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ozanimod用于溃疡性结肠炎的诱导和维持治疗
Ozanimod as Induction and Maintenance Therapy for Ulcerative Colitis


William J. Sandborn ... 其他 • 2021.09.30
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小分子口服药有效治疗中重度溃疡性结肠炎

 

夏璐

上海嘉会国际医院消化内科

 

溃疡性结肠炎(UC)是炎性肠病(IBD)的一种亚型,目前病因尚不十分明确,一般认为其与肠黏膜的免疫应答异常相关。该病目前尚无根治性药物,传统治疗包括氨基水杨酸类、糖皮质激素及免疫抑制剂,新型治疗方式包括生物制剂和小分子药物等。其中,小分子药物因其给药方便、无免疫原性、半衰期短、制造成本低等优势为IBD的治疗提供了新选择。

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摘要


背景

ozanimod是选择性鞘氨醇-1-磷酸受体调节剂,目前正被研究用于治疗炎性肠病。

 

方法

我们开展了一项将ozanimod用于中度至重度活动性溃疡性结肠炎患者诱导和维持治疗的3期、多中心、随机、双盲、安慰剂对照试验。在10周诱导期,我们以双盲方式将队列1患者分配接受每日一次口服ozanimod hydrochloride(剂量1 mg,相当于0.92 mg ozanimod)或安慰剂治疗,队列2患者以相同日剂量接受ozanimod开放标签治疗。10周时,任一队列中对ozanimod有临床应答的患者被再次随机分组,两组在维持期分别接受双盲ozanimod或安慰剂治疗(至第52周)。两个时期的主要终点是发生临床缓解的患者百分比(使用包括三部分的Mayo评分评估)。关键次要临床、内镜和组织学终点应用有排序的分级检验法进行评估。本研究还评估了安全性。

 

结果

在诱导期,645例患者被纳入队列1,367例被纳入队列2;共计457例患者被纳入维持期。在诱导期(18.4% vs. 6.0%,P<0.001)和维持期(37.0% vs. 18.5%[在第10周时有应答的患者中],P<0.001),接受ozanimod患者的临床缓解率均显著高于接受安慰剂的患者。在诱导期(47.8% vs. 25.9%,P<0.001)和维持期(60.0% vs. 41.0%,P<0.001),ozanimod组的临床应答率也显著高于安慰剂组。在两个时期,与安慰剂组相比,ozanimod组的所有其他关键次要终点均显著改善。ozanimod组的(任何严重程度)感染发生率在诱导期与安慰剂组相似,在维持期高于安慰剂组。在52周试验期间,各组均有不到2%的患者发生严重感染。ozanimod组中肝脏转氨酶升高的发生率较高。

 

结论

在中度至重度活动性溃疡性结肠炎患者中,用于诱导和维持治疗ozanimod比安慰剂更有效(由百时美施贵宝资助,True North在ClinicalTrials.gov注册号为NCT02435992)。





作者信息

William J. Sandborn, M.D., Brian G. Feagan, M.D., Geert D’Haens, M.D., Douglas C. Wolf, M.D., Igor Jovanovic, M.D., Stephen B. Hanauer, M.D., Subrata Ghosh, M.D., AnnKatrin Petersen, M.D., Steven Y. Hua, Ph.D., Ji Hwan Lee, M.S., Lorna Charles, M.D., Denesh Chitkara, M.D., Keith Usiskin, M.D., Jean-Frederic Colombel, M.D., Loren Laine, M.D., and Silvio Danese, M.D. for the True North Study Group*
From the University of California San Diego, La Jolla (W.J.S.); Western University, London, ON, Canada (B.G.F.); the Inflammatory Bowel Disease Center, Academic Medical Center, Amsterdam (G.D.); the Center for Crohn’s Disease and Ulcerative Colitis, Atlanta Gastroenterology Associates, Atlanta (D.C.W.); the Division of Gastroenterology, University Hospital Medical Center Bežanijska Kosa, Belgrade, Serbia (I.J.); the Feinberg School of Medicine, Chicago (S.B.H.); APC Microbiome Ireland, College of Medicine and Health, University College Cork, Cork, Ireland (S.G.); Bristol Myers Squibb, Princeton, NJ (A.P., S.Y.H., J.H.L., L.C., D.C., K.U.); the Department of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York (J.-F.C.); Yale School of Medicine, New Haven, and the Veterans Affairs Connecticut Healthcare System, West Haven — both in Connecticut (L.L.); and IRCCS Humanitas Research Hospital and University Vita-Salute San Raffaele, Milan (S.D.). Address reprint requests to Dr. Sandborn at the Division of Gastroenterology, University of California San Diego, 9500 Gilman Dr., La Jolla, CA 92093-0956, or at wsandborn@ucsd.edu. *A complete list of the members of the True North Study Group is provided in the Supplementary Appendix, available at NEJM.org.

 

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