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verubecestat治疗前驱期阿尔茨海默病的随机试验
Randomized Trial of Verubecestat for Prodromal Alzheimer’s Disease


Michael F. Egan ... 其他 • 2019.04.11
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摘要


背景

对于在痴呆出现之前改变脑内淀粉样蛋白沉积的药物,前驱期阿尔茨海默病为其提供了药效检验机会。verubecestat是一种口服的淀粉样前体蛋白β位点裂解酶-1(BACE-1)抑制剂,能够阻断淀粉样蛋白β(Aβ)的产生。在对阿尔茨海默病所致轻至中度痴呆患者开展的一项试验中,本药未能阻止疾病的临床进展。

 

方法

我们开展了一项为期104周的随机、双盲、安慰剂对照试验,在有记忆障碍和脑内淀粉样蛋白水平升高,但病情不符合痴呆定义的患者中比较了每日12 mg和40 mg剂量的verubecestat与安慰剂。主要结局是临床痴呆评定量表-总分(Clinical Dementia Rating Scale - Sum of Boxes [CDR-SB];评分范围为0~18分,较高的评分表示较差的认知和日常功能)从基线至第104周的变化。次要结局包括对认知和日常功能的其他评估。

 

结果

纳入1,454例患者后,本试验因无效(futility)而终止;485例患者被分配接受12 mg/d剂量的verubecestat治疗(12 mg组),484例接受40 mg/d剂量的verubecestat治疗(40 mg组),485例接受安慰剂治疗。各组分别共有234例患者、231例患者和239例患者完成了104周的试验治疗方案。在12 mg组、40 mg组和安慰剂组中,CDR-SB评分从基线至第104周的估计平均变化分别为1.65、2.02和1.58(12 mg组和安慰剂组之间的比较,P=0.67;40 mg组和安慰剂组之间的比较,P=0.01),这些结果提示,较大剂量组的结局比安慰剂组差。在12 mg组、40 mg组和安慰剂组中,进展至阿尔茨海默病所致痴呆的发生率分别为24.5起事件/100患者-年、25.5起事件/100患者-年和19.3起事件/100患者-年(40 mg vs.安慰剂的风险比,1.38;97.51%置信区间,1.07~1.79,未进行多重比较校正),安慰剂的结果较好。verubecestat组的不良事件发生率高于安慰剂组。

 

结论

在前驱期阿尔茨海默病患者中,verubecestat未改善痴呆的临床评分,并且一些指标提示,verubecestat组患者的认知和日常功能比安慰剂组患者差(由默沙东公司资助;在ClinicalTrials.gov注册号为NCT01953601)。





作者信息

Michael F. Egan, M.D., James Kost, Ph.D., Tiffini Voss, M.D., Yuki Mukai, M.D., Paul S. Aisen, M.D., Jeffrey L. Cummings, M.D., Sc.D., Pierre N. Tariot, M.D., Bruno Vellas, M.D., Ph.D., Christopher H. van Dyck, M.D., Merce Boada, M.D., Ying Zhang, Ph.D., Wen Li, Ph.D., Christine Furtek, B.S., Erin Mahoney, B.A., Lyn Harper Mozley, Ph.D., Yi Mo, Ph.D., Cyrille Sur, Ph.D., and David Michelson, M.D.
From Merck, Kenilworth, NJ (M.F.E., J.K., T.V., Y. Mukai, Y.Z., W.L., C.F., E.M., L.H.M., Y. Mo, C.S., D.M.); the University of Southern California, San Diego (P.S.A.); Cleveland Clinic Lou Ruvo Center for Brain Health, Las Vegas (J.L.C.); Banner Alzheimer’s Institute, Phoenix, AZ (P.N.T.); Gerontopole, INSERM Unité 1027, Alzheimer’s Disease Research and Clinical Center, Toulouse University Hospital, Toulouse, France (B.V.); Yale University School of Medicine, New Haven, CT (C.H.D.); and the Research Center and Memory Clínic, Fundació Alzheimer Centre Educacional, Institut Català de Neurociènces Aplicades–Universitat Internacional de Catalunya, Barcelona, and the Network Center for Biomedical Research in Neurodegenerative Diseases (CIBERNED), Instituto de Salud Carlos III, Madrid — both in Spain (M.B.). Address reprint requests to Dr. Egan at Merck, UG 4C-06, P.O. Box 1000, North Wales, PA 19454-1099, or at michael.egan@merck.com.

 

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