Oral p38 mitogen-activated protein kinase inhibition with BIRB 796 for active Crohn's disease: A randomized, double-blind, placebo-controlled trial
Oral p38 mitogen-activated protein kinase inhibition with BIRB 796 for active Crohn's disease: A randomized, double-blind, placebo-controlled trial
复制标题
DOI：
10.1016/j.cgh.2005.11.013
复制
发表时间：
2006-03-01
影响因子：
12.6
通讯作者：
Steffgen, J
中科院分区：
文献类型：
--
作者：
Schreiber, S;Feagan, B;Steffgen, J
背景&施舍：p38丝裂原活化蛋白激酶（MAPK）调节促炎细胞因子的表达，其在克罗恩病（CD）的病理生理学中起关键作用。本研究研究了BIRB 796（一种高效p38 MAPK抑制剂）在慢性活动性CD中的疗效和安全性。研究方法：在一项多中心、多国试验中，284例中重度CD患者随机接受安慰剂或：10、20、30或60 mg BIRB 796，每日两次，持续8周。临床终点基于标准安全性评估、CD活动指数、C反应蛋白水平和生活质量（炎症性肠病问卷）。在一项子研究中，评估了克罗恩病内镜严重程度指数和活检标本的组织学结果。结果如下：与安慰剂相比，BIRB 796未观察到临床疗效（主要终点，临床缓解;次要终点，临床反应;炎症性肠病问卷;克罗恩病内镜严重程度指数）。BIRB 796给药1周后，观察到C反应蛋白水平一过性显著剂量依赖性降低，并随时间恢复至基线水平。所有治疗组之间不良事件的发生率相当，但转氨酶水平轻度升高除外，该升高在BIRB 796组中更常见。观察到地理中心效应，在安慰剂组和活性治疗组中，俄罗斯中心的缓解率和应答率明显高于其他国家，不良事件发生率低于其他国家。结论：没有证据表明BIRB 796在CD中的临床疗效。俄罗斯和非俄罗斯中心在CD过程中存在显着差异。
Background & Alms: The p38 mitogen-activated protein kinase (MAPK) regulates the expression of proinflammatory cytokines, which play a critical role in the pathophysiology of Crohn's disease (CD). This study investigated the efficacy and safety of BIRB 796, a highly potent inhibitor of p38 MAPK, in chronic active CD. Methods: In a multicenter, multinational trial, 284 patients with moderate to severe CD were randomized to receive placebo, or :10, 20, 30, or 60 mg of BIRB 796 twice daily for 8 weeks. Clinical endpoints were based on standard safety assessments, CD Activity Index, C-reactive protein levels, and quality of life (inflammatory Bowel Disease Questionnaire). In a substudy, the Crohn's Disease Endoscopic Index of Severity and histologic results of biopsy specimens were assessed. Results: No clinical efficacy (primary end point, clinical remission; secondary end point, clinical response; Inflammatory Bowel Disease Questionnaire; Crohn's Disease Endoscopic Index of Severity) was seen for BIRB 796 in comparison with placebo. A significant, dose-dependent decrease of C-reactive protein level was observed transiently after BIRB 796 after 1 week with a return to baseline level over time. The incidence of adverse events was comparable between all treatment groups, with the exception of a mild increase of transaminase levels that was seen more frequently in the BIRB 796 groups. Geographic center effects were observed with Russian centers producing distinctly higher remission and response rates and lower adverse event rates than in other countries in both placebo and active treatment groups. Conclusions: There was no evidence for clinical efficacy of BIRB 796 in CD. A remarkable difference in the course of CD exists between Russia and non-Russian centers.