BMJ Open (Feb 2023)
Systematic, comprehensive, evidence-based approach to identify neuroprotective interventions for motor neuron disease: using systematic reviews to inform expert consensus
- Jeremy Chataway,
- Tim Soane,
- Suvankar Pal,
- Malcolm Macleod,
- Jing Liao,
- Fraser S Brown,
- Charis Wong,
- Ankur Singh,
- Gavin Langlands,
- Elizabeth Elliott,
- Jenna M Gregory,
- Siddharthan Chandran,
- Robert Swingler,
- Peter Connick,
- Suzanne Quigley,
- Peter Foley,
- Alexandra Thompson,
- Stella A Glasmacher,
- D Leighton,
- Arpan R Mehta,
- Aimal Ahmad Khan,
- John Cafferkey,
- Kieren Egan,
- Hanna M Vesterinen,
- Maarij Anwar,
- Caitlin Beagan,
- Alessandra Cardinali,
- Jane Yi Chiam,
- Claire Chiang,
- Victoria Collins,
- Joyce Dormido,
- Yu Cheng Foo,
- Lily Fulton-Humble,
- Angus B Gane,
- Áine Heffernan,
- Kiran Jayaprakash,
- Nimesh Jayasuriya,
- Amina Kaddouri,
- Jamie Kiernan,
- Jiaming Liu,
- James Lyon,
- Alyssa Meng,
- Vivienne Nguyen,
- Na Hyun Park,
- Yousuf Rashid,
- Andrea Salzinger,
- Bethany Shiell,
- Olaf Tomala,
- Fergal M Waldron,
- Bhuvaneish T Selvaraj
Affiliations
- Jeremy Chataway
- Medical Research Council Clinical Trials Unit at UCL, Institute of Clinical Trials and Methodology, University College London, London, UK
- Tim Soane
- Neurology Department, NHS Forth Valley, Stirling, UK
- Suvankar Pal
- Anne Rowling Regenerative Neurology Clinic, The University of Edinburgh, Edinburgh, UK
- Malcolm Macleod
- 7 Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, UK
- Jing Liao
- Department of Nephrology A, Longhua Hospital Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Fraser S Brown
- Anne Rowling Regenerative Neurology Clinic, The University of Edinburgh, Edinburgh, UK
- Charis Wong
- Anne Rowling Regenerative Neurology Clinic, The University of Edinburgh, Edinburgh, UK
- Ankur Singh
- Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, University of Melbourne, Melbourne, Victoria, Australia
- Gavin Langlands
- Institute of Neurological Sciences, NHS Greater Glasgow and Clyde, Glasgow, UK
- Elizabeth Elliott
- Anne Rowling Regenerative Neurology Clinic, The University of Edinburgh, Edinburgh, UK
- Jenna M Gregory
- Euan MacDonald Centre for Motor Neuron Disease Research, The University of Edinburgh, Edinburgh, UK
- Siddharthan Chandran
- Edinburgh Medical School & Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, UK
- Robert Swingler
- Euan MacDonald Centre for Motor Neuron Disease Research, The University of Edinburgh, Edinburgh, UK
- Peter Connick
- Anne Rowling Regenerative Neurology Clinic, The University of Edinburgh, Edinburgh, UK
- Suzanne Quigley
- Anne Rowling Regenerative Neurology Clinic, The University of Edinburgh, Edinburgh, UK
- Peter Foley
- 5The University of Melbourne, St Vincent’s Hospital Melbourne and Probity Medical Research, Skin and Cancer Foundation Inc, Melbourne, Australia
- Alexandra Thompson
- College of Medicine and Veterinary Medicine, The University of Edinburgh, Edinburgh, UK
- Stella A Glasmacher
- Anne Rowling Regenerative Neurology Clinic, The University of Edinburgh, Edinburgh, UK
- D Leighton
- Euan MacDonald Centre for Motor Neuron Disease Research, The University of Edinburgh, Edinburgh, UK
- Arpan R Mehta
- 1 National Hospital for Neurology & Neurosurgery, University College London Hospitals NHS Foundation Trust, London, UK
- Aimal Ahmad Khan
- Edinburgh Medical School, The University of Edinburgh, Edinburgh, UK
- John Cafferkey
- Royal Infirmary of Edinburgh, NHS Lothian, Edinburgh, UK
- Kieren Egan
- Centre for Clinical Brain Sciences, The University of Edinburgh, Edinburgh, UK
- Hanna M Vesterinen
- Centre for Clinical Brain Sciences, The University of Edinburgh, Edinburgh, UK
- Maarij Anwar
- Edinburgh Medical School, The University of Edinburgh, Edinburgh, UK
- Caitlin Beagan
- Edinburgh Medical School, The University of Edinburgh, Edinburgh, UK
- Alessandra Cardinali
- Euan MacDonald Centre for Motor Neuron Disease Research, The University of Edinburgh, Edinburgh, UK
- Jane Yi Chiam
- Edinburgh Medical School, The University of Edinburgh, Edinburgh, UK
- Claire Chiang
- Edinburgh Medical School, The University of Edinburgh, Edinburgh, UK
- Victoria Collins
- Edinburgh Medical School, The University of Edinburgh, Edinburgh, UK
- Joyce Dormido
- Borders General Hospital, NHS Borders, Melrose, UK
- Yu Cheng Foo
- Edinburgh Medical School, The University of Edinburgh, Edinburgh, UK
- Lily Fulton-Humble
- Institute of Medical Sciences, University of Aberdeen, Aberdeen, UK
- Angus B Gane
- College of Medicine and Veterinary Medicine, The University of Edinburgh, Edinburgh, UK
- Áine Heffernan
- UK Dementia Research Institute, University of Edinburgh, Edinburgh, UK
- Kiran Jayaprakash
- Anne Rowling Regenerative Neurology Clinic, The University of Edinburgh, Edinburgh, UK
- Nimesh Jayasuriya
- Royal Infirmary of Edinburgh, NHS Lothian, Edinburgh, UK
- Amina Kaddouri
- Edinburgh Medical School, The University of Edinburgh, Edinburgh, UK
- Jamie Kiernan
- Edinburgh Medical School, The University of Edinburgh, Edinburgh, UK
- Jiaming Liu
- Edinburgh Medical School, The University of Edinburgh, Edinburgh, UK
- James Lyon
- Royal Infirmary of Edinburgh, NHS Lothian, Edinburgh, UK
- Alyssa Meng
- Centre for Discovery Brain Sciences, The University of Edinburgh, Edinburgh, UK
- Vivienne Nguyen
- Edinburgh Medical School, The University of Edinburgh, Edinburgh, UK
- Na Hyun Park
- Royal Infirmary of Edinburgh, NHS Lothian, Edinburgh, UK
- Yousuf Rashid
- Edinburgh Medical School, The University of Edinburgh, Edinburgh, UK
- Andrea Salzinger
- Centre for Clinical Brain Sciences, The University of Edinburgh, Edinburgh, UK
- Bethany Shiell
- College of Medicine and Veterinary Medicine, The University of Edinburgh, Edinburgh, UK
- Olaf Tomala
- Edinburgh Medical School, The University of Edinburgh, Edinburgh, UK
- Fergal M Waldron
- Institute of Medical Sciences, University of Aberdeen, Aberdeen, UK
- Bhuvaneish T Selvaraj
- Anne Rowling Regenerative Neurology Clinic, The University of Edinburgh, Edinburgh, UK
- DOI
- https://doi.org/10.1136/bmjopen-2022-064169
- Journal volume & issue
-
Vol. 13,
no. 2
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.
