Clinical Trial Readiness for Multiple System Atrophy - Resubmission - 1

多系统萎缩的临床试验准备 - 重新提交 - 1

基本信息

批准号：
10355913
负责人：
HORACIO KAUFMANN
金额：
$ 105.02万
依托单位：
NEW YORK UNIVERSITY SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-04-15 至 2027-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10355913
关键词：
Address Adult Advisory Committees Advocacy Affect Antibodies Antisense Oligonucleotides Autophagocytosis Biochemical Biological Biological Markers Blood Brain Clinical Clinical Data Clinical Research Clinical Trials Cohort Studies Collaborations Collection Controlled Clinical Trials Data Development Diffusion Disease Disease Progression Drug Industry Drug Targeting Enrollment Europe European Future Goals Image Industry Infrastructure International Iron Iron Chelating Agents Light Link Magnetic Resonance Imaging Measurement Measures Multiple System Atrophy Natural History Neurodegenerative Disorders Neuroglia Neurons Observational Study Orphan Outcome Measure Parkinson Disease Pathogenicity Patients Pharmaceutical Preparations Pharmacologic Substance Phase Placebo Control Process Proteins Rare Diseases Reproducibility Research Research Personnel Role Safety Serum Sirolimus Site Study Subject Symptoms Testing Therapeutic Effect United States National Institutes of Health Validation Visit alpha synuclein base biomedical referral center brain morphology clinical outcome assessment clinical outcome measures clinical trial readiness cohort combat drug candidate drug development effective therapy follow-up impression improved multimodality neurofilament neuroimaging neuroinflammation novel patient advocacy group preclinical development primary endpoint prospective rate of change research clinical testing response small molecule success synucleinopathy targeted treatment therapeutic development therapeutic target tool trial readiness

项目摘要

The overall aim of this study is to develop and validate sensitive clinical and biological outcome measures for clinical trials of patients with multiple system atrophy (MSA), a fatally progressive rare neurodegenerative disorder with no cure. Recent breakthroughs in MSA research have identified the crucial role of misfolded α- synuclein as disease-causative mechanism and there are finally a number of candidate drugs in the pipeline aimed at slowing or arresting disease progression. Multiple drug companies are now working toward MSA- targeted therapies and two placebo-controlled clinical trials are ongoing. However, MSA experts along with industry and regulatory agencies, have identified several weaknesses in our current clinical trial arsenal, with the lack of sensitive outcome measures as the main limitation. At present, there is only one clinical rating scale for MSA (the UMSARS) validated as outcome measure for use in clinical trials. The downside is that the UMSARS is only moderately responsive to change, so it requires large cohorts of study subjects and a long follow-up period to achieve sufficient statistical power to test the effect of candidate drugs, which is not ideal for a rare rapidly progressive disorder. There is also a lack of imaging or biochemical biomarkers to track disease progression. To reach clinical trial readiness for MSA, we propose an international, multicenter, prospective observational study enrolling 100 patients with MSA followed for a year at 4 sites. We will leverage the existing infrastructure of the Natural History Study of the Synucleinopathies (an initiative started within the NIH RDCRN Autonomic Rare Disorders Clinical Research Consortium), and the European MSA Study Group, both of which include an established network of highly collaborative academic sites sharing their data. With the support of three pharmaceutical companies working on disease-modifying candidates for MSA, and the endorsement of the major MSA advocacy groups, we have a unique opportunity for a tight collaboration of all stakeholders to jointly address the remaining challenges and establish clinical trial readiness for MSA. Our GOALS are: AIM 1. To develop a novel clinical outcome assessment (COA) and determine its validity. We will determine the ability to detect change and the response rate of each item of the UMSARS and other clinical scales from historical data already collected from 400 patients with MSA who were enrolled in the RDCRN Natural History Study of the Synucleinopathies. We will remove redundant items or with little ability to detect change, and, with the input of patient advocacy groups, will develop a new COA, which we will validate prospectively in newly enrolled MSA patients. AIM 2. To compare the responsiveness of the new COA against the UMSARS and determine the minimally clinically important difference. AIM 3. To validate neuroimaging and biochemical biomarkers of disease progression in MSA for their use in clinical trials. Providing the tools necessary for accelerating drug development will have a significant impact on ~15,000 living patients with MSA in the U.S. An external Advisory Committee will provide guidance. Study data will be available to investigators or companies pursuing treatments for MSA.

这项研究的总体目标是为多系统萎缩 (MSA) 患者的临床试验开发和验证敏感的临床和生物学结果指标，MSA 是一种致命的进展性罕见神经退行性疾病，无法治愈。MSA 研究的最新突破已经确定了其关键作用。错误折叠的 α-突触核蛋白是导致疾病的机制，最终有许多候选药物正在研发中，旨在减缓或阻止疾病进展。多家制药公司目前正在致力于 MSA 靶向治疗，并且正在进行两项安慰剂对照临床试验。然而，MSA 专家以及行业和监管机构发现了我们当前临床试验库中的一些弱点，其中缺乏敏感的结果测量是临床试验中使用的结果测量的主要限制。 UMSARS对变化的反应只有中度，因此需要大量的研究对象和较长的随访期才能达到足够的统计功效来检验候选药物的效果，这就是对于一种罕见的快速进展性疾病来说并不理想，而且还缺乏追踪疾病进展的影像学或生化生物标志物，为了为 MSA 的临床试验做好准备，我们提出了一项国际、多中心、前瞻性观察研究，招募了 100 名 MSA 患者进行随访。我们将利用突触核蛋白病自然历史研究（NIH RDCRN 自主罕见疾病临床研究联盟发起的一项计划）和欧洲 MSA 研究小组的现有基础设施，两者都包括一个高度协作的学术网站网络，在三个致力于 MSA 疾病缓解候选药物的制药公司的支持下，以及主要 MSA 倡导团体的认可下，我们有一个独特的机会来进行紧密的合作。我们的目标是：目标 1. 开发新的临床结果评估 (COA) 并确定其有效性。每个项目的响应率UMSARS 和其他临床量表来自已从参加 RDCRN 突触核蛋白病自然史研究的 400 名 MSA 患者收集的历史数据，我们将删除多余的项目或几乎无法检测变化的项目，并且根据患者倡导团体的意见。，将开发一种新的 COA，我们将在新入组的 MSA 患者中进行前瞻性验证。 AIM 2。比较新 COA 与 UMSARS 的反应性，并确定最小的临床重要差异。目标 3. 验证 MSA 疾病进展的神经影像和生化生物标志物在临床试验中的使用，提供加速药物开发所需的工具将对美国约 15,000 名 MSA 活着的患者产生重大影响。研究数据将提供给寻求 MSA 治疗的研究人员或公司。