. 2023 Feb 1;13(2):e064169.

doi: 10.1136/bmjopen-2022-064169.

Systematic, comprehensive, evidence-based approach to identify neuroprotective interventions for motor neuron disease: using systematic reviews to inform expert consensus

Charis Wong^{1

2

3

4}, Jenna M Gregory^{2

3

5}, Jing Liao³, Kieren Egan^{3

6}, Hanna M Vesterinen³, Aimal Ahmad Khan⁷, Maarij Anwar⁷, Caitlin Beagan⁷, Fraser S Brown^{1

3}, John Cafferkey⁸, Alessandra Cardinali^{2

3

9}, Jane Yi Chiam⁷, Claire Chiang⁷, Victoria Collins⁷, Joyce Dormido¹⁰, Elizabeth Elliott^{1

2

3}, Peter Foley^{1

3}, Yu Cheng Foo⁷, Lily Fulton-Humble⁵, Angus B Gane¹¹, Stella A Glasmacher^{1

3}, Áine Heffernan⁹, Kiran Jayaprakash^{1

3}, Nimesh Jayasuriya^{8

11}, Amina Kaddouri⁷, Jamie Kiernan⁷, Gavin Langlands¹², D Leighton^{2

3

13}, Jiaming Liu⁷, James Lyon⁸, Arpan R Mehta^{1

2

3

9}, Alyssa Meng¹⁴, Vivienne Nguyen⁷, Na Hyun Park⁸, Suzanne Quigley^{1

3}, Yousuf Rashid⁷, Andrea Salzinger^{3

9}, Bethany Shiell¹¹, Ankur Singh¹¹, Tim Soane¹⁵, Alexandra Thompson¹¹, Olaf Tomala⁷, Fergal M Waldron^{5

16}, Bhuvaneish T Selvaraj^{1

2

3

9}, Jeremy Chataway^{4

17

18}, Robert Swingler², Peter Connick^{1

3}, Suvankar Pal^{1

2

3}, Siddharthan Chandran^{1

2

3

9}, Malcolm Macleod¹⁹

Affiliations

¹ Anne Rowling Regenerative Neurology Clinic, The University of Edinburgh, Edinburgh, UK.
² Euan MacDonald Centre for Motor Neuron Disease Research, The University of Edinburgh, Edinburgh, UK.
³ Centre for Clinical Brain Sciences, The University of Edinburgh, Edinburgh, UK.
⁴ Medical Research Council Clinical Trials Unit at UCL, Institute of Clinical Trials and Methodology, University College London, London, UK.
⁵ Institute of Medical Sciences, University of Aberdeen, Aberdeen, UK.
⁶ Computer and Information Science, University of Strathclyde, Glasgow, UK.
⁷ Edinburgh Medical School, The University of Edinburgh, Edinburgh, UK.
⁸ Royal Infirmary of Edinburgh, NHS Lothian, Edinburgh, UK.
⁹ UK Dementia Research Institute, University of Edinburgh, Edinburgh, UK.
¹⁰ Borders General Hospital, NHS Borders, Melrose, UK.
¹¹ College of Medicine and Veterinary Medicine, The University of Edinburgh, Edinburgh, UK.
¹² Institute of Neurological Sciences, NHS Greater Glasgow and Clyde, Glasgow, UK.
¹³ School of Psychology and Neuroscience, University of Glasgow, Glasgow, UK.
¹⁴ Centre for Discovery Brain Sciences, The University of Edinburgh, Edinburgh, UK.
¹⁵ Neurology Department, NHS Forth Valley, Stirling, UK.
¹⁶ Institute of Evolutionary Biology, The University of Edinburgh, Edinburgh, UK.
¹⁷ Queen Square Multiple Sclerosis Centre, Department of Neuroinflammation, UCL Queen Square Institute of Neurology, London, UK.
¹⁸ University College London Hospitals, Biomedical Research Centre, National Institute for Health Research, London, UK.
¹⁹ Centre for Clinical Brain Sciences, The University of Edinburgh, Edinburgh, UK Malcolm.macleod@ed.ac.uk.

PMID: 36725099
PMCID: PMC9896226
DOI: 10.1136/bmjopen-2022-064169

Systematic, comprehensive, evidence-based approach to identify neuroprotective interventions for motor neuron disease: using systematic reviews to inform expert consensus

Charis Wong et al. BMJ Open. 2023.

. 2023 Feb 1;13(2):e064169.

doi: 10.1136/bmjopen-2022-064169.

