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
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
复制标题
DOI：
10.1002/art.33383
复制
发表时间：
2012-03-01
影响因子：
--
通讯作者：
Zwillich, Samuel H.
中科院分区：
文献类型：
--
作者：
Fleischmann, Roy;Cutolo, Maurizio;Zwillich, Samuel H.
目的比较5种剂量的口服托法替尼（CP-690，550）或阿达木单抗单药治疗与安慰剂治疗对缓解疾病的抗风湿药物疗效不佳的活动性类风湿关节炎（RA）患者的疗效、安全性和耐受性。方法.在这项为期24周、双盲、IIb期研究中，RA患者（n = 384）随机接受安慰剂、托法替尼1、3、5、10或15 mg口服给药，每日两次，或阿达木单抗40 mg皮下注射，每2周一次（共6次注射），随后口服托法替尼5 mg，每日两次，持续12周。主要终点为第12周根据美国流变学会20%改善标准（ACR 20）的应答率。结果如主要终点所示，与安慰剂相比，托法替尼剂量> 3 mg，每日两次治疗可产生快速反应，且疗效显著（第12周时的ACR 20应答），39.2%的患者达到（3 mg; P < 0.05），59.2%（5 mg; P < 0.0001），70.5%（10 mg; P < 0.0001），71.9%（15 mg; P < 0.0001），阿达木单抗组为35.9%（P = 0.105），安慰剂组为22.0%。根据ACR 20、ACR 50和ACR 70缓解率以及根据使用C反应蛋白的28个关节的3变量疾病活动性评分（DAS 28）和使用红细胞沉降率的4变量DAS 28的缓解分类，在第24周时持续改善。所有托法替布治疗组（n = 272）患者中最常见的治疗后出现的不良事件（AE）为尿路感染（7. 7%）、腹泻（4. 8%）、头痛（4. 8%）和支气管炎（4. 8%）。结论托法替尼单药治疗（> 3 mg，每日两次）在治疗活动性RA患者中有效超过24周，并显示出可管理的安全性特征。
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%). Conclusion. 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.