title: A phase 2 dose-ranging study of subcutaneous tabalumab for the treatment of patients with active rheumatoid arthritis and an inadequate response to methotrexate.
abstract: OBJECTIVE
  To assess the dose-response relationship, efficacy and safety of tabalumab, a human monoclonal antibody that neutralises membrane-bound and soluble B-cell activating factor (BAFF), in patients with rheumatoid arthritis (RA) with inadequate response to methotrexate (MTX).
  
  
  METHODS
  In this phase 2, 24-week, double-blind, placebo-controlled, dose-ranging study, patients with RA (N=158) on stable  MTX were randomised by Bayesian-adaptive method to receive 1, 3, 10, 30, 60, or 120 mg tabalumab or placebo subcutaneously every 4 weeks for 24 weeks. The primary objective was to test for a significant dose-response relationship using a statistical model of the proportion of patients having ≥50% improvement in American College of Rheumatology (ACR) criteria (ACR50) at week 24 (prespecified α=0.10).
  
  
  RESULTS
  At week 24, a significant dose-response relationship was observed using ACR50 (p=0.059) and ACR20 (p=0.044) response rates. Using model-estimated data, only 120 mg had significantly higher ACR50 and ACR20 response rates versus placebo (p<0.05). Observed response rates were significantly higher for 120 mg versus placebo as measured by ACR50 at weeks 12 (p=0.039) and 20 (p=0.018), but not week 24, and by ACR20 at weeks 12 (p=0.011) and 24 (p=0.039). Mean DAS28 C-reactive protein  improved with 120 mg at week 24 (p=0.048). Frequency of TEAEs was similar across groups (range 50-69%, p=0.884). Ten (8.2%) tabalumab and 5 (13.9%) placebo patients reported a serious adverse event (SAE). Infections occurred more frequently in patients exposed to tabalumab (30.3% vs 19.4%). Serious infections were reported in 3 (2.5%) tabalumab-treated patients only.
  
  
  CONCLUSIONS
  A dose-response relationship was detected with monthly subcutaneous tabalumab. A significant effect was detected with the 120 mg dose with no unexpected safety signals. CLINICAL TRIAL #: NCT00785928.
authors.affiliation: Division of Immunology and Rheumatology, Stanford University Medical Center, , Palo Alto, California 94304, USA. Genovese@Stanford.edu
authors.forename: Mark C
authors.initials: MC
authors.lastname: Genovese
authors.forename: Eric
authors.initials: E
authors.lastname: Lee
authors.forename: Julie
authors.initials: J
authors.lastname: Satterwhite
authors.forename: Melissa
authors.initials: M
authors.lastname: Veenhuizen
authors.forename: Damon
authors.initials: D
authors.lastname: Disch
authors.forename: Pierre-Yves
authors.initials: PY
authors.lastname: Berclaz
authors.forename: Stephen
authors.initials: S
authors.lastname: Myers
authors.forename: Gregory
authors.initials: G
authors.lastname: Sides
authors.forename: Olivier
authors.initials: O
authors.lastname: Benichou
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D018501:Antirheumatic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001172:Arthritis, Rheumatoid / Q000188:drug therapy* / Q000503:physiopathology; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004351:Drug Resistance; D005260:Female; D006304:Health Status; D006801:Humans; D007279:Injections, Subcutaneous; D007596:Joints / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D008297:Male; D008727:Methotrexate / Q000627:therapeutic use*; D008875:Middle Aged; D010865:Pilot Projects; D012720:Severity of Illness Index; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D018501:Antirheumatic Agents; C575974:tabalumab; D008727:Methotrexate
keywords: Autoimmune Diseases; B cells; Rheumatoid Arthritis; TNF-alpha