: DH
authors.lastname: Miller
authors.forename: J Theodore
authors.initials: JT
authors.lastname: Phillips
authors.forename: Michael
authors.initials: M
authors.lastname: Hutchinson
authors.forename: Eva
authors.initials: E
authors.lastname: Havrdova
authors.forename: Mariko
authors.initials: M
authors.lastname: Kita
authors.forename: Minhua
authors.initials: M
authors.lastname: Yang
authors.forename: Kartik
authors.initials: K
authors.lastname: Raghupathi
authors.forename: Mark
authors.initials: M
authors.lastname: Novas
authors.forename: Marianne T
authors.initials: MT
authors.lastname: Sweetser
authors.forename: Vissia
authors.initials: V
authors.lastname: Viglietta
authors.forename: Katherine T
authors.initials: KT
authors.lastname: Dawson
mesh_terms: D000284:Administration, Oral; D000328:Adult; D001921:Brain / Q000473:pathology; D000069462:Dimethyl Fumarate; D004311:Double-Blind Method; D005260:Female; D005650:Fumarates / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D000068717:Glatiramer Acetate; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D007239:Infections / Q000209:etiology; D057194:Intention to Treat Analysis; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D020529:Multiple Sclerosis, Relapsing-Remitting / Q000188:drug therapy* / Q000473:pathology; D010455:Peptides / Q000009:adverse effects / Q000627:therapeutic use*
chemical_list: D005650:Fumarates; D007166:Immunosuppressive Agents; D010455:Peptides; D000068717:Glatiramer Acetate; D000069462:Dimethyl Fumarate