{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T08:55:13Z","timestamp":1790326513217,"version":"4.1.0"},"reference-count":50,"publisher":"BMJ","issue":"2","license":[{"start":{"date-parts":[[2023,2,1]],"date-time":"2023-02-01T00:00:00Z","timestamp":1675209600000},"content-version":"unspecified","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Rowling Fellowship","award":["N\/A"],"award-info":[{"award-number":["N\/A"]}]},{"DOI":"10.13039\/501100000320","name":"Alzheimer's Society","doi-asserted-by":"publisher","award":["N\/A"],"award-info":[{"award-number":["N\/A"]}],"id":[{"id":"10.13039\/501100000320","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Marie Sklodowska-Curie","award":["N\/A"],"award-info":[{"award-number":["N\/A"]}]},{"DOI":"10.13039\/501100000265","name":"Medical Research Council","doi-asserted-by":"publisher","award":["MR\/R001162\/1"],"award-info":[{"award-number":["MR\/R001162\/1"]}],"id":[{"id":"10.13039\/501100000265","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Alzheimer's Research UK","award":["N\/A"],"award-info":[{"award-number":["N\/A"]}]},{"DOI":"10.13039\/501100000406","name":"Motor Neurone Disease Association","doi-asserted-by":"publisher","award":["MR\/R001162\/1"],"award-info":[{"award-number":["MR\/R001162\/1"]}],"id":[{"id":"10.13039\/501100000406","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Doddie Foundation","award":["DOD\/14\/15"],"award-info":[{"award-number":["DOD\/14\/15"]}]},{"DOI":"10.13039\/501100000589","name":"Chief Scientist Office","doi-asserted-by":"publisher","award":["217ARF R45951"],"award-info":[{"award-number":["217ARF R45951"]}],"id":[{"id":"10.13039\/501100000589","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100017510","name":"UK DRI Ltd","doi-asserted-by":"crossref","award":["N\/A"],"award-info":[{"award-number":["N\/A"]}],"id":[{"id":"10.13039\/501100017510","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100011776","name":"MND Scotland","doi-asserted-by":"publisher","award":["N\/A"],"award-info":[{"award-number":["N\/A"]}],"id":[{"id":"10.13039\/100011776","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["BMJ Open"],"accepted":{"date-parts":[[2023,1,10]]},"published-print":{"date-parts":[[2023,2]]},"abstract":"<jats:sec>\n                  <jats:title>Objectives<\/jats:title>\n                  <jats:p>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: <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"clintrialgov\" xlink:href=\"NCT04302870\">NCT04302870<\/jats:ext-link>), 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.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>We conducted a two-stage systematic review to identify potential neuroprotective interventions. First, we reviewed clinical studies in MND, Alzheimer\u2019s disease, Huntington\u2019s disease, Parkinson\u2019s 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.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>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.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Discussion<\/jats:title>\n                  <jats:p>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.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1136\/bmjopen-2022-064169","type":"journal-article","created":{"date-parts":[[2023,2,1]],"date-time":"2023-02-01T11:15:50Z","timestamp":1675250150000},"page":"e064169","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":17,"title":["Systematic, comprehensive, evidence-based approach to identify neuroprotective interventions for motor neuron disease: using systematic reviews to inform expert consensus"],"prefix":"10.1136","volume":"13","clinical-trial-number":[{"clinical-trial-number":"nct04302870","registry":"10.18810\/clinical-trials-gov"},{"clinical-trial-number":"nct04302870","registry":"10.18810\/clinical-trials-gov"}],"author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8488-037X","authenticated-orcid":false,"given":"Charis","family":"Wong","sequence":"first","affiliation":[{"name":"Anne Rowling Regenerative Neurology Clinic, The University of Edinburgh, Edinburgh, UK"},{"name":"Euan MacDonald Centre for Motor Neuron Disease Research, The University of Edinburgh, Edinburgh, UK"},{"name":"Centre for Clinical Brain Sciences, The University of Edinburgh, Edinburgh, UK"},{"name":"Medical Research Council Clinical Trials Unit at UCL, Institute of Clinical Trials and Methodology, University College London, London, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jenna M","family":"Gregory","sequence":"additional","affiliation":[{"name":"Euan MacDonald Centre for Motor Neuron Disease Research, The University of Edinburgh, Edinburgh, UK"},{"name":"Centre for Clinical Brain Sciences, The University of Edinburgh, Edinburgh, UK"},{"name":"Institute of Medical Sciences, University of Aberdeen, Aberdeen, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Liao","sequence":"additional","affiliation":[{"name":"Centre for Clinical Brain Sciences, The University of Edinburgh, Edinburgh, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1639-4281","authenticated-orcid":false,"given":"Kieren","family":"Egan","sequence":"additional","affiliation":[{"name":"Centre for Clinical Brain Sciences, The University of Edinburgh, Edinburgh, UK"},{"name":"Computer and Information Science, University of Strathclyde, Glasgow, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hanna M","family":"Vesterinen","sequence":"additional","affiliation":[{"name":"Centre 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