278570 20250613100542.0 10.1001/jamaneurol.2025.0241 doi pmid:40126464 pmid pmc:PMC11933997 pmc 2168-6149 ISSN 0003-9942 ISSN 0375-8540 ISSN 1538-3687 ISSN 2168-6157 ISSN 2330-9644 ISSN altmetric:175443380 altmetric DZNE-2025-00603 English 610 Shefner, Jeremy M 0 Reldesemtiv in Amyotrophic Lateral Sclerosis: Results From the COURAGE-ALS Randomized Clinical Trial. Chicago, Ill. 2025 American Medical Association article DRIVER Output Types/Journal article DataCite Journal Article journal journal PUB:(DE-HGF)16 1748428005_4359 PUB:(DE-HGF) ARTICLE BibTeX JOURNAL_ARTICLE ORCID Journal Article 0 EndNote Treatment options for amyotrophic lateral sclerosis (ALS) remain suboptimal. Results from a phase 2 study of reldesemtiv in ALS suggested that it may slow disease progression.To assess the effect of reldesemtiv vs placebo on functional outcomes in ALS.A Study to Evaluate the Efficacy and Safety of Reldesemtiv in Patients With Amyotrophic Lateral Sclerosis (COURAGE-ALS) was a double-blind, placebo-controlled phase 3 randomized clinical trial conducted at 83 ALS centers in 16 countries from August 2021 to July 2023. The first 24-week period was placebo controlled vs reldesemtiv. All participants received reldesemtiv during the second 24-week period with a 4-week follow-up. Two interim analyses were planned, the first for futility and the second for futility and possible resizing. This was a hybrid decentralized trial with approximately half the trial visits performed remotely and the remaining visits in the clinic. Eligible participants met criteria for definite, probable, or possible ALS with lower motor neuron signs by modified El Escorial Criteria, ALS symptoms for 24 months or less, ALS Functional Rating Scale-Revised (ALSFRS-R) total score of 44 or less, and forced vital capacity of greater than or equal to 65% of predicted.Oral reldesemtiv, 300 mg, or placebo twice daily.The primary end point was change in ALSFRS-R total score from baseline to week 24.Of the 696 participants screened, 207 were screen failures. A total of 486 participants (mean [SD] age, 59.4 [10.9] years; 309 male [63.6%]) were randomized to reldesemtiv (n = 325) or placebo (n = 161); 3 randomized patients were not dosed. The second interim analysis at 24 weeks after randomization included 256 participants. The data monitoring committee recommended that the trial should end due to futility, and the sponsor agreed. The mean (SE) group difference in the ALSFRS-R score from baseline to week 24 was -1.1 (0.53; 95% CI, -2.17 to -0.08; P = .04, favoring placebo). Given excess missing data from early termination, the combined assessment assumed greater importance; it, too, failed to show a benefit from treatment with reldesemtiv (win probability was 0.44 for reldesemtiv and 0.49 for placebo, with a win ratio of 0.91; 95% CI of win ratio, 0.77-1.10; P = .11).This randomized clinical trial failed to demonstrate efficacy for reldesemtiv in slowing functional decline in ALS.ClinicalTrials.gov Identifier: NCT04944784. 