A Study To Evaluate The Mechanism Of Action Of CP-690,550 In Patients With Rheumatoid Arthritis

• Drug: CP-690,550 + methotrexate
  
  CP-690,550 dose is 10 mg twice daily, oral tablets, for 4 weeks Methotrexate dose is ? 7.5 mg / week and ? 25 mg / week
• Drug: Placebo + Methotrexate
  
  Methotrexate dose is ? 7.5 mg / week and ? 25 mg / week

• Experimental: CP-690,550 + methotrexate
  
  Intervention: Drug: CP-690,550 + methotrexate
• Placebo Comparator: Placebo + methotrexate
  
  Intervention: Drug: Placebo + Methotrexate

• Cohen SB, Tanaka Y, Mariette X, Curtis JR, Lee EB, Nash P, Winthrop KL, Charles-Schoeman C, Thirunavukkarasu K, DeMasi R, Geier J, Kwok K, Wang L, Riese R, Wollenhaupt J. Long-term safety of tofacitinib for the treatment of rheumatoid arthritis up to 8.5 years: integrated analysis of data from the global clinical trials. Ann Rheum Dis. 2017 Jul;76(7):1253-1262. doi: 10.1136/annrheumdis-2016-210457. Epub 2017 Jan 31.
• Boyle DL, Soma K, Hodge J, Kavanaugh A, Mandel D, Mease P, Shurmur R, Singhal AK, Wei N, Rosengren S, Kaplan I, Krishnaswami S, Luo Z, Bradley J, Firestein GS. The JAK inhibitor tofacitinib suppresses synovial JAK1-STAT signalling in rheumatoid arthritis. Ann Rheum Dis. 2015 Jun;74(6):1311-6. doi: 10.1136/annrheumdis-2014-206028. Epub 2014 Nov 14.
• Cohen S, Radominski SC, Gomez-Reino JJ, Wang L, Krishnaswami S, Wood SP, Soma K, Nduaka CI, Kwok K, Valdez H, Benda B, Riese R. Analysis of infections and all-cause mortality in phase II, phase III, and long-term extension studies of tofacitinib in patients with rheumatoid arthritis. Arthritis Rheumatol. 2014 Nov;66(11):2924-37. doi: 10.1002/art.38779.

Inclusion Criteria:

• Subject must have a diagnosis of rheumatoid arthritis based on the American College of Rheumatology Association

• The subject has active disease at both Screening and Baseline, as defined:

  • ?4 joints tender or painful on motion, AND
  • ?4 joints swollen;
• The subject must have at least one knee, one elbow, one wrist or two metacarpophalangeal joints with active synovitis suitable for biopsy by the shaver technique

Exclusion Criteria:

• No arthroscopy should have been performed in the past 3 months in the same joint that is to be biopsied in this study.
• No intra-articular steroids should have been injected in the joint to be biopsied in this study in the previous 3 months.
• Subjects with evidence of hematopoietic disorders or evidence of hemoglobin levels < 9.0 gm/dL or hematocrit < 30 % at screening visit or within the 3 months prior to baseline synovial biopsy.
• An absolute white blood cell (WBC) count of < 3.0 x 109/L (<3000/mm3) or absolute neutrophil count of <1.2 X 109/L (<1200/mm3) at screening visit or within the 3 months prior to baseline synovial biopsy.
• Thrombocytopenia, as defined by a platelet count <100 x 109/L (< 100,000/mm3) at screening visit or within the 3 months prior to baseline synovial biopsy.
• Estimated GFR less than 40 ml/min based on Cockcroft Gault calculation .