DIAN-TU: Tau Next Generation Prevention Trial

DIAN-TU：Tau 下一代预防试验

• 批准号: 10261442
• 负责人: RANDALL J BATEMAN
• 金额: $ 1497.54万
• 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/10261442
• 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.

项目摘要 DIAN-TU平台的形成是为了设计和管理介入治疗试验， 为那些肯定会发展为显性遗传性AD（DIAD）的人提供认知益处的治疗。的 DIAN-TU试验平台现已在13个国家和37个研究中心全面运行。目前的DIAN-TU中学 预防试验是一项为期4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 用于测试靶向tau或tau和淀粉样蛋白-β（Aβ）的组合的治疗， 淀粉样蛋白试验，是提供纯形式tau治疗的关键生物学结果的理想平台 的AD。如果Aβ药物的结果为阳性，这将支持所有受试者接受治疗， 联合治疗并给予tau药物更大的成功机会。如果Aβ药物是阴性的，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，无论结果如何，都可以而且应该进行tau NexGen研究。 目前淀粉样蛋白试验。 DIAN-TU下一代（NexGen）试验的下一阶段将在DIAD中测试不同的tau靶点。 使用三种机制：tau抗体，遗传治疗和聚集抑制剂。的 DIAN-TU Tau NexGen将进行随机、双盲、汇总安慰剂对照、为期2年的II期研究 在216例DIAD突变患者中进行的三种抗tau或抗tau/抗A β联合治疗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例）， 估计症状发作年（EYO）前15年至EYO后10年。审判平台有五个 新的试验设计方面：1）安全地最大化靶点参与的剂量递增算法; 2） 共同关闭设计，因此当最后一名入组受试者完成两项- 3）合并安慰剂/对照设计，增加了导致 主要分析; 4）新的成像（例如，最新一代tau PET示踪剂，扩散基谱 成像MRI）和可溶性tau种类、神经变性和炎症的生物流体测量;和5）a 认知和tau PET磨合期。 DIAN-TU的贡献预计将是对关键τ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，研究AD的治疗靶点。这 这一贡献将为AD领域提供更大的可能性，将有前景的抗tau疗法转化为 大型3期研究，加速DIAD的疾病改善治疗，并可能转化为更多的 常见的散发性AD。我们未来的目标是成功过渡到2期生物标志物结果 3期认知终点结果研究，以使成功的药物注册。