DIAN-TU: Next Generation Prevention Trial

项目总结 成立DIAN-TU的目的是设计和管理介入治疗试验，并找到一种治疗方法 为那些肯定会患上常染色体显性阿尔茨海默病(ADAD)的人提供认知益处。甸-图试验 该平台现已在6个国家/地区、24个站点、3种语言全面运行，并已接近完成#年的注册 2015年10月为前两种药物。DIAN-TU试验平台的初始资金建立了 在ADAD执行临床试验的基础设施和操作，并认识到发展的必要性 在这个平台上。 点图下一代预防试验将在点图试验平台上增加两个新的毒品武器 并提出关键的设计更改，使平台能够测试具有不同种类的下一代药物 更快的行动机制。重大创新包括：(1)药物前的认知磨合期 给药以提供更大的权力来检测药物效果，(2)自我管理的认知测试，(3)预 定义剂量递增算法，以安全地最大化目标参与度，(4)四年认知终点 适应性试验设计，既包括早期生物标志物，也包括后来的认知干预，以告知早期疗效或 无用，(5)新的成像(例如，Tau PET和扩散基础谱成像MRI)和脑脊液 措施(6)ADAD疾病进展模型更早、更少地检测认知变化 受试者采用混合效应模型进行重复测量。总而言之，这种创新的方法 对于测试疾病，修改疗法有可能最终测试淀粉样蛋白假说和 加快筛选防治阿尔茨海默病的有效药物。 目前正在开发的许多疾病修改疗法以Aβ为靶点，据信它是发起人 以及AD过程中最早的变化。这些Aβ疗法可能对ADAD人群最有益 并在疾病早期延缓痴呆症的发病。一个根本而悬而未决的问题是， 目标将提供最好的认知反应。 该试验设计为多中心、双盲、随机、安慰剂对照、为期四年的认知试验 230名高危人群中两种可能的疾病修饰疗法的终点登记研究 主要是遗传性阿尔茨海默病。这项研究将测试BACEI和抗寡聚体Aβ的能力 用于减缓或防止无症状(CDR 0，70%)或轻度症状(CDR 0.5)的认知功能下降的抗体 或30%)-15岁至+10岁范围内的ADAD突变携带者 认知症状出现。每个药物计划的115名受试者将以3：1的比例接受药物或安慰剂 随机对照四年以确定Dian-TU认知功能主要结局的临床益处 认知和临床措施、安全性和AD生物标记物的综合和次要结果。

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 and nearing completion of enrollment in October 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 two new drug arms to the DIAN-TU trial platform and propose key design changes that allow the platform to test next generation drugs with diverse mechanisms of action more quickly. Significant innovations include: (1) 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 year cognitive endpoint adaptive trial design that includes both early biomarker and later cognitive interims to inform early efficacy or futility, (5) novel imaging (e.g. Tau PET and diffusion basis spectrum imaging MRI) and cerebrospinal fluid measures (6) ADAD Disease Progression Model to detect changes in cognition earlier and with fewer participants compared to Mixed-Effect Model Repeated Measure. Taken together, this innovative approach for testing disease modifying therapies has the potential to definitively test the amyloid hypothesis and accelerate identification of effective drugs for the prevention and treatment of AD. 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 trial design is a multi-center, double blind, randomized, placebo-controlled, four year cognitive endpoint registration study of two potential disease modifying therapies in 230 individuals at risk for and with dominantly inherited Alzheimer's disease. The study will test the ability of a BACEi and an anti-oligomeric Aβ antibody to slow or prevent cognitive decline in asymptomatic (CDR 0, >70%) or mildly symptomatic (CDR 0.5 or 1, <30%) ADAD mutation carriers in the range of -15 to +10 years with respect to estimated age of cognitive symptom onset. 115 subjects per drug program will receive either drug or placebo with 3:1 randomization for four years to determine clinical benefit of the primary outcome of DIAN-TU cognitive composite and secondary outcomes of cognitive and clinical measures, safety, and AD biomarkers.