TY - JOUR
T1 - Statistical Analysis Plan for the Motor Neuron Disease Systematic Multi-Arm Adaptive Randomised Trial (MND-SMART)
AU - Parker, Richard A
AU - Weir, Christopher J
AU - My Pham, Tra
AU - White, Ian
AU - Stallard, Nigel
AU - Parmer, Mahesh
AU - Swingler, Robert
AU - Dakin, Rachel S.
AU - Pal, Suvankar
AU - Chandran, Siddharthan
N1 - Funding Information:
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.
Funding Information:
MND-SMART is funded by grants from MND Scotland, My Name’5 Doddie Foundation (DOD/14/15), and specific donations to the Euan MacDonald Centre. CJW and RAP were supported in this work by NHS Lothian via Edinburgh Clinical Trials Unit. IW and TMP were supported by the Medical Research Council [grant number MC_UU_00004/07]. SC 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 . For the purpose of open access, the author has applied a Creative Commons Attribution (CC BY) licence to any Author Accepted Manuscript version arising from this submission.
Publisher Copyright:
© 2023, The Author(s).
PY - 2023/1/16
Y1 - 2023/1/16
N2 - 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.
AB - 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.
KW - Amyotrophic Lateral Sclerosis/diagnosis
KW - Humans
KW - Motor Neuron Disease/diagnosis
KW - Therapies, Investigational
KW - Transcranial Magnetic Stimulation
KW - Treatment Outcome
U2 - 10.1186/s13063-022-07007-z
DO - 10.1186/s13063-022-07007-z
M3 - Article
C2 - 36647114
SN - 1745-6215
VL - 24
SP - 29
JO - Trials
JF - Trials
IS - 1
M1 - 29
ER -