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

• 批准号: 10606484
• 负责人: HORACIO KAUFMANN
• 金额: $ 100.74万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 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/10606484
• 关键词: Acceleration; Address; Adult; Advisory Committees; Advocacy; Affect; Antibodies; Antisense Oligonucleotides; Autophagocytosis; Biochemical; Biological; Biological Markers; Blood; 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 Chelation; Light; Link; 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; biomedical referral center; brain magnetic resonance imaging; 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; neuroprotection; novel; participant enrollment; 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

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.

这项研究的总体目的是开发和验证多个系统萎缩患者（MSA）的临床试验的敏感临床和生物学结局指标，这是一种致命的稀有神经退行性疾病，无法治愈。 MSA研究的最新突破已经确定了错误折叠的α-突触核蛋白是疾病造成的机制的关键作用，并且最终在管道中有许多候选药物旨在减慢或阻止疾病进展。现在，多家制药公司正在努力实现MSA靶向疗法，并正在进行两项安慰剂控制的临床试验。但是，MSA专家以及行业和监管机构在我们当前的临床试验中确定了几个弱点，缺乏敏感的结果措施是主要限制。目前，MSA（UMSAR）仅有一个临床评级量表，被证实为用于临床试验的结果指标。缺点是，UMSARS仅对变化有适度的响应，因此它需要大量的研究对象和较长的随访期才能获得足够的统计能力来测试候选药物的效果，这对于罕见的快速促进疾病并不理想。还缺乏成像或生化生物标志物来跟踪疾病进展。为了达到MSA的临床试验准备，我们提出了一项国际，多中心，前瞻性观察性研究，在4个地点招收100例MSA患者一年。我们将利用突触性核酸疾病自然史研究的现有基础设施（在NIH RDCRN自主稀有疾病临床研究联盟内开始的一项倡议）和欧洲的MSA研究小组，其中包括一个既定的高度协作学术网站网络，共享了他们的数据。在三家制药公司的支持下，从事MSA疾病改良候选者的支持，并认可了主要的MSA倡导组织，我们为所有利益相关者的紧密合作提供了独特的机会，可以共同解决剩余的挑战并为MSA建立临床试验阅读。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。我们将确定从已经从400名参与Synucleinopathies的RDCRN自然历史研究的MSA患者那里收集的UMSARS和其他临床量表的变化和其他临床量表的反应率的能力。我们将删除冗余物品或很少检测变化的能力，并且随着患者倡导组的输入，将开发出一种新的COA，我们将在新入学的MSA患者中前景验证。目标2。要比较新COA对UMSAR的响应性，并确定最小临床上重要的差异。目的3。验证MSA中疾病进展的神经影像学和生化生物标志物用于临床试验。提供加速药物开发必要的工具将对美国的约15,000名MSA患者产生重大影响，外部咨询委员会将提供指导。研究数据将提供给寻求MSA治疗的研究人员或公司。