DIAN-TU Next Generation Prevention Trial

项目摘要 DIAN-TU的成立是为了设计和管理介入治疗试验，并找到一种治疗方法， 为那些确定发展为常染色体显性AD（ADAD）的人提供认知益处。DIAN-TU试验 平台成功启动并完成了前两个药物组（均为单克隆抗- abeta抗体），并将于2020年初公布结果。在 2017年，随着DIAN-TU NexGen资助（R 01 AG 053267，RJ Bateman，PI），DIAN-TU增加了第三个药物分支 （一种BACE抑制剂），并实施了关键的设计变更，允许平台测试其他药物， 更快、更有效地采取各种行动机制。重大创新包括：（1） 给药前计划的认知导入（CRI）期，（2）自我管理的认知测试，（3） 预定义的剂量递增算法，以安全地最大限度地提高目标参与度，（4）4年以上的认知 终点适应性试验设计，包括生物标志物和认知功能，以告知早期疗效或无效性， (5)新的成像（例如Tau PET），和（6）ADAD疾病进展模型（ADAD），以检测 早期认知这些创新的方法有望加速有效药物的鉴定， AD的预防和治疗。 2018年，由于安全性问题，第三个药物组被停止。为了最好地利用在启动一个 第四个药物组，并收集额外的随机化前数据，DIAN-TU将在 第四个药物组的随机化。CRI将包括Tau成像，以更好地 本发明的目的在于进一步了解ADAD中的tau聚集，并进一步验证新的tau示踪剂（MK-6240，Cerveau）。作为 如上所述，CRI期，包括招募符合试验条件的受试者，以收集认知、临床和 在随机化之前的生物标志物数据，包括在原始的赠款研究计划中，以利用 第三药物组入组完成与第四药物组随机化之间的间隔时间。 然而，这项工作的资金没有列入赠款预算，因为预计到2010年才会发生。 补助期结束时。由于第三个药物组的提前终止， 第四支毒品队伍正在加速发展。此外，赠款资金旨在支持启动， 启动和维护一个单一的药物部门。与启动，启动，终止和关闭的费用- 在第三个毒品分支中，支持第四个毒品分支的资金现在很有限。本行政补充 要求提供额外资金，以支持tau成像的CRI期间，并在2015年启动第四个药物分支。 与最初的目标一致。实施一个磨合期可以提高功率，减少可变性 在认知测试性能和实践效果，提高遵守试验方案，并减少流失 rates.包括tau成像支持过渡到第四药物臂的tau靶向治疗。

PROJECT SUMMARY The DIAN-TU was formed to design and manage interventional therapeutic trials and find a treatment that provides cognitive benefit for those certain to develop autosomal dominant AD (ADAD). The DIAN-TU trial platform successfully launched and completed enrollment for the first two drugs arms (both monoclonal anti- abeta antibodies) in 6 countries (3 languages) and 24 sites, and results will be available in early 2020. In 2017, with the DIAN-TU NexGen grant (R01AG053267, RJ Bateman, PI), the DIAN-TU added a third drug arm (a BACE inhibitor) and implemented key design changes that allow the platform to test additional drugs with diverse mechanisms of action more quickly and efficiently. Significant innovations include implementation of (1) a planned cognitive run-in (CRI) period prior to drug administration, (2) self-administered cognitive testing, (3) a pre-defined dose escalation algorithm to safely maximize target engagement, (4) four plus year cognitive endpoint adaptive trial design which includes biomarker and cognitive interims to inform early efficacy or futility, (5) novel imaging (e.g. Tau PET), and (6) ADAD Disease Progression Model (DPM) to detect changes in cognition earlier. These innovative approaches promise to accelerate identification of effective drugs for prevention and treatment of AD. In 2018, the third drug arm was stopped due to safety concerns. To best utilize the time before launching a fourth drug arm and collect additional pre-randomization data, the DIAN-TU will implement a CRI period prior to randomization for a fourth drug arm. Tau imaging will be included with the CRI to enable better understanding of tau aggregation in ADAD and further validate a new tau tracer (MK-6240, Cerveau). As noted above, a CRI period, which involves enrolling trial-eligible participants to collect cognitive, clinical, and biomarker data prior to randomization, was included in the original grant research plan to take advantage of the intervening time between enrollment completion of the third drug arm and randomization for a fourth drug arm. However, funding for this effort was not included in the grant budget because it was not expected to occur until the end of the grant period. Due to the early termination of the third drug arm, the timelines to launch CRI and a fourth drug arm have been accelerated. In addition, the grant funding was intended to support start-up, launch, and maintenance of a single drug arm. With the expenses of start-up, launch, termination, and close- out of the third drug arm, funds to support a fourth drug arm are now limited. This administrative supplement requests additional funding to support a CRI period with tau imaging and launch a fourth drug arm in accordance with the original grant aims. Implementing a run-in period can improve power, decrease variability in cognitive test performance and practice effects, improve adherence to the trial protocol, and reduce attrition rates. Including tau imaging supports the transition to tau-targeted therapeutics for the fourth drug arm.