PREVENTION OF ALZHEIMER DEMENTIA & COGNITIVE DECLINE

一项将阿尔茨海默病(AD)发病推迟数年的干预措施将产生巨大的公共健康效益。几项研究表明，非类固醇抗炎药(NSAIDs)可能会产生这种延迟。非类固醇抗炎药也可以减轻进行性年龄相关性认知衰退(ARCD)，当这种情况代表AD的前驱症状时。这两种预防策略只能在随机试验中进行最终评估。这样的试验还可以检查长期使用非甾体抗炎药的相关风险，中等剂量似乎提供了对AD和ARCD的保护。选择性环氧合酶-2(COX-2)抑制剂可以改善安全性，但目前尚不清楚COX-2抑制是否能提供与传统非类固醇抗炎药明显的保护作用。因此，我们建议进行一项关于普通非甾体抗炎药布洛芬和选择性COX-2抑制剂塞来昔布与安慰剂的平行试验，以预防AD和减弱ARCD。这项试验将涉及四个地点，招募2625名年龄在72-88岁之间、有阿尔茨海默氏样痴呆症病史的无痴呆症受试者作为一级亲属。因此，周期性认知筛查测试结果的明显下降将识别出疑似偶发痴呆症的受试者。我们将使用结构化、标准化的评估和诊断方法对这些受试者进行临床评估。建议的样本假设观察7年，并对死亡率和其他原因造成的磨损以及治疗“中断”和“中断”进行了现实的估计。它应该提供80%的力量(双尾a=0.05)，以检测到在治疗组中发病率降低30%。在这项申请中，我们提出了前42-54个月的治疗，并在最后登记的受试者完成30个月后的中期疗效分析。在这一点上，这项研究将有80%的力量来检测使用任何一种药物的AD发病率降低50%，在这种情况下，试验可以停止。如果治疗没有明显的好处，或者如果安全问题强制进行，也应该取消试验。否则，对治疗效果的间歇估计将决定竞争续签申请的形式，即额外的0.25至4年的观察和最终分析。作为次要结果，我们将检查认知分数的轨迹来评估ARCD。

An intervention that delayed onset of Alzheimer's disease (AD) by several years would yield huge public health benefits. Several studies suggest that non-steroidal anti-inflammatory drugs (NSAIDs) may produce such a delay. NSAIDs may also attenuate progressive age-related cognitive decline (ARCD) when this conditions represents a prodrome of AD. Both prevention strategies can be evaluated definitively only in randomized trials. Such trials can also examine attendant risks of long- term NSAID use in the moderate doses that appear to afford protection against AD and ARCD. Improved safety may be available with selective cyclooxygenase-2 (COX-2) inhibitors, but it is not clear that COX-2 inhibition offers the protective effect apparent with conventional NSAIDs. We therefore propose a parallel trial of the common NSAID ibuprofen and the selective COX-2 inhibitor celecoxib vs. placebo for prevention of AD and for attenuation of ARCD. The trial will involve four sites and enroll 2625 dementia-free subjects aged 72-88 with a history of Alzheimer-like dementia for a first degree relative. Therefore, a conspicuous decline in periodic cognitive screening test results will identify subjects with suspected incident dementia. We will evaluate these subjects clinically using structured, standardized methods of assessment and diagnosis. The proposed sample presumes 7 years of observation, with realistic estimates of attrition through mortality and other causes, and of treatment "drop-outs" and "drop-ins." It should provide 80% power (2-tailed a=0.05) to detect a 30% reduction in incidence among the treated groups. In this application we proposed the first 42-54 months of treatment with an interim analysis of efficacy after the last-enrolled subject has completed 30 months. At that point, the study will have 80% power to detect a 50% reduction in AD incidence with either agent, in which case the trial can be stopped. The trial should also be stropped if there is no apparent benefit of treatment, or if safety issues mandate. Otherwise, the intermit estimate of treatment effects will dictate the shape of a competing renewal application an additional 0.25 to 4 years of observation and a final analysis. As a secondary outcome, we will examine the trajectory of cognitive scores to assess ARCD.