Authors

Affiliations

¹ Anne Rowling Regenerative Neurology Clinic, The University of Edinburgh, Edinburgh, UK.
² Euan MacDonald Centre for Motor Neuron Disease Research, The University of Edinburgh, Edinburgh, UK.
³ Centre for Clinical Brain Sciences, The University of Edinburgh, Edinburgh, UK.
⁴ Medical Research Council Clinical Trials Unit at UCL, Institute of Clinical Trials and Methodology, University College London, London, UK.
⁵ Institute of Medical Sciences, University of Aberdeen, Aberdeen, UK.
⁶ Computer and Information Science, University of Strathclyde, Glasgow, UK.
⁷ Edinburgh Medical School, The University of Edinburgh, Edinburgh, UK.
⁸ Royal Infirmary of Edinburgh, NHS Lothian, Edinburgh, UK.
⁹ UK Dementia Research Institute, University of Edinburgh, Edinburgh, UK.
¹⁰ Borders General Hospital, NHS Borders, Melrose, UK.
¹¹ College of Medicine and Veterinary Medicine, The University of Edinburgh, Edinburgh, UK.
¹² Institute of Neurological Sciences, NHS Greater Glasgow and Clyde, Glasgow, UK.
¹³ School of Psychology and Neuroscience, University of Glasgow, Glasgow, UK.
¹⁴ Centre for Discovery Brain Sciences, The University of Edinburgh, Edinburgh, UK.
¹⁵ Neurology Department, NHS Forth Valley, Stirling, UK.
¹⁶ Institute of Evolutionary Biology, The University of Edinburgh, Edinburgh, UK.
¹⁷ Queen Square Multiple Sclerosis Centre, Department of Neuroinflammation, UCL Queen Square Institute of Neurology, London, UK.
¹⁸ University College London Hospitals, Biomedical Research Centre, National Institute for Health Research, London, UK.
¹⁹ Centre for Clinical Brain Sciences, The University of Edinburgh, Edinburgh, UK Malcolm.macleod@ed.ac.uk.

PMID: 36725099
PMCID: PMC9896226
DOI: 10.1136/bmjopen-2022-064169

Abstract

Objectives: Motor neuron disease (MND) is an incurable progressive neurodegenerative disease with limited treatment options. There is a pressing need for innovation in identifying therapies to take to clinical trial. Here, we detail a systematic and structured evidence-based approach to inform consensus decision making to select the first two drugs for evaluation in Motor Neuron Disease-Systematic Multi-arm Adaptive Randomised Trial (MND-SMART: NCT04302870), an adaptive platform trial. We aim to identify and prioritise candidate drugs which have the best available evidence for efficacy, acceptable safety profiles and are feasible for evaluation within the trial protocol.

Methods: We conducted a two-stage systematic review to identify potential neuroprotective interventions. First, we reviewed clinical studies in MND, Alzheimer's disease, Huntington's disease, Parkinson's disease and multiple sclerosis, identifying drugs described in at least one MND publication or publications in two or more other diseases. We scored and ranked drugs using a metric evaluating safety, efficacy, study size and study quality. In stage two, we reviewed efficacy of drugs in MND animal models, multicellular eukaryotic models and human induced pluripotent stem cell (iPSC) studies. An expert panel reviewed candidate drugs over two shortlisting rounds and a final selection round, considering the systematic review findings, late breaking evidence, mechanistic plausibility, safety, tolerability and feasibility of evaluation in MND-SMART.

Results: From the clinical review, we identified 595 interventions. 66 drugs met our drug/disease logic. Of these, 22 drugs with supportive clinical and preclinical evidence were shortlisted at round 1. Seven drugs proceeded to round 2. The panel reached a consensus to evaluate memantine and trazodone as the first two arms of MND-SMART.

Discussion: For future drug selection, we will incorporate automation tools, text-mining and machine learning techniques to the systematic reviews and consider data generated from other domains, including high-throughput phenotypic screening of human iPSCs.

Keywords: Adult neurology; Clinical trials; Motor neurone disease; NEUROLOGY; THERAPEUTICS.

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Conflict of interest statement

Competing interests: In the last 3 years, JC has received support from the Efficacy and Evaluation (EME) Programme, a Medical Research Council (MRC) and National Institute for Health Research (NIHR) partnership and the Health Technology Assessment (HTA) Programme (NIHR), the UK MS Society, the US National MS Society and the Rosetrees Trust. He is supported in part by the NIHR University College London Hospitals (UCLH) Biomedical Research Centre, London, UK. He has been a local principal investigator for a trial in MS funded by the Canadian MS society. A local principal investigator for commercial trials funded by: Actelion, Novartis and Roche; and has taken part in advisory boards/consultancy for Azadyne, Janssen, Merck, NervGen, Novartis and Roche.

Figures

**Figure 1**
Diagram illustrating two-stage systematic review approach to inform identification and selection of putative treatments to take forward to clinical trial. MND, motor neuron disease.

**Figure 2**
Preferred Reporting Items for Systematic Reviews and Meta-Analyses diagram for clinical systematic review. MND, motor neuron disease; MS-SMART, Multiple Sclerosis-Secondary Progressive Multi-Arm Randomisation Trial; Ti/Ab, title/abstract.

See this image and copyright information in PMC

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Systematic, comprehensive, evidence-based approach to identify neuroprotective interventions for motor neuron disease: using systematic reviews to inform expert consensus

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Systematic, comprehensive, evidence-based approach to identify neuroprotective interventions for motor neuron disease: using systematic reviews to inform expert consensus

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Conflict of interest statement

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