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

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.

Conflict of interest statement

Competing interests: SP reports grant support from Amylyx during the conduct of the study; grant support from Revalesio, Biohaven, UCB, Clene, Prilenia, and Seelos outside the submitted work; and consulting fees from Orion, Cytokinetics, and Medscape outside the submitted work. SH is owner, and SH, SPD, and NK are employees of Pentara Corporation, which was contracted by Amylyx for statistical analysis. JDB reports clinical trial support from Amylyx Pharmaceuticals, Inc, during the conduct of the study; grant support from Alexion, Biogen, Mitsubishi Tanabe Pharma America (MTPA), Anelixis Therapeutics, Brainstorm Cell Therapeutics, nQ Medical, the National Institute of Neurological Disorders and Stroke, the Muscular Dystrophy Association, ALS One, Amylyx, MT Pharma Holdings of America, The ALS Association, ALS Finding a Cure®, and RAPA Therapeutics outside the submitted work; and personal fees from Biogen, Clene Nanomedicine, MTPA, MT Pharma Holdings of America, Sawai Pharmaceutical Co, Ltd, and Janssen outside the submitted work. MAE reports payment and personal fees from Amylyx for advisory board and speakers bureau participation outside the submitted work. CK reports consulting fees from Alnylam, Takeda, CSL Behring, Argenx, Akcea/Ionis, and Sanofi; honoraria from Alnylam; and advisory board participation fees from Alnylam and Orphazyme, all outside the submitted work. JBC reports grants from AZ Therapies Inc, MTB Pharmaceuticals, and Cytokinetics Inc, lecture honorarium from Northwest Area Health Education Center, and consulting fees from the Department of Defense Congressionally Directed Medical Research Programs grant review board, all outside the submitted work. JW reports research funding from Amylyx during the conduct of the study and presentation honoraria from Amylyx outside the submitted work. SAG reports institutional funding from Amylyx and The ALS Association during the conduct of the study; institutional funding from the National Institute of Environmental Health Sciences and The ALS Association outside the submitted work; consulting fees from Biogen and ITF Pharma outside the submitted work; lecture fees from Illinois State Neurological Society Lecture and Spectrum Health outside the submitted work; and personal fees for Data Safety Monitoring Board (DSMB) participation from Watermark outside the submitted work; and is an inventor on institutional patent US10660895B2. DH reports advisory board participation for Amylyx outside the submitted work. TDH-P reports clinical trial funding from Amylyx during the conduct of the study; institutional grant support from Cytokinetics, Orion, Bio 3, MTPA, the Sean M. Healey and AMG Center for ALS & the Neurological Clinical Research Institute, UCB Pharma, Alexion, and AB Sciences outside the submitted work; institutional contract work with Samus outside the submitted work; consulting fees from Samus, Alpha Insights, and Evidera outside the submitted work; payment for educational deliverables from Platform Q Health, WebMD, MJH Holdings, IQVIA, P Value, and Vindico Medical Education outside the submitted work; and advisory board fees from MTPA, Cytokinetics, AB Bio, Alexion, Biogen, and Orphazyme outside the submitted work; and is President of the ALS Hope Foundation. CEJ reports grant support from the Muscular Dystrophy Association, The ALS Association, and the National Institutes of Health and advisory board participation for Brainstorm Cell Therapeutics, MTPA, and Anelixis, all outside the submitted work, and is President Elect of the American Academy of Neurology. CQ reports advisory board fees from Amylyx outside the submitted work. JDR reports clinical trial funding from Amylyx during the conduct of the study; licensing agreement and nonfinancial support from Ionis Pharmaceuticals; nonfinancial support from Calico, Biogen, and IBM Watson; research grant support from the National Institute of Neurological Disorders and Stroke, National Institute on Aging, Department of Defense, the Chan Zuckerberg Initiative, Microsoft, The ALS Association, the Muscular Dystrophy Association, Target ALS, F Prime, ALS Finding A Cure, Answer ALS, Robert Packard Center for ALS Research, GlaxoSmithKline, Travelers Insurance, American Airlines, Caterpillar, and the National Football League; and personal consulting fees from Expansion Therapeutics and Team Gleason, all outside the submitted work. JK reports consulting fees from Calico, Denali, Biogen, MTPA, and Amylyx outside the submitted work. LJ reports advisory board participation for Cytokinetics outside the