Atacicept in Patients With Rheumatoid Arthritis and an Inadequate Response to Tumor Necrosis Factor Antagonist Therapy Results of a Phase II, Randomized, Placebo-Controlled, Dose-Finding Trial
Atacicept in Patients With Rheumatoid Arthritis and an Inadequate Response to Tumor Necrosis Factor Antagonist Therapy Results of a Phase II, Randomized, Placebo-Controlled, Dose-Finding Trial
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DOI：
10.1002/art.30373
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发表时间：
2011-07-01
影响因子：
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通讯作者：
Tak, P. P.
中科院分区：
文献类型：
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作者：
Genovese, M. C.;Kinnman, N.;Tak, P. P.
目标。目的：评价阿他塞普在对肿瘤坏死因子拮抗剂治疗反应不充分的类风湿关节炎（RA）患者中的有效性、安全性和生物活性。阿他塞普减轻类风湿关节炎体征和症状试验（8月1日）是一项多中心、II期、双盲、安慰剂对照剂量研究，涉及256例患者，以1:1:1:1:1随机分组，接受阿他塞普（25mg、75mg或150mg）或安慰剂治疗，每周两次，持续4周，然后每周接受21周，13周无治疗随访期（第38周）。主要终点是根据美国风湿病学会（American College of Rheumatology）的疾病严重程度改善20%的标准（使用c反应蛋白水平），第26周的缓解。26周疗效终点差异无统计学意义（总治疗效果P = 0.410）。然而，阿他塞普显著降低免疫球蛋白和类风湿因子（RF）水平，但不降低抗瓜氨酸化蛋白抗体水平，呈剂量依赖性，在随访期间水平恢复到基线值。治疗对IgG- rf和IgA- rf的影响明显大于对总IgG和IgA的影响。不良事件（ae），包括严重ae，导致停药在阿他赛普组患者中比安慰剂组更常见。ae在性质上是可变的，没有观察到剂量依赖的趋势。不同治疗组感染相关不良反应的发生频率相似。治疗开始后，未观察到治疗对免疫状态（保护性滴度与非保护性滴度）的显著影响。本研究未达到主要疗效终点。然而，观察到与所提出的作用机制一致的明确生物活性。结果提示，降低RF的表达可能不足以诱导RA的临床改善。在该患者群体中，阿他赛普的安全性被认为是可以接受的。
Objective. To assess the efficacy, safety, and biologic activity of atacicept in patients with rheumatoid arthritis (RA) in whom the response to treatment with tumor necrosis factor antagonists was inadequate.Methods. The Atacicept for Reduction of Signs and Symptoms in Rheumatoid Arthritis Trial (AUGUST I) was a multicenter, phase II, double-blind, placebo-controlled dose-finding study involving 256 patients randomized 1:1:1:1 to receive atacicept (25 mg, 75 mg, or 150 mg) or placebo twice weekly for 4 weeks, then weekly for 21 weeks, with a 13-week treatment-free followup period (week 38). The primary end point was a response at week 26 according to the American College of Rheumatology criteria for 20% improvement in disease severity, using the C-reactive protein level.Results. No statistically significant differences were observed in the efficacy end points at week 26 (P = 0.410 for overall treatment effect). However, atacicept significantly reduced immunoglobulin and rheumatoid factor (RF) levels, but not anti-citrullinated protein antibody levels, in a dose-dependent manner, with levels returning toward baseline values during followup. The effects of treatment on IgG-RF and IgA-RF were more pronounced than the effects on total IgG and IgA. Adverse events (AEs), including serious AEs, leading to withdrawal were more common among patients treated with atacicept compared with placebo. AEs were variable in nature, and no dose-dependent trends were observed. The frequency of infection-related AEs was similar across treatments. No notable effect of treatment on immunization status (protective versus non-protective titer) was observed after initiation of treatment.Conclusion. This study did not meet the primary efficacy end point. However, clear biologic activity consistent with the proposed mechanism of action was observed. The results suggest that decreasing the expression of RF may not be sufficient to induce clinical improvement in RA. The safety of atacicept was considered acceptable in this patient population.