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: 10554282
• 负责人: Paul S. Aisen
• 金额: $ 694.16万
• 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/10554282
• 关键词: Acceleration; 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; Classification; Clinical; Clinical Trials; Cognition; Cognitive; Companions; Data; Dedications; Dementia; 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; blind; cognitive function; cohort; comparison group; data sharing; design; efficacy evaluation; eligible participant; functional decline; functional outcomes; high risk; imaging biomarker; inclusion criteria; indexing; meetings; monomer; 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，旨在启用反病毒的开放标签扩展 (OLE) 无症状阿尔茨海默病 (A4) 研究中的淀粉样蛋白治疗。 A4 研究于 2014 年启动， 这是首个针对临床正常 (CN) 老年人的二级预防试验，有证据表明 筛查 PET 扫描时β-淀粉样蛋白 (Aβ) 积累升高。 A4 合格参与者处于临床前阶段 AD（无症状）阶段，认知能力下降的高风险。 A4研究的总体目标是测试 针对 Aβ 的免疫疗法（solanezumab）可以预防相关认知能力下降的假设 如果开始得足够早，就会出现早期 AD 病理。 A4 研究筛选了 6700 多名参与者（年龄 65-85 岁， 14% 的少数族裔），超过了我们随机分配的 1169 名参与者的入学目标。我们初步预测 PET 筛查会议中 29.5% 的参与者证明 30% 的“淀粉样蛋白阳性”是正确的 “淀粉样蛋白升高”标准。我们还推出了淀粉样蛋白风险纵向评估和 2015 年“淀粉样蛋白阴性”CN（n=541）中的神经退行性变（LEARN）观察性研究。基于 sola 根据 AD 痴呆症的试验结果，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 参与者将于 2019 年初完成 DB 协议，最后一个参与者将于 2019 年中旬完成 2022 年。保持初始治疗分配的盲性，A4 OLE 将使我们能够继续评估 这些参与者在完成 DB 后进行研究，并调查暴露在阳光下的长期影响 临床前 AD 的认知和功能下降。此外，我们将探索最优的“关键窗口” 使用 OLE 开始时获得的淀粉样蛋白 PET、MRI 和 tau PET（子集）来评估抗 Aβ 疗法的反应。 A4 研究是一项公私慈善合作伙伴关系，由 NIA、礼来公司、阿尔茨海默病协会、 Fidelity Biosciences、GHR 基金会和 Accelerated Medicines Partnership (AMP)。在这里我们寻求 NIH 为 A4 OLE 提供部分资金，礼来公司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专注的 A4 参与者提供 OLE 中的研究药物，并且 继续收集关于最大的可用 CN 群体的极其有价值的纵向数据，其特征是 淀粉样蛋白状态，直到 2022 年底完成主要疗效分析。我们已经开始分享 来自A4筛选数据的数据和生物样本，以及A4/LEARN纵向数据将被制作 A4 研究的主要疗效分析完成后一年内公开。 A4 研究 能够很好地用更高剂量的 solanezumab 严格检验淀粉样蛋白假说，并且在 疾病的适当阶段，估计 Aβ 积累可提前 15 年 过程比以前的 AD 痴呆试验要多。 A4 研究的附加纵向数据， 与 LEARN 中获得的类似数据相结合，有可能从根本上改变检测和 AD 的治疗，使我们更接近 NAPA 的目标，即到 2025 年找到成功的预防疗法。