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
Albany Medical College, Albany, New York 12206, USA.
Arthritis Rheum. 2012 Apr;64(4):970-81. doi: 10.1002/art.33419. Epub 2011 Oct 17.
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.
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.
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.
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.
比较6种剂量的口服托法替布（CP - 690,550）与安慰剂用于治疗对甲氨蝶呤（MTX）单药治疗反应不足且正在接受稳定剂量MTX背景治疗方案的活动性类风湿关节炎（RA）患者的疗效、安全性和耐受性。
在这项为期24周的双盲IIb期研究中，活动性RA患者（n = 507）被随机分配接受安慰剂或托法替布（20mg/天、1mg每日两次、3mg每日两次、5mg每日两次、10mg每日两次或15mg每日两次）。所有患者继续接受稳定剂量的MTX。主要终点是第12周时美国风湿病学会20%改善标准（ACR20）反应率。
在第12周时，所有每日两次剂量≥3mg的托法替布组患者的ACR20反应率（每日两次3mg组为52.9%，每日两次5mg组为50.7%，每日两次10mg组为58.1%，每日两次15mg组为56.0%，20mg/天组为53.8%）显著（P≤0.05）高于安慰剂组（33.3%）。在第24周时，ACR20、ACR50和ACR70反应、健康评估问卷残疾指数评分、使用C反应蛋白水平的28个关节的三变量疾病活动评分（DAS28 - CRP）以及DAS28 - CRP＜2.6的三变量评分均持续改善。在任何托法替布组中，超过10%的患者出现的最常见治疗中出现的不良事件为腹泻、上呼吸道感染和头痛；21例患者（4.1%）发生严重不良事件。观察到转氨酶水平偶尔升高、胆固醇和血清肌酐水平升高以及中性粒细胞和血红蛋白水平降低。
在对MTX反应不足的活动性RA患者中，每日两次添加剂量≥3mg的托法替布在24周内显示出持续疗效和可控制的安全性。
