Motor Neuron Disease Systematic Multi-Arm Adaptive Randomised Trial (MND-SMART): a multi-arm, multi-stage, adaptive, platform, phase III randomised, double-blind, placebo-controlled trial of repurposed drugs in motor neuron disease
Introduction Motor neuron disease (MND) is a rapidly fatal neurodegenerative disease. Despite decades of research and clinical trials there remains no cure and only one globally approved drug, riluzole, which prolongs survival by 2–3 months. Recent improved mechanistic understanding of MND heralds a...
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BMJ Publishing Group
2022-07-01
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| Online Access: | https://bmjopen.bmj.com/content/12/7/e064173.full |
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| author | Jeremy Chataway Suvankar Pal Charis Wong Elizabeth Elliott Jenna M Gregory Siddharthan Chandran Judith Newton Shuna Colville Maria Stavrou Christopher J Weir Nigel Stallard Malcolm R Macleod Michelle Steven Richard Anthony Parker Arpan R Mehta Robert J Swingler Mahesh K B Parmar Rachel S Dakin Jill Williamson |
| author_facet | Jeremy Chataway Suvankar Pal Charis Wong Elizabeth Elliott Jenna M Gregory Siddharthan Chandran Judith Newton Shuna Colville Maria Stavrou Christopher J Weir Nigel Stallard Malcolm R Macleod Michelle Steven Richard Anthony Parker Arpan R Mehta Robert J Swingler Mahesh K B Parmar Rachel S Dakin Jill Williamson |
| author_sort | Jeremy Chataway |
| collection | DOAJ |
| description | Introduction Motor neuron disease (MND) is a rapidly fatal neurodegenerative disease. Despite decades of research and clinical trials there remains no cure and only one globally approved drug, riluzole, which prolongs survival by 2–3 months. Recent improved mechanistic understanding of MND heralds a new translational era with many potential targets being identified that are ripe for clinical trials. Motor Neuron Disease Systematic Multi-Arm Adaptive Randomised Trial (MND-SMART) aims to evaluate the efficacy of drugs efficiently and definitively in a multi-arm, multi-stage, adaptive trial. The first two drugs selected for evaluation in MND-SMART are trazodone and memantine.Methods and analysis Initially, up to 531 participants (177/arm) will be randomised 1:1:1 to oral liquid trazodone, memantine and placebo. The coprimary outcome measures are the Amyotrophic Lateral Sclerosis Functional Rating Scale Revised (ALSFRS-R) and survival. Comparisons will be conducted in four stages. The decision to continue randomising to arms after each stage will be made by the Trial Steering Committee who receive recommendations from the Independent Data Monitoring Committee. The primary analysis of ALSFRS-R will be conducted when 150 participants/arm, excluding long survivors, have completed 18 months of treatment; if positive the survival effect will be inferentially analysed when 113 deaths have been observed in the placebo group. The trial design ensures that other promising drugs can be added for evaluation in planned trial adaptations. Using this novel trial design reduces time, cost and number of participants required to definitively (phase III) evaluate drugs and reduces exposure of participants to potentially ineffective treatments.Ethics and dissemination MND-SMART was approved by the West of Scotland Research Ethics Committee on 2 October 2019. (REC reference: 19/WS/0123) Results of the study will be submitted for publication in a peer-reviewed journal and a summary provided to participants.Trial registration numbers European Clinical Trials Registry (2019-000099-41); NCT04302870. |
| format | Article |
| id | doaj-art-5e965243774d4c02bc888f34d9e8e037 |
| institution | Kabale University |
| issn | 2044-6055 |
| language | English |
| publishDate | 2022-07-01 |
| publisher | BMJ Publishing Group |
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| series | BMJ Open |
| spelling | doaj-art-5e965243774d4c02bc888f34d9e8e0372025-01-31T11:55:09ZengBMJ Publishing GroupBMJ Open2044-60552022-07-0112710.1136/bmjopen-2022-064173Motor Neuron Disease Systematic Multi-Arm Adaptive Randomised Trial (MND-SMART): a multi-arm, multi-stage, adaptive, platform, phase III randomised, double-blind, placebo-controlled trial of repurposed drugs in motor neuron diseaseJeremy Chataway0Suvankar Pal1Charis Wong2Elizabeth Elliott3Jenna M Gregory4Siddharthan Chandran5Judith Newton6Shuna Colville7Maria Stavrou8Christopher J Weir9Nigel Stallard10Malcolm R Macleod11Michelle Steven12Richard Anthony Parker13Arpan R Mehta14Robert J Swingler15Mahesh K B Parmar16Rachel S Dakin17Jill Williamson182 University College London Hospitals, Biomedical Research Centre, National Institute for Health and Care Research, London, UK2 Euan MacDonald Centre for Motor Neuron Disease Research, University of Edinburgh, Edinburgh, UKCentre of Clinical Brain Sciences, University of Edinburgh, Edinburgh, UK21 UCL Anthropology, University College London, London, UK6 Institute of Medical Sciences, University of Aberdeen, Aberdeen, UK5 UK Dementia Research Institute Edinburgh, University of Edinburgh, Edinburgh, UK1 Centre of Clinical Brain Sciences, University of Edinburgh, Edinburgh, UK1 Centre of Clinical Brain Sciences, University of Edinburgh, Edinburgh, UK2 Euan MacDonald Centre for Motor Neuron Disease Research, University of Edinburgh, Edinburgh, UK4 Edinburgh