353 - Clinical and Health Care Research (POF4-353) G:(DE-HGF)POF4-353 POF4-353 POF IV 0 Dataset connected to CrossRef, PubMed, , Journals: pub.dzne.de CK-2017357 NLM Chemicals Oxadiazoles NLM Chemicals reldesemtiv 4S0HBYW6QE NLM Chemicals Pyrazines NLM Chemicals Pyrimidines NLM Chemicals Imidazoles NLM Chemicals Pyrroles NLM Chemicals Pyridines NLM Chemicals Humans MeSH Amyotrophic Lateral Sclerosis: drug therapy MeSH Male MeSH Female MeSH Middle Aged MeSH Double-Blind Method MeSH Aged MeSH Treatment Outcome MeSH Oxadiazoles: therapeutic use MeSH Disease Progression MeSH Pyrazines MeSH Pyrimidines MeSH Imidazoles MeSH Pyrroles MeSH Pyridines MeSH Cudkowicz, Merit E 1 Genge, Angela 2 Hardiman, Orla 3 Al-Chalabi, Ammar 4 Andrews, Jinsy A 5 Chio, Adriano 6 Corcia, Philippe 7 Couratier, Philippe 8 de Carvalho, Mamede 9 Heiman-Patterson, Terry 10 Henderson, Robert D 11 Ingre, Caroline 12 Johnston, Wendy 13 Ludolph, Albert P:(DE-2719)2812633 14 dzne Maragakis, Nicholas J 15 Miller, Timothy M 16 Mora, Jesus S 17 Petri, Susanne 18 Simmons, Zachary 19 van den Berg, Leonard H 20 Zinman, Lorne 21 Kupfer, Stuart 22 Malik, Fady I 23 Meng, Lisa 24 Simkins, Tyrell J 25 Wei, Jenny 26 Wolff, Andrew A 27 Rudnicki, Stacy A 28 Group, COURAGE-ALS Study 29 Collaboration Author Kiernan, Matthew C 30 Contributor Schultz, David 31 Contributor Needham, Merrilee 32 Contributor Vucic, Steve 33 Contributor Matte, Genevieve 34 Contributor O'Connell, Colleen M 35 Contributor Korngut, Lawrence 36 Contributor Dionne, Annie 37 Contributor Turnbull, John 38 Contributor Schellenberg, Kerri 39 Contributor Shoesmith, Christen 40 Contributor Zwicker, Jocelyn 41 Contributor Salveson, Lisette 42 Contributor Bernard, Emilien 43 Contributor Salachas, Froncois 44 Contributor Danel, Veronique 45 Contributor Attarian, Shahram 46 Contributor Soriani, Marie-Helene 47 Contributor Rodiger, Annekathrin 48 Contributor Großkreutz, Julian 49 Contributor Weydt, Patrick P:(DE-2719)9001116 50 Contributor dzne Meyer, Thomas 51 Contributor Silani, Vincenzo 52 Contributor Cerri, Frederica 53 Contributor Calvo, Andrea 54 Contributor Lunetta, Christian 55 Contributor Kusma-Kozakiewicz, Magdelena 56 Contributor Vazquez-Costa, Jaun Francisco 57 Contributor Povedano, Monica 58 Contributor Nilsson, Christer 59 Contributor Weber, Markus 60 Contributor Young, Caroline 61 Contributor Bradshaw, Deborah 62 Contributor Paganoni, Sabrina 63 Contributor Statland, Jeffrey 64 Contributor Grogan, James 65 Contributor Rothstein, Jeffrey 66 Contributor Oskarrson, Bjorn 67 Contributor Vu, Tuen 68 Contributor Olney, Nicholas 69 Contributor Lewis, Richared 70 Contributor Katz, Jonnathon 71 Contributor Quan, Dianna 72 Contributor Mccluskey, Leonard H 73 Contributor Goyal, Namita 74 Contributor Pavlakis, Pantellis 75 Contributor Swenson, Andrea 76 Contributor Bayat, Elham 77 Contributor Goutman, Stephen 78 Contributor Fee, Dominic 79 Contributor Creigh, Peter 80 Contributor Peltier, Amanda 81 Contributor Heitzman, Daragh 82 Contributor Patee, Gary 83 Contributor Bodkin, Cynthia 84 Contributor Owegi, Margeret 85 Contributor Arcilla-London, Ximena 86 Contributor Chahin, Nizar 87 Contributor Ladha, Shafeeq 88 Contributor So, Yuen 89 Contributor Rezania, Kourosh 90 Contributor Tandan, Rup 91 Contributor Kuenzler, Rebecca 92 Contributor Gwathmey, Kelly 93 Contributor Pulley, Michael 94 Contributor 10.1001/jamaneurol.2025.0241 Vol. 82, no. 5, p. 477 - 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