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@ARTICLE{Shefner:278570,
      author       = {Shefner, Jeremy M and Cudkowicz, Merit E and Genge, Angela
                      and Hardiman, Orla and Al-Chalabi, Ammar and Andrews, Jinsy
                      A and Chio, Adriano and Corcia, Philippe and Couratier,
                      Philippe and de Carvalho, Mamede and Heiman-Patterson, Terry
                      and Henderson, Robert D and Ingre, Caroline and Johnston,
                      Wendy and Ludolph, Albert and Maragakis, Nicholas J and
                      Miller, Timothy M and Mora, Jesus S and Petri, Susanne and
                      Simmons, Zachary and van den Berg, Leonard H and Zinman,
                      Lorne and Kupfer, Stuart and Malik, Fady I and Meng, Lisa
                      and Simkins, Tyrell J and Wei, Jenny and Wolff, Andrew A and
                      Rudnicki, Stacy A},
      collaboration = {Group, COURAGE-ALS Study},
      othercontributors = {Kiernan, Matthew C and Schultz, David and Needham, Merrilee
                          and Vucic, Steve and Matte, Genevieve and O'Connell, Colleen
                          M and Korngut, Lawrence and Dionne, Annie and Turnbull, John
                          and Schellenberg, Kerri and Shoesmith, Christen and Zwicker,
                          Jocelyn and Salveson, Lisette and Bernard, Emilien and
                          Salachas, Froncois and Danel, Veronique and Attarian,
                          Shahram and Soriani, Marie-Helene and Rodiger, Annekathrin
                          and Großkreutz, Julian and Weydt, Patrick and Meyer, Thomas
                          and Silani, Vincenzo and Cerri, Frederica and Calvo, Andrea
                          and Lunetta, Christian and Kusma-Kozakiewicz, Magdelena and
                          Vazquez-Costa, Jaun Francisco and Povedano, Monica and
                          Nilsson, Christer and Weber, Markus and Young, Caroline and
                          Bradshaw, Deborah and Paganoni, Sabrina and Statland,
                          Jeffrey and Grogan, James and Rothstein, Jeffrey and
                          Oskarrson, Bjorn and Vu, Tuen and Olney, Nicholas and Lewis,
                          Richared and Katz, Jonnathon and Quan, Dianna and Mccluskey,
                          Leonard H and Goyal, Namita and Pavlakis, Pantellis and
                          Swenson, Andrea and Bayat, Elham and Goutman, Stephen and
                          Fee, Dominic and Creigh, Peter and Peltier, Amanda and
                          Heitzman, Daragh and Patee, Gary and Bodkin, Cynthia and
                          Owegi, Margeret and Arcilla-London, Ximena and Chahin, Nizar
                          and Ladha, Shafeeq and So, Yuen and Rezania, Kourosh and
                          Tandan, Rup and Kuenzler, Rebecca and Gwathmey, Kelly and
                          Pulley, Michael},
      title        = {{R}eldesemtiv in {A}myotrophic {L}ateral {S}clerosis:
                      {R}esults {F}rom the {COURAGE}-{ALS} {R}andomized {C}linical
                      {T}rial.},
      journal      = {JAMA neurology},
      volume       = {82},
      number       = {5},
      issn         = {2168-6149},
      address      = {Chicago, Ill.},
      publisher    = {American Medical Association},
      reportid     = {DZNE-2025-00603},
      pages        = {477 - 485},
      year         = {2025},
      abstract     = {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.},
      keywords     = {Humans / Amyotrophic Lateral Sclerosis: drug therapy / Male
                      / Female / Middle Aged / Double-Blind Method / Aged /
                      Treatment Outcome / Oxadiazoles: therapeutic use / Disease
                      Progression / Pyrazines / Pyrimidines / Imidazoles /
                      Pyrroles / Pyridines / CK-2017357 (NLM Chemicals) /
                      Oxadiazoles (NLM Chemicals) / reldesemtiv (NLM Chemicals) /
                      Pyrazines (NLM Chemicals) / Pyrimidines (NLM Chemicals) /
                      Imidazoles (NLM Chemicals) / Pyrroles (NLM Chemicals) /
                      Pyridines (NLM Chemicals)},
      cin          = {Clinical Study Center (Ulm)},
      ddc          = {610},
      cid          = {I:(DE-2719)5000077},
      pnm          = {353 - Clinical and Health Care Research (POF4-353)},
      pid          = {G:(DE-HGF)POF4-353},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:40126464},
      pmc          = {pmc:PMC11933997},
      doi          = {10.1001/jamaneurol.2025.0241},
      url          = {https://pub.dzne.de/record/278570},
}