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: 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
• 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

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.

本研究的总体目的是为多发性系统萎缩（MSA）患者的临床试验开发和验证敏感的临床和生物学结果测量，MSA是一种致命的进行性罕见神经退行性疾病，无法治愈。最近MSA研究的突破已经确定了错误折叠的α-突触核蛋白作为致病机制的关键作用，并且最终有一些旨在减缓或阻止疾病进展的候选药物正在开发中。多家制药公司目前正致力于MSA靶向治疗，两项安慰剂对照临床试验正在进行中。然而，MSA专家以及行业和监管机构已经确定了我们目前临床试验库中的几个弱点，缺乏敏感的结果测量是主要限制。目前，只有一种MSA的临床评定量表（UMSARS）被验证为临床试验中使用的结果衡量标准。缺点是UMSARS对变化只有中等反应，因此需要大量的研究对象和长时间的随访才能获得足够的统计能力来测试候选药物的效果，这对于一种罕见的快速进展的疾病来说并不理想。也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，我们建议进行一项国际、多中心、前瞻性观察性研究，在4个地点招募100名MSA患者，随访一年。我们将利用现有的Synucleinopathies自然历史研究的基础设施（一项由NIH RDCRN自主罕见疾病临床研究联盟发起的倡议）和欧洲MSA研究小组，这两个研究小组都包括一个建立的高度协作的学术网站网络，共享他们的数据。在三家致力于MSA疾病修饰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，我们有一个独特的机会，可以与所有利益相关者紧密合作，共同应对剩余的挑战，并建立MSA的临床试验准备。我们的目标是：目的：建立一种新的临床结果评估方法（COA）并确定其有效性。我们将从已经收集的400名MSA患者的历史数据中确定检测变化的能力和UMSARS和其他临床量表的每个项目的反应率，这些患者参加了RDCRN Synucleinopathies的自然史研究。我们将删除冗余项目或检测变化能力不足的项目，并根据患者权益团体的意见，制定新的COA，我们将在新入组的MSA患者中对其进行前瞻性验证。目标2。比较新COA对UMSARS的反应性，并确定最小临床重要差异。目标3。验证MSA疾病进展的神经影像学和生化生物标志物在临床试验中的应用。提供加速药物开发所需的工具将对美国约1.5万名MSA患者产生重大影响。一个外部咨询委员会将提供指导。研究数据将提供给研究人员或寻求MSA治疗的公司。