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 Owegi, Adam Quick, James Wymer, Stephen A. Goutman, Daragh Heitzman, Terry Heiman‐Patterson, Carlayne E. Jackson, Colin Quinn, Jeffrey D. Rothstein, Edward J. Kasarskis, Jonathan Katz, Liberty Jenkins, Shafeeq Ladha, Timothy M. Miller, Stephen N. Scelsa, Tuan Vu, Christina Fournier, Kristin Johnson, Andrea Swenson, Namita Goyal, Gary L. Pattee, Suma Babu, Marianne Chase, Derek D’Agostino, Meghan Hall, Gale Kittle, Mathew Eydinov, Joseph Ostrow, Lindsay Pothier, Rebecca Randall, Jeremy M. Shefner, Alexander Sherman, Eric Tustison, Prasha Vigneswaran, Hong Yu, Joshua Cohen, Justin Klee, Rudolph E. Tanzi, Walter Gilbert, Patrick Yeramian, Merit Cudkowicz
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.