Two phase 3 trials of bapineuzumab in mild-to-moderate Alzheimer's disease.
Two phase 3 trials of bapineuzumab in mild-to-moderate Alzheimer's disease.
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DOI：
10.1056/nejmoa1304839
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发表时间：
2014-01-23
期刊：
影响因子：
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通讯作者：
Bapineuzumab 301 and 302 Clinical Trial Investigators
中科院分区：
文献类型：
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作者：
Salloway S;Sperling R;Fox NC;Blennow K;Klunk W;Raskind M;Sabbagh M;Honig LS;Porsteinsson AP;Ferris S;Reichert M;Ketter N;Nejadnik B;Guenzler V;Miloslavsky M;Wang D;Lu Y;Lull J;Tudor IC;Liu E;Grundman M;Yuen E;Black R;Brashear HR;Bapineuzumab 301 and 302 Clinical Trial Investigators
Bapineuzumab是一种人源化抗淀粉样蛋白β单克隆抗体，正在临床开发用于治疗阿尔茨海默病。我们进行了两项双盲、随机、安慰剂对照、3期临床试验，涉及轻度至中度阿尔茨海默病患者-一项涉及1121名载脂蛋白E（APOE）ε4等位基因携带者，另一项涉及1331名非携带者。Bapineuzumab或安慰剂，剂量因研究而异，每13周静脉输注一次，持续78周。主要结局指标为阿尔茨海默病评估量表（ADAS-cog 11，评分范围为0至70，评分越高表示损伤越大）和痴呆症残疾评估（DAD，评分范围为0至100，评分越高表示损伤越小）的11项认知子量表评分。共有1090名携带者和1114名非携带者被纳入疗效分析。次要结果测量包括使用匹兹堡化合物B（PIB-PET）和脑脊液磷酸化tau（磷酸化tau）浓度的正电子发射断层扫描淀粉样蛋白成像结果。在主要结局方面，组间无显著差异。第78周时，ADAS-cog 11和DAD评分较基线变化的组间差异（bapineuzumab组减去安慰剂组）为-0.2（P = 0.80）和-1.2（P = 0.34）;非携带者研究中的相应差异为-0.3 0.5 mg/kg剂量的bapineuzumab分别为0.4（P = 0.64）和2.8（P = 0.07），1.0 mg/kg剂量的bapineuzumab分别为0.4（P = 0.62）和0.9（P = 0.55）。主要安全性结果是接受bapineuzumab治疗的患者中淀粉样蛋白相关的影像学异常伴水肿，其随bapineuzumab剂量和APOE ε4等位基因数量增加而增加，导致2.0 mg/kg剂量停药。在APOE ε4等位基因携带者中观察到PIB-PET和脑脊液磷酸化tau浓度的组间差异，但在非携带者中未观察到。尽管在APOE ε4携带者中观察到生物标志物的治疗差异，但Bapineuzumab并未改善阿尔茨海默病患者的临床结局。（由Janssen Alzheimer Immunotherapy和Pfizer资助; Bapineuzumab 301和302 ClinicalTrials.gov编号，NCT 00575055和NCT 00574132，以及EudraCT编号，2009-012748-17。）
Bapineuzumab, a humanized anti–amyloid-beta monoclonal antibody, is in clinical development for the treatment of Alzheimer’s disease. We conducted two double-blind, randomized, placebo-controlled, phase 3 trials involving patients with mild-to-moderate Alzheimer’s disease — one involving 1121 carriers of the apolipoprotein E (APOE) ε4 allele and the other involving 1331 noncarriers. Bapineuzumab or placebo, with doses varying by study, was administered by intravenous infusion every 13 weeks for 78 weeks. The primary outcome measures were scores on the 11-item cognitive subscale of the Alzheimer’s Disease Assessment Scale (ADAS-cog11, with scores ranging from 0 to 70 and higher scores indicating greater impairment) and the Disability Assessment for Dementia (DAD, with scores ranging from 0 to 100 and higher scores indicating less impairment). A total of 1090 carriers and 1114 noncarriers were included in the efficacy analysis. Secondary outcome measures included findings on positron-emission tomographic amyloid imaging with the use of Pittsburgh compound B (PIB-PET) and cerebrospinal fluid phosphorylated tau (phospho-tau) concentrations. There were no significant between-group differences in the primary outcomes. At week 78, the between-group differences in the change from baseline in the ADAS-cog11 and DAD scores (bapineuzumab group minus placebo group) were −0.2 (P = 0.80) and −1.2 (P = 0.34), respectively, in the carrier study; the corresponding differences in the noncarrier study were −0.3 (P = 0.64) and 2.8 (P = 0.07) with the 0.5-mg-per-kilogram dose of bapineuzumab and 0.4 (P = 0.62) and 0.9 (P = 0.55) with the 1.0-mg-per-kilogram dose. The major safety finding was amyloid-related imaging abnormalities with edema among patients receiving bapineuzumab, which increased with bapineuzumab dose and APOE ε4 allele number and which led to discontinuation of the 2.0-mg-per-kilogram dose. Between-group differences were observed with respect to PIB-PET and cerebrospinal fluid phospho-tau concentrations in APOE ε4 allele carriers but not in noncarriers. Bapineuzumab did not improve clinical outcomes in patients with Alzheimer’s disease, despite treatment differences in biomarkers observed in APOE ε4 carriers. (Funded by Janssen Alzheimer Immunotherapy and Pfizer; Bapineuzumab 301 and 302 ClinicalTrials.gov numbers, NCT00575055 and NCT00574132, and EudraCT number, 2009-012748-17.)