TY - JOUR
T1 - Systematic, comprehensive, evidence-based approach to identify neuroprotective interventions for motor neuron disease
T2 - using systematic reviews to inform expert consensus
AU - Wong, Charis
AU - Gregory, Jenna M
AU - Liao, Jing
AU - Egan, Kieren
AU - Vesterinen, Hanna M
AU - Ahmad Khan, Aimal
AU - Anwar, Maarij
AU - Beagan, Caitlin
AU - Brown, Fraser S
AU - Cafferkey, John
AU - Cardinali, Alessandra
AU - Chiam, Jane Yi
AU - Chiang, Claire
AU - Collins, Victoria
AU - Dormido, Joyce
AU - Elliott, Elizabeth
AU - Foley, Peter
AU - Foo, Yu Cheng
AU - Fulton-Humble, Lily
AU - Gane, Angus B
AU - Glasmacher, Stella A
AU - Heffernan, Áine
AU - Jayaprakash, Kiran
AU - Jayasuriya, Nimesh
AU - Kaddouri, Amina
AU - Kiernan, Jamie
AU - Langlands, Gavin
AU - Leighton, D
AU - Liu, Jiaming
AU - Lyon, James
AU - Mehta, Arpan R
AU - Meng, Alyssa
AU - Nguyen, Vivienne
AU - Park, Na Hyun
AU - Quigley, Suzanne
AU - Rashid, Yousuf
AU - Salzinger, Andrea
AU - Shiell, Bethany
AU - Singh, Ankur
AU - Soane, Tim
AU - Thompson, Alexandra
AU - Tomala, Olaf
AU - Waldron, Fergal M
AU - Selvaraj, Bhuvaneish T
AU - Chataway, Jeremy
AU - Swingler, Robert
AU - Connick, Peter
AU - Pal, Suvankar
AU - Chandran, Siddharthan
AU - Macleod, Malcolm
PY - 2023/2/1
Y1 - 2023/2/1
N2 - 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.
AB - 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.
KW - neurology
KW - motor neuron disease
KW - neuroprotective interventions
KW - systematic reviews
U2 - 10.1136/bmjopen-2022-064169
DO - 10.1136/bmjopen-2022-064169
M3 - Article
SN - 2044-6055
VL - 13
JO - BMJ open
JF - BMJ open
IS - 2
M1 - e064169
ER -
