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

摘要 这是一份申请美国国立卫生研究院公共-私人-慈善合作伙伴关系的申请书，目的是进行一项 旨在“淀粉样阳性”的当前阈值之前启动抗淀粉样蛋白治疗的预防试验 (Aβ+)。我们在临床上提出了阿尔茨海默病(AD)的淀粉样蛋白前预防--A3研究 接受PET筛查的淀粉样蛋白水平“非升高”的正常老年人患糖尿病的风险增加 进一步的β积累。A3研究将利用大量筛选失败的热切参与者 目前的二级预防试验(A4和早期/“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 识别和登记600名年龄在60-75岁之间、尚未达到 Aβ+，但表现出中等水平的SuVR(AβI)，并具有进展到Aβ+的最高风险。我们的 初步数据显示，这些AβI参与者的Aβ积累量将显著增加 2-4年，以及表现出新皮质tau扩散，皮质变薄，甚至轻微下降的证据 向Aβ+进军的认知测试。我们的最终目标是促进AD的初级预防试验。 A3设计将在Aβ积聚阶段测试口服治疗(BACE抑制剂)，据估计 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后期阶段进行大规模试验的抑制剂显示Aβ产量强劲下降， 良好的安全性，适合在这一非常早期的高危人群中启动试验。A3研究设计是一项 2b/3期双盲、随机、为期3年、为期4年的BACE抑制剂试验，剂量为2剂，对照组为安慰剂(n=200 每只手臂)。主要结果将是在系列淀粉样正电子发射计算机断层扫描中Aβ的沉积率，以及其他 结果使用Tau PET成像、脑脊液分析、容量磁共振成像和敏感的认知测量。我们的目标是 建立一个“证据链”，将A-β早期积累的放缓与预防 临床前阿尔茨海默病后期出现的神经退行性变和认知能力下降。类似于A4 在这项研究中，A3研究将是一个公私慈善合作伙伴关系，我们的行业合作伙伴提供 大部分资金支持研究工作的开展。我们已经选择了3个潜在的行业合作伙伴。一个 治疗选择委员会将根据以下因素做出BACE抑制剂和行业合作伙伴的最终选择 赞助商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预防试验的设计提供信息。A3的研究还包括 支持对更早的高危人群进行监管批准的可能性，以及认知能力 临床前或先兆AD后期的终点试验。我们希望A3的研究将有助于催化 下一个时代的预防试验，以帮助我们的领域走向AD的初级预防。

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.