Randomized Trial of Verubecestat for Prodromal Alzheimer's Disease
Randomized Trial of Verubecestat for Prodromal Alzheimer's Disease
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DOI：
10.1056/nejmoa1812840
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发表时间：
2019-04-11
影响因子：
158.5
通讯作者：
Michelson, David
中科院分区：
文献类型：
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作者：
Egan, Michael F.;Kost, James;Michelson, David
背景：前驱阿尔茨海默病提供了一个机会来测试药物的作用，这些药物可以在痴呆发作前改变淀粉样蛋白在大脑中的沉积。Verubecestat是一种口服β位点淀粉样前体蛋白裂解酶1（BACE-1）抑制剂，可阻断淀粉样蛋白β（A β）的产生。在一项涉及阿尔茨海默病所致轻度至中度痴呆患者的试验中，该药并没有阻止临床进展。方法我们进行了一项随机、双盲、安慰剂对照、为期104周的试验，以评估verubecestat每天12 mg和40 mg剂量与安慰剂相比，在记忆障碍和脑淀粉样蛋白水平升高但不符合痴呆病例定义的患者中的疗效。主要结局是临床痴呆评定量表-方框总和（CDR-SB;评分范围为0 - 18，评分越高表示认知和日常功能越差）评分从基线至第104周的变化。次要结局包括认知和日常功能的其他评估。结果在1454名患者入组后，试验因无效而终止; 485名患者被分配接受verubecestat，剂量为12 mg/天（12 mg组），484名患者接受verubecestat，剂量为40 mg/天（40 mg组），485名患者接受安慰剂。每组分别有234例、231例和239例患者完成了104周的试验方案。12 mg组、40 mg组和安慰剂组从基线至第104周CDR-SB评分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），表明高剂量组的结果比安慰剂组更差。在12 mg组、40 mg组和安慰剂组中，阿尔茨海默病进展为痴呆的估计发生率分别为24.5、25.5和19.3起事件/100患者-年（40 mg与安慰剂的风险比为1.38; 97.51%置信区间为1.07 - 1.79，未调整多重比较），有利于安慰剂。不良事件在verubecestat组比安慰剂组更常见。结论Verubecestat并没有改善前驱阿尔茨海默病患者的痴呆临床评分，一些措施表明，接受verubecestat的患者的认知和日常功能比接受安慰剂的患者更差。（由Merck Sharp & Dohme资助; ClinicalTrials.gov编号，。）在一项随机试验中，患有脑淀粉样蛋白沉积但没有痴呆的患者接受β位点淀粉样蛋白前体蛋白裂解酶1抑制剂治疗，在临床结局方面没有获益，并且在认知和日常功能的某些指标上恶化。
Background Prodromal Alzheimer's disease offers an opportunity to test the effect of drugs that modify the deposition of amyloid in the brain before the onset of dementia. Verubecestat is an orally administered beta-site amyloid precursor protein-cleaving enzyme 1 (BACE-1) inhibitor that blocks production of amyloid-beta (A beta). The drug did not prevent clinical progression in a trial involving patients with mild-to-moderate dementia due to Alzheimer's disease. Methods We conducted a randomized, double-blind, placebo-controlled, 104-week trial to evaluate verubecestat at doses of 12 mg and 40 mg per day, as compared with placebo, in patients who had memory impairment and elevated brain amyloid levels but whose condition did not meet the case definition of dementia. The primary outcome was the change from baseline to week 104 in the score on the Clinical Dementia Rating Scale-Sum of Boxes (CDR-SB; scores range from 0 to 18, with higher scores indicating worse cognition and daily function). Secondary outcomes included other assessments of cognition and daily function. Results The trial was terminated for futility after 1454 patients had been enrolled; 485 had been assigned to receive verubecestat at a dose of 12 mg per day (the 12-mg group), 484 to receive verubecestat at a dose of 40 mg per day (the 40-mg group), and 485 to receive placebo. A total of 234 patients, 231 patients, and 239 patients per group, respectively, completed 104 weeks of the trial regimen. The estimated mean change from baseline to week 104 in the CDR-SB score was 1.65 in the 12-mg group, 2.02 in the 40-mg group, and 1.58 in the placebo group (P=0.67 for the comparison between the 12-mg group and the placebo group and P=0.01 for the comparison between the 40-mg group and the placebo group), suggesting a worse outcome in the higher-dose group than in the placebo group. The estimated rate of progression to dementia due to Alzheimer's disease was 24.5, 25.5, and 19.3 events per 100 patient-years in the 12-mg group, the 40-mg group, and the placebo group, respectively (hazard ratio for 40 mg vs. placebo, 1.38; 97.51% confidence interval, 1.07 to 1.79, not adjusted for multiple comparisons), favoring placebo. Adverse events were more common in the verubecestat groups than in the placebo group. Conclusions Verubecestat did not improve clinical ratings of dementia among patients with prodromal Alzheimer's disease, and some measures suggested that cognition and daily function were worse among patients who received verubecestat than among those who received placebo. (Funded by Merck Sharp & Dohme; ClinicalTrials.gov number, .)In a randomized trial, patients with brain amyloid deposition but no dementia who received a beta-site amyloid precursor protein-cleaving enzyme 1 inhibitor had no benefit with respect to clinical outcomes and worsening on some measures of cognition and daily function.