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

Charis Wong, Jenna M Gregory, Jing Liao, Kieren Egan, Hanna M Vesterinen, Aimal Ahmad khan, Maarij Anwar, Caitlin Beagan, Fraser S Brown, John Cafferkey, Alessandra Cardinali, Jane Yi Chiam, Claire Chiang, Victoria Collins, Joyce Dormido, Elizabeth Elliott, Peter Foley, Yu Cheng Foo, Lily Fulton-Humble, Angus B GaneStella A Glasmacher, Áine Heffernan, Kiran Jayaprakash, Nimesh Jayasuriya, Amina Kaddouri, Jamie Kiernan, Gavin Langlands, D Leighton, Jiaming Liu, James Lyon, Arpan R Mehta, Alyssa Meng, Vivienne Nguyen, Na Hyun Park, Suzanne Quigley, Yousuf Rashid, Andrea Salzinger, Bethany Shiell, Ankur Singh, Tim Soane, Alexandra Thompson, Olaf Tomala, Fergal M Waldron, Bhuvaneish T Selvaraj, Jeremy Chataway, Robert Swingler, Peter Connick, Suvankar Pal, Siddharthan Chandran, Malcolm Macleod

Research output: Contribution to journalArticlepeer-review

Abstract / Description of output

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.
Original languageEnglish
Pages (from-to)e064169
JournalBMJ Open
Issue number2
Early online date1 Feb 2023
Publication statusE-pub ahead of print - 1 Feb 2023


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