Sabrina Paganoni1, Eric A Macklin1, Suzanne Hendrix1, James D Berry1, Michael A Elliott1, Samuel Maiser1, Chafic Karam1, James B Caress1, Margaret A Owegi1, Adam Quick1, James Wymer1, Stephen A Goutman1, Daragh Heitzman1, Terry Heiman-Patterson1, Carlayne E Jackson1, Colin Quinn1, Jeffrey D Rothstein1, Edward J Kasarskis1, Jonathan Katz1, Liberty Jenkins1, Shafeeq Ladha1, Timothy M Miller1, Stephen N Scelsa1, Tuan H Vu1, Christina N Fournier1, Jonathan D Glass1, Kristin M Johnson1, Andrea Swenson1, Namita A Goyal1, Gary L Pattee1, Patricia L Andres1, Suma Babu1, Marianne Chase1, Derek Dagostino1, Samuel P Dickson1, Noel Ellison1, Meghan Hall1, Kent Hendrix1, Gale Kittle1, Michelle McGovern1, Joseph Ostrow1, Lindsay Pothier1, Rebecca Randall1, Jeremy M Shefner1, Alexander V Sherman1, Eric Tustison1, Prasha Vigneswaran1, Jason Walker1, Hong Yu1, James Chan1, Janet Wittes1, Joshua Cohen1, Justin Klee1, Kent Leslie1, Rudolph E Tanzi1, Walter Gilbert1, Patrick D Yeramian1, David Schoenfeld1, Merit E Cudkowicz1. 1. From the Sean M. Healey and AMG Center for ALS and the Neurological Clinical Research Institute, Massachusetts General Hospital, Harvard Medical School (S.P., J.D.B., S.B., M.C., D.D., M.M., J.O., L.P., A.V.S., E.T., P.V., J. Walker, H.Y., R.E.T., M.E.C.), the Biostatistics Center, Massachusetts General Hospital, Harvard Medical School (E.A.M., J. Chan, D.S.), and Spaulding Rehabilitation Hospital, Harvard Medical School (S.P.), Boston, the University of Massachusetts Memorial Medical Center, Worcester (M.A.O.), and Amylyx Pharmaceuticals (J. Cohen, J. Klee, K.L., P.D.Y.) and Harvard University (W.G.), Cambridge - all in Massachusetts; Pentara, Millcreek, UT (S.H., S.P.D., N.E., K.H.); Swedish Neuroscience Institute, Seattle (M.A.E.); Hennepin Healthcare, Minneapolis (S.M.); the Department of Neurology, Oregon Health and Science University, Portland (C.K.); the Department of Neurology, Wake Forest School of Medicine, Winston-Salem, NC (J.B.C.); the Department of Neurology, Ohio State University College of Medicine, Columbus (A.Q.); the Department of Neurology, University of Florida College of Medicine, Gainesville (J. Wymer); the Department of Neurology, University of Michigan, Ann Arbor (S.A.G.); Texas Neurology, Dallas (D.H.); the Department of Neurology, Lewis Katz School of Medicine, Temple University (T.H.-P.), and the Department of Neurology, University of Pennsylvania Perelman School of Medicine (C.Q.) - both in Philadelphia; Glenn Biggs Institute for Alzheimer's and Neurodegenerative Disease, University of Texas Health Science Center at San Antonio, San Antonio (C.E.J.); the Brain Science Institute and Department of Neurology, Johns Hopkins University, Baltimore (J.D.R.); the Department of Neurology, University of Kentucky College of Medicine, Lexington (E.J.K.); California Pacific Medical Center and Forbes Norris MDA-ALS Research and Treatment Center, San Francisco (J. Katz, L.J.); Barrow Neurological Institute, Phoenix, AZ (S.L., M.H., G.K., R.R., J.M.S.); the Department of Neurology, Washington University School of Medicine in St. Louis, St. Louis (T.M.M.); the Department of Neurology, Mount Sinai Beth Israel, Icahn School of Medicine at Mount Sinai, New York (S.N.S.); the Department of Neurology, University of South Florida Morsani College of Medicine, Tampa (T.H.V.); the Departments of Neurology and Pathology, Emory University School of Medicine, Atlanta (C.N.F., J.D.G.); Ochsner Health System, New Orleans (K.M.J.); the Department of Neurology, University of Iowa Carver College of Medicine, Iowa City (A.S.); the Department of Neurology, University of California, Irvine, School of Medicine, Irvine (N.A.G.); Neurology Associates, Lincoln, NB (G.L.P.); independent consultant, Nobleboro, ME (P.L.A.); and Statistics Collaborative, Washington, DC (J. Wittes).
