title: A 24-week, randomized, double-blind, placebo-controlled, parallel group study of the efficacy of oral SCIO-469, a p38 mitogen-activated protein kinase inhibitor, in patients with active rheumatoid arthritis.
abstract: OBJECTIVE
  To evaluate the efficacy, safety, and tolerability of oral SCIO-469, a p38 MAPK inhibitor that blocks tumor necrosis factor-α, interleukin-1ß, and cyclooxygenase-2 synthesis in patients with active rheumatoid arthritis (RA).
  
  
  METHODS
  Patients were randomized to receive SCIO-469 at either 30 or 60 mg three times daily in an immediate-release (IR) formulation or at 100 mg once daily in an extended-release (ER) formulation, or placebo for 24 weeks. The primary endpoint was American College of Rheumatology (ACR)20 response at Week 12. Safety was monitored through Week 26.
  
  
  RESULTS
  Overall, 302 patients were randomized: 76 to placebo, 75 to 30 mg IR, 73 to 60 mg IR, and 78 to 100 mg ER. There were no significant differences in ACR20 responses at Week 12 between SCIO-469 and placebo. Declines in C-reactive protein and erythrocyte sedimentation rate during early treatment did not persist to Week 12 and were not a consequence of decreased SCIO-469 plasma levels. The 60 mg IR regimen showed a dose-limiting toxicity manifested by elevations in alanine aminotransferase. Adverse events were common in all groups (79.7% and 86.7% through 13 and 26 weeks, respectively). Twenty-one patients reported 28 serious adverse events (SAE). SAE were more common with IR SCIO-469 than with placebo (7% vs 4%) but were not reported with ER SCIO-469.
  
  
  CONCLUSIONS
  In all regimens tested, SCIO-469 showed no greater efficacy compared to placebo in patients with RA. The transient effect of SCIO-469 on acute-phase reactants suggests a complex role of p38 MAPK in inflammation.
authors.affiliation: Division of Immunology and Rheumatology,Stanford University, 1000 Welch Road #203, Palo Alto, CA 94304, USA. genovese@stanford.edu
authors.forename: Mark C
authors.initials: MC
authors.lastname: Genovese
authors.forename: Stanley B
authors.initials: SB
authors.lastname: Cohen
authors.forename: David
authors.initials: D
authors.lastname: Wofsy
authors.forename: Michael E
authors.initials: ME
authors.lastname: Weinblatt
authors.forename: Gary S
authors.initials: GS
authors.lastname: Firestein
authors.forename: Ernest
authors.initials: E
authors.lastname: Brahn
authors.forename: Vibeke
authors.initials: V
authors.lastname: Strand
authors.forename: Daniel G
authors.initials: DG
authors.lastname: Baker
authors.forename: Sandra E
authors.initials: SE
authors.lastname: Tong
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D001172:Arthritis, Rheumatoid / Q000188:drug therapy* / Q000503:physiopathology; D001799:Blood Sedimentation; D002097:C-Reactive Protein / Q000378:metabolism; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D007211:Indoles / Q000008:administration & dosage* / Q000009:adverse effects; D008297:Male; D008875:Middle Aged; D012720:Severity of Illness Index; D016896:Treatment Outcome; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors*
chemical_list: D007211:Indoles; C499748:SCIO-469; D002097:C-Reactive Protein; D048051:p38 Mitogen-Activated Protein Kinases