{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T00:04:02Z","timestamp":1789085042597,"version":"build-2803163510"},"reference-count":42,"publisher":"Oxford University Press (OUP)","issue":"4","license":[{"start":{"date-parts":[[2024,12,6]],"date-time":"2024-12-06T00:00:00Z","timestamp":1733443200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000092","name":"National Institutes of Health","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000092","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,4,3]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>There is a long history in amyotrophic lateral sclerosis (ALS) of promoting therapies based on phase 2 data, which then fail in phase 3 trials. Experience suggests that studies of 6 months in duration are too short, especially with function-based outcome measures. Multiplicity poses a serious threat to data interpretation, and strategies to impute missing data may not be appropriate for ALS where progression is always expected.<\/jats:p>\n               <jats:p>Emerging surrogate markers of clinical benefit such as reduction of neurofilament light chain levels may be better suited to phase 2 go\/no-go decisions. Over-interpretation of phase 2 data, and overly optimistic communication of exploratory analyses must be avoided to ensure optimal prioritization for the investment needed for definitive phase 3 trials and to minimize the harm of false hope for people living with ALS. Delivering on advances in understanding of the neurobiology of ALS requires urgent attention to phase 2 design and implementation.<\/jats:p>","DOI":"10.1093\/brain\/awae396","type":"journal-article","created":{"date-parts":[[2024,12,10]],"date-time":"2024-12-10T21:48:30Z","timestamp":1733867310000},"page":"1106-1111","source":"Crossref","is-referenced-by-count":13,"title":["Rethinking phase 2 trials in amyotrophic lateral sclerosis"],"prefix":"10.1093","volume":"148","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4241-5135","authenticated-orcid":false,"given":"Michael","family":"Benatar","sequence":"first","affiliation":[{"name":"Department of Neurology, University of Miami Miller School of Medicine , Miami, FL 33136 ,","place":["USA"]},{"name":"ALS Center, University of Miami , Miami, FL 33136 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher","family":"McDermott","sequence":"additional","affiliation":[{"name":"Division of Neuroscience, Sheffield Institute for Translational Neuroscience, University of Sheffield , Sheffield S11 9EJ ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0267-3180","authenticated-orcid":false,"given":"Martin R","family":"Turner","sequence":"additional","affiliation":[{"name":"Nuffield Department of Clinical Neurosciences, Oxford University , Oxford OX3 9DU ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7132-5967","authenticated-orcid":false,"given":"Ruben P A","family":"van Eijk","sequence":"additional","affiliation":[{"name":"Department of Neurology, UMC Utrecht Brain Center, University Medical Center Utrecht , Utrecht 3584CX ,","place":["The Netherlands"]},{"name":"Biostatistics & Research Support, Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht , Utrecht 3584CX ,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2024,12,6]]},"reference":[{"key":"2025040316595730500_awae396-B1","doi-asserted-by":"crossref","first-page":"104","DOI":"10.1038\/s41582-020-00434-z","article-title":"Improving clinical trial outcomes in amyotrophic lateral sclerosis","volume":"17","author":"Kiernan","year":"2021","journal-title":"Nat Rev Neurol."},{"key":"2025040316595730500_awae396-B2","doi-asserted-by":"crossref","first-page":"1127","DOI":"10.1016\/S1474-4422(14)70129-2","article-title":"Clinical trials in amyotrophic lateral sclerosis: Why so many negative trials and how can trials be improved?","volume":"13","author":"Mitsumoto","year":"2014","journal-title":"Lancet Neurol"},{"key":"2025040316595730500_awae396-B3","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1002\/ana.26285","article-title":"Adaptive platform trials to transform amyotrophic lateral sclerosis therapy development","volume":"91","author":"Paganoni","year":"2022","journal-title":"Ann Neurol."