Effect of sodium phenylbutyrate/taurursodiol on tracheostomy/ventilation-free survival and hospitalisation in amyotrophic lateral sclerosis: long-term results from the CENTAUR trial

Sabrina Paganoni; Suzanne Hendrix; Samuel P Dickson; Newman Knowlton; James D Berry; Michael A Elliott; Samuel Maiser; Chafic Karam; James B Caress; Margaret Ayo Owegi; Adam Quick; James Wymer; Stephen A Goutman; Daragh Heitzman; Terry D Heiman-Patterson; Carlayne Jackson; Colin Quinn; Jeffrey D Rothstein; Edward J Kasarskis; Jonathan Katz; Liberty Jenkins; Shafeeq S Ladha; Timothy M Miller; Stephen N Scelsa; Tuan H Vu; Christina Fournier; Kristin M Johnson; Andrea Swenson; Namita Goyal; Gary L Pattee; Suma Babu; Marianne Chase; Derek Dagostino; Meghan Hall; Gale Kittle; Mathew Eydinov; Joseph Ostrow; Lindsay Pothier; Rebecca Randall; Jeremy M Shefner; Alexander V Sherman; Eric Tustison; Prasha Vigneswaran; Hong Yu; Joshua Cohen; Justin Klee; Rudolph Tanzi; Walter Gilbert; Patrick Yeramian; Merit Cudkowicz

doi:10.1136/jnnp-2022-329024

Effect of sodium phenylbutyrate/taurursodiol on tracheostomy/ventilation-free survival and hospitalisation in amyotrophic lateral sclerosis: long-term results from the CENTAUR trial

J Neurol Neurosurg Psychiatry. 2022 May 16;93(8):871-875. doi: 10.1136/jnnp-2022-329024. Online ahead of print.

Authors

Sabrina Paganoni^{1

2}, Suzanne Hendrix³, Samuel P Dickson³, Newman Knowlton³, James D Berry⁴, Michael A Elliott⁵, Samuel Maiser⁶, Chafic Karam⁷, James B Caress⁸, Margaret Ayo Owegi⁹, Adam Quick¹⁰, James Wymer¹¹, Stephen A Goutman¹², Daragh Heitzman¹³, Terry D Heiman-Patterson¹⁴, Carlayne Jackson¹⁵, Colin Quinn⁷, Jeffrey D Rothstein¹⁶, Edward J Kasarskis¹⁷, Jonathan Katz¹⁸, Liberty Jenkins¹⁸, Shafeeq S Ladha¹⁹, Timothy M Miller²⁰, Stephen N Scelsa²¹, Tuan H Vu²², Christina Fournier²³, Kristin M Johnson²⁴, Andrea Swenson²⁵, Namita Goyal²⁶, Gary L Pattee²⁷, Suma Babu²⁸, Marianne Chase²⁸, Derek Dagostino²⁸, Meghan Hall¹⁹, Gale Kittle¹⁹, Mathew Eydinov²⁸, Joseph Ostrow²⁸, Lindsay Pothier²⁸, Rebecca Randall^{29

30}, Jeremy M Shefner¹⁹, Alexander V Sherman²⁸, Eric Tustison²⁸, Prasha Vigneswaran²⁸, Hong Yu²⁸, Joshua Cohen³¹, Justin Klee³¹, Rudolph Tanzi³², Walter Gilbert³³, Patrick Yeramian³¹, Merit Cudkowicz²⁸