submitted work. SL reports advisory board fees from Amylyx outside the submitted work. TMM reports licensing agreements with Ionis Pharmaceuticals and C2N, consulting fees from Cytokinetics, Ionis Pharmaceuticals, and Disarm Therapeutics, lecture honorarium from Regeneron, advisory board participation for Biogen and UCB Pharma, and receipt of reagents from Ionis Pharmaceuticals, all outside the submitted work, and is co-chair of the Northeast ALS Consortium. SNS reports funding from Amylyx during the conduct of the study; grant support from Orion Pharma and Alexion outside the submitted work; lecture (grand rounds) honorarium from New York University outside the submitted work; and payment for expert testimony from Martin Clearwater & Bell LLP; Shaub, Ahmuty, Citrin & Spratt LLP; MCIC Vermont; and Aaronson Rappaport Feinstein and Deutsch, LLP outside the submitted work. THV reports institutional funding from Amylyx during the conduct of the study; institutional grant support from Alexion, Alector, Annexon Bio, Apellis, Biogen, Cytokinetics, Healey ALS Platform Trial, MT Pharma, and Sanofi outside the submitted work; and honoraria from Amylyx, Alexion, and Cytokinetics outside the submitted work. CNF reports institutional funding from Amylyx during the conduct of the study. AS reports institutional grant support from Amylyx during the conduct of the study and from the Rare Diseases Clinical Research Network, National Institutes of Health, Healey ALS Platform Trial, Cytokinetics, and Wyck Foundation outside the submitted work; honorarium from Weill Cornell Medicine – Qatar (residency recruitment seminar) outside the submitted work; uncompensated DSMB participation for the University of Kansas outside the submitted work; and compensated independent data monitoring committee participation for Alexion outside the submitted work. NAG reports grants from Alexion, Annelixis, Annexon, Brainstorm Cell Therapeutics, Cytokinetics, Fulcrum, the Sean M. Healey and AMG Center for ALS & the Neurological Clinical Research Institute, Kezar, Medicinova, Octapharma, Orion, and Orphazyme and advisory board participation for Alexion, Argenx, AstraZeneca, CSL Behring, MT Pharma, Sanofi Genzyme, Sarepta, and UCB, all outside the submitted work. GLP reports consulting fees from MT Pharma and honoraria from MT Pharma and Cytokinetics, all outside the submitted work. GK reports provision of trial supplies from Amylyx during the conduct of the study. JMS reports grant support from the National Institutes of Health, The ALS Association, Amylyx, Biogen, Biotie Therapies (now Acorda Therapeutics), Cytokinetics Incorporated, MTPA, Alexion, Medicinova, Ionis, Alector, and Orphazyme; royalties from UpToDate; consulting fees from Amylyx, Apic Biosciences, Neurosense, Cytokinetics, Denali, GSK, MTPA, Orphazyme, Pinteon, RRD, Swanbio, Helixsmith, Novartis, Sanofi, and EMD Serono; and honoraria from Amylyx (symposium) and Oakstone (online presentation); all outside the submitted work. JC and JK are co-CEOs of and own stock in Amylyx, the trial sponsor, and report grant support from ALS Finding a Cure and The ALS Association during the conduct of the study. RET is Founding Chair of Amylyx’s Scientific Advisory Board and holds equity in Amylyx. Dr Gilbert reports stock ownership in Amylyx. PDY reports full-time employment and stock option ownership with Amylyx outside the submitted work. MEC reports consulting fees from Faze, Regeneron, AB Sciences, Avexis, Orion, Lilly, Biohaven, Mt Pharma, Revalasio, Aclipse, Anelexis, Cytokinetics, Disarm, ALS Pharma, Immunity Pharma, Wave, Sunovian, Pontifex, Denali, Transposen, Quralis, Helixsmith, and RRD and is a board member for Praxis, all outside the submitted work.

© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

Figures

Figure 1

Kaplan-Meier analyses of time to key events. Time to (A) any key event (ie, death, tracheostomy, PAV or first hospitalisation), (B) death or tracheostomy/PAV and (C) first hospitalisation and corresponding median event-free duration estimates are shown for each originally randomised group in the modified intent-to-treat population (ie, all randomised participants who received at least one dose of originally assigned trial drug and had at least one postbaseline Amyotrophic Lateral Sclerosis Functional Rating Scale–Revised assessment; N=135). HRs and p values were estimated using a Cox proportional hazards model. The numbers at risk exclude participants who experienced the analysed event(s) or were censored before that time point. OLE, open-label extension; PAV, permanent assisted ventilation (defined as non-invasive ventilation >22 hours/day for >7 days); PB/TURSO, sodium phenylbutyrate/taurursodiol.