Jeremy M Shefner1, Jinsy A Andrews2, Angela Genge3, Carlayne Jackson4, Noah Lechtzin5, Timothy M Miller6, Bettina M Cockroft7, Lisa Meng7, Jenny Wei7, Andrew A Wolff7, Fady I Malik7, Cynthia Bodkin8, Benjamin R Brooks9, James Caress10, Annie Dionne11, Dominic Fee12, Stephen A Goutman13, Namita A Goyal14, Orla Hardiman15, Ghazala Hayat16, Terry Heiman-Patterson17, Daragh Heitzman18, Robert D Henderson19, Wendy Johnston20, Chafic Karam21, Matthew C Kiernan22, Stephen J Kolb23, Lawrence Korngut24, Shafeeq Ladha25, Genevieve Matte26, Jesus S Mora27, Merrilee Needham28, Bjorn Oskarsson29, Gary L Pattee30, Erik P Pioro31, Michael Pulley32, Dianna Quan33, Kourosh Rezania34, Kerri L Schellenberg35, David Schultz36, Christen Shoesmith37, Zachary Simmons38, Jeffrey Statland39, Shumaila Sultan40, Andrea Swenson41, Leonard H Van Den Berg42, Tuan Vu43, Steve Vucic44, Michael Weiss45, Ashley Whyte-Rayson46, James Wymer47, Lorne Zinman48, Stacy A Rudnicki7. 1. Barrow Neurological Institute, Phoenix, AZ, USA. 2. The Eleanor and Lou Gehrig ALS Center, The Neurological Institute, New York, NY, USA. 3. Montreal Neurological Institute, Montreal, QC, Canada. 4. University of Texas Health Science Center, San Antonio, TX, USA. 5. Johns Hopkins School of Medicine, Baltimore, MD, USA. 6. Washington University School of Medicine, St. Louis, MO, USA. 7. Cytokinetics, Inc, South San Francisco, CA, USA. 8. Indiana University School of Medicine, Indianapolis, IN, USA. 9. Atrium Health Neurosciences Institute-Carolinas Neuromuscular/ALS MDA Care Center, Charlotte, NC, USA. 10. Wake Forest Health Sciences, Winston-Salem, NC, USA. 11. CHU de Québec, Université Laval, Quebec, Canada. 12. Medical College of Wisconsin, Milwaukee, WI, USA. 13. University of Michigan, Ann Arbor, MI, USA. 14. The ALS & Neuromuscular Center, UCI Health, Orange, CA, USA. 15. Trinity College, Beaumont Hospital, Dublin, Ireland. 16. St. Louis University, St. Louis, MO, USA. 17. Lewis Katz School of Medicine, Temple University, Philadelphia, PA, USA. 18. Texas Neurology, Dallas, TX, USA. 19. Royal Brisbane and Women's Hospital, Herston, Australia. 20. University of Alberta, Edmonton, AB, Canada. 21. Oregon Health & Science University, Portland, OR, USA. 22. Royal Prince Alfred Hospital, University of Sydney, Sydney, Australia. 23. Wexner Medical Center, Ohio State University, Columbus, OH, USA. 24. University of Calgary, Calgary, AB, Canada. 25. St. Joseph's Hospital and Medical Center, Neurological Institute, AZ, USA Barrow Phoenix. 26. Centre Hospitalier de l'Université de Montréal, Montreal, QC, Canada. 27. Hospital San Rafael, Madrid, Germany. 28. Perron Institute, Department of Neurology, Fiona Stanley Hospital, The University of Notre Dame Australia, Murdoch University, Perth, Australia. 29. Mayo Clinic Florida, Jacksonville, FL, USA. 30. Neurology Associates, Lincoln, NE, USA. 31. Cleveland Clinic, Cleveland, OH, USA. 32. University of Florida, Jacksonville, FL, USA. 33. University of Colorado Denver, Aurora, CO, USA. 34. University of Chicago Medical Center, Chicago, IL, USA. 35. University of Saskatchewan, Saskatoon, SK, Canada. 36. Flinders Medical Centre, Bedford Park, Australia. 37. London Health Sciences Centre, London, ON, Canada. 38. Penn State Hershey Medical Center, Hershey, PA, USA. 39. University of Kansas Medical Center, Kansas City, KS, USA. 40. West Virginia University, Morgantown, WV, USA. 41. University of Iowa, Iowa City, IA, USA. 42. Department of Neurology, UMC Utrecht Brain Center, University Medical Center Utrecht, Utrecht, The Netherlands. 43. University of South Florida, Tampa, FL, USA. 44. Westmead Hospital, Sydney, Australia. 45. University of Washington, Seattle, WA, USA. 46. Duke University School of Medicine, Durham, NC, USA. 47. University of Florida, Gainesville, FL, USA. 48. ALS/Neuromuscular Clinic Sunnybrook Health Sciences Centre, University of Toronto, Toronto, ON, Canada.
