Limitations of the Unified Multiple System Atrophy Rating Scale as outcome measure for clinical trials and a roadmap for improvement

Abstract

Purpose: The unified multiple system atrophy (MSA) rating scale (UMSARS) was developed almost 20 years ago as a clinical rating scale to capture multiple aspects of the disease. With its widespread use, the shortcomings of the UMSARS as a clinical outcome assessment (COA) have become increasingly apparent. We here summarize the shortcomings of the scale, confirm some of its limitations with data from the Natural History Study of the Synucleinopathies (NHSS), and suggest a framework to develop and validate an improved COA to be used in future clinical trials of disease-modifying drugs in patients with MSA.

Methods: Expert consensus assessment of the limitations of the UMSARS and recommendations for the development and validation of a novel COA for MSA. We used UMSARS data from the ongoing NHSS (ClinicalTrials.gov: NCT01799915) to showcase some of these limitations.

Results: The UMSARS in general, and specific items in particular, have limitations to detect change resulting in a ceiling effect. Some items have specific limitations including unclear anchoring descriptions, lack of correlation with disease severity, susceptibility to improve with symptomatic therapies (e.g., orthostatic hypotension, constipation, and bladder dysfunction), and redundancy, among others.

Conclusions: Because of the limitations of the UMSARS, developing and validating an improved COA is a priority. The time is right for academic MSA clinicians together with industry, professional societies, and patient advocacy groups to develop and validate a new COA.

Keywords: Clinical outcome assessment; Endpoint; Orphan diseases; Synucleinopathies; Validation.

Conflict of interest statement

Dr. Palma: salary from Novartis Gene Therapies. Research funding from the NIH, Michael J. Fox Foundation, MSA Coalition, Familial Dysautonomia Foundation, FDA, and Biogen; advisory board member for Lundbeck, Biogen, PTC Therapeutics, Astellas, and Dr. Reddy’s Laboratories; managing editor of Clinical Autonomic Research; principal investigator in MSA studies funded by Biohaven Pharmaceuticals, Theravance Biopharma, and Biogen. Dr. Millar: research funding from the Familial Dysautonomia Foundation and Theravance Biopharma. Mr. Perez: research funding from the Familial Dysautonomia Foundation. Dr. Krismer: funding support from MSA Coalition, non-financial support from International Parkinson’s Disease and Movement Disorders Society, non-financial support from Austrian Parkinson’s Disease Society. Dr. Fanciulli: royalties from Springer Nature Publishing Group, Thieme Verlag and IOS Press, speaker fees and honoraria from the Austrian Parkinson Society, International Parkinson Disease and Movement Disorders Society, French Cardiology Society, Theravance Biopharma and research Grants from the Stichting Parkinson Fond, the Österreichischer Austausch Dienst and the MSA Coalition. Dr. Norcliffe-Kaufmann: research funding from the NIH, Michael J. Fox Foundation, MSA Coalition, Familial Dysautonomia Foundation, FDA; advisory fees from Theravance Biopharma, and PTC Therapeutics. Dr. Kim: research finding from Seoul National University Hospital and C-TRI. Dr. Merello: Editor-in-Chief of Movement Disorders Clinical Practice. Dr. Stankovic: speaker honoraria from International Parkinson Disease and Movement Disorders Society. Dr. Kaufmann: research funding from the NIH, Michael J. Fox Foundation, MSA Coalition, Familial Dysautonomia Foundation, FDA, and Biogen; is an advisory Board Member for Lundbeck, Biogen, Biohaven, Theravance, PTC Therapeutics, ONO and Lilly; is Editor-in-Chief of Clinical Autonomic Research.

Figures

Fig. 1

Relationship between UMSARS, disease progression, and duration of disease. Panels A and B depict 143 patients with probable or possible MSA enrolled in the Natural History Study of the Synucleinopathies who completed at least a 1-year evaluation (61 completed a 2-year evaluation). Both panels illustrate how patients with lower UMSARS tend to have progression rates in the UMSARS, significantly for UMSARS-1 (R2 = 0.041; P = 0.0153) and close to significance in UMSARS-2 (R2 = 0.039; P = 0.0917). While this has been interpreted as faster progression in patients with earlier disease stages, an alternative plausible explanation is the that the UMSARS may have poor ability to capture disease progression in advanced patients. To illustrate this, panels C and D depict correlations between the UMSARS at each visit (baseline, 1 year and 2 years) and the patient’s duration of disease at each visit as defined by the time from onset of motor symptoms. There is an apparent ceiling effect at 43 in UMSARS-1 and at 49 in UMSARS-2 (denoted with dashed line), meaning that no patient ever reached higher scores, despite the fact that these are not the highest possible UMSARS scores. This suggests that UMSARS is not a suitable tool to capture disease progression at advanced disease stages

Fig. 2

Percent mean annual change in the total score (a) and effect size of the yearly change in the total score (b) according to the number of items included in the scale. The dotted line shows the corresponding values for an 11-item abridged version of the UMSARS, showing that further addition of items does not increase its sensitivity to change. Note that this is only a quick example showcasing the feasibility of improving the UMSARS and developing a new clinical outcome assessment (COA) tool for MSA that can be used in future clinical trials of disease modification. We are not proposing using this 11-item UMSARS instead of the conventional UMSARS. A proper development and validation process for the new COA will be necessary