Article

Revised ALS Disability Assessment Shows Promise as Clinical Trial Outcome Measure

Author(s):

The newly created 28-question assessment showed improved item targeting compared with the current standard Amyotrophic Lateral Sclerosis Functional Rating Scale.

Christina Fournier, MD, MSc

Christina Fournier, MD, MSc

Research shows that the Rasch-Built Overall Amyotrophic Lateral Sclerosis Disability Scale (ROADS), a 28-question, self-reported questionnaire, is associated with improved item targeting compared to the Amyotrophic Lateral Sclerosis (ALS) Functional Rating Scale (ALSFRS-R) and may be a valuable outcome measure in future ALS trials.

While use of the ALSFRS-R is the current standard primary outcome measure for ALS clinical trials, the scale is plagued by poor responsiveness, which can hinder detection of treatment effect. In order to improve upon this assessment, researchers explored the creation of a Rasch-build scale that is linearly weighted and unidimensional. Patients with ALS were recruited from January 2017 to June 2019 and completed a draft Rasch questionnaire and the revised ALSFRS-R. Following completion, investigators assessed and revised the questionnaire, removing items that were based on missing data, model fit, disordered thresholds, bias, and clinical judgment. Items that saw more than 10% of missing values were immediately discontinued.

Originally 119 questions, investigators settled on 28 for the final ROADS. The assessment records basic daily functional activities such as taking a shower, eating a large meal, and getting into bed, among others. The threshold map demonstrates the difficulty order and item targeting for each question, with the most difficult task to perform appearing on the top and the easiest task to perform on the bottom. Each item is scored 0, 1, or 2.

Overall, 243 patients completed the draft questionnaire, and 230 were included for Rasch analyses. Of these, 96 patients (39.5%) had lower extremity onset, 88 had (36.2%) upper extremity onset, and 56 (23.0%) had bulbar onset.

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The ROADS fulfilled Rasch model requirements, and demonstrated improved item targeting compared to the ALSFRS-R, as well as a test-retest reliability of 0.97. Individual question fit statistics showed infit values ranging between 0.68 to 1.37 and outfit values ranging from 0.66 to 1.43.

In a previous trial, patients reported a test-retest reliability of 0.93 for the ALSFRS-R. Notably, 13 of 48 answer responses on the ALSFRS-R were never the most probable answer choice for any functional rating ability, and the ALSFRS-R demonstrated disordered thresholds for 9 of 12 questions while violating Rasch model expectations.

Overall, the ROADS assessment “demonstrates a wider range of item targeting compared with the ALSFRS-R, meaning that while both scales contain questions targeting respondents of average disability level, only the ROADS contains questions targeting respondents with higher and lower levels of overall disability, and thus the ROADS is expected to be able to better differentiate levels of overall disability for respondents with very high or very low levels of overall disability. The breadth of item targeting is expected to improve scale responsiveness, meaning that the scale is more likely to detect change when change has actually occurred,” the authors wrote, noting that performance of the scale will need to be examined longitudinally.

“Selection of an appropriate primary outcome measure is vital for the success and efficiency of clinical trials. Creation of an improved outcome measure to quantify overall disability level, a highly relevant and important clinical outcome, is particularly important for ALS where there is no criterion standard to measure disease progression, there is no objective measure of overall disability or functional status, and current candidate biomarkers are still in exploratory stages,” they wrote. “Even if biomarkers of disease activity are validated in the future, clinically meaningful outcome measures will still remain relevant for patients and clinicians and are strongly encouraged by the US Food and Drug Administration for use in clinical trials.”

REFERENCE

Fournier CN, Bedlack R, Quinn C, et al. Development and validation of the Rasch-Built Overall Amyotrophic Lateral Sclerosis Disability Scale (ROADS). JAMA Neurol. Published online December 30, 2019. doi:10.1001/jamaneurol.2019.4490.

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