ARTHRITIS & RHEUMATISM Vol. 64, No. 4, April 2012, pp 970–981 DOI 10.1002/art.33419 © 2012, American College of Rheumatology A Phase IIb Dose-Ranging Study of the Oral JAK Inhibitor Tofacitinib (CP-690,550) Versus Placebo in Combination With Background Methotrexate in Patients With Active Rheumatoid Arthritis and an Inadequate Response to Methotrexate Alone Joel M. Kremer, 1 Stanley Cohen, 2 Bethanie E. Wilkinson, 3 Carol A. Connell, 3 Jonathan L. French, 3 Juan Gomez-Reino, 4 David Gruben, 3 Keith S. Kanik, 3 Sriram Krishnaswami, 3 Virginia Pascual-Ramos, 5 Gene Wallenstein, 3 and Samuel H. Zwillich 3 Objective. To compare the efficacy, safety, and tolerability of 6 dosages of oral tofacitinib (CP-690,550) with placebo for the treatment of active rheumatoid arthritis (RA) in patients receiving a stable background regimen of methotrexate (MTX) who have an inade- quate response to MTX monotherapy. Methods. In this 24-week, double-blind, phase IIb study, patients with active RA (n  507) were random- ized to receive placebo or tofacitinib (20 mg/day, 1 mg twice daily, 3 mg twice daily, 5 mg twice daily, 10 mg twice daily, or 15 mg twice daily). All patients continued to receive a stable dosage of MTX. The primary end point was the American College of Rheumatology 20% improvement criteria (ACR20) response rate at week 12. Results. At week 12, ACR20 response rates for patients receiving all tofacitinib dosages >3 mg twice daily (52.9% for 3 mg twice daily, 50.7% for 5 mg twice daily, 58.1% for 10 mg twice daily, 56.0% for 15 mg twice daily, and 53.8% for 20 mg/day) were significantly (P < 0.05) greater than those for placebo (33.3%). Improvements were sustained at week 24 for the ACR20, ACR50, and ACR70 responses, scores for the Health Assessment Questionnaire disability index, the 3-variable Disease Activity Score in 28 joints using the C-reactive protein level (DAS28-CRP), and a 3-variable DAS28-CRP of <2.6. The most common treatment- emergent adverse events occurring in >10% of patients in any tofacitinib group were diarrhea, upper respira- tory tract infection, and headache; 21 patients (4.1%) experienced serious adverse events. Sporadic increases in transaminase levels, increases in cholesterol and serum creatinine levels, and decreases in neutrophil and hemoglobin levels were observed. Conclusion. In patients with active RA in whom the response to MTX has been inadequate, the addition of tofacitinib at a dosage >3 mg twice daily showed sustained efficacy and a manageable safety profile over 24 weeks. Tofacitinib (CP-690,550) is a novel, orally admin- istered JAK inhibitor that is being investigated as a ClinicalTrials.gov identifier: NCT00413660. Presented in part at the 75th and 76th Annual Scientific Meetings of the American College of Rheumatology/Association of Rheumatology Health Professionals, San Francisco, CA, October 2008 and Philadelphia, PA, October 2009, respectively. Supported by Pfizer. Dr. Kremer has received consulting fees from Pfizer (less than $10,000). Dr. Cohen owns stock in Pfizer. Drs. Wilkinson, Connell, French, Gruben, Kanik, Krishnaswami, and Wallenstein own stock or stock options in Pfizer. Dr. Gomez-Reino has received consulting fees, speaking fees, and/or honoraria from Schering-Plough, Bristol-Myers Squibb, Wyeth, Roche, and UCB (less than $10,000 each). 1 Joel M. Kremer, MD: Albany Medical College, Albany, New York; 2 Stanley Cohen, MD: Metroplex Clinical Research Center, Dallas, Texas; 3 Bethanie E. Wilkinson, PhD, Carol A. Connell, PhD, Jonathan L. French, ScD, David Gruben, PhD, Keith S. Kanik, MD, Sriram Krishnaswami, PhD, Gene Wallenstein, PhD, Samuel H. Zwillich, MD: Pfizer, Groton, Connecticut; 4 Juan Gomez-Reino, PhD: Hospital Clinico Universitario, University of Santiago, Santiago de Compostela, Spain; 5 Virginia Pascual-Ramos, MD: Instituto Nacional de Ciencias Me ´dicas y Nutricio ´n Salvador Zubira ´n, Mexico City, Mexico. Address correspondence to Joel M. Kremer, MD, Director of Research, The Center for Rheumatology, Albany Medical College, 1367 Washington Avenue, Suite 101, Albany, NY 12206. E-mail: jkremer@joint-docs.com. Submitted for publication July 12, 2010; accepted in revised form October 11, 2011. 970