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 该平台现已在6个国家、24个地点、3种语言全面运行， 评估和约3%的流失，并已于2015年11月完成前两种药物的招募。初始 DIAN-TU试验平台的资金建立了执行临床试验的基础设施和操作 并承认需要在这一平台内进行演变。 DIAN-TU下一代预防试验将在DIAN-TU试验平台上增加一个新的药物组， 实施关键的设计变更，允许平台测试具有不同机制的其他药物， 行动更快。重要的创新和具体目标包括：（1）有计划的 给药前的认知磨合期，以提供更大的能力来检测药物作用， (2)自 给予认知测试，（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，（4）针对无症状受试者的4年以上认知终点适应性试验设计， 包括早期生物标志物和后期认知功能，以告知早期疗效或无效性，并最大限度地提高 在有限的研究人群中的功效，（5）新型成像（例如Tau PET和 MRI）和脑脊液（CSF）测量，和（6）ADAD疾病进展模型（ADAD）以检测 认知的变化更早。这些创新的方法有望加快识别有效的 预防和治疗AD的药物。 扩散基谱成像 目前正在开发的许多疾病改善疗法的目标是 Aβ被认为是AD过程中的启动者和最早的变化。这些Aβ疗法可能是 在ADAD人群中最有益，并且在疾病早期延迟痴呆症的发作。一 一个根本的、尚未解决的问题是，哪个目标将提供最佳的认知反应。 NexGen试验设计是一项多中心、双盲、随机、合并安慰剂对照、4 + 一项204例患者的潜在疾病改善治疗的1年认知复合终点注册研究 存在显性遗传AD风险或患有显性遗传AD的个体。这项研究的主要目的是测试一个人的能力， β分泌酶抑制剂（BACEi）预防或减缓100例无症状（CDR 0）ADAD患者的认知功能下降 突变携带者在-15至+10岁的范围内，相对于症状发作的估计年龄。一 研究的次要目的是减缓140例CDR ≤1突变携带者的认知功能下降和进展 科目受试者将以3：1的比例随机接受药物或安慰剂，平均持续5.1年， 确定DIAN-TU认知复合终点的主要结局的临床获益， 结果包括多种认知测量和液体和成像生物标志物。

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 is now fully operational in 6 countries, 24 sites, 3 languages with ~100% completion of all assessments and ~3% attrition, and has completed enrollment in November 2015 for the first two drugs. Initial funding for the DIAN-TU trial platform established the infrastructure and operations for executing clinical trials in ADAD and acknowledged the need for evolution within this platform. The DIAN-TU Next Generation Prevention Trial will add a new drug arm to the DIAN-TU trial platform and implement key design changes that allow the platform to test additional drugs with diverse mechanisms of action more quickly. Significant innovations and specific aims include implementation of: (1) a planned cognitive run-in period prior to drug administration to provide greater power to detect drug effects, (2) self- administered cognitive testing, (3) pre-defined dose escalation algorithm to safely maximize target engagement, (4) four plus year cognitive endpoint adaptive trial design for asymptomatic subjects that includes both early biomarker and later cognitive interims to inform early efficacy or futility, and maximize power in a limited study population, (5) novel imaging (e.g. Tau PET and MRI) and cerebrospinal fluid (CSF) measures, 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. diffusion basis spectrum imaging Many disease modifying therapies currently in development target Aβ, which is believed to be the initiator and earliest change in the AD process. These Aβ therapies may be most beneficial in the ADAD population and earlier in the disease to delay the onset of dementia. A fundamental and unresolved question is which target will provide the best cognitive response. The NexGen trial design is a multi-center, double blind, randomized, pooled placebo-controlled, four plus year cognitive composite endpoint registration study of a potential disease modifying therapy in 204 individuals at risk for or with dominantly inherited AD. The primary aim of this study will test the ability of a beta secretase inhibitor (BACEi) to prevent or slow cognitive decline in 100 asymptomatic (CDR 0) ADAD mutation carriers in the range of -15 to +10 years with respect to estimated age of symptom onset. A secondary aim of the study is to slow cognitive decline and progression in 140 CDR ≤1 mutation carrier subjects. Subjects will receive either drug or placebo with 3:1 randomization for an average of 5.1 years to determine clinical benefit of the primary outcome of the DIAN-TU cognitive composite and secondary outcomes including multiple cognitive measures and fluid and imaging biomarkers.