Assessment of the Reliability, Responsiveness, and Meaningfulness of the Scale for the Assessment and Rating of Ataxia (SARA) for Lysosomal Storage Disorders

Objective To evaluate the reliability, responsiveness, and validity of the Scale for the Assessment and Rating of Ataxia (SARA) in patients with Lysosomal Storage Disorders (LSDs) who present with neurological symptoms and quantify the threshold for a clinically meaningful change. Methods We analyzed data from three clinical trial cohorts (IB1001-201, IB1001-202, IB1001-301) of patients with Niemann-Pick disease type C (NPC) and GM2 Gangliosidoses (Tay-Sachs and Sandhoff disease) comprising 122 patients and 703 visits. Reproducibility was described as retest reliability between repeat baseline visits or baseline vs. post-treatment washout visits. Responsiveness was determined in relation to the Investigator’s, Caregiver’s, and Patient’s Clinical Global Impression of Improvement (CGI-I). The CGI-I data was also used to quantify a threshold for a clinically meaningful improvement on the SARA scale. Using a qualitative methods approach, patient/caregiver interviews from the IB1001-301 trial were further used to assess a threshold of meaningful change as well as the breadth of neurological signs and symptoms captured and evaluated by the SARA scale. Results The Inter-Class Correlation (ICC) was 0.95 or greater for all three trials, indicating a high internal consistency/reliability. The mean change in SARA between repeat baseline or post-treatment washout visit assessments in all trials was -0.05, SD 1.98, i.e. minimal, indicating no significant differences, learning effects or other systematic biases. For the CGI-I responses and change in SARA scores Area Under the Curve (AUC) values were 0.82, 0.71, and 0.77 for the Investigator’s, Caregiver’s, and Patient’s CGI-I respectively, indicating strong agreement. Further qualitative analyses of the patient/caregiver interviews demonstrated a 1-point or greater change on SARA to be a clinically meaningful improvement which is directly relevant to the patient’s everyday functioning and quality of life. Changes captured by the SARA were also paralleled by improvement in a broad range of neurological signs and symptoms and beyond cerebellar ataxia. Conclusion Qualitative and quantitative data demonstrate the reliability and responsiveness of the SARA score as a valid measure of neurological signs and symptoms in LSDs. A 1-point change represents a clinically meaningful transition reflecting the gain or loss of complex function. Statements and Declarations The IB1001-201, IB1001-202, and IB1001-301 trials were funded by IntraBio Inc. No funding was received to assist with the preparation of this manuscript. T. Bremova-Ertl received honoraria for lecturing from Sanofi and Acetlion and fees from IntraBio to serve as a blinded rater for the IB1001-201 and IB1001-202 clinical trials. P. Gissen received consulting fees from Mandos Health and is the Co-Founder and shareholder of Bloomsbury Genetic Therapies. M. Patterson is a shareholder in IntraBio and his institution has received research grants from Azafaros, Glycomine, Idorsia, Maggie’s Pearl, Takeda, and Zevra, and consulting fees (directed to his institution) from Zevra. U. Ramaswami has received research and/or investigator-initiated research grants from Amicus and Takeda and honoraria for advisory boards and lectures from Amicus, Takeda, and Sanofi. All other authors The authors have no competing interests to declare that are relevant to the content of this article.