Survival analyses from the CENTAUR trial in amyotrophic lateral sclerosis: Evaluating the impact of treatment crossover on outcomes
Open accessAbstract
Introduction/Aims: Trials incorporating placebo‐to‐active treatment crossover are encouraged in fatal conditions like amyotrophic lateral sclerosis (ALS) but may underestimate active treatment survival benefit. Here, we apply methods for modeling survival without crossover, including the rank‐preserving structural failure time model (RPSFTM), to data from the CENTAUR trial of sodium phenylbutyrate and taurursodiol (PB and TURