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Clinical trials in amyotrophic lateral sclerosis (ALS) aim to identify treatments that can slow functional decline or prolong survival time. In the absence of objective biomarkers, questionnaires, such as the ALS Functional Rating Scale (ALSFRS), are used to evaluate treatment effects in clinical trials.1 Although questionnaires are easy to administer and hold prognostic value, they may miss important treatment clues if questions are not selected appropriately. For example, the ALSFRS was originally designed as a 10-item functional score across bulbar, fine and gross motor and respiratory domains. The ALSFRS was revised in 1999 by adding two respiratory items.1 Whether this revision resulted in an improved endpoint is debatable, as the questionnaire’s construct validity may have worsened, resulting in weaker correlations with respiratory function and survival.1 2 Nevertheless, the ultimate, real-world application of the ALSFRS is to serve as efficacy endpoint. Solely assessing validity may not suffice to evaluate whether a revision, or new questionnaire, is more suitable as endpoint. We propose, therefore, to evaluate longitudinal biomarkers and questionnaires, not only in terms of validity, but also in terms of trial design. Ultimately, this strategy may aid the selection of optimal efficacy endpoints for ALS or other neurodegenerative disease clinical trials.
Individual participant data
We used 12-month data from PRO-ACT to compare the ALSFRS and the ALSFRS-Revised (ALSFRS-R). PRO-ACT contains anonymised data from 23 clinical trials, conducted since 1990.3 Only data from trials that included the ALSFRS-R were used. To make the PRO-ACT data set comparable to common trial populations, we excluded patients with a symptom duration >36 months, vital capacity <60% or who were over 80 years of age.
ALSFRS and ALSFRS-R total scores were calculated as …
Contributors ADdJ, RPAvE and LHvdB designed the study. ADdJ and RPAvE analysed the data and drafted the manuscript. RPAvE and LHvdB critically reviewed the manuscript.
Funding This study was supported by the Netherlands ALS Foundation (Project TRICALS-Reactive 2018-66).
Competing interests ADdJ and RPAvE report no disclosures. LHvdB reports grants from Netherlands ALS Foundation, the Netherlands Organization for Health Research and Development (Vici scheme), the Netherlands Organization for Health Research and Development (SOPHIA, STRENGTH, ALS-CarE project), funded through the EU Joint Programme – Neurodegenerative Disease Research, JPND), served on the Scientific Advisory Board of Biogen, Cytokinetics, Prinses Beatrix SpierFonds and the Latran Foundation.
Provenance and peer review Not commissioned; externally peer reviewed.
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