},{"key":"2025040316595730500_awae396-B4","doi-asserted-by":"crossref","first-page":"2711","DOI":"10.1093\/brain\/awac394","article-title":"Neurofilament light chain in drug development for amyotrophic lateral sclerosis: A critical appraisal","volume":"146","author":"Benatar","year":"2023","journal-title":"Brain."},{"key":"2025040316595730500_awae396-B5","doi-asserted-by":"crossref","first-page":"1099","DOI":"10.1056\/NEJMoa2204705","article-title":"Trial of antisense oligonucleotide tofersen for SOD1 ALS","volume":"387","author":"Miller","year":"2022","journal-title":"N Engl J Med."},{"key":"2025040316595730500_awae396-B6","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1002\/ana.26860","article-title":"Biomarker qualification for neurofilament light chain in amyotrophic lateral sclerosis: Theory and practice","volume":"95","author":"Benatar","year":"2024","journal-title":"Ann Neurol."},{"key":"2025040316595730500_awae396-B7","doi-asserted-by":"crossref","first-page":"1425","DOI":"10.1016\/S0140-6736(96)91680-3","article-title":"Dose-ranging study of riluzole in amyotrophic lateral sclerosis","volume":"347","author":"Lacomblez","year":"1996","journal-title":"Lancet"},{"key":"2025040316595730500_awae396-B8","doi-asserted-by":"crossref","first-page":"88","DOI":"10.1212\/01.wnl.0000191326.40772.62","article-title":"Pentoxifylline in ALS: A double-blind, randomized, multicenter, placebo-controlled trial","volume":"66","author":"Meininger","year":"2006","journal-title":"Neurology"},{"key":"2025040316595730500_awae396-B9","doi-asserted-by":"crossref","first-page":"407","DOI":"10.1002\/pst.1931","article-title":"Statistical considerations in a delayed-start design to demonstrate disease modification effect in neurodegenerative disorders","volume":"18","author":"Wang","year":"2019","journal-title":"Pharm Stat"},{"key":"2025040316595730500_awae396-B10","doi-asserted-by":"crossref","first-page":"2475","DOI":"10.1177\/0962280218780856","article-title":"Causal inference for long-term survival in randomised trials with treatment switching: Should re-censoring be applied when estimating counterfactual survival times?","volume":"28","author":"Latimer","year":"2019","journal-title":"Stat Methods Med Res."},{"key":"2025040316595730500_awae396-B11","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1016\/S0022-510X(99)00210-5","article-title":"The ALSFRS-R: A revised ALS functional rating scale that incorporates assessments of respiratory function. BDNF ALS Study Group (Phase III)","volume":"169","author":"Cedarbaum","year":"1999","journal-title":"J Neurol Sci."},{"key":"2025040316595730500_awae396-B12","doi-asserted-by":"crossref","first-page":"311","DOI":"10.1080\/21678421.2022.2153607","article-title":"Clinically meaningful change: Evaluation of the Rasch-built Overall Amyotrophic Lateral Sclerosis Disability Scale (ROADS) and the ALSFRS-R","volume":"24","author":"Fournier","year":"2023","journal-title":"Amyotroph Lateral Scler Frontotemporal Degener"},{"key":"2025040316595730500_awae396-B13","doi-asserted-by":"crossref","first-page":"919","DOI":"10.1056\/NEJMoa1916945","article-title":"Trial of sodium phenylbutyrate-taurursodiol for amyotrophic lateral sclerosis","volume":"383","author":"Paganoni","year":"2020","journal-title":"N Engl J Med."