Anti-Amyloid Treatment in Asymptomatic Alzheimer's Disease (A4) Open-Label Extension Study

无症状阿尔茨海默病 (A4) 开放标签扩展研究中的抗淀粉样蛋白治疗

• 批准号: 9930020
• 负责人: Paul S. Aisen
• 金额: $ 694.49万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-05-15 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9930020
• 关键词: Address; Age; Alzheimer disease prevention; Alzheimer' s Disease; Alzheimer' s disease pathology; Alzheimer’s disease biomarker; Amyloid; Amyloid beta-Protein; Applications Grants; Atrophic; Attenuated; Australia; Biological Sciences; Blinded; Brain; Canada; Clinical; Clinical Trials; Cognition; Cognitive; Companions; Data; Dedications; Detection; Disease; Dose; Double-Blind Method; Education; Eligibility Determination; Enrollment; Evaluation; Foundations; Functional disorder; Funding; Gender; Goals; Immunotherapy; Impaired cognition; Individual; Intervention; Japan; Learning; Long-Term Effects; Longterm Follow-up; Magnetic Resonance Imaging; Medicine; Minority; Modification; Monoclonal Antibodies; Nerve Degeneration; Observational Study; Participant; Performance; Pharmaceutical Preparations; Pharmacodynamics; Phase; Placebos; Population; Positioning Attribute; Positron-Emission Tomography; Prevention therapy; Prevention trial; Prior Therapy; Privatization; Process; Protocols documentation; Randomized; Reporting; Risk; Secondary Prevention; Senile Plaques; Site; Testing; United States; United States National Institutes of Health; abeta accumulation; active method; asymptomatic Alzheimer' s disease; base; blind; cognitive function; cohort; comparison group; data sharing; design; efficacy evaluation; eligible participant; functional decline; functional outcomes; high risk; imaging biomarker; inclusion criteria; meetings; open label; placebo controlled trial; pre-clinical; prevent; primary outcome; public-private partnership; response; screening; tau Proteins; treatment effect

SUMMARY: This is an application for NIH support to enable an Open Label Extension (OLE) of the Anti- Amyloid Treatment in Asymptomatic Alzheimer’s disease (A4) Study. The A4 Study was launched in 2014 as the first of its kind secondary prevention trial in clinically normal (CN) older individuals with evidence of elevated amyloid-beta (Aβ) accumulation on screening PET scan. A4 eligible participants are in the preclinical (asymptomatic) stages of AD and at high risk for cognitive decline. The overall goal of the A4 study is to test the hypothesis that immunotherapy targeting Aβ (solanezumab) can prevent the cognitive decline associated with early AD pathology, if initiated early enough. The A4 Study screened over 6700 participants (age 65-85, 14% minority) and exceeded our enrollment target with 1169 participants randomized. Our initial prediction of 30% “amyloid positivity” was proven correct with 29.5% of the participants with screening PET meeting “elevated amyloid” criteria. We also launched the companion Longitudinal Evaluation of Amyloid Risk and Neurodegeneration (LEARN) observational study in “amyloid negative” CN (n=541) in 2015. Based on the sola trial results in AD dementia, we quadrupled the dose and extended the double-blind (DB) protocol to 4.5 years. The first A4 participant will complete the DB protocol in early 2019, with the last participant completing in mid- 2022. Maintaining the blind of the initial treatment assignment, the A4 OLE will enable us to continue to assess these participants after they complete the DB, and to investigate the long-term effects of sola exposure on cognitive and functional decline in preclinical AD. In addition, we will explore the “critical window” for optimal response to anti-Aβ therapy utilizing amyloid PET, MRI, and tau PET (in a subset) acquired at start of OLE. The A4 Study is a public-private-philanthropic partnership with funding from NIA, Lilly, Alzheimer’s Association, Fidelity Biosciences, GHR Foundation, and the Accelerating Medicines Partnership (AMP). Here we seek partial funding from the NIH for the A4 OLE with Lilly providing the remainder of funding and in-kind support. This funding will allow us to offer all of the very dedicated A4 participants access to study drug in the OLE, and continue to collect extremely valuable longitudinal data on the largest available cohort of CN characterized by amyloid status, until the primary efficacy analyses are completed in late 2022. We have already begun to share the data and biosamples from the A4 screening data, and the A4/LEARN longitudinal data will be made publicly available within one year of completion of the primary efficacy analyses of the A4 Study. The A4 Study is well positioned to rigorously test the amyloid hypothesis with a higher dose of solanezumab and at the appropriate stage of disease, in a population estimated to be up to 15 years earlier in the Aβ accumulation process than the previous AD dementia trials. The additional longitudinal data from the A4 Study, in combination with similar data acquired in LEARN, has the potential to fundamentally alter the detection and treatment of AD, and move us closer to the NAPA goal of finding a successful prevention therapy by 2025.

摘要：这是NIH支持的应用 非对称阿尔茨海默氏病（A4）研究中的淀粉样蛋白治疗。 A4研究于2014年启动 临床上正常（CN）老年人的同类二级预防试验中的第一个有证据 在筛选PET扫描时，淀粉样蛋白β（Aβ）的积累升高。 A4合格的参与者在临床前 （无症状）AD阶段和认知能力下降的高风险。 A4研究的总体目标是测试 靶向Aβ（Solanezumab）的免疫疗法的假设可以防止与认知能力下降 如果提早开始，则有了早期的广告病理学。 A4研究筛选了6700多名参与者（65-85岁， 14％的少数族裔），超过了我们的入学目标，有1169名参与者随机分组。我们最初的预测 30％的“淀粉样蛋白阳性”被证明是正确的，有29.5％的参与者在筛查宠物会议上 “高架淀粉样蛋白”标准。我们还启动了对淀粉样蛋白风险和 2015年“淀粉样蛋白阴性” CN（n = 541）中的神经变性（学习）研究。基于Sola 试验结果在AD痴呆症中，我们将剂量增加了三倍，并将双盲（DB）方案扩展到4。5年。 第一个A4参与者将在2019年初完成数据库协议，最后一名参与者在中期完成 2022年。维护初始治疗作业的盲目，A4 OLE将使我们能够继续评估 这些参与者完成数据库后，并研究固体暴露对 临床前AD的认知和功能下降。此外，我们将探索最佳的“关键窗口” 使用淀粉样蛋白PET，MRI和TAU PET（在OLE开始时获得的子集）对抗Aβ治疗的反应。 A4研究是一种公私 - 菲兰人的合作伙伴关系 Fidelity Biosciences，GHR基金会和加速药物合作伙伴关系（AMP）。我们在这里寻找 NIH为A4 Ole提供的部分资金，礼来公司提供其余的资金和实物支持。 这笔资金将使我们能够为所有非常专门的A4参与者访问OLE学习药物，并且 继续收集最有价值的纵向数据，以最大的可用CN队列为特征 淀粉样蛋白状态，直到2022年底进行主要效率分析。我们已经开始分享 将从A4筛选数据中的数据和生物示例，以及A4/学习纵向数据 在完成A4研究的主要效率分析后的一年内，公开可用。 A4研究 可以很好地确定严格测试淀粉样假说，并在较高剂量 适当的疾病阶段，在Aβ积累中估计长达15年的人群中 过程比以前的AD痴呆试验。来自A4研究的其他纵向数据， 结合学习中获得的类似数据，有可能从根本上改变检测和 治疗AD，并使我们更接近NAPA到2025年成功预防疗法的目标。