DIAN-TU: Tau Next Generation Prevention Trial

DIAN-TU：Tau 下一代预防试验

基本信息

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
项目类别：
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&apos s Disease Alzheimer&apos 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

项目摘要

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.

项目概要 DIAN-TU 平台的成立是为了设计和管理介入治疗试验并寻找为那些确定患有遗传性 AD (DIAD) 的人提供认知益处的治疗。 DIAN-TU 试验平台现已在 13 个国家和 37 个站点全面运行。预防试验是一项为期四年的 3 期认知终点试验，试验对象是两种抗淀粉样蛋白药物 solanezumab 和 gantenerumab，结果将于 2020 年初公布。DIAN-TU 平台现已成熟并准备就绪用于根据结果测试针对 tau 或 tau 和淀粉样蛋白 (Aβ) 组合的治疗淀粉样蛋白试验的一部分，是提供纯 tau 治疗关键生物学结果的理想平台如果 Aβ 药物有积极的结果，这将支持所有受试者接受治疗，从而使联合治疗并给予 tau 药物成功的机会更大如果 Aβ 药物呈阴性，那么我们需要解决 tau 靶向药物影响 AD 生物学的能力以及减缓或缓解 AD 的潜力因此，无论结果如何，tau NexGen 研究都可以而且应该进行。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 中的不同 tau 靶点使用三种机制对人群进行治疗：tau 抗体、基因治疗和聚集抑制剂。 DIAN-TU Tau NexGen 将进行随机、双盲、汇总安慰剂对照、为期两年的 2 期研究三种抗 tau 或抗 tau/抗 Aβ 联合疗法治疗 216 DIAD 突变的生物标志物终点试验轻度症状（CDR 0.5 或 1）或无症状的携带者（MC，每个药物组 72 名）估计症状发作年份 (EYO) 之前 15 年到之后 10 年该试验平台有五个。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度；2）a 共闭设计，因此当最后一名受试者完成两步时，所有受试者都将停止治疗年治疗；3）联合安慰剂/对照设计，增加了参与治疗的受试者数量初步分析；4）新颖的成像（例如最新一代的tau PET示踪剂、扩散基础光谱）成像 MRI）和可溶性 tau 物种、神经变性和炎症的生物流体测量；以及 5）a 认知和 tau PET 磨合期。 DIAN-TU 的贡献预计是对关键 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实现 AD 的治疗目标。贡献将为 AD 领域提供更大的可能性，将有前途的抗 tau 疗法转化为大型 3 期研究，加速 DIAD 的疾病缓解疗法，并可能转化为更多我们未来的目标是成功过渡 2 期生物标志物结果。第三阶段认知终点结果研究，以实现成功药物的注册。