Randomized Trial of Verubecestat for Mild-to-Moderate Alzheimer's Disease

被引:491
作者
Egan, Michael F. [1 ]
Kost, James [1 ]
Tariot, Pierre N. [2 ]
Aisen, Paul S. [3 ]
Cummings, Jeffrey L. [4 ]
Vellas, Bruno [5 ]
Sur, Cyrille [1 ]
Mukai, Yuki [1 ]
Voss, Tiffini [1 ]
Furtek, Christine [1 ]
Mahoney, Erin [1 ]
Mozley, Lyn Harper [1 ]
Vandenberghe, Rik [6 ,7 ,8 ]
Mo, Yi [1 ]
Michelson, David [1 ]
机构
[1] Merck, Merck Res Labs, Kenilworth, NJ USA
[2] Banner Alzheimers Inst, Phoenix, AZ USA
[3] Univ Southern Calif, San Diego, CA USA
[4] Cleveland Clin, Lou Ruvo Ctr Brain Hlth, Las Vegas, NV USA
[5] Toulouse Univ Hosp, Alzheimers Dis Res & Clin Ctr, INSERM Unite 1027, Gerontopole, Toulouse, France
[6] Katholieke Univ Leuven, Alzheimer Res Ctr, Leuven Inst Neurosci & Dis, Leuven, Belgium
[7] Katholieke Univ Leuven, Dept Neurosci, Lab Cognit Neurol, Leuven, Belgium
[8] Univ Hosp, Neurol, Leuven, Belgium
关键词
BETA IMMUNIZATION AN1792; CLINICAL-TRIALS; RATING-SCALE; BAPINEUZUMAB; SOLANEZUMAB; INVENTORY; DEMENTIA; OUTCOMES; VOLUME;
D O I
10.1056/NEJMoa1706441
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
BACKGROUND Alzheimer's disease is characterized by the deposition of amyloid-beta (A beta) plaques in the brain. A beta is produced from the sequential cleavage of amyloid precursor protein by beta-site amyloid precursor protein-cleaving enzyme 1 (BACE-1) followed by gamma-secretase. Verubecestat is an oral BACE-1 inhibitor that reduces the A beta level in the cerebrospinal fluid of patients with Alzheimer's disease. METHODS 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). RESULTS 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. CONCLUSIONS 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.
引用
收藏
页码:1691 / 1703
页数:13
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