Clinical Trial Readiness for Multiple System Atrophy - Resubmission - 1

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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.