title: Safety and efficacy of ocrelizumab in patients with rheumatoid arthritis and an inadequate response to at least one tumor necrosis factor inhibitor: results of a forty-eight–week randomized, double-blind, placebo-controlled, parallel-group phase III trial.
abstract: OBJECTIVE
  To evaluate the safety and efficacy of ocrelizumab plus methotrexate (MTX) or leflunomide (LEF) in patients with active rheumatoid arthritis (RA) and an inadequate response to tumor necrosis factor α inhibitors.
  
  
  METHODS
  This was a multicenter randomized, double-blind, placebo-controlled, parallel-group study that continued over 48 weeks. Patients receiving stable doses of MTX or LEF were randomized to receive 2 infusions of placebo (n = 277), ocrelizumab 200 mg (n = 278), or ocrelizumab 500 mg (n = 285) on days 1 and 15 as well as at weeks 24 and 26. Coprimary end points were the proportion of patients with response according to the American College of Rheumatology 20% improvement criteria (ACR20) at weeks 24 and 48. Secondary end points included the change from baseline in the modified Sharp/van der Heijde score (SHS) and the ACR50/70 responses.
  
  
  RESULTS
  ACR20 responses were 22.0% in the placebo group, 42.2% in the ocrelizumab 200 mg group, and 47.9% in the ocrelizumab 500 mg group at 24 weeks and 19.5%, 48.7%, and 50.7%, respectively, at 48 weeks (P < 0.0001 versus placebo for each comparison at each time point). At 48 weeks, patients receiving both doses of ocrelizumab showed significantly improved ACR50 and ACR70 responses of ~3-fold versus placebo. Only those in the ocrelizumab 500 mg group showed statistically significant (P = 0.0017) inhibition of joint damage progression (mean change in the SHS) relative to placebo (61% inhibition) at 48 weeks. Overall adverse events and infections during the 48 weeks of study were comparable in all treatment groups. Serious infections were observed more frequently in patients taking ocrelizumab (5.1% and 4.3%) than in those taking placebo (2.5%).
  
  
  CONCLUSIONS
  Patients in both of the ocrelizumab groups met the clinical primary efficacy end points. Inhibition of change in the SHS was statistically significant at 48 weeks for those in the ocrelizumab 500 mg group. The rate of serious infections in this trial was higher for both ocrelizumab doses as compared with placebo.
authors.affiliation: Division of Clinical Immunology and Rheumatology, Academic Medical Centre and University of Amsterdam, Amsterdam, The Netherlands. p.p.tak@amc.uva.nl
authors.forename: P P
authors.initials: PP
authors.lastname: Tak
authors.forename: P J
authors.initials: PJ
authors.lastname: Mease
authors.forename: M C
authors.initials: MC
authors.lastname: Genovese
authors.forename: J
authors.initials: J
authors.lastname: Kremer
authors.forename: B
authors.initials: B
authors.lastname: Haraoui
authors.forename: Y
authors.initials: Y
authors.lastname: Tanaka
authors.forename: C O
authors.initials: CO
authors.lastname: Bingham
authors.forename: A
authors.initials: A
authors.lastname: Ashrafzadeh
authors.forename: H
authors.initials: H
authors.lastname: Travers
authors.forename: S
authors.initials: S
authors.lastname: Safa-Leathers
authors.forename: S
authors.initials: S
authors.lastname: Kumar
authors.forename: W
authors.initials: W
authors.lastname: Dummer
mesh_terms: D000328:Adult; D000368:Aged; D061067:Antibodies, Monoclonal, Humanized / Q000009:adverse effects / Q000627:therapeutic use*; D018501:Antirheumatic Agents / Q000009:adverse effects / Q000627:therapeutic use*; D001172:Arthritis, Rheumatoid / Q000188:drug therapy*; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D016896:Treatment Outcome; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors*
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D018501:Antirheumatic Agents; D014409:Tumor Necrosis Factor-alpha; C533411:ocrelizumab