van Eijk, R.P.A., de Jongh, A.D., Nikolakopoulos, S. et al. (4 more authors) (2021) An old friend who has overstayed their welcome : the ALSFRS-R total score as primary endpoint for ALS clinical trials. Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration, 22 (3-4). pp. 300-307. ISSN 2167-8421
Abstract
Objective: The ALSFRS-R is limited by multidimensionality, which originates from the summation of various subscales. This prevents a direct comparison between patients with identical total scores. We aim to evaluate how multidimensionality affects the performance of the ALSFRS-R in clinical trials. Methods: We simulated clinical trial data with different treatment effects for the ALSFRS-R total score and its subscales (i.e. bulbar, fine motor, gross motor and respiratory). We considered scenarios where treatment reduced the rate of ALSFRS-R subscale decline either uniformly (i.e. all subscales respond identically to treatment) or non-uniformly (i.e. subscales respond differently to treatment). Two main analytical strategies were compared: (1) analyzing only the total score or (2) utilizing a subscale-based test (i.e. alternative strategy). For each analytical strategy, we calculated the empirical power and required sample size. Results: Both strategies are valid when there is no treatment benefit and provide adequate control of type 1 error. If all subscales respond identically to treatment, using the total score is the most powerful approach. As the differences in treatment responses between subscales increase, the more the total score becomes affected. For example, to detect a 40% reduction in the bulbar rate of decline with 80% power, the total score requires 1380 patients, whereas this is 336 when using the alternative strategy. Conclusions: Ignoring the multidimensional structure of the ALSFRS-R total score could have negative consequences for ALS clinical trials. We propose determining treatment benefit on a subscale level, prior to stating whether a treatment is generally effective.
Metadata
Item Type: | Article |
---|---|
Authors/Creators: |
|
Copyright, Publisher and Additional Information: | © 2021 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group. This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License (http://creativecommons.org/licenses/by-nc-nd/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited, and is not altered, transformed, or built upon in any way. |
Keywords: | ALSFRS-R; clinical trials; models; multidimensionality; therapy |
Dates: |
|
Institution: | The University of Sheffield |
Academic Units: | The University of Sheffield > Sheffield Teaching Hospitals |
Depositing User: | Symplectic Sheffield |
Date Deposited: | 09 Mar 2021 12:11 |
Last Modified: | 20 Oct 2021 10:34 |
Status: | Published |
Publisher: | Taylor & Francis |
Refereed: | Yes |
Identification Number: | 10.1080/21678421.2021.1879865 |
Related URLs: | |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:171282 |