DIAN-TU: Tau Next Generation Prevention Trial

DIAN-TU：Tau 下一代预防试验

• 批准号: 10035004
• 负责人: RANDALL J BATEMAN
• 金额: $ 1497.32万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-15 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10035004
• 关键词: Address; Affect; Algorithms; Alzheimer' s Disease; Alzheimer' s disease pathology; Amyloid; Amyloid beta-Protein; Antibodies; Antisense Oligonucleotides; Apolipoprotein E; Atrophic; Biological; Biological Markers; Biology; Cerebrospinal Fluid; Clinical; Cognitive; Combined Modality Therapy; Country; Dementia; Development; Diffusion; Disease; Dose; Double-Blind Method; Drug Combinations; Drug Targeting; Enrollment; Family; Functional disorder; Future; Generations; Genetic; Goals; Growth; Image; Impaired cognition; Individual; Inflammation; Inflammatory; Inherited; International; Liquid substance; Magnetic Resonance Imaging; Measures; Modification; Monoclonal Antibodies; Nerve Degeneration; Neuronal Injury; Noise; Observational Study; Outcome; Outcome Study; Pathology; Performance; Pharmaceutical Preparations; Phase; Phenotype; Placebo Control; Placebos; Population; Positron-Emission Tomography; Prevention trial; Process; Production; Protein Isoforms; Randomized; Role; Running; S-nitro-N-acetylpenicillamine; Secondary Prevention; Seminal; Signal Transduction; Site; Small Interfering RNA; Staging; Sum; Symptoms; Testing; Therapeutic; Therapeutic Intervention; Therapeutic Trials; Tracer; Translating; Translations; VSNL1 gene; adeno-associated viral vector; arm; base; brain metabolism; cerebral atrophy; clinical effect; cognitive benefits; comorbidity; design; fluorodeoxyglucose positron emission tomography; human subject; imaging biomarker; improved; inhibitor/antagonist; innovation; mutation carrier; next generation; novel; phase 2 study; phase 3 study; phase II trial; phase III trial; preclinical trial; prevent; primary outcome; rate of change; recruit; secondary outcome; small molecule; spectrograph; success; tau Proteins; tau aggregation; tau-1; therapeutic target; therapy design; trial design; validation studies

PROJECT SUMMARY The DIAN-TU platform was formed to design and manage interventional therapeutic trials and find a treatment that provides cognitive benefit for those certain to develop dominantly inherited AD (DIAD). The DIAN-TU trial platform is now fully operational in 13 countries and 37 sites. The current DIAN-TU secondary prevention trial is a four-year phase 3 cognitive endpoint trial of two anti-amyloid drugs, solanezumab and gantenerumab, with results to be announced in early 2020. The DIAN-TU platform is now mature and primed for testing treatments targeting tau or a combination of tau and amyloid-beta (Aβ) depending on the outcomes of the amyloid trials, and is the ideal platform to provide pivotal biologic results of tau treatment in a pure form of AD. If there is a positive outcome of Aβ drugs, this would support all subjects to be on therapy, enabling combination treatment and giving tau drugs a greater chance of success. If Aβ drugs are negative, then we will need to address the ability of tau-targeted drugs to impact the biology of AD and the potential to slow or prevent the disease. Thus, the tau NexGen studies can and should be done regardless of the outcomes of current amyloid trials. The next phase of the DIAN-TU Next Generation (NexGen) trial will test diverse tau targets in the DIAD population using three mechanisms: a tau antibody, a genetic treatment, and an aggregation inhibitor. The DIAN-TU Tau NexGen will conduct randomized, double blind, pooled placebo-controlled, two-year phase 2 biomarker endpoint trials of three anti-tau or anti-tau/anti-Aβ combination therapies in 216 DIAD mutation carriers (MCs, 72 in each drug arm) who are mildly symptomatic (CDR 0.5 or 1) or asymptomatic with an estimated year of symptom onset (EYO) 15 years before to 10 years after EYO. The trial platform has five novel trial design aspects: 1) a dose escalation algorithm to safely maximize target engagement; 2) a common-close design, so all subjects will stop treatment when the last enrolled subject completes the two- year treatment; 3) a pooled placebo/control design, which increases the number of subjects who contribute to the primary analysis; 4) novel imaging (e.g., the latest generation tau PET tracer, diffusion basis spectrum imaging MRI) and biofluid measures of soluble tau species, neurodegeneration, and inflammation; and 5) a cognitive and tau PET run-in period. The DIAN-TU's contribution is expected to be a substantial understanding of the key tau and combination therapeutic targets in AD through the use of an innovative trial platform in an ideal population. This contribution would provide the AD field with a greater likelihood of translating promising anti-tau therapies to large phase 3 studies, accelerating disease-modifying therapies in DIAD, and possibly translating to the more common sporadic form of AD. Our future aims are to transition successful phase 2 biomarker outcome studies to phase 3 cognitive endpoint outcome studies to enable registration of successful drugs.

项目总结 DIAN-TU平台的成立是为了设计和管理介入治疗试验，并找到一个 为那些肯定会发展为显性遗传性阿尔茨海默病(DIAD)的人提供认知益处的治疗。这个 Dian-TU试验平台目前已在13个国家和37个地点全面运营。当前的殿图次要 预防试验是两种抗淀粉样蛋白药物Solanezumab和Solanezumab的为期四年的第三阶段认知终点试验 Gantenerumab，结果将于2020年初公布。点图平台现已成熟并已做好准备 根据结果测试针对tau或tau和淀粉样β蛋白(Aβ)组合的治疗 是淀粉样蛋白试验的理想平台，是以纯形式提供tau治疗的关键生物学结果的理想平台 公元一代的。如果Aβ药物有积极的结果，这将支持所有受试者接受治疗，使 联合治疗和给予tau药物更大的成功机会。如果Aβ药物呈阴性，那么我们 将需要解决tau靶向药物影响AD生物学的能力以及减缓或 预防疾病。因此，tau NexGen研究可以而且应该进行，无论结果如何 目前的淀粉样蛋白试验。 DIAN-TU下一代(NexGen)试验的下一阶段将测试DIAD中的各种tau靶标 使用三种机制的种群：tau抗体、基因治疗和聚集抑制物。这个 Dian-Tau Tau NexGen将进行随机、双盲、混合安慰剂对照、为期两年的第二阶段 3种抗tau或抗tau/抗Aβ联合治疗DIAD突变的生物标志物终点试验 携带者(每个药物臂有72个MC)，症状轻微(CDR 0.5或1)或无症状 估计出现症状的年份(EYO)在EYO前15年至EYO后10年。试验平台有五个 新颖的试验设计方面：1)剂量递增算法，以安全地最大化目标参与；2)a) 通用-闭合设计，因此当最后一名登记的受试者完成两项- 一年的治疗；3)安慰剂/对照的混合设计，它增加了对 初步分析；4)新的成像(例如，最新一代的tau PET示踪剂、扩散基础光谱 成像核磁共振)和可溶tau物种、神经退行性变和炎症的生物流体测量；以及5)a 认知期和tau-PET磨合期。 DIAN-TU的贡献预计将是对关键tau和组合的实质性理解 通过在理想人群中使用创新的试验平台来治疗阿尔茨海默病。这 贡献将为AD领域提供更大的可能性，将有希望的抗tau疗法转化为 大型3期研究，加速DIAD的疾病修改治疗，并可能转化为更多 常见的散发性AD。我们未来的目标是过渡成功的第二阶段生物标记物结果 研究到第三阶段认知终点结果研究，以实现成功药物的注册。