Alzheimer's Prevention Initiative APOE4 Trial

产品说明：阿尔茨海默病预防计划（API）的建立是为了快速评估研究性临床前阿尔茨海默病（AD）治疗在认知未受损的人，谁基于他们的遗传背景和年龄，是在最高的临床进展的迫在眉睫的风险，以帮助推进一个新时代的AD预防研究，并找到治疗工作尽快。本申请寻求对104-260周多中心随机临床试验的初始阶段的五年部分支持，该临床试验使用临床前AD的最佳认知、脑成像和脑脊液（CSF）测量，在650名认知未受损的60-75岁载脂蛋白E（APOE）4纯合子（HM）中进行研究性淀粉样蛋白（A）修饰治疗。主要结果是经验预定的复合认知测试分数的变化。其他结局包括体积磁共振成像（MRI）、氟脱氧葡萄糖正电子发射断层扫描（FDG PET）局部脑葡萄糖代谢率（rCMRgl）、氟脱氧葡萄糖PET纤维A <$和CSF A <$42、总tau（t-tau）和磷酸化tau（p-tau）测量值的变化。适应性要素包括系列徒劳评估、104周中期分析以及数据和安全监测委员会（DSMB）-促进有关研究继续、研究扩展和其他风险群体评估的决策。探索性分析将确定治疗的24个月治疗效果是否与治疗的临床效果相关，以及较不广泛疾病的生物标志物证据是否与更大的治疗反应相关。这项研究补充了API资助的常染色体显性AD（ADAD）突变携带者试验。它利用了我们长期以来的努力，以表征APOE 4 HM，杂合子（HT）和非携带者（NC）的临床前生物标志物和认知变化，API的几个既定政策，程序和合作关系，其数据和样本共享范式和不断增长的阿尔茨海默氏症预防登记，以及至少5000万美元的额外行业和慈善资金。我们潜在的许可证启用APOE 4和ADAD突变载体试验已经过领先的学术，行业，NIA，监管机构和社区利益相关者的审查。该项目的目标是：评估一项研究A？- 修改未受损HM中的治疗，以提供对淀粉样蛋白假说的更好检验，以确定是否在具有迟发性AD风险的其他人中评估治疗，以帮助澄清治疗的生物标志物效应可以预测临床应答的程度，并在未来的临床前试验中有资格作为“合理可能的”替代终点，提供关于APOE基因检测在AD预防研究新时代的影响的信息，在试验结束后提供数据和样本的公共资源，并补充和支持与临床前AD治疗评估相关的其他研究计划。该项目旨在帮助尽快找到有效的迟发性AD临床前治疗方法。

DESCRIPTION: The Alzheimer's Prevention Initiative (API) was established to rapidly evaluate investigational preclinical Alzheimer's disease (AD) treatments in cognitively unimpaired people who, based on their genetic background and age, are at the highest imminent risk for clinical progression, to help advance a new era in AD prevention research, and to find treatments that work as soon as possible. This application seeks five years of partial support for the initial stag of a 104-260 week multi-center randomized clinical trial of an investigational amyloid-¿ (A¿) modifying treatment in 650 cognitively unimpaired 60-75 year-old apolipoprotein E (APOE) ¿4 homozygotes (HMs) using the best established cognitive, brain imaging and cerebrospinal fluid (CSF) measurements of preclinical AD. The primary outcome is change in an empirically predefined composite cognitive test score. Other outcomes include changes in volumetric magnetic resonance imaging (MRI), fluorodeoxyglucose positron emission tomography (FDG PET) regional cerebral metabolic rate for glucose (rCMRgl), flutemetamol PET fibrillar A¿, and CSF A¿42, total tau (t-tau) and phospho-tau (p-tau) measurements. Adaptive elements include serial futility assessments, a 104-week interim analysis, and data and safety monitoring board (DSMB)-facilitated decisions about study continuation, study expansion, and the evaluation of other at-risk groups. Exploratory analyses will determine whether the treatment's 24-month treatment effects are related to the treatment's clinical effects and whether biomarker evidence of less extensive disease is associated with a greater therapeutic response. This study complements API's funded trial in autosomal dominant AD (ADAD) mutation carriers. It capitalizes on our longstanding efforts to characterize the preclinical biomarker and cognitive changes in APOE ¿4 HM, heterozygotes (HTs) and noncarriers (NCs), several of the API's established policies, procedures, and collaborative relationships, its data and sample-sharing paradigm and growing Alzheimer's Prevention Registry, and at least $50 million in additional industry and philanthropic funding. Our potentially license-enabling APOE ¿4 and ADAD mutation carrier trials have been vetted by leading academic, industry, NIA, regulatory agency, and community stakeholders. The project's aims: to evaluate an investigational A¿-modifying treatment in unimpaired HMs, to provide a better test of the amyloid hypothesis, to determine whether to evaluate the treatment in others at risk for late-onset AD, to help clarify the extent t which a treatment's biomarker effects may predict a clinical response and qualify as "reasonably likely" surrogate endpoints in future preclinical trials, to provide information about the impact o APOE genetic test disclosure in this new era of AD prevention research, to provide a public resource of data and samples after the trial is over, and to complement and support other research programs related to the evaluation of preclinical AD treatments. The project is intended to help find effective preclinical treatments for late-onset AD as soon as possible.