DIAN-TU: Next Generation Prevention Trial

DIAN-TU：下一代预防试验

基本信息

批准号：
10263141
负责人：
RANDALL J BATEMAN
金额：
$ 647.33万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-01 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10263141
关键词：
Age Age of Onset Algorithms Alzheimer disease prevention Alzheimer&apos s Disease Amyloid Amyloid beta-Protein Antibodies Biological Biological Markers Cerebrospinal Fluid Clinical Clinical Trials Cognition Cognitive Country Data Data Set Dementia Development Diffusion Disease Disease Progression Dose Double-Blind Method Enrollment Enzyme Inhibitor Drugs Evolution Family Functional disorder Funding Futility Future Grant Home Image Impaired cognition Individual Infrastructure Inherited Intervention Language Lead Letters Liquid substance Magnetic Resonance Imaging Measures Metabolism Modeling Mutation Observational Study Outcome Participant Pathogenicity Pharmaceutical Preparations Phase Placebo Control Placebos Population Positron-Emission Tomography Prevention Prevention trial Process Protocols documentation Randomized Registries Risk Running Safety Sampling Self Administration Site Statistical Data Interpretation Surrogate Markers Symptoms Testing Therapeutic Intervention Therapeutic Trials United States National Institutes of Health Visit arm autosomal dominant Alzheimer&apos s disease base beta secretase cognitive benefits cognitive testing design early detection biomarkers eligible participant fluorodeoxyglucose positron emission tomography imaging biomarker inhibitor innovation mutation carrier next generation novel novel strategies novel therapeutics operation prevent primary outcome rapid testing recruit response secondary outcome spectrograph study population targeted biomarker tau Proteins therapeutic development trial design

项目摘要

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.

项目概要 DIAN-TU 的成立是为了设计和管理介入治疗试验并寻找一种治疗方法 DIAN-TU 试验为那些确定患有常染色体显性 AD (ADAD) 的人提供认知益处。平台现已在 6 个国家、24 个站点、3 种语言全面运营，所有任务完成度约为 100% 评估和约 3% 的流失，并于 2015 年 11 月完成了前两种药物的注册。 DIAN-TU试验平台的资金建立了执行临床试验的基础设施和运营 ADAD 并承认该平台内需要不断发展。 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，使平台能够通过不同的机制测试其他药物更快地采取行动重大创新和具体目标包括实施： (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)自我进行认知测试，(3) 预先定义的剂量递增算法以安全地最大化目标参与度，(4) 针对无症状受试者的四年多认知终点适应性试验设计，包括早期生物标志物和后来的认知中期，以告知早期疗效或无效性，并最大化在有限的研究人群中具有强大的能力，(5) 新颖的成像技术（例如 Tau PET 和 MRI）和脑脊液（CSF）测量，以及（6）ADAD疾病进展模型（DPM）来检测这些创新方法有望加速有效性的识别。用于预防和治疗AD的药物。扩散基础光谱成像目前正在开发目标中的许多疾病修饰疗法 Aβ被认为是AD过程的始作俑者和最早的改变，这些Aβ疗法可能是。对于 ADAD 人群和疾病早期最有利于延缓痴呆 A 的发作。基本且尚未解决的问题是哪个目标将提供最佳的认知反应。 NexGen 试验设计是多中心、双盲、随机、汇总安慰剂对照、四项以上 204 年潜在疾病修饰疗法的认知复合终点注册研究有患 AD 风险或患有显性遗传性 AD 的个体本研究的主要目的是测试 AD 的能力。 β 分泌酶抑制剂 (BACEi) 可预防或减缓 100 名无症状 (CDR 0) ADAD 患者的认知能力下降突变携带者的症状发作年龄在 -15 至 +10 岁之间。该研究的次要目的是减缓 140 CDR ≤ 1 突变携带者的认知能力下降和进展受试者将接受药物或安慰剂，平均 5.1 年，按照 3:1 随机分组。确定 DIAN-TU 认知复合的主要结果和次要结果的临床益处结果包括多种认知测量以及液体和成像生物标志物。