Affiliations

¹ Harvard Medical School, Sean M. Healey and AMG Center for ALS & the Neurological Clinical Research Institute, Massachusetts General Hospital, Boston, Massachusetts, USA [email protected].
² Department of PM & R, Spaulding Rehabilitation Hospital, Charlestown, Massachusetts, USA.
³ Pentara Corporation, Millcreek, Utah, USA.
⁴ Neurological Clinical Research Institute, Massachusetts General Hospital, Boston, Massachusetts, USA.
⁵ Swedish Neuroscience Institute, Seattle, Washington, USA.
⁶ Department of Neurology, Hennepin Healthcare, Minneapolis, Minnesota, USA.
⁷ Department of Neurology, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA.
⁸ Department of Neurology, Wake Forest University School of Medicine, Winston-Salem, North Carolina, USA.
⁹ Department of Neurology, University of Massachusetts Memorial Medical Center, Worcester, Massachusetts, USA.
¹⁰ Department of Neurology, Ohio State University, Columbus, Ohio, USA.
¹¹ Department of Neurology, College of Medicine, University of Florida, Gainesville, Florida, USA.
¹² Department of Neurology, University of Michigan, Ann Arbor, Michigan, USA.
¹³ ALS Clinic, Texas Neurology, Dallas, Texas, USA.
¹⁴ Department of Neurology, Lewis Katz School of Medicine at Temple University, Philadelphia, Pennsylvania, USA.
¹⁵ Department of Neurology, The University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA.
¹⁶ Department of Neurology, Johns Hopkins University Brain Science Institute, Baltimore, Maryland, USA.
¹⁷ Department of Neurology, University of Kentucky, Lexington, Kentucky, USA.
¹⁸ California Pacific Medical Center Research Institute and Forbes Norris MDA/ALS Research and Treatment Center, San Francisco, California, USA.
¹⁹ Department of Neurology, Barrow Neurological Institute, Phoenix, Arizona, USA.
²⁰ Hope Center for Neurological Disorders, Washington University in Saint Louis School of Medicine, Saint Louis, Missouri, USA.
²¹ Department of Neurology, Mount Sinai Beth Israel, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
²² Department of Neurology, University of South Florida Morsani College of Medicine, Tampa, Florida, USA.
²³ Department of Neurology, Emory University, Atlanta, Georgia, USA.
²⁴ Department of Neurology, Ochsner Health System, New Orleans, Louisiana, USA.
²⁵ Department of Neurology, University of Iowa Health Care, Iowa City, Iowa, USA.
²⁶ Department of Neurology, University of California Irvine School of Medicine, Irvine, California, USA.
²⁷ Neurology Associates, Lincoln, Nebraska, USA.
²⁸ Harvard Medical School, Sean M. Healey and AMG Center for ALS & the Neurological Clinical Research Institute, Massachusetts General Hospital, Boston, Massachusetts, USA.
²⁹ Worldwide Clinical Trials, Research Triangle Park, North Carolina, USA.
³⁰ Formerly With Gregory W. Fulton ALS Center, Barrow Neurological Institute, Phoenix, Arizona, USA.
³¹ Amylyx Pharmaceuticals Inc, Cambridge, Massachusetts, USA.
³² Department of Neurology, Genetics and Aging Research Unit, McCance Center for Brain Health, Massachusetts General Hospital, Harvard University, Boston, Massachusetts, USA.
³³ Carl M. Loeb University Professor Emeritus and Chair of the Society of Fellows at Harvard, Harvard University, Cambridge, Massachusetts, USA.

Abstract

Background: Coformulated sodium phenylbutyrate/taurursodiol (PB/TURSO) was shown to prolong survival and slow functional decline in amyotrophic lateral sclerosis (ALS).

Objective: Determine whether PB/TURSO prolonged tracheostomy/ventilation-free survival and/or reduced first hospitalisation in participants with ALS in the CENTAUR trial.

Methods: Adults with El Escorial Definite ALS ≤18 months from symptom onset were randomised to PB/ TURSO or placebo for 6 months. Those completing randomised treatment could enrol in an open-label extension (OLE) phase and receive PB/TURSO for ≤30 months. Times to the following individual or combined key events were compared in the originally randomised treatment groups over a period spanning trial start through July 2020 (longest postrandomisation follow-up, 35 months): death, tracheostomy, permanent assisted ventilation (PAV) and first hospitalisation.

Results: Risk of any key event was 47% lower in those originally randomised to PB/TURSO (n=87) versus placebo (n=48, 71% of whom received delayed-start PB/TURSO in the OLE phase) (HR=0.53; 95% CI 0.35 to 0.81; p=0.003). Risks of death or tracheostomy/PAV (HR=0.51; 95% CI 0.32 to 0.84; p=0.007) and first hospitalisation (HR=0.56; 95% CI 0.34 to 0.95; p=0.03) were also decreased in those originally randomised to PB/TURSO.

Conclusions: Early PB/TURSO prolonged tracheostomy/PAV-free survival and delayed first hospitalisation in ALS.

Trial registration number: NCT03127514; NCT03488524.

Keywords: ALS; MOTOR NEURON DISEASE; NEUROMUSCULAR; RANDOMISED TRIALS.

Associated data

ClinicalTrials.gov/NCT03488524
ClinicalTrials.gov/NCT03127514

Grants and funding

UL1 TR001414/TR/NCATS NIH HHS/United States