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

作者：Kremer, Joel M.^*; Cohen, Stanley; Wilkinson, Bethanie E.; Connell, Carol A.; French, Jonathan L.; Gomez-Reino, Juan; Gruben, David; Kanik, Keith S.; Krishnaswami, Sriram; Pascual-Ramos, Virginia; Wallenstein, Gene; Zwillich, Samuel H.

来源：Arthritis and Rheumatism, 2012, 64(4): 970-981.

DOI：10.1002/art.33419

• CLINICAL-TRIALS
• VALIDATION
• CRITERIA

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 inadequate response to MTX monotherapy. @@@ Methods. In this 24-week, double-blind, phase IIb study, patients with active RA (n = 507) were randomized 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 respiratory 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.

• 出版日期2012-4