Trial of Solanezumab for Mild Dementia Due to Alzheimer's Disease
Trial of Solanezumab for Mild Dementia Due to Alzheimer's Disease
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DOI：
10.1056/nejmoa1705971
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发表时间：
2018-01-25
影响因子：
158.5
通讯作者：
Siemers, Eric
中科院分区：
文献类型：
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作者：
Honig, Lawrence S.;Vellas, Bruno;Siemers, Eric
阿尔茨海默病的特征是淀粉样β蛋白（A β）斑块和神经元缠结。人源化单克隆抗体solanezumab被设计为增加可溶性A β肽从脑中的清除，所述可溶性A β肽可能导致突触中的毒性作用并且先于淀粉样蛋白的沉积。定义为简易精神状态检查（MMSE）评分为20 - 26（评分范围为0 - 30，评分越高表示认知越好），并且通过florbetapir正电子发射断层扫描或脑脊液中A β 1-42测量显示淀粉样蛋白沉积。患者被随机分配接受solanezumab 400 mg或安慰剂静脉给药，每4周一次，持续76周。主要结局是阿尔茨海默病评估量表的14项认知子量表评分从基线至第80周的变化（ADAS-cog 14;评分范围为0至90，评分越高表明认知障碍越大）。共有2129名患者入组了CRTSA，其中1057名患者被分配接受solanezumab，1072名患者接受安慰剂。solanezumab组ADAS-cog 14评分较基线的平均变化为6.65，安慰剂组为7.44，第80周时无显著组间差异（差异，-0.80; 95%置信区间，-1.73至0.14; P = 0.10）。由于在预先规定的分层分析中，主要结局未能达到显著性，因此认为次要结局是描述性的，报告时未进行显著性检验。Solanezumab组和安慰剂组MMSE评分较基线的变化分别为-3.17和-3.66。随机分组后，在磁共振成像上观察到的不良脑水肿或渗出性病变发生在solanezumab组的1例患者和安慰剂组的2例患者中。
BACKGROUNDAlzheimer's disease is characterized by amyloid-beta (A beta) plaques and neurofibrillary tangles. The humanized monoclonal antibody solanezumab was designed to increase the clearance from the brain of soluble A beta, peptides that may lead to toxic effects in the synapses and precede the deposition of fibrillary amyloid.METHODSWe conducted a double-blind, placebo-controlled, phase 3 trial involving patients with mild dementia due to Alzheimer's disease, defined as a Mini-Mental State Examination (MMSE) score of 20 to 26 (on a scale from 0 to 30, with higher scores indicating better cognition) and with amyloid deposition shown by means of florbetapir positron-emission tomography or A beta 1-42 measurements in cerebrospinal fluid. Patients were randomly assigned to receive solanezumab at a dose of 400 mg or placebo intravenously every 4 weeks for 76 weeks. The primary outcome was the change from baseline to week 80 in the score on the 14-item cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-cog14; scores range from 0 to 90, with higher scores indicating greater cognitive impairment).RESULTSA total of 2129 patients were enrolled, of whom 1057 were assigned to receive solanezumab and 1072 to receive placebo. The mean change from baseline in the ADAS-cog14 score was 6.65 in the solanezumab group and 7.44 in the placebo group, with no significant between-group difference at week 80 (difference, -0.80; 95% confidence interval, -1.73 to 0.14; P = 0.10). As a result of the failure to reach significance with regard to the primary outcome in the prespecified hierarchical analysis, the secondary outcomes were considered to be descriptive and are reported without significance testing. The change from baseline in the MMSE score was -3.17 in the solanezumab group and -3.66 in the placebo group. Adverse cerebral edema or effusion lesions that were observed on magnetic resonance imaging after randomization occurred in 1 patient in the solanezumab group and in 2 in the placebo group.CONCLUSIONSSolanezumab at a dose of 400 mg administered every 4 weeks in patients with mild Alzheimer's disease did not significantly affect cognitive decline.