Randomized Trial of Verubecestat for Prodromal Alzheimer’s Disease

作者：Michael Egan, James Kost, Tiffini Voss, Yuki Mukai, Paul Aisen, Jeffrey L. Cummings, Pierre N. Tariot, Bruno Vellas, Christopher H. van Dyck, Merçé Boada, Ying Zhang, Wen Li, Christine Furtek, Erin Mahoney, Lyn Harper Mozley, Mo Yi, Cyrille Sur, David Michelson · 发表于：New England Journal of Medicine · 年份：2019 · DOI：10.1056/nejmoa1812840 · 被引用次数：559 · 研究领域：Alzheimer's disease research and treatments、Dementia and Cognitive Impairment Research、Cholinesterase and Neurodegenerative Diseases

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 β-site amyloid precursor protein-cleaving enzyme 1 (BACE-1) inhibitor that blocks production of amyloid-beta (Aβ). 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 mea...