title: Placebo-controlled phase 3 study of oral BG-12 for relapsing multiple sclerosis.
abstract: BACKGROUND
  BG-12 (dimethyl fumarate) was shown to have antiinflammatory and cytoprotective properties in preclinical experiments and to result in significant reductions in disease activity on magnetic resonance imaging (MRI) in a phase 2, placebo-controlled study involving patients with relapsing-remitting multiple sclerosis.
  
  
  METHODS
  We conducted a randomized, double-blind, placebo-controlled phase 3 study involving patients with relapsing-remitting multiple sclerosis. Patients were randomly assigned to receive oral BG-12 at a dose of 240 mg twice daily, BG-12 at a dose of 240 mg three times daily, or placebo. The primary end point was the proportion of patients who had a relapse by 2 years. Other end points included the annualized relapse rate, the time to confirmed progression of disability, and findings on MRI.
  
  
  RESULTS
  The estimated proportion of patients who had a relapse was significantly lower in the two BG-12 groups than in the placebo group (27% with BG-12 twice daily and 26% with BG-12 thrice daily vs. 46% with placebo, P<0.001 for both comparisons). The annualized relapse rate at 2 years was 0.17 in the twice-daily BG-12 group and 0.19 in the thrice-daily BG-12 group, as compared with 0.36 in the placebo group, representing relative reductions of 53% and 48% with the two BG-12 regimens, respectively (P<0.001 for the comparison of each BG-12 regimen with placebo). The estimated proportion of patients with confirmed progression of disability was 16% in the twice-daily BG-12 group, 18% in the thrice-daily BG-12 group, and 27% in the placebo group, with significant relative risk reductions of 38% with BG-12 twice daily (P=0.005) and 34% with BG-12 thrice daily (P=0.01). BG-12 also significantly reduced the number of gadolinium-enhancing lesions and of new or enlarging T(2)-weighted hyperintense lesions (P<0.001 for the comparison of each BG-12 regimen with placebo). Adverse events associated with BG-12 included flushing and gastrointestinal events, such as diarrhea, nausea, and upper abdominal pain, as well as decreased lymphocyte counts and elevated liver aminotransferase levels.
  
  
  CONCLUSIONS
  In patients with relapsing-remitting multiple sclerosis, both BG-12 regimens, as compared with placebo, significantly reduced the proportion of patients who had a relapse, the annualized relapse rate, the rate of disability progression, and the number of lesions on MRI. (Funded by Biogen Idec; DEFINE ClinicalTrials.gov number, NCT00420212.).
authors.affiliation: Department of Neurology, St. Josef-Hospital/Ruhr-University Bochum, Bochum, Germany. ralf.gold@ruhr-uni-bochum.de
authors.forename: Ralf
authors.initials: R
authors.lastname: Gold
authors.forename: Ludwig
authors.initials: L
authors.lastname: Kappos
authors.forename: Douglas L
authors.initials: DL
authors.lastname: Arnold
authors.forename: Amit
authors.initials: A
authors.lastname: Bar-Or
authors.forename: Gavin
authors.initials: G
authors.lastname: Giovannoni
authors.forename: Krzysztof
authors.initials: K
authors.lastname: Selmaj
authors.forename: Carlo
authors.initials: C
authors.lastname: Tornatore
authors.forename: Marianne T
authors.initials: MT
authors.lastname: Sweetser
authors.forename: Minhua
authors.initials: M
authors.lastname: Yang
authors.forename: Sarah I
authors.initials: SI
authors.lastname: Sheikh
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*; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D007239:Infections / Q000209:etiology; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D020529:Multiple Sclerosis, Relapsing-Remitting / Q000188:drug therapy* / Q000473:pathology
chemical_list: D005650:Fumarates; D007166:Immunosuppressive Agents; D000069462:Dimethyl Fumarate