The Alzheimer's Disease Tau Platform Clinical Trial

项目总结/摘要 Tau蛋白是一种有吸引力的AD治疗靶点，因为不溶性Tau蛋白的量和解剖学分布与AD的治疗靶点不同。 尸体解剖时的tau与生命中疾病的症状和严重程度密切相关。多种tau治疗 目前正在进行AD的临床试验，许多新药物进入临床。新的方法来加速他们的 迫切需要临床开发。现在存在多种AD生物标志物，包括CSF和血浆β-淀粉样蛋白。 淀粉样蛋白比率和磷酸化tau（P-tau）水平，以及淀粉样蛋白和tau PET示踪剂，提供了工具， 测量淀粉样蛋白和tau治疗对AD核心生物学的药效学作用。的目标 阿尔茨海默氏症Tau平台（ATP）试验是在阿尔茨海默氏症患者中进行一项随机、安慰剂对照、2期平台试验。 临床前前驱AD将同时测试至少两种不同的tau导向疗法，单独或联合 联合抗淀粉样蛋白治疗，以确定安全性、耐受性和基于生物学的概念验证 基于tau PET示踪剂18F MK6240和其他tau生物标志物。平台试验通过以下方式提高效率 制定共同的临床试验方案和共享安慰剂组，以允许更多的治疗 与进行多个独立试验相比，可以在更短的时间内以更少的费用进行测试。本次试验将测试5 涉及3种药物与安慰剂组合的治疗假设：两种tau疗法将在一项研究中进行研究。 2 × 3析因设计（安慰剂与抗淀粉样蛋白[n = 2] × 2种tau治疗或安慰剂[n = 3]），持续24个月，在6个 平行的手臂ATP的关键入选标准是淀粉样蛋白PET吸收> 20厘泊，18 F MK 6240 时间ROI SUVr> 1.25，总体临床痴呆评级（CDR）为0或0.5，MMSE> 23。使用这些 标准，我们估计每组需要150名参与者才能有80%的把握度检测到30%的减速， 在24个月的盲法治疗中18F MK 6240信号的累积。关键次要终点为 血浆P-tau种类的变化（-217等）和神经丝轻链（NfL），临床评定量表和 容积MRI。利用NIH AD临床试验联盟（ACTC）的经验和资源，我们 建议在24个月内在约100个ACTC中心招募900名参与者，将他们以5：1的药物：安慰剂随机分配24 6个月的盲态治疗，随后是24个月的开放标签扩展。我们的目标是：1）测试两个能力 tau导向疗法，单独或与抗淀粉样蛋白疗法组合，以减缓 与单独的安慰剂或抗淀粉样蛋白治疗相比，24个月内的tau PET信号; 2）测试安全性和 24个月盲态治疗的耐受性，随后是可选的24个月开放标签扩展组合 tau/抗淀粉样蛋白疗法;和3）探索两种tau定向疗法中的每一种减缓疾病的能力 通过CSF和血浆生物标志物（血浆P-tau、NfL）、体积MRI和临床 评估（临床前阿尔茨海默综合征[PACC]等）。如果成功，ATP将提供数据， 关于在更大的疗效研究中采用哪种tau疗法或组合的决策， 该研究旨在测试tau以外的新治疗方法，并将提高对AD生物学的理解。

PROJECT SUMMARY / ABSTRACT Tau protein is an attractive AD therapeutic target because the amount and anatomical distribution of insoluble tau at autopsy is strongly correlated with the symptoms and severity of disease during life. Multiple tau therapies are now in clinical trials for AD, with many new agents entering the clinic. New approaches to accelerating their clinical development are urgently needed. A variety of AD biomarkers now exist, including CSF and plasma beta amyloid ratios and phosphorylated tau (P-tau) levels, and amyloid and tau PET tracers, providing tools to measure pharmacodynamic effects of amyloid and tau therapies on the core biology of AD. The goal of the Alzheimer’s Tau Platform (ATP) trial is to conduct a randomized, placebo controlled, Phase 2 platform trial in preclinical-prodromal AD that will simultaneously test at least two different tau-directed therapies, alone or in combination with an anti-amyloid therapy, to determine safety, tolerability, and biological based proof of concept based on the tau PET tracer 18F MK6240 and other tau biomarkers. Platform trials create efficiencies through generation of a common clinical trial protocol and shared placebo groups to allow a greater number of therapies to be tested in less time with less expense than by conducting multiple independent trials. This trial will test 5 therapeutic hypotheses involving combinations of 3 drugs versus placebo: Two tau therapies will be studied in a 2 x 3 factorial design (placebo vs. anti-amyloid [n=2] x two tau therapies or placebo [n=3]) for 24 months, in six parallel arms. The key inclusion criteria for ATP will be >20 centiloids of amyloid PET uptake, 18F MK6240 temporal ROI SUVr >1.25, with a global Clinical Dementia Rating (CDR) of 0 or 0.5 and MMSE >23. Using these criteria, we estimate that 150 participants per arm will be necessary to have 80% power to detect a 30% slowing in the accumulation 18F MK6240 signal over 24 months of blinded therapy. Key secondary endpoints will be changes in plasma P-tau species (-217, etc.) and neurofilament light chain (NfL), clinical rating scales and volumetric MRI. Leveraging the experience and resources of the NIH AD Clinical Trial Consortium (ACTC), we propose to enroll 900 participants at ~100 ACTC sites over 24 months, randomize them 5:1 drug:placebo for 24 months of blinded treatment, followed by a 24 month open label extension. We aim to: 1) test the ability of two tau-directed therapies, either alone or in combination with an anti-amyloid therapy, to slow the accumulation of tau PET signal over 24 months as compared to placebo or anti-amyloid therapy alone; 2) test the safety and tolerability of 24 months of blinded therapy followed by an optional 24 month open label extension of combination tau/anti-amyloid therapy; and 3) explore the ability of each of two tau directed therapies to slow disease progression as measured by CSF and plasma biomarkers (plasma P-tau, NfL), volumetric MRI and clinical assessments (Preclinical Alzheimer’s Composite [PACC], etc.). If successful, the ATP will provide data for decision-making about which tau therapies or combinations to pursue in larger efficacy studies, an ongoing resource to test new therapeutic approaches beyond tau, and will improve understanding of AD biology.