Clinical Trials Unit, The University of Edinburgh, Usher Institute of Population Health Sciences and Informatics, Edinburgh, UK11 Statistics and Epidemiology, Division of Health Sciences, Warwick Medical School, University of Warwick, Coventry, UK1 Centre of Clinical Brain Sciences, University of Edinburgh, Edinburgh, UK4 Edinburgh Clinical Trials Unit, Usher Institute of Population Health Sciences and Informatics, University of Edinburgh, Edinburgh, UK4 Edinburgh Clinical Trials Unit, Usher Institute of Population Health Sciences and Informatics, University of Edinburgh, Edinburgh, UK1 Centre of Clinical Brain Sciences, University of Edinburgh, Edinburgh, UK2 Euan MacDonald Centre for Motor Neuron Disease Research, University of Edinburgh, Edinburgh, UK9 Medical Research Council Clinical Trials Unit at UCL, Institute of Clinical Trials and Methodology, University College London, London, UK1 Centre of Clinical Brain Sciences, University of Edinburgh, Edinburgh, UK1 Centre of Clinical Brain Sciences, University of Edinburgh, Edinburgh, UKIntroduction Motor neuron disease (MND) is a rapidly fatal neurodegenerative disease. Despite decades of research and clinical trials there remains no cure and only one globally approved drug, riluzole, which prolongs survival by 2–3 months. Recent improved mechanistic understanding of MND heralds a new translational era with many potential targets being identified that are ripe for clinical trials. Motor Neuron Disease Systematic Multi-Arm Adaptive Randomised Trial (MND-SMART) aims to evaluate the efficacy of drugs efficiently and definitively in a multi-arm, multi-stage, adaptive trial. The first two drugs selected for evaluation in MND-SMART are trazodone and memantine.Methods and analysis Initially, up to 531 participants (177/arm) will be randomised 1:1:1 to oral liquid trazodone, memantine and placebo. The coprimary outcome measures are the Amyotrophic Lateral Sclerosis Functional Rating Scale Revised (ALSFRS-R) and survival. Comparisons will be conducted in four stages. The decision to continue randomising to arms after each stage will be made by the Trial Steering Committee who receive recommendations from the Independent Data Monitoring Committee. The primary analysis of ALSFRS-R will be conducted when 150 participants/arm, excluding long survivors, have completed 18 months of treatment; if positive the survival effect will be inferentially analysed when 113 deaths have been observed in the placebo group. The trial design ensures that other promising drugs can be added for evaluation in planned trial adaptations. Using this novel trial design reduces time, cost and number of participants required to definitively (phase III) evaluate drugs and reduces exposure of participants to potentially ineffective treatments.Ethics and dissemination MND-SMART was approved by the West of Scotland Research Ethics Committee on 2 October 2019. (REC reference: 19/WS/0123) Results of the study will be submitted for publication in a peer-reviewed journal and a summary provided to participants.Trial registration numbers European Clinical Trials Registry (2019-000099-41); NCT04302870.https://bmjopen.bmj.com/content/12/7/e064173.full |
| spellingShingle | Jeremy Chataway Suvankar Pal Charis Wong Elizabeth Elliott Jenna M Gregory Siddharthan Chandran Judith Newton Shuna Colville Maria Stavrou Christopher J Weir Nigel Stallard Malcolm R Macleod Michelle Steven Richard Anthony Parker Arpan R Mehta Robert J Swingler Mahesh K B Parmar Rachel S Dakin Jill Williamson Motor Neuron Disease Systematic Multi-Arm Adaptive Randomised Trial (MND-SMART): a multi-arm, multi-stage, adaptive, platform, phase III randomised, double-blind, placebo-controlled trial of repurposed drugs in motor neuron disease BMJ Open |
| title | Motor Neuron Disease Systematic Multi-Arm Adaptive Randomised Trial (MND-SMART): a multi-arm, multi-stage, adaptive, platform, phase III randomised, double-blind, placebo-controlled trial of repurposed drugs in motor neuron disease |
| title_full | Motor Neuron Disease Systematic Multi-Arm Adaptive Randomised Trial (MND-SMART): a multi-arm, multi-stage, adaptive, platform, phase III randomised, double-blind, placebo-controlled trial of repurposed drugs in motor neuron disease |
| title_fullStr | Motor Neuron Disease Systematic Multi-Arm Adaptive Randomised Trial (MND-SMART): a multi-arm, multi-stage, adaptive, platform, phase III randomised, double-blind, placebo-controlled trial of repurposed drugs in motor neuron disease |
| title_full_unstemmed | Motor Neuron Disease Systematic Multi-Arm Adaptive Randomised Trial (MND-SMART): a multi-arm, multi-stage, adaptive, platform, phase III randomised, double-blind, placebo-controlled trial of repurposed drugs in motor neuron disease |
| title_short | Motor Neuron Disease Systematic Multi-Arm Adaptive Randomised Trial (MND-SMART): a multi-arm, multi-stage, adaptive, platform, phase III randomised, double-blind, placebo-controlled trial of repurposed drugs in motor neuron disease |
| title_sort | motor neuron disease systematic multi arm adaptive randomised trial mnd smart a multi arm multi stage adaptive platform phase iii randomised double blind placebo controlled trial of repurposed drugs in motor neuron disease |
| url | https://bmjopen.bmj.com/content/12/7/e064173.full |
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