Smolen Josef S, Beaulieu Andre, Rubbert-Roth Andrea, Ramos-Remus Cesar, Rovensky Josef, Alecock Emma, Woodworth Thasia, Alten Rieke
Division of Rheumatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria.
Lancet. 2008 Mar 22;371(9617):987-97. doi: 10.1016/S0140-6736(08)60453-5.
Interleukin 6 is involved in the pathogenesis of rheumatoid arthritis via its broad effects on immune and inflammatory responses. Our aim was to assess the therapeutic effects of blocking interleukin 6 by inhibition of the interleukin-6 receptor with tocilizumab in patients with rheumatoid arthritis.
In this double-blind, randomised, placebo-controlled, parallel group phase III study, 623 patients with moderate to severe active rheumatoid arthritis were randomly assigned with an interactive voice response system, stratified by site with a randomisation list provided by the study sponsor, to receive tocilizumab 8 mg/kg (n=205), tocilizumab 4 mg/kg (214), or placebo (204) intravenously every 4 weeks, with methotrexate at stable pre-study doses (10-25 mg/week). Rescue therapy with tocilizumab 8 mg/kg was offered at week 16 to patients with less than 20% improvement in both swollen and tender joint counts. The primary endpoint was the proportion of patients with 20% improvement in signs and symptoms of rheumatoid arthritis according to American College of Rheumatology criteria (ACR20 response) at week 24. Analyses were by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00106548.
The intention-to-treat analysis population consisted of 622 patients: one patient in the 4 mg/kg group did not receive study treatment and was thus excluded. At 24 weeks, ACR20 responses were seen in more patients receiving tocilizumab than in those receiving placebo (120 [59%] patients in the 8 mg/kg group, 102 [48%] in the 4 mg/kg group, 54 [26%] in the placebo group; odds ratio 4.0 [95% CI 2.6-6.1], p<0.0001 for 8 mg/kg vs placebo; and 2.6 [1.7-3.9], p<0.0001 for 4 mg/kg vs placebo). More people receiving tocilizumab than those receiving placebo had at least one adverse event (143 [69%] in the 8 mg/kg group; 151 [71%] in the 4 mg/kg group; 129 [63%] in the placebo group). The most common serious adverse events were serious infections or infestations, reported by six patients in the 8 mg/kg group, three in the 4 mg/kg group, and two in the placebo group.
Tocilizumab could be an effective therapeutic approach in patients with moderate to severe active rheumatoid arthritis.
F Hoffmann-La Roche, Chugai Pharmaceutical.
白细胞介素6通过对免疫和炎症反应的广泛影响参与类风湿关节炎的发病机制。我们的目的是评估用托珠单抗抑制白细胞介素6受体来阻断白细胞介素6对类风湿关节炎患者的治疗效果。
在这项双盲、随机、安慰剂对照、平行组III期研究中，623例中度至重度活动性类风湿关节炎患者通过交互式语音应答系统进行随机分组，根据研究申办者提供的随机分组列表按部位分层，每4周静脉注射托珠单抗8mg/kg（n = 205）、托珠单抗4mg/kg（214例）或安慰剂（204例），同时使用研究前稳定剂量的甲氨蝶呤（10 - 25mg/周）。在第16周时，对肿胀和压痛关节计数改善均不到20%的患者给予8mg/kg托珠单抗进行挽救治疗。主要终点是根据美国风湿病学会标准（ACR20反应）在第24周时类风湿关节炎体征和症状改善20%的患者比例。分析采用意向性分析。该试验已在ClinicalTrials.gov注册，编号为NCT00106548。
意向性分析人群包括622例患者：4mg/kg组有1例患者未接受研究治疗，因此被排除。在第24周时，接受托珠单抗治疗的患者中达到ACR20反应的比例高于接受安慰剂治疗的患者（8mg/kg组120例[59%]，4mg/kg组102例[48%]，安慰剂组54例[26%]；优势比4.0[95%CI 2.6 - 6.1]，8mg/kg组与安慰剂组相比p<0.0001；2.6[1.7 - 3.9]，4mg/kg组与安慰剂组相比p<0.0001）。接受托珠单抗治疗的患者中发生至少1次不良事件的人数多于接受安慰剂治疗的患者（8mg/kg组143例[69%]；4mg/kg组151例[71%]；安慰剂组129例[63%]）。最常见的严重不良事件是严重感染或寄生虫感染，8mg/kg组有6例患者报告，4mg/kg组有3例，安慰剂组有2例。
托珠单抗可能是中度至重度活动性类风湿关节炎患者的一种有效治疗方法。
F. Hoffmann - La Roche，中外制药株式会社。