},{"key":"2025040316595730500_awae396-B14","doi-asserted-by":"crossref","first-page":"528","DOI":"10.1212\/WNL.0000000000012545","article-title":"Innovating clinical trials for amyotrophic lateral sclerosis: Challenging the established order","volume":"97","author":"van Eijk","year":"2021","journal-title":"Neurology"},{"key":"2025040316595730500_awae396-B15","doi-asserted-by":"crossref","first-page":"105323","DOI":"10.1016\/j.ebiom.2024.105323","article-title":"Prognostic clinical and biological markers for amyotrophic lateral sclerosis disease progression: Validation and implications for clinical trial design and analysis","volume":"108","author":"Benatar","year":"2024","journal-title":"EBioMedicine"},{"key":"2025040316595730500_awae396-B16","article-title":"Evidence that minocycline treatment confounds the interpretation of neurofilament as a biomarker","author":"Gentile","journal-title":"medRxiv"},{"key":"2025040316595730500_awae396-B17","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1080\/21678421.2019.1632346","article-title":"Masitinib as an add-on therapy to riluzole in patients with amyotrophic lateral sclerosis: A randomized clinical trial","volume":"21","author":"Mora","year":"2020","journal-title":"Amyotroph Lateral Scler Frontotemporal Degener"},{"key":"2025040316595730500_awae396-B18","doi-asserted-by":"crossref","first-page":"505","DOI":"10.1016\/S1474-4422(17)30115-1","article-title":"Safety and efficacy of edaravone in well defined patients with amyotrophic lateral sclerosis: A randomised, double-blind, placebo-controlled trial","volume":"16","author":"Writing Group; Edaravone (MCI-186) ALS 19 Study Group","year":"2017","journal-title":"Lancet Neurol"},{"key":"2025040316595730500_awae396-B19","doi-asserted-by":"crossref","first-page":"218","DOI":"10.1016\/j.cct.2011.09.013","article-title":"Modeling drop-outs in amyotrophic lateral sclerosis","volume":"33","author":"Messina","year":"2012","journal-title":"Contemp Clin Trials."},{"key":"2025040316595730500_awae396-B20","author":"Combined FDA and Applicant Briefing Document"},{"key":"2025040316595730500_awae396-B21","author":"PharmAust"},{"key":"2025040316595730500_awae396-B22","author":"Clene Nanomedicine"},{"key":"2025040316595730500_awae396-B23","author":"Prilenia"},{"key":"2025040316595730500_awae396-B24","doi-asserted-by":"crossref","first-page":"657","DOI":"10.1007\/s40272-022-00538-7","article-title":"Innovations in clinical development in rare diseases of children and adults: Small populations and\/or small patients","volume":"24","author":"Beckman","year":"2022","journal-title":"Paediatr Drugs"},{"key":"2025040316595730500_awae396-B25","doi-asserted-by":"crossref","first-page":"1652","DOI":"10.1038\/nm.2579","article-title":"The effects of dexpramipexole (KNS-760704) in individuals with amyotrophic lateral sclerosis","volume":"17","author":"Cudkowicz","year":"2011","journal-title":"Nat Med."},{"key":"2025040316595730500_awae396-B26","doi-asserted-by":"crossref","first-page":"1059","DOI":"10.1016\/S1474-4422(13)70221-7","article-title":"Dexpramipexole versus placebo for patients with amyotrophic lateral sclerosis (EMPOWER): A randomised, double-blind, phase 3 trial","volume":"12","author":"Cudkowicz","year":"2013","journal-title":"Lancet Neurol"},{"key":"2025040316595730500_awae396-B27","doi-asserted-by":"crossref","first-page":"523","DOI":"10.1080\/21678421.2023.2216223","article-title":"COURAGE-ALS: A randomized, double-blind phase 3 study designed to improve participant experience and increase the probability of success","volume":"24","author":"Shefner","year":"2023","journal-title":"Amyotroph Lateral Scler Frontotemporal Degener"},{"key":"2025040316595730500_awae396-B28","doi-asserted-by":"crossref","first-page":"287","DOI":"10.1080\/21678421.2020.1822410","article-title":"A phase 2, double-blind, randomized, dose-ranging trial of Reldesemtiv in patients with ALS","volume":"22","author":"Shefner","year":"2021","journal-title":"Amyotroph Lateral Scler Frontotemporal Degener"},{"key":"2025040316595730500_awae396-B29","doi-asserted-by":"crossref","first-page":"e2294","DOI":"10.1212\/WNL.0000000000008620","article-title":"NurOwn, phase 2, randomized, clinical trial in patients with ALS: Safety, clinical, and biomarker results","volume":"93","author":"Berry","year":"2019","journal-title":"Neurology"},{"key":"2025040316595730500_awae396-B30","doi-asserted-by":"crossref","first-page":"291","DOI":"10.1002\/mus.27472","article-title":"A randomized placebo-controlled phase 3 study of mesenchymal stem cells induced to secrete high levels of neurotrophic factors in amyotrophic lateral sclerosis","volume":"65","author":"Cudkowicz","year":"2022","journal-title":"Muscle Nerve."