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: 10358480
• 负责人: Paul S. Aisen
• 金额: $ 694.33万
• 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/10358480
• 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支持的一个应用程序，用于启用抗- 淀粉样蛋白治疗无症状阿尔茨海默病（A4）研究。A4研究于2014年启动， 在临床正常（CN）老年人中进行的第一项二级预防试验， 筛选PET扫描显示β淀粉样蛋白（Aβ）蓄积升高。A4合格受试者处于临床前阶段 在AD的（无症状的）阶段和认知下降的高风险中。A4研究的总体目标是测试 假设靶向Aβ（solanezumab）的免疫治疗可以预防与A β相关的认知功能下降， 早期AD病理，如果开始得足够早。A4研究筛选了6700多名参与者（年龄65-85岁， 14%的少数民族），并超过了我们的招募目标，1169名参与者随机化。我们最初的预测 30%的“淀粉样蛋白阳性”被证明是正确的，29.5%的参与者参加了筛查PET会议 “淀粉样蛋白升高”标准。我们还启动了淀粉样蛋白风险的纵向评估， 2015年在“淀粉样蛋白阴性”CN（n=541）中进行的神经变性（LEARN）观察性研究。基于索拉 在AD痴呆的试验结果中，我们将剂量增加了四倍，并将双盲（DB）方案延长至4.5年。 第一个A4参与者将在2019年初完成DB协议，最后一个参与者将在2019年年中完成。 2022.保持初始治疗分配的盲态，A4 OLE将使我们能够继续评估 这些参与者完成DB后，并调查sola暴露对 临床前AD的认知和功能下降。此外，我们还将探讨“关键窗口”， 利用在OLE开始时采集的淀粉样蛋白PET、MRI和tau PET（在一个子集中）对抗A β治疗的反应。 A4研究是一项公私慈善合作项目，由NIA、礼来公司、阿尔茨海默氏症协会、 Fidelity Biosciences、GHR Foundation和Accelerating Medicines Partnership（AMP）。在这里我们寻求 NIH为A4 OLE提供部分资金，礼来提供剩余资金和实物支持。 这笔资金将使我们能够为所有非常敬业的A4参与者提供OLE中的研究药物， 继续收集最大的CN队列的极有价值的纵向数据，其特征是 淀粉样蛋白状态，直至2022年底完成主要疗效分析。我们已经开始分享 将从A4筛选数据和A4/LEARN纵向数据中获取数据和生物样本 在完成A4研究的主要疗效分析后一年内公开提供。A4研究 能够用更高剂量的solanezumab严格检验淀粉样蛋白假说， 在估计Aβ蓄积早至15年的人群中，疾病处于适当阶段 比以前的AD痴呆症试验过程。来自A4研究的额外纵向数据， 与LEARN中获得的类似数据相结合，有可能从根本上改变检测， 这将使我们更接近NAPA的目标，即到2025年找到一种成功的预防治疗方法。