Benatar, M. orcid.org/0000-0003-4241-5135, McDermott, C. orcid.org/0000-0002-1269-9053, Turner, M.R. orcid.org/0000-0003-0267-3180 et al. (1 more author) (2024) Rethinking phase 2 trials in amyotrophic lateral sclerosis. Brain. awae396. ISSN 0006-8950
Abstract
There is a long history in amyotrophic lateral sclerosis (ALS) of promoting therapies based on Phase 2 data, which then fail in Phase 3 trials. Experience suggests that studies of 6 months in duration are too short, especially with function-based outcome measures. Multiplicity poses a serious threat to data interpretation, and strategies to impute missing data may not be appropriate for ALS where progression is always expected. Emerging surrogate markers of clinical benefit such as reduction of neurofilament light chain levels may be better suited to Phase 2 go/no-go decisions. Over-interpretation of Phase 2 data, and overly optimistic communication of exploratory analyses must be avoided to ensure optimal prioritisation for the investment needed for definitive Phase 3 trials and to minimize the harm of false hope for people living with ALS. Delivering on advances in understanding of the neurobiology of ALS requires urgent attention to Phase 2 design and implementation.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain. This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License (https://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com. |
Keywords: | biomarkers; go/no-go decisions; multiplicity; outcome measures; result communication; trial design |
Dates: |
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Institution: | The University of Sheffield |
Academic Units: | The University of Sheffield > Faculty of Medicine, Dentistry and Health (Sheffield) > School of Medicine and Population Health |
Depositing User: | Symplectic Sheffield |
Date Deposited: | 11 Feb 2025 13:05 |
Last Modified: | 11 Feb 2025 13:05 |
Status: | Published online |
Publisher: | Oxford University Press (OUP) |
Refereed: | Yes |
Identification Number: | 10.1093/brain/awae396 |
Related URLs: | |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:223174 |
Commentary/Response Threads
- Benatar, M., McDermott, C., Turner, M.R. and van Eijk, R.P.A. Rethinking phase 2 trials in amyotrophic lateral sclerosis. (deposited 11 Feb 2025 13:05) [Currently Displayed]