},{"key":"2025040316595730500_awae396-B31","author":"Ferrer"},{"key":"2025040316595730500_awae396-B32","author":"Amylyx"},{"key":"2025040316595730500_awae396-B33","author":"TUDCA ALS"},{"key":"2025040316595730500_awae396-B34","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1111\/ene.12664","article-title":"Tauroursodeoxycholic acid in the treatment of patients with amyotrophic lateral sclerosis","volume":"23","author":"Elia","year":"2016","journal-title":"Eur J Neurol"},{"key":"2025040316595730500_awae396-B35","doi-asserted-by":"crossref","first-page":"247\u2013","DOI":"10.1080\/17482960600881870","article-title":"Investigation of the therapeutic effects of edaravone, a free radical scavenger, on amyotrophic lateral sclerosis (Phase II study)","volume":"7","author":"Yoshino","year":"2006","journal-title":"Amyotroph Lateral Scler"},{"key":"2025040316595730500_awae396-B36","author":"Food and Drug Administration Center for Drug Evaluation and Research"},{"key":"2025040316595730500_awae396-B37","doi-asserted-by":"crossref","first-page":"737","DOI":"10.1002\/ana.26371","article-title":"Regulatory approval in ALS; when is a single study enough?","volume":"91","author":"Cudkowicz","year":"2022","journal-title":"Ann Neurol."},{"key":"2025040316595730500_awae396-B38","doi-asserted-by":"crossref","first-page":"232","DOI":"10.1002\/mus.28169","article-title":"Multicenter expanded access program for access to investigational products for amyotrophic lateral sclerosis","volume":"70","author":"Neel","year":"2024","journal-title":"Muscle Nerve."},{"key":"2025040316595730500_awae396-B39","volume-title":"Evaluating Inclusion and Exclusion Criteria in Clinical Trials","author":"Food and Drug Administration"},{"key":"2025040316595730500_awae396-B40","doi-asserted-by":"crossref","first-page":"e1610","DOI":"10.1212\/WNL.0000000000007242","article-title":"Revised Airlie House consensus guidelines for design and implementation of ALS clinical trials","volume":"92","author":"van den Berg","year":"2019","journal-title":"Neurology"},{"key":"2025040316595730500_awae396-B41","doi-asserted-by":"crossref","first-page":"e064173","DOI":"10.1136\/bmjopen-2022-064173","article-title":"Motor Neuron Disease Systematic Multi-Arm Adaptive Randomised Trial (MND-SMART): A multi-arm, multi-stage, adaptive, platform, phase III randomised, double-blind, placebo-controlled trial of repurposed drugs in motor neuron disease","volume":"12","author":"Wong","year":"2022","journal-title":"BMJ Open"},{"key":"2025040316595730500_awae396-B42","doi-asserted-by":"crossref","first-page":"423","DOI":"10.1093\/jmp\/jhz010","article-title":"Is there a problem with false hope?","volume":"44","author":"Musschenga","year":"2019","journal-title":"J Med Philos"}],"container-title":["Brain"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/brain\/advance-article-pdf\/doi\/10.1093\/brain\/awae396\/60965123\/awae396.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/brain\/article-pdf\/148\/4\/1106\/60965123\/awae396.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/brain\/article-pdf\/148\/4\/1106\/60965123\/awae396.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,4,3]],"date-time":"2025-04-03T22:48:59Z","timestamp":1743720539000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/brain\/article\/148\/4\/1106\/7917655"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,12,6]]},"references-count":42,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2024,12,6]]},"published-print":{"date-parts":[[2025,4,3]]}},"URL":"https:\/\/doi.org\/10.1093\/brain\/awae396","relation":{},"ISSN":["0006-8950","1460-2156"],"issn-type":[{"value":"0006-8950","type":"print"},{"value":"1460-2156","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2025,4]]},"published":{"date-parts":[[2024,12,6]]}}}