Abstract
BACKGROUND: Sodium phenylbutyrate and taurursodiol have been found to reduce neuronal death in experimental models. The efficacy and safety of a combination of the two compounds in persons with amyotrophic lateral sclerosis (ALS) are not known. METHODS: In this multicenter, randomized, double-blind trial, we enrolled participants with definite ALS who had had an onset of symptoms within the previous 18 months. Participants were randomly assigned in a 2:1 ratio to receive sodium phenylbutyrate-taurursodiol (3 g of sodium phenylbutyrate and 1 g of taurursodiol, administered once a day for 3 weeks and then twice a day) or placebo. The primary outcome was the rate of decline in the total score on the Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R; range, 0 to 48, with higher scores indicating better function) through 24 weeks. Secondary outcomes were the rates of decline in isometric muscle strength, plasma phosphorylated axonal neurofilament H subunit levels, and the slow vital capacity; the time to death, tracheostomy, or permanent ventilation; and the time to death, tracheostomy, permanent ventilation, or hospitalization. RESULTS: A total of 177 persons with ALS were screened for eligibility, and 137 were randomly assigned to receive sodium phenylbutyrate-taurursodiol (89 participants) or placebo (48 participants). In a modified intention-to-treat analysis, the mean rate of change in the ALSFRS-R score was -1.24 points per month with the active drug and -1.66 points per month with placebo (difference, 0.42 points per month; 95% confidence interval, 0.03 to 0.81; P = 0.03). Secondary outcomes did not differ significantly between the two groups. Adverse events with the active drug were mainly gastrointestinal. CONCLUSIONS: Sodium phenylbutyrate-taurursodiol resulted in slower functional decline than placebo as measured by the ALSFRS-R score over a period of 24 weeks. Secondary outcomes were not significantly different between the two groups. Longer and larger trials are necessary to evaluate the efficacy and safety of sodium phenylbutyrate-taurursodiol in persons with ALS. (Funded by Amylyx Pharmaceuticals and others; CENTAUR ClinicalTrials.gov number, NCT03127514.).
BACKGROUND: Sodium phenylbutyrate and taurursodiol have been found to reduce neuronal death in experimental models. The efficacy and safety of a combination of the two compounds in persons with amyotrophic lateral sclerosis (ALS) are not known. METHODS: In this multicenter, randomized, double-blind trial, we enrolled participants with definite ALS who had had an onset of symptoms within the previous 18 months. Participants were randomly assigned in a 2:1 ratio to receive sodium phenylbutyrate-taurursodiol (3 g of sodium phenylbutyrate and 1 g of taurursodiol, administered once a day for 3 weeks and then twice a day) or placebo. The primary outcome was the rate of decline in the total score on the Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R; range, 0 to 48, with higher scores indicating better function) through 24 weeks. Secondary outcomes were the rates of decline in isometric muscle strength, plasma phosphorylated axonal neurofilament H subunit levels, and the slow vital capacity; the time to death, tracheostomy, or permanent ventilation; and the time to death, tracheostomy, permanent ventilation, or hospitalization. RESULTS: A total of 177 persons with ALS were screened for eligibility, and 137 were randomly assigned to receive sodium phenylbutyrate-taurursodiol (89 participants) or placebo (48 participants). In a modified intention-to-treat analysis, the mean rate of change in the ALSFRS-R score was -1.24 points per month with the active drug and -1.66 points per month with placebo (difference, 0.42 points per month; 95% confidence interval, 0.03 to 0.81; P = 0.03). Secondary outcomes did not differ significantly between the two groups. Adverse events with the active drug were mainly gastrointestinal. CONCLUSIONS: Sodium phenylbutyrate-taurursodiol resulted in slower functional decline than placebo as measured by the ALSFRS-R score over a period of 24 weeks. Secondary outcomes were not significantly different between the two groups. Longer and larger trials are necessary to evaluate the efficacy and safety of sodium phenylbutyrate-taurursodiol in persons with ALS. (Funded by Amylyx Pharmaceuticals and others; CENTAUR ClinicalTrials.gov number, NCT03127514.).
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