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dupilumab治疗中至重度未得到控制的哮喘的疗效和安全性
Dupilumab Efficacy and Safety in Moderate-to-Severe Uncontrolled Asthma


Mario Castro ... 呼吸系统疾病 • 2018.06.28
相关阅读
• 治疗哮喘的另外一种新生物制剂 • dupilumab治疗糖皮质激素依赖型重度哮喘的疗效和安全性 • dupilumab在嗜酸性粒细胞水平升高的持续性哮喘中的应用 • 美泊利单抗在嗜酸性粒细胞哮喘中减少口服糖皮质激素用量的作用

摘要


背景

dupilumab是一种完全人源性抗白细胞介素-4受体α单克隆抗体,可阻断白细胞介素-4和白细胞介素-13的信号传导。我们在未得到控制的哮喘患者中评估了dupilumab的疗效和安全性。

 

方法

我们以2∶2∶1∶1的比例,将1,902例年龄≥12岁,病情未得到控制的哮喘患者随机分组,分别接受dupilumab皮下给药添加治疗(200 mg或300 mg剂量,每2周1次)或容积匹配的安慰剂治疗52周。主要终点为在整个试验人群中的年哮喘重度发作率,以及支气管扩张药用药前的第一秒用力呼气量(FEV1)从基线至第12周的绝对变化。次要终点包括血嗜酸性粒细胞计数≥300/mm3患者的哮喘发作率和FEV1。还对哮喘控制和dupilumab安全性进行了评估。

 

结果

在被分配接受每2周1次200 mg dupilumab治疗的患者和被分配接受匹配安慰剂治疗的患者中,年哮喘重度发作率分别为0.46(95%置信区间[CI],0.39~0.53)和0.87(95% CI,0.72~1.05),dupilumab组的发作率比安慰剂组低47.7%(P<0.001);使用每2周1次300 mg dupilumab治疗时,观察到了相似的结果。在第12周时,在被分配接受较小剂量dupilumab治疗的患者中,观察到FEV1增加了0.32L(与匹配安慰剂的差异,0.14L;P<0.001);使用较大剂量时观察到了类似的结果。在血嗜酸性粒细胞计数≥300/mm3的患者中,在接受较小剂量dupilumab治疗的患者和接受匹配安慰剂治疗的患者中,年哮喘重度发作率分别为0.37(95% CI,0.29~0.48)和1.08(95% CI,0.85~1.38)(dupilumab组的发作率比安慰剂组低65.8%;95% CI,52.0~75.6);使用较大剂量时观察到了类似的结果。52例(4.1%)接受dupilumab治疗的患者和4例(0.6%)接受安慰剂治疗的患者在开始干预之后出现了血嗜酸性粒细胞增多。

 

结论

在这项试验中,接受dupilumab治疗患者的哮喘重度发作率显著低于接受安慰剂治疗的患者,并且具有较好的肺功能和哮喘控制。在基线嗜酸性粒细胞水平较高的患者中观察到的获益较大。在一些患者中观察到高嗜酸性粒细胞增多(hypereosinophilia)(由赛诺菲和再生元制药[Regeneron Pharmaceuticals]资助;LIBERTY ASTHMA QUEST在ClinicalTrials.gov注册号为NCT02414854)。





作者信息

Mario Castro, M.D., Jonathan Corren, M.D., Ian D. Pavord, M.D., Jorge Maspero, M.D., Sally Wenzel, M.D., Klaus F. Rabe, M.D., William W. Busse, M.D., Linda Ford, M.D., Lawrence Sher, M.D., J. Mark FitzGerald, M.D., Constance Katelaris, M.D., Yuji Tohda, M.D., Bingzhi Zhang, Ph.D., Heribert Staudinger, M.D., Gianluca Pirozzi, M.D., Ph.D., Nikhil Amin, M.D., Marcella Ruddy, M.D., Bolanle Akinlade, M.D., Asif Khan, M.B., B.S., M.P.H., Jingdong Chao, Ph.D., Renata Martincova, M.D., Neil M.H. Graham, M.B., B.S., M.D., Jennifer D. Hamilton, Ph.D., Brian N. Swanson, Ph.D., Neil Stahl, Ph.D., George D. Yancopoulos, M.D., Ph.D., and Ariel Teper, M.D.
From the Washington University School of Medicine, St. Louis (M.C.); David Geffen School of Medicine at the University of California, Los Angeles, Los Angeles (J. Corren), and Peninsula Research Associates, Rolling Hills Estates (L.S.) — both in California; Oxford Respiratory National Institute for Health Research Biomedical Research Centre, University of Oxford, Oxford, United Kingdom (I.D.P.); Fundación CIDEA (Centro de Investigación de Enfermedades Alérgicas y Respiratorias), Buenos Aires (J.M.); the University of Pittsburgh Asthma Institute, University of Pittsburgh, Pittsburgh (S.W.); LungenClinic Grosshansdorf, Grosshansdorf, and Christian Albrechts University Kiel, Kiel — both in Germany (K.F.R.); the Division of Allergy, Pulmonary, and Critical Care Medicine, University of Wisconsin School of Medicine and Public Health, Madison (W.W.B.); the Asthma and Allergy Center, Bellevue, NE (L.F.); the University of British Columbia, Vancouver, Canada (J.M.F.); Campbelltown Hospital and Western Sydney University, Sydney (C.K.); the Faculty of Medicine, Kindai University, Osakasayama, Japan (Y.T.); Sanofi, Bridgewater, NJ (B.Z., H.S., G.P., B.N.S., A.T.); Regeneron Pharmaceuticals, Tarrytown, NY (N.A., M.R., B.A., J. Chao, N.M.H.G., J.D.H., N.S., G.D.Y.); Sanofi, Chilly-Mazarin, France (A.K.); and Sanofi, Prague, Czech Republic (R.M.). Address reprint requests to Dr. Castro at Washington University School of Medicine, Campus Box 8052, 660 S. Euclid Ave., St. Louis, MO 63110-1093, or at castrom@wustl.edu. A complete list of investigators is provided in the Supplementary Appendix, available at NEJM.org.

 

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