Abstract
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 2textendash3 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.
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.
| Original language | English |
|---|---|
| Article number | e064173 |
| Number of pages | 11 |
| Journal | BMJ Open |
| Volume | 12 |
| Issue number | 7 |
| DOIs | |
| Publication status | Published - 7 Jul 2022 |
Bibliographical note
AcknowledgementsThe authors would like to thank all the MND-SMART participants and collaborators involved in the trial. Particular thanks to the trial public patient involvement group who informed trial design and patient facing documents. The authors would like to thank the members of the Independent Data Monitoring Committee: Stephen Wroe (Chair), Camille Caroll, Sue Todd; and the members of the Trial Steering Committee: Helen Ford (Chair), Hadi Manji, James Carpenter, Beverley Gray and former member Alan Gray. Additional thanks to Ronnie Harkess for designing the trial database and Catriona Keerie for statistical analysis. Particularly thanks also to all research nurses and practitioners involved in the trial. MND-SMART is cosponsored by University of Edinburgh and NHS Lothian Academic and Clinical Central Office for Research and Development (ACCORD). The current MND-SMART sites and investigators are; Aberdeen Royal Cornhill Hospital, NHS Grampian, Dr Callum Duncan; Barts Health NHS Trust, Royal London Hospital, Dr Aleksandar Radunovic; Birmingham Queen Elizabeth Hospital, University Hospitals Birmingham NHS Foundation Trust, Dr Venkataramanan Srinivasan; Cambridge University Hospitals NHS Foundation Trust, Dr Rhys Roberts; Cardiff and Value University Health Board, University Hospital Wales, Dr Ken Dawson; Dundee Ninewells Hospital, NHS Tayside, Dr Ian Morrison, Edinburgh Anne Rowling Regenerative Neurology Clinic, NHS Lothian, Dr Suvankar Pal, Royal Devon and Exeter NHS Foundation Trust, Dr Timothy Harrower, Glasgow Queen Elizabeth University Hospital, NHS Greater Glasgow and Clyde, Dr George Gorrie, Inverness Raigmore Hospital, NHS Highland, Dr Javier Carod-Artal, Ipswich Hospital, East Suffolk and North Essex NHS Foundation Trust, Dr Clare Galton, Newcastle MND Care and Research Centre, Newcastle upon Tyne Hospitals NHS Foundation Trust, Dr Timothy Williams; Norfolk and Norwich University Hospitals NHS Foundation Trust, Dr Godwin Mamutse; Salford Royal NHS Foundation Trust, Dr Hisham Hamdalla, University Hospital Southampton NHS Foundation Trust, Dr Ashwin Pinto, St George’s University Hospital NHS Foundation Trust, Dr Pablo Garcia Reitboeck; West Suffolk NHS Foundation Trust, Dr Francesca Crawley
Funding
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. CW, RAP and MiS were supported in this work by NHS Lothian via
Edinburgh Clinical Trials Unit. SCh receives funding from UK Research and
Innovation (Medical Research Council) (DRI-CORE-2017-EDI). The study funders
have no role in study design, data collection, data analysis, data interpretation or
writing of publications. 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. EE is a clinical academic fellow jointly
funded by MND Scotland (MNDS) and the Chief Scientist Office (CSO) (217ARF
R45951). ARM is a Lady Edith Wolfson Clinical Fellow and is jointly funded by the
Medical Research Council (MRC) and the Motor Neurone Disease Association (MR/
R001162/1).