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.

项目摘要 /摘要 tau蛋白是一个有吸引力的AD治疗靶标，因为不溶性的量和解剖分布尸检时Tau与生活中疾病的症状和严重程度密切相关。多种tau疗法现在正在进行AD的临床试验中，许多新代理商进入诊所。加速他们的新方法迫切需要临床发展。现在已经存在各种广告生物标志物，包括CSF和血浆β 淀粉样蛋白比和磷酸化的TAU（P-TAU）水平以及淀粉样蛋白和TAU PET示踪剂，为工具提供工具测量淀粉样蛋白和TAU疗法对AD核心生物学的药效作用。目标的目标阿尔茨海默氏症的tau平台（ATP）试验将在临床前产物AD，将仅测试至少两种单独或单独或IN两种不同的TAU定向疗法结合抗淀粉样疗法，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生物标志物。平台试验通过生成常见的临床试验方案和共享安慰剂组，以允许更多的疗法与进行多个独立试验相比，在费用少的时间内进行测试。该试验将测试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A中研究 2 x 3阶乘设计（安慰剂与抗淀粉样蛋白[n = 2] x两种tau疗法或安慰剂[n = 3]），持续24个月，六个月平行手臂。 ATP的关键纳入标准将> 20厘米的淀粉样蛋白宠物吸收，18F MK6240 临时ROI SUVR> 1.25，全球临床痴呆率评级（CDR）为0或0.5，MMSE> 23。使用这些标准，我们估计每只手臂有150名参与者才能拥有80％的功率来检测30％的速度在24个月的盲疗中，积累18F MK6240信号。关键的次要终点将是血浆P-TAU物种（-217等）和神经丝轻链（NFL）的变化，临床评级量表和体积MRI。利用NIH AD临床试验联盟（ACTC）的经验和资源，我们在24个月内招募约100个ACTC站点的900名参与者的提议，随机分配5：1药物：安慰剂24 几个月的盲人治疗，然后进行24个月的开放标签扩展。我们的目标是：1）测试两个的能力单独或与抗淀粉样疗法结合的TAU定向疗法，以减慢与安慰剂或抗淀粉样疗法相比，tau宠物信号在24个月内； 2）测试安全性和 24个月盲疗法的耐受性，然后是可选的24个月开放标签延伸的组合标签 tau/抗淀粉样疗法； 3）探索两种tau指导疗法中每种疾病的能力通过CSF和血浆生物标志物（血浆P-TAU，NFL），体积MRI和临床测量的进展评估（临床前阿尔茨海默氏症的综合[PACC]等）。如果成功，ATP将为关于在更大的效率研究中要购买哪种tau疗法或组合的决策，这是一种持续的用于测试TAU以外的新治疗方法的资源，并将改善对AD生物学的理解。