API A4 Alzheimer's Prevention Trial

API A4 阿尔茨海默病预防试验

基本信息

批准号：
9768303
负责人：
Paul S. Aisen
金额：
$ 716.23万
依托单位：
BANNER HEALTH
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-01 至 2024-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9768303
关键词：
Address Aducanumab Affect Affective Alleles Alzheimer disease prevention Alzheimer&apos s Disease Alzheimer&apos s disease patient Alzheimer&apos s disease risk Alzheimer’s disease biomarker Amyloid Amyloid beta-Protein Antibodies Antibody Therapy Binding Biological Biological Markers Biological Testing Blinded Characteristics Clinical Cognition Cognitive Collaborations Data Disclosure Dose Double-Blind Method Excision Financial Support Functional disorder Genetic Genetic Risk Goals Health Image Impaired cognition Impairment Incidence Intervention Learning Licensing Life Magnetic Resonance Imaging Marketing Measurement Memory Loss Modeling Moods Nature Outcome Participant Pathology Persons Pharmaceutical Preparations Phase Phase Ib Clinical Trial Phase Ib Trial Placebos Positron-Emission Tomography Prevention Guidelines Prevention therapy Prevention trial Procedures Quality of life Randomized Reporting Resources Risk Safety Sampling Secure Senile Plaques Surrogate Endpoint Surrogate Markers Test Result Testing Time United States National Institutes of Health Visit abeta oligomer asymptomatic Alzheimer&apos s disease base behavioral outcome clinical effect cognitive benefits cost data resource industry partner open label phase III trial placebo group pre-clinical prevent primary outcome programs public-private partnership social relationships tau Proteins therapy adverse effect treatment group

项目摘要

Project Summary/Abstract There is an urgent need to find and accelerate approval of Alzheimer’s disease (AD) prevention therapies. Aducanumab is an antibody that binds selectively to amyloid-β (Aβ) oligomers and fibrils. In a Phase 1b trial of clinically affected AD patients with Aβ plaques, it dramatically reduced Aβ plaque burden and appeared to slow cognitive decline. Alzheimer’s Prevention Initiative (API) and Anti-Amyloid Treatment in Asymptomatic Alzheimer’s (A4) Trials leaders have come together to propose a 24-month, multicenter, double blind, placebo- controlled prevention trial of aducanumab using AD biomarker endpoints as primary outcomes, along with cognitive/clinical, safety, and tolerability outcomes, in cognitively unimpaired 65-80 year-old Aβ PET+ persons stratified for presence or absence of the APOE4 allele. We will continue the blinded, randomized treatment past 24 months until we learn the results of the ongoing Phase 3 aducanumab program in persons with early AD. If the Phase 3 program shows significant cognitive and/or clinical benefit and also shows that aducanumab’s Aβ PET effects, alone or in combination with downstream biomarker effects, are associated with clinical benefit, and our 24-month trial showed identical biomarker effects, the findings would be used to support aducanumab’s “accelerated approval” in unimpaired Aβ+ persons based on those biomarker effects; in doing so, it would advance the potential use of surrogate biomarker endpoints to rapidly test prevention therapies in almost everyone at biomarker or genetic risk. At that point, participants would receive open-label treatment and Biogen would conduct post-marketing studies following FDA’s guidance to confirm that the treatment’s 24-month biomarker are associated with subsequent clinical benefit, as required under the FDA’s accelerated approval provisions. Our deliberately ambitious proposal is intended to 1) find an approved prevention therapy as early as 2023, ahead of the National Plan to Address AD’s goal to “prevent AD by 2025,” and 2) advance the use of surrogate biomarkers to rapidly test and support accelerated approval of prevention therapies in almost everyone at biomarker or genetic risk, even in earlier preclinical AD stages when some treatments may have their greatest benefit. However, if the Phase 3 program does not show significant benefit, the stakes would be even higher for our trial, since the question would remain whether intervention before clinical stages of AD is necessary to attain benefit. We would modify the trial by using the Preclinical Alzheimer Composite Endpoint-Revised (PACC-R) as the primary outcome and continuing blinded treatment until the last participant’s 48-month visit, clarify whether the treatment’s 24 month biomarker effects are associated with subsequent cognitive benefit, and seek to achieve our goals by 2025. Regardless of the Phase 3 results, the proposed trial offers an unprecedented chance to find, approve and support the availability of prevention therapies as soon as possible. It would capitalize on a public-private partnership, NIH support, $5-10M in philanthropy, access to aducanumab and most of the financial support from Biogen, provide a public resource of data and samples, and have the maximum public benefit.

项目概要/摘要迫切需要寻找并加速批准阿尔茨海默病（AD）预防疗法。 Aducanumab 是一种在 1b 期试验中选择性结合淀粉样蛋白-β (Aβ) 寡聚物和原纤维的抗体。临床上影响患有 Aβ 斑块的 AD 患者，它显着减少了 Aβ 斑块负担，并似乎减缓了阿尔茨海默病预防计划 (API) 和无症状患者的抗淀粉样蛋白治疗。阿尔茨海默病 (A4) 试验领导者齐聚一堂，提出一项为期 24 个月、多中心、双盲、安慰剂的方案使用 AD 生物标志物终点作为主要结局的 aducanumab 对照预防试验，以及认知/临床、安全性和耐受性结果，针对认知未受损的 65-80 岁 Aβ PET+ 人群根据是否存在 APOE4 等位基因进行分层我们将继续过去的盲法、随机治疗。距离我们了解正在进行的 3 期 aducanumab 项目在早期 AD 患者中的结果还有 24 个月。 3 期计划显示出显着的认知和/或临床益处，还表明 aducanumab 的 Aβ PET 效应，单独或与下游生物标志物效应结合，与临床效益相关，并且我们为期 24 个月的试验显示出相同的生物标志物效果，研究结果将用于支持 aducanumab 基于这些生物标志物效应，在未受损的 Aβ+ 人群中“加速批准”；推进替代生物标志物终点的潜在用途，以快速测试几乎所有国家的预防疗法届时，每个人都面临生物标志物或遗传风险，参与者将接受开放标签治疗和百健（Biogen）治疗。将按照 FDA 的指导进行上市后研究，以确认该治疗的 24 个月疗效根据 FDA 加速批准的要求，生物标志物与后续临床获益相关我们刻意雄心勃勃的提议旨在 1) 尽早找到经批准的预防疗法。到 2023 年，先于国家解决 AD 计划“到 2025 年预防 AD”的目标，以及 2) 推进使用替代生物标记物可快速测试并支持加速批准几乎所有人的预防疗法处于生物标志物或遗传风险下，即使是在早期临床前 AD 阶段，此时某些治疗可能会发挥最大作用然而，如果第三阶段计划没有显示出显着的效益，那么风险将会更高。我们的试验，因为问题仍然是在 AD 临床阶段之前进行干预是否有必要实现我们将使用临床前阿尔茨海默病复合终点修订版 (PACC-R) 来修改试验。主要结局和持续盲法治疗直至最后一位参与者的 48 个月访视，澄清是否该治疗的 24 个月生物标志物效果与随后的认知益处相关，并寻求到 2025 年实现我们的目标。无论第三阶段结果如何，拟议的试验都提供了前所未有的机会尽快找到、批准和支持预防疗法的可用性。公私合作伙伴关系、NIH 支持、5-1000 万美元的慈善事业、获得 aducanumab 和大部分财务百健（Biogen）的支持，提供数据和样本的公共资源，并获得最大的公共利益。