title: Phase IIb dose-ranging study of the oral JAK inhibitor tofacitinib (CP-690,550) or adalimumab monotherapy versus placebo in patients with active rheumatoid arthritis with an inadequate response to disease-modifying antirheumatic drugs.
abstract: OBJECTIVE
  To compare the efficacy, safety, and tolerability of 5 doses of oral tofacitinib (CP-690,550) or adalimumab monotherapy with placebo for the treatment of active rheumatoid arthritis (RA) in patients with an inadequate response to disease-modifying antirheumatic drugs.
  
  
  METHODS
  In this 24-week, double-blind, phase IIb study, patients with RA (n = 384) were randomized to receive placebo, tofacitinib at 1, 3, 5, 10, or 15 mg administered orally twice a day, or adalimumab at 40 mg injected subcutaneously every 2 weeks (total of 6 injections) followed by oral tofacitinib at 5 mg twice a day for 12 weeks. The primary end point was the responder rate according to the American College of Rheumatology 20% improvement criteria (ACR20) at week 12.
  
  
  RESULTS
  Treatment with tofacitinib at a dose of ≥3 mg twice a day resulted in a rapid response with significant efficacy when compared to placebo, as indicated by the primary end point (ACR20 response at week 12), achieved in 39.2% (3 mg; P ≤ 0.05), 59.2% (5 mg; P < 0.0001), 70.5% (10 mg; P < 0.0001), and 71.9% (15 mg; P < 0.0001) in the tofacitinib group and 35.9% of patients in the adalimumab group (P = 0.105), compared with 22.0% of patients receiving placebo. Improvements were sustained at week 24, according to the ACR20, ACR50, and ACR70 response rates as well as classifications of remission according to the 3-variable Disease Activity Score in 28 joints (DAS28) using C-reactive protein and the 4-variable DAS28 using the erythrocyte sedimentation rate. The most common treatment-emergent adverse events (AEs) in patients across all tofacitinib treatment arms (n = 272) were urinary tract infection (7.7%), diarrhea (4.8%), headache (4.8%), and bronchitis (4.8%).
  
  
  CONCLUSIONS
  Tofacitinib monotherapy at ≥3 mg twice a day was efficacious in the treatment of patients with active RA over 24 weeks and demonstrated a manageable safety profile.
authors.affiliation: Metroplex Clinical Research Center and University of Texas Southwestern Medical Center, Dallas, TX 75231, USA. rfleischmann@arthdocs.com
authors.forename: Roy
authors.initials: R
authors.lastname: Fleischmann
authors.forename: Maurizio
authors.initials: M
authors.lastname: Cutolo
authors.forename: Mark C
authors.initials: MC
authors.lastname: Genovese
authors.forename: Eun Bong
authors.initials: EB
authors.lastname: Lee
authors.forename: Keith S
authors.initials: KS
authors.lastname: Kanik
authors.forename: Seth
authors.initials: S
authors.lastname: Sadis
authors.forename: Carol A
authors.initials: CA
authors.lastname: Connell
authors.forename: David
authors.initials: D
authors.lastname: Gruben
authors.forename: Sriram
authors.initials: S
authors.lastname: Krishnaswami
authors.forename: Gene
authors.initials: G
authors.lastname: Wallenstein
authors.forename: Bethanie E
authors.initials: BE
authors.lastname: Wilkinson
authors.forename: Samuel H
authors.initials: SH
authors.lastname: Zwillich
mesh_terms: D000068879:Adalimumab; D000284:Administration, Oral; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage / Q000627:therapeutic use*; D018501:Antirheumatic Agents / Q000627:therapeutic use*; D001172:Arthritis, Rheumatoid / Q000188:drug therapy*; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D057915:Drug Substitution; D004361:Drug Tolerance; D005260:Female; D006304:Health Status; D006801:Humans; D007279:Injections, Subcutaneous; D053616:Janus Kinase 3 / Q000037:antagonists & inhibitors; D007596:Joints / Q000187:drug effects / Q000503:physiopathology; D008297:Male; D008727:Methotrexate / Q000627:therapeutic use; D008875:Middle Aged; D010865:Pilot Projects; D010880:Piperidines; D011743:Pyrimidines / Q000008:administration & dosage / Q000627:therapeutic use*; D011758:Pyrroles / Q000008:administration & dosage / Q000627:therapeutic use*; D020127:Recovery of Function
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D018501:Antirheumatic Agents; D010880:Piperidines; D011743:Pyrimidines; D011758:Pyrroles; C479163:tofacitinib; D053616:Janus Kinase 3; D000068879:Adalimumab; D008727:Methotrexate