The Alzheimer's Disease Tau Platform Clinical Trial

阿尔茨海默病 Tau 平台临床试验

基本信息

批准号：
10655872
负责人：
ADAM L. BOXER
金额：
$ 3088.72万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-21 至 2028-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10655872
关键词：
Acceleration Address Alzheimer&apos s Disease Alzheimer&apos s disease pathology Alzheimer&apos s disease therapeutic Alzheimer&apos s disease therapy Alzheimer’s disease biomarker Amyloid Amyloid Proteins Amyloid beta-Protein Anatomy Autopsy Biological Biological Markers Biology Blinded Blood Tests Brain Brain scan Chemotherapy-Oncologic Procedure Clinic Clinical Clinical Trials Clinical Trials Design Clinical assessments Combined Modality Therapy Data Decision Making Dementia Deposition Disease Disease Progression Enrollment Failure Future Gene Mutation Generations Goals Individual Inherited Intervention Life Light Magnetic Resonance Imaging Measures Nerve Degeneration Neurodegenerative Disorders New Agents Oncology Outcome PET positivity Participant Pathogenicity Patients Pharmaceutical Preparations Pharmacodynamics Phase Placebo Control Placebos Plasma Positron-Emission Tomography Randomized Regimen Resources Safety Sampling Severity of illness Signal Transduction Site Sum Symptoms Syndrome Temporal Lobe Testing Therapeutic Therapeutic Effect Time Tracer United States National Institutes of Health abeta accumulation anticancer research arm clinical development clinical trial protocol design efficacy study efficacy trial experience improved inclusion criteria neurofilament novel strategies novel therapeutic intervention open label placebo group pre-clinical prodromal Alzheimer&apos s disease programs recruit safety testing secondary analysis secondary endpoint targeted agent tau Proteins tau aggregation tau mutation tau-1 therapeutic target tool treatment effect uptake

项目摘要

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.

项目概要/摘要 Tau 蛋白是一个有吸引力的 AD 治疗靶点，因为不溶性蛋白的数量和解剖分布尸检时的 tau 蛋白与一生中多种 tau 蛋白疗法的症状和严重程度密切相关。目前正在进行 AD 的临床试验，许多新药物进入临床，加速其临床试验。目前迫切需要临床开发多种AD生物标志物，包括脑脊液和血浆β。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，为测量淀粉样蛋白和 tau 蛋白疗法对 AD 核心生物学的药效作用。阿尔茨海默病 Tau 平台 (ATP) 试验将在以下国家进行一项随机、安慰剂对照的 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，单独或联合与抗淀粉样蛋白治疗相结合，以确定安全性、耐受性和基于生物学的概念证明基于 tau PET 示踪剂 18F MK6240 和其他 tau 生物标记物的平台试验通过提高效率。生成通用的临床试验方案和共享的安慰剂组，以允许更多的治疗与进行多次独立试验相比，该试验将在更短的时间内以更少的费用进行测试。涉及 3 种药物与安慰剂组合的治疗假设：将在一项研究中研究两种 tau 疗法 2 x 3 析因设计（安慰剂与抗淀粉样蛋白 [n=2] x 两种 tau 疗法或安慰剂 [n=3]），为期 24 个月，共 6 个月平行臂的 ATP 关键纳入标准是淀粉样蛋白 PET 摄取量 >20 个厘粒，18F MK6240。时间 ROI SUVr >1.25，全球临床痴呆评分 (CDR) 为 0 或 0.5，MMSE >23。标准，我们估计每组需要 150 名参与者才能有 80% 的能力来检测 30% 的减速在 24 个月的盲法治疗中积累的 18F MK6240 信号将是关键的次要终点。血浆 P-tau 种类（-217 等）和神经丝轻链 (NfL)、临床评定量表和利用 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，将他们按照 5:1 药物：安慰剂的比例随机分配 24 个月几个月的盲法治疗，然后是 24 个月的开放标签扩展，我们的目标是：1）测试两个人的能力。 tau 定向疗法，单独或与抗淀粉样蛋白疗法联合，以减缓与单独使用安慰剂或抗淀粉样蛋白治疗相比，tau PET 信号持续 24 个月；2) 测试安全性； 24 个月的盲法治疗的耐受性，然后是可选的 24 个月开放标签扩展组合 tau/抗淀粉样蛋白疗法；3) 探索两种 tau 靶向疗法减缓疾病的能力通过脑脊液和血浆生物标志物（血浆 P-tau、NfL）、体积 MRI 和临床测量来测量评估（临床前阿尔茨海默病综合评估 [PACC] 等）如果成功，ATP 将提供数据。决定在更大规模的疗效研究中采用哪种 tau 疗法或组合，这是一项正在进行的研究测试 tau 以外的新治疗方法的资源，并将增进对 AD 生物学的理解。