A Phase 3 Trial of Semagacestat for Treatment of Alzheimer's Disease
A Phase 3 Trial of Semagacestat for Treatment of Alzheimer's Disease
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DOI：
10.1056/nejmoa1210951
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发表时间：
2013-07-25
影响因子：
158.5
通讯作者：
Mohs, Richard
中科院分区：
文献类型：
--
作者：
Doody, Rachelle S.;Raman, Rema;Mohs, Richard
背景：阿尔茨海默病的特征是皮层淀粉样蛋白斑块的存在，这是由-分泌酶和-分泌酶对淀粉样前体蛋白的顺序作用引起的。Semagacestat是一种小分子分泌酶抑制剂，被开发为治疗阿尔茨海默病的潜在药物。方法：我们进行了一项双盲、安慰剂对照试验，在1537例可能患有阿尔茨海默病的患者中，随机分组，每天接受100 mg、140 mg或安慰剂治疗。使用阿尔茨海默病认知评估量表（ADAS-cog）的认知亚量表评估从基线到第76周的认知变化，得分范围从0到70，得分越高表明认知障碍越严重；使用阿尔茨海默病日常生活合作研究活动（ADCS-ADL）量表评估功能变化，得分范围从0到78，得分越高表明功能越好。采用混合模型重复测量分析。结果根据数据和安全监测委员会的建议，试验在完成前终止。终止时，189名患者接受安慰剂治疗，153名患者接受100 mg的semagacestat治疗，121名患者接受140 mg的semagacestat治疗。ADAS-cog评分在所有三组中均恶化（平均变化，安慰剂组为6.4分，服用100 mg研究药物组为7.5分，服用140 mg研究药物组为7.8分；与安慰剂相比，P=0.15和P=0.07）。所有组的ADCS-ADL评分也均恶化(76周时平均变化，安慰剂组为-9.0分，100 mg组为-10.5分，140 mg组为-12.6分；P=0.14和P
BACKGROUNDAlzheimer's disease is characterized by the presence of cortical amyloid-beta (A) protein plaques, which result from the sequential action of -secretase and -secretase on amyloid precursor protein. Semagacestat is a small-molecule -secretase inhibitor that was developed as a potential treatment for Alzheimer's disease.METHODSWe conducted a double-blind, placebo-controlled trial in which 1537 patients with probable Alzheimer's disease underwent randomization to receive 100 mg of semagacestat, 140 mg of semagacestat, or placebo daily. Changes in cognition from baseline to week 76 were assessed with the use of the cognitive subscale of the Alzheimer's Disease Assessment Scale for cognition (ADAS-cog), on which scores range from 0 to 70 and higher scores indicate greater cognitive impairment, and changes in functioning were assessed with the Alzheimer's Disease Cooperative Study-Activities of Daily Living (ADCS-ADL) scale, on which scores range from 0 to 78 and higher scores indicate better functioning. A mixed-model repeated-measures analysis was used.RESULTSThe trial was terminated before completion on the basis of a recommendation by the data and safety monitoring board. At termination, there were 189 patients in the group receiving placebo, 153 patients in the group receiving 100 mg of semagacestat, and 121 patients in the group receiving 140 mg of semagacestat. The ADAS-cog scores worsened in all three groups (mean change, 6.4 points in the placebo group, 7.5 points in the group receiving 100 mg of the study drug, and 7.8 points in the group receiving 140 mg; P=0.15 and P=0.07, respectively, for the comparison with placebo). The ADCS-ADL scores also worsened in all groups (mean change at week 76, -9.0 points in the placebo group, -10.5 points in the 100-mg group, and -12.6 points in the 140-mg group; P=0.14 and P