Randomized Trial of Verubecestat for Mild-to-Moderate Alzheimer's Disease.
Randomized Trial of Verubecestat for Mild-to-Moderate Alzheimer's Disease.
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DOI：
10.1056/nejmoa1706441
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发表时间：
2018-05-03
期刊：
影响因子：
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通讯作者：
Michelson D
中科院分区：
文献类型：
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作者：
Egan MF;Kost J;Tariot PN;Aisen PS;Cummings JL;Vellas B;Sur C;Mukai Y;Voss T;Furtek C;Mahoney E;Harper Mozley L;Vandenberghe R;Mo Y;Michelson D
阿尔茨海默病的特征在于淀粉样蛋白β（Aβ）斑块在脑中的沉积。Aβ是由淀粉样前体蛋白通过β位点淀粉样前体蛋白裂解酶1（BACE-1）随后通过γ-分泌酶连续裂解而产生的。Verubecestat是一种口服BACE-1抑制剂，可降低阿尔茨海默病患者脑脊液中的Aβ水平。我们进行了一项随机、双盲、安慰剂对照、78周的试验，以评估verubecestat每天12 mg和40 mg剂量与安慰剂相比在临床诊断为轻度至中度阿尔茨海默病的患者中的作用。共同主要结局是阿尔茨海默病评估量表认知子量表评分从基线到第78周的变化（ADAS-cog;评分范围从0到70，评分越高表明痴呆越严重）和阿尔茨海默病合作研究日常生活活动量表评分（ADCS-ADL;评分范围为0 - 78，评分越低表示功能越差）。共有1958例患者接受随机分组; 653例患者随机分配接受verubecestat 12 mg/天（12 mg组），652例患者接受verubecestat 40 mg/天（40 mg组），653例患者接受匹配的安慰剂。该试验在开始后50个月（即计划完成前5个月内）以及计划的1958名患者入组完成后，因无效而提前终止。12 mg组、40 mg组和安慰剂组ADAS-cog评分自基线至第78周的估计平均变化分别为7.9、8.0和7.7（12 mg组和安慰剂组之间比较P=0.63，40 mg组和安慰剂组之间比较P=0.46）。12 mg组、40 mg组和安慰剂组ADCS-ADL评分自基线至第78周的估计平均变化分别为−8.4、−8.2和−8.9（12 mg组和安慰剂组之间比较P=0.49，40 mg组和安慰剂组之间比较P=0.32）。不良事件，包括皮疹、福尔斯和受伤、睡眠障碍、自杀意念、体重减轻和头发颜色改变，在verubecestat组比安慰剂组更常见。Verubecestat并没有减少轻度至中度阿尔茨海默病患者的认知或功能下降，并且与治疗相关的不良事件有关。（ClinicalTrials.gov.）
Alzheimer’s disease is characterized by the deposition of amyloid-beta (Aβ) plaques in the brain. Aβ is produced from the sequential cleavage of amyloid precursor protein by β-site amyloid precursor protein–cleaving enzyme 1 (BACE-1) followed by y-secretase. Verubecestat is an oral BACE-1 inhibitor that reduces the Aβ level in the cerebrospinal fluid of patients with Alzheimer’s disease. We conducted a randomized, double-blind, placebo-controlled, 78-week trial to evaluate verubecestat at doses of 12 mg and 40 mg per day, as compared with placebo, in patients who had a clinical diagnosis of mild-to-moderate Alzheimer’s disease. The coprimary outcomes were the change from baseline to week 78 in the score on the cognitive subscale of the Alzheimer’s Disease Assessment Scale (ADAS-cog; scores range from 0 to 70, with higher scores indicating worse dementia) and in the score on the Alzheimer’s Disease Cooperative Study Activities of Daily Living Inventory scale (ADCS-ADL; scores range from 0 to 78, with lower scores indicating worse function). A total of 1958 patients underwent randomization; 653 were randomly assigned to receive verubecestat at a dose of 12 mg per day (the 12-mg group), 652 to receive verubecestat at a dose of 40 mg per day (the 40-mg group), and 653 to receive matching placebo. The trial was terminated early for futility 50 months after onset, which was within 5 months before its scheduled completion, and after enrollment of the planned 1958 patients was complete. The estimated mean change from baseline to week 78 in the ADAS-cog score was 7.9 in the 12-mg group, 8.0 in the 40-mg group, and 7.7 in the placebo group (P=0.63 for the comparison between the 12-mg group and the placebo group and P=0.46 for the comparison between the 40-mg group and the placebo group). The estimated mean change from baseline to week 78 in the ADCS-ADL score was −8.4 in the 12-mg group, −8.2 in the 40-mg group, and −8.9 in the placebo group (P=0.49 for the comparison between the 12-mg group and the placebo group and P=0.32 for the comparison between the 40-mg group and the placebo group). Adverse events, including rash, falls and injuries, sleep disturbance, suicidal ideation, weight loss, and hair-color change, were more common in the verubecestat groups than in the placebo group. Verubecestat did not reduce cognitive or functional decline in patients with mild-to-moderate Alzheimer’s disease and was associated with treatment-related adverse events.(ClinicalTrials.gov.)