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Statistical analysis plan for the motor neuron disease systematic multi-arm adaptive randomised trial (MND-SMART)
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Parker, Richard A., Weir, Christopher J., Pham, Tra My, White, Ian R., Stallard, Nigel, Parmar, Mahesh K. B., Swingler, Robert J., Dakin, Rachel S., Pal, Suvankar and Chandran, Siddharthan (2023) Statistical analysis plan for the motor neuron disease systematic multi-arm adaptive randomised trial (MND-SMART). Trials, 24 (1). 29. doi:10.1186/s13063-022-07007-z ISSN 1745-6215.
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Official URL: https://doi.org/10.1186/s13063-022-07007-z
Abstract
Background: MND-SMART is a platform, multi-arm, multi-stage, multi-centre, randomised controlled trial recruiting people with motor neuron disease. Initially, the treatments memantine and trazodone will each be compared against placebo, but other investigational treatments will be introduced into the trial later. The co-primary outcomes are the Amyotrophic Lateral Sclerosis Functional Rating Scale Revised (ALS-FRS-R) functional outcome, which is assessed longitudinally, and overall survival. Methods: Initially in MND-SMART, participants are randomised 1:1:1 via a minimisation algorithm to receive placebo or one of the two investigational treatments with up to 531 to be randomised in total. The comparisons between each research arm and placebo will be conducted in four stages, with the opportunity to cease further randomisations to poorly performing research arms at the end of stages 1 or 2. The final ALS-FRS-R analysis will be at the end of stage 3 and final survival analysis at the end of stage 4. The estimands for the co-primary outcomes are described in detail. The primary analysis of ALS-FRS-R at the end of stages 1 to 3 will involve fitting a normal linear mixed model to the data to calculate a mean difference in rate of ALS-FRS-R change between each research treatment and placebo. The pairwise type 1 error rate will be controlled, because each treatment comparison will generate its own distinct and separate interpretation. This publication is based on a formal statistical analysis plan document that was finalised and signed on 18 May 2022. Discussion: In developing the statistical analysis plan, we had to carefully consider several issues such as multiple testing, estimand specification, interim analyses, and statistical analysis of the repeated measurements of ALS-FRS-R. This analysis plan attempts to balance multiple factors, including minimisation of bias, maximising power and precision, and deriving clinically interpretable summaries of treatment effects. Trial registration: EudraCT Number, 2019–000099-41. Registered 2 October 2019, https://www.clinicaltrialsregister.eu/ctr-search/search?query=mnd-smart ClinicalTrials.gov, NCT04302870. Registered 10 March 2020.
Item Type: | Journal Article | ||||||
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Divisions: | Faculty of Science, Engineering and Medicine > Medicine > Warwick Medical School > Health Sciences Faculty of Science, Engineering and Medicine > Medicine > Warwick Medical School > Health Sciences > Statistics and Epidemiology Faculty of Science, Engineering and Medicine > Medicine > Warwick Medical School |
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SWORD Depositor: | Library Publications Router | ||||||
Journal or Publication Title: | Trials | ||||||
Publisher: | BioMed Central | ||||||
ISSN: | 1745-6215 | ||||||
Official Date: | 16 January 2023 | ||||||
Dates: |
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Volume: | 24 | ||||||
Number: | 1 | ||||||
Article Number: | 29 | ||||||
DOI: | 10.1186/s13063-022-07007-z | ||||||
Status: | Peer Reviewed | ||||||
Publication Status: | Published | ||||||
Reuse Statement (publisher, data, author rights): | ** From Springer Nature via Jisc Publications Router ** History: received 20-05-2022; accepted 12-12-2022; registration 13-12-2022; pub-electronic 16-01-2023; online 16-01-2023; collection 12-2023. ** Licence for this article: http://creativecommons.org/licenses/by/4.0/ ** Acknowledgements: Acknowledgements: The authors would like to thank the trial public patient involvement group and wider ACORD collaboration (A Collaboration Of groups developing, Running and reporting multi-arm multi-stage trials in neurodegenerative Diseases) who helped provide input into trial design. Particular thanks to John Norrie for providing statistical advice, Ronnie Harkess for developing and managing the trial database, and Catriona Keerie for preparing statistical reports for Independent Data Monitoring Committee meetings. MND-SMART is co-sponsored by University of Edinburgh and NHS Lothian Academic and Clinical Central Office for Research and Development (ACCORD). This work is supported by the UK Dementia Research Institute which receives its funding from UK DRI Ltd, funded by the UK Medical Research Council, Alzheimer’s Society and Alzheimer’s Research UK. | ||||||
Access rights to Published version: | Open Access (Creative Commons) | ||||||
Date of first compliant deposit: | 21 February 2023 | ||||||
Date of first compliant Open Access: | 21 February 2023 | ||||||
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