The A3 Study: Ante-Amyloid Prevention of Alzheimer's disease

总结 这是一份申请，要求NIH支持公私慈善合作， 一项旨在在当前“淀粉样蛋白阳性”阈值之前启动抗淀粉样蛋白治疗的预防试验 （Aβ+）。我们提出了阿尔茨海默病（AD）的抗淀粉样蛋白预防-“A3”研究-在临床上 PET筛查中淀粉样蛋白水平“非升高”的正常老年人， Aβ的进一步积累。A3研究将利用大量筛选失败的渴望参与者， 目前的二级预防试验（A4和EARLY/“A5”试验）基于非升高的淀粉样蛋白水平， 筛选淀粉样蛋白PET扫描（florbetapir SUVr）。我们将使用年龄x APOE x淀粉样蛋白PET SUVr风险 算法，以确定和登记600名年龄在60-75岁之间的人，他们还没有达到 Aβ+，但显示中等水平的SUVr（Aβi），并且进展为Aβ+的风险最高。我们 初步数据表明，这些Aβi参与者将显示Aβ蓄积显著增加， 2-4年，以及显示新皮质tau蛋白扩散，皮质变薄，甚至微妙的下降的证据， 随着他们向Aβ+的发展，他们会进行认知测试。我们的最终目标是促进AD的一级预防试验。 A3设计将在Aβ蓄积阶段（估计为 比目前的二级预防试验（“临床前AD”）早5年。有几个BACE 目前在AD晚期进行的大规模试验中显示出Aβ产生的稳健降低， 良好的安全性特征适合在极早期风险人群中启动试验。A3研究设计是 一项2b/3期双盲、随机、3组、4年试验，使用2种剂量的BACE抑制剂与安慰剂（n=200 每臂）。主要结局将是连续淀粉样蛋白PET成像上的Aβ沉积率， 使用Tau PET成像、CSF测定、体积MRI和敏感的认知测量结果。我们的目标是 建立一个“证据链”，将减缓早期Aβ积累与预防 在临床前AD的后期阶段发生的神经变性和认知下降。与A4相似 研究，A3研究将是一个公共-私人-慈善合作伙伴关系，我们的行业合作伙伴提供 大部分资金支持研究的开展。我们选择了3个潜在的行业合作伙伴。一 治疗选择委员会将根据以下因素最终选择BACE抑制剂和行业合作伙伴 申办者提供的最新疗效和安全性数据。这项研究将提供关键的纵向 生物标志物和认知数据也将为未来的预防试验设计提供信息。A3研究也有 支持监管机构批准更早处于风险中的人群的潜力， 临床前或前驱AD后期的终点试验。我们希望A3研究能促进 下一个预防试验的时代，以帮助推动我们的领域向一级预防AD。

SUMMARY This is an application for NIH support of a public-private-philanthropic partnership to conduct a novel prevention trial aimed at initiating anti-amyloid therapy prior to the current threshold for “amyloid positivity” (Aβ+). We propose the Ante-Amyloid prevention of Alzheimer's disease (AD)—the “A3” Study—in clinically normal older individuals with “non-elevated” amyloid levels on screening PET who are at increased risk for further Aβ accumulation. The A3 Study will leverage the large number of eager participants who screen-fail for current secondary prevention trials (A4 and EARLY/“A5” trials) on the basis of non-elevated amyloid levels on screening Amyloid PET scans (florbetapir SUVr). We will utilize an Age x APOE x Amyloid PET SUVr risk algorithm to identify and enroll 600 individuals between the ages of 60-75 who are not yet at the threshold for Aβ+, but who show intermediate levels of SUVr (Aβi) and are at the highest risk for progressing to Aβ+. Our preliminary data suggest these Aβi participants will demonstrate significant increases in Aβ accumulation over 2-4 years, as well as show evidence of neocortical tau spreading, cortical thinning, and even subtle declines on cognitive testing as they progress towards Aβ+. Our ultimate goal is to facilitate primary prevention trials in AD. The A3 design will test an oral treatment (BACE inhibitor) at a stage of Aβ accumulation that is estimated to be 5 years earlier than current secondary prevention trials (“pre-preclinical AD”). There are several BACE inhibitors currently in large-scale trials at later stages of AD that show robust lowering of Aβ production, with good safety profiles suitable for initiating trials in this very early at-risk population. The A3 Study design is a Phase 2b/3 double-blind, randomized, 3-arm, 4 year trial with a BACE inhibitor at 2 doses vs. placebo (n=200 per arm). The primary outcome will be rate of Aβ deposition on serial Amyloid PET imaging, with additional outcomes using Tau PET imaging, CSF assays, volumetric MRI, and sensitive cognitive measures. We aim to build a “chain of evidence” that will link the slowing of very early Aβ accumulation to the prevention of neurodegeneration and cognitive decline that occurs in the later stages of preclinical AD. Similar to the A4 Study, the A3 Study will be a public-private-philanthropic partnership with our industry partner providing the majority of the financial support for the study conduct. We have selected 3 potential industry partners. A therapeutic selection committee will make the final choice of the BACE inhibitor and industry partner based on the up-to-date efficacy and safety data provided by the sponsors. This study will provide critical longitudinal biomarker and cognitive data that will also inform the design of future prevention trials. The A3 Study also has the potential to support regulatory approval for an even-earlier at-risk population, in combination with cognitive endpoint trials at later stages of preclinical or prodromal AD. We hope the A3 Study will serve to catalyze the next era of prevention trials to help move our field towards the primary prevention of AD.