Clinical Trial Readiness for Multiple System Atrophy - Resubmission - 1

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是一种无法治愈的致命进行性罕见神经退行性疾病。最近在多发性硬化症研究中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，最终有一些候选药物正在酝酿中，旨在减缓或阻止疾病的进展。多家制药公司现在正致力于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发现，我们目前的临床试验武器库存在几个弱点，主要限制因素是缺乏敏感的结果衡量标准。目前，只有一种MSA(UMSARS)临床分级标准被验证为临床试验中使用的结果衡量标准。缺点是，UMSARS对变化的反应只是中等程度，所以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，这对一种罕见的快速进展性疾病来说并不理想。也缺乏跟踪疾病进展的成像或生化生物标记物。为了达到MSA的临床试验准备，我们建议进行一项国际性、多中心、前瞻性的观察性研究，纳入100名MSA患者，在4个地点进行为期一年的跟踪研究。我们将利用联体核病自然史研究(NIH RDCRN自主罕见疾病临床研究联盟内发起的一项倡议)和欧洲MSA研究小组的现有基础设施，这两个组织都包括一个由高度协作的学术站点组成的共享数据的已建立网络。在致力于MSA疾病修改候选药物的三家制药公司的支持下，以及主要MSA倡导团体的支持下，我们有一个独特的机会，让所有利益相关者密切合作，共同应对剩余的挑战，并为MSA建立临床试验准备。我们的目标是：目标1。开发一种新的临床结果评估(COA)并确定其有效性。我们将从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一项的响应率，这些患者是参加RDCRN自然病史研究的共核病患者。我们将删除多余的项目或几乎没有检测到变化的能力，并将在患者权益团体的参与下制定新的COA，我们将在新登记的MSA患者中进行前瞻性验证。目的2.比较新的COA与UMSARS的反应性，并确定临床上最小的重要差异。目的3.验证MSA疾病进展的神经影像和生化生物标记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15,000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治疗MSA的公司。

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.