Requiring an amyloid-β1-42 biomarker for prodromal Alzheimer's disease or mild cognitive impairment does not lead to more efficient clinical trials
Requiring an amyloid-β1-42 biomarker for prodromal Alzheimer's disease or mild cognitive impairment does not lead to more efficient clinical trials
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DOI：
10.1016/j.jalz.2010.07.004
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发表时间：
2010-09-01
影响因子：
14
通讯作者：
Cutter, Gary R.
中科院分区：
文献类型：
--
作者：
Schneider, Lon S.;Kennedy, Richard E.;Cutter, Gary R.
背景资料：低脑脊液（CSF）淀粉样蛋白β（1-42）浓度和高总tau/A β（1-42）比值已被推荐用于支持遗忘型轻度认知障碍（aMCI）患者前驱阿尔茨海默病（AD）的诊断，并选择患者进行临床试验（Shaw等，Ann Neurol 2009;65：403-13; Dubois等，Lancet Neurol 2007;6：734-46）。方法：我们使用来自阿尔茨海默病神经成像倡议的满足以下入选标准的患者，用临床试验模拟测试了该推荐：（1）aMCI，（2）CSF A β（1-42）0.39的aMCI。对于每个标准，我们对数据库进行随机重新采样，为每个试验场景获得1000个试验的样本，计划进行1年或2年的试验，每个治疗组或安慰剂组的样本为50至400例患者，脱落率高达40%，使用AD评估量表-认知子量表和临床痴呆评定量表后的结果，效应量范围为0.15至0.75，结果：大约70%至74%的aMCI患者的CSF指标符合生物标志物标准。与不需要生物标志物标准的aMCI入组相比，增加低A β（1-42）或高tau/A β（1-42）要求导致试验的把握度增加最小或没有增加。安慰剂组和治疗组之间满足生物标志物标准的平均差异稍大，但被组内结果变异性增加所抵消。尽管符合CSF生物标志物标准的aMCI患者或前驱AD患者的认知受损程度略高于未考虑生物标志物诊断的aMCI患者，对生物标志物阳性患者的要求很可能不会导致更有效的临床试验，而且试验将需要更长的时间，因为可用的患者会更少。然而，CSF A β（1-41）标志物在药物作用下可能作为解释变量或协变量。(c)2010年，阿尔茨海默氏症协会。All rights reserved.
Background: Low cerebrospinal fluid (CSF) amyloid-beta(1-42) concentration and high total-tau/A beta(1-42) ratio have been recommended to support the diagnosis of prodromal Alzheimer's disease (AD) in patients with amnestic mild cognitive impairment (aMCI) and also to select patients for clinical trials (Shaw et al, Ann Neurol 2009;65:403-13; Dubois et al, Lancet Neurol 2007;6:734-46).Methods: We tested this recommendation with clinical trials simulations using patients from the Alzheimer Disease Neuroimaging Initiative who fulfilled the following entry criteria: (1) aMCI, (2) aMCI with CSF A beta(1-42) 0.39. For each criterion, we randomly resampled the database obtaining samples for 1000 trials for each trial scenario, planning for 1 or 2 year trials with samples from 50 to 400 patients per treatment or placebo group, with up to 40% dropouts, outcomes after using the AD assessment scale-cognitive subscale and clinical dementia rating scale with effect sizes ranging from 0.15 to 0.75, and calculated statistical power.Findings: Approximately 70% to 74% of aMCI patients with CSF measures met biomarker criteria. The addition of the low A beta(1-42) or high tau/A beta(1-42) requirement resulted in minimal or no increase in the power of the trials compared with enrolling aMCI without requiring the biomarker criteria. Slightly larger mean differences between the placebo and treatment groups fulfilling biomarker criteria were offset by increased outcome variability within the groups.Interpretations: Although patients with aMCI or patients with prodromal AD meeting CSF biomarkers criteria were slightly more cognitively impaired and showed greater decline than patients with aMCI diagnosed without considering the biomarkers, the requirement of biomarker-positive patients would most likely not result in more efficient clinical trials, and trials would take longer because fewer patients would be available. A CSF A beta(1-41) marker, however, could be useful as an explanatory variable or covariate when warranted by the action of a drug. (c) 2010 The Alzheimer's Association. All rights reserved.