Abstract
OBJECTIVE: To evaluate safety, dose response, and preliminary efficacy of reldesemtiv over 12 weeks in patients with amyotrophic lateral sclerosis (ALS). Methods: Patients (≤2 years since diagnosis) with slow upright vital capacity (SVC) of ≥60% were randomized 1:1:1:1 to reldesemtiv 150, 300, or 450 mg twice daily (bid) or placebo; active treatment was 12 weeks with 4-week follow-up. Primary endpoint was change in percent predicted SVC at 12 weeks; secondary measures included ALS Functional Rating Scale-Revised (ALSFRS-R) and muscle strength mega-score. Results:Patients (N = 458) were enrolled; 85% completed 12-week treatment. The primary analysis failed to reach statistical significance (p = 0.11); secondary endpoints showed no statistically significant effects (ALSFRS-R, p = 0.09; muscle strength mega-score, p = 0.31). Post hoc analyses pooling all active reldesemtiv-treated patients compared against placebo showed trends toward benefit in all endpoints (progression rate for SVC, ALSFRS-R, and muscle strength mega-score (nominal p values of 0.10, 0.01 and 0.20 respectively)). Reldesemtiv was well tolerated, with nausea and fatigue being the most common side effects. A dose-dependent decrease in estimated glomerular filtration rate was noted, and transaminaseelevations were seen in approximately 5% of patients. Both hepatic and renal abnormalities trended toward resolution after study drug discontinuation. Conclusions: Although the primary efficacy analysis did not demonstrate statistical significance, there were trends favoring reldesemtiv for all three endpoints, with effect sizes generally regarded as clinically important. Tolerability was good; modest hepatic and renal abnormalities were reversible. The impact of reldesemtiv on patients with ALS should be assessed in a pivotal Phase 3 trial. (ClinicalTrials.gov Identifier: NCT03160898).
RCT Entities:
OBJECTIVE: To evaluate safety, dose response, and preliminary efficacy of reldesemtiv over 12 weeks in patients with amyotrophic lateral sclerosis (ALS). Methods:Patients (≤2 years since diagnosis) with slow upright vital capacity (SVC) of ≥60% were randomized 1:1:1:1 to reldesemtiv 150, 300, or 450 mg twice daily (bid) or placebo; active treatment was 12 weeks with 4-week follow-up. Primary endpoint was change in percent predicted SVC at 12 weeks; secondary measures included ALS Functional Rating Scale-Revised (ALSFRS-R) and muscle strength mega-score. Results:Patients (N = 458) were enrolled; 85% completed 12-week treatment. The primary analysis failed to reach statistical significance (p = 0.11); secondary endpoints showed no statistically significant effects (ALSFRS-R, p = 0.09; muscle strength mega-score, p = 0.31). Post hoc analyses pooling all active reldesemtiv-treated patients compared against placebo showed trends toward benefit in all endpoints (progression rate for SVC, ALSFRS-R, and muscle strength mega-score (nominal p values of 0.10, 0.01 and 0.20 respectively)). Reldesemtiv was well tolerated, with nausea and fatigue being the most common side effects. A dose-dependent decrease in estimated glomerular filtration rate was noted, and transaminase elevations were seen in approximately 5% of patients. Both hepatic and renal abnormalities trended toward resolution after study drug discontinuation. Conclusions: Although the primary efficacy analysis did not demonstrate statistical significance, there were trends favoring reldesemtiv for all three endpoints, with effect sizes generally regarded as clinically important. Tolerability was good; modest hepatic and renal abnormalities were reversible. The impact of reldesemtiv on patients with ALS should be assessed in a pivotal Phase 3 trial. (ClinicalTrials.gov Identifier: NCT03160898).
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