Alzheimer's Prevention Initiative APOE4 Trial

描述：阿尔茨海默病预防倡议(API)的建立是为了根据他们的遗传背景和年龄，快速评估认知正常人群的阿尔茨海默病(AD)临床前研究治疗，这些人是临床进展的最高风险人群，帮助推动AD预防研究的新纪元，并尽快找到有效的治疗方法。这项申请寻求为104-260周的多中心随机临床试验的初始STG提供五年的部分支持。该试验采用临床前AD的最佳认知、脑成像和脑脊液(CSF)测量方法，对650名认知正常的60-75岁的载脂蛋白E(APOE)纯合子(HMS)进行了研究中的淀粉样蛋白(A？)修饰治疗。主要结果是根据经验预先定义的综合认知测试分数的变化。其他结果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)、脑局部葡萄糖代谢率(RCMRgl)、氟替他莫PET纤维A？和脑脊液A？42、总tau(t-tau)和磷酸tau(p-tau)测量的变化。适应性因素包括系列无效性评估、104周的中期分析，以及数据和安全监测委员会(DSMB)推动的关于研究继续、研究扩展和其他高危人群评估的决定。探索性分析将确定治疗24个月的治疗效果是否与治疗的临床效果有关，以及疾病范围较小的生物标记物证据是否与较大的治疗反应有关。这项研究是对API资助的常染色体显性AD(ADAD)突变携带者试验的补充。它利用了我们长期以来在APOE？4 HM、杂合子(HTS)和非携带者(NCS)中表征临床前生物标记物和认知变化的努力、API的几项既定政策、程序和协作关系、其数据和样本共享范例以及不断增长的阿尔茨海默氏症预防登记，以及至少5,000万美元的额外行业和慈善资金。我们可能获得许可的APOE？4和ADAD突变载体试验已经通过了领先的学术、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：评估未受损的HMS中的研究性A？修饰治疗，提供对淀粉样蛋白假说的更好测试，确定是否在其他有晚发性AD风险的患者中评估该治疗，帮助澄清治疗的生物标记物效应可在多大程度上预测临床反应，并在未来的临床前试验中被视为“合理可能性”的替代终点，提供有关APOE基因测试披露在AD预防研究的新时代的影响的信息，在试验结束后提供公共数据和样本资源，以及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晚发性AD的有效临床前治疗方法。

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.