依那西普治疗中国接受甲氨蝶呤治疗的活动性类风湿关节炎患者随机 双盲多中心 对照研究

A multi-center, double-blind, randomized, placebo-controlled study on the efficacy and safety of etanercept and methotrexate in the treatment of active rheumatoid arthritis

目的研究依那西普每周1次皮下注射50mg对接受甲氨蝶呤（MTX）治疗的中国活动性类风湿关节炎（RA）患者的疗效及安全性。方法本研究由2部分组成：12周双盲治疗阶段和12周安全性开放研究阶段。双盲期间的随机通过临床操作随机化（CORE）系统完成。在双盲阶段，RA患者被随机分配到依那西普50mg治疗组或安慰剂组，每周1次皮下注射给药，同时坚持一定剂量MTX给药。完成双盲治疗的RA患者在开放治疗中均接受每周1次依那西普50mg和MTX给药。以美国风湿病学会（ACR）疗效评价指标ACR20为主要终点疗效指标。次要终点疗效指标包括医生和患者总体评价、晨僵持续时间、疼痛目视模拟测试表（VAS）、健康评估问卷（HAQ）、C反应蛋白（CRP）值、疼痛和肿胀关节数。并且比较2组的安全性结果。采用Fisher精确概率法对主要终点疗效指标第12周ACR20应答情况及其他次要终点疗效指标进行分析。使用协方差方法分析连续终点相对于基线的变化。结果双盲治疗期间修正的意向性治疗人群（mITT）共有156例患者，其中依那西普＋MTX组77例，安慰剂＋MTX组79例，149例患者完成双盲阶段的治疗。治疗4周时，依那西普＋MTX组ACR20有效率为39％（30／77），安慰剂＋MTX组为16％（13／79），差异有统计学意义（P〈0．01）；12周时，依那西普＋MTX组ACR20有效率为62％（48／77），安慰剂＋MTX组为23％（18／79），差异有统计学意义（P〈0．01）。其他疗效指标包括医生和患者总体评价、晨僵持续时间、疼痛VAS、HAQ、CRP、触痛关节数、肿胀关节数等均从第4周开始，在依那西普＋MTX组明显优于安慰剂＋MTX组（P〈0．01）。总的不良反应发生率在2组间差异无统计学意义。结论与安慰剂治疗活动性RA相比，依那西普治疗活动性RA起效迅速、疗效显著。依那西普50mg＋MTX每周1次给药治疗中国成年活动性RA患者24周，耐受性良好。

Objective To compare the efficacy and safety of etanercept injection 50 mg once weekly combined with methotrexate （MTX） therapy for patients with active rheumatoid arthritis. Methods This study consists of 2 parts： a 12-week double-blind treatment period （part A） followed by a 12-week open-label safety study period （part B）. The randomization of treatments in double-blind treatment period was completed through the clinical operations randomization environment （CORE） system. During part A, the subjects were randomly assigned to the etanercept 50 mg or placebo group. The dosage regimen for etanercept was 50 mg administered subcutaneously once weekly while MTX was adnfinistered orally. All subjects who completed part A received 50 mg etanercept once weekly and MTX during the open-label treatment. The primary endpoint was ACR 20 response at week 12. Secondary endpoint variables included physician/patient global assessments of disease activities, duration of morning stiffness, pain visual analog scale （VAS）, health assessment questionnaire （HAQ）, CRP level and tender and swollen joint counts. The results of safety between the two groups were compared. The primary endpoint and other secondary binary endpoints were analyzed using the Fisher＇s exact test. For continuous endpoints, the change from baseline was analyzed with analysis of covariance. Results One hundred and fifty six subjects satisfied modified intent-to-treat （mlTF） population were enrolled during part A, of which 77 subjects were in the etanercept ＋ MTX group, and 79 subjects were in the placebo ＋ MTX group respectively. A total of 149 subjects completed part A. As early as week 4, the ACR 20 response achieved 39%（30/77 ） in the etanercept group, which was signit3cantly higher than that of the placebo group [16%（13/79）, P〈0.01]. At week 12, the ACR 20 response achieved 62%（48/77） in the etanercept group and 23%（18/79） in the placebo group （P〈0.01）. From week 4, other study endpoints including physician global assessment, patient global assessment, duration of morning stiffness, pain VAS, HAQ, CRP level, tender joint counts, swollen joint counts were also compared. The results showed that all above efficacy endpoints in the etanercept ＋ MTX group were better than those of the placebo ＋ MTX group （P〈0.01）. But there was no significant difference in the total adverse effects between the two groups. Conclusion Etanercept 50 mg once weekly ＋ MTX treatment for 24 weeks is well toleratedl During the first 12-week treatment period, the etanercept group has shown a rapid efficacy onset and a significantly better therapeutic effect compared to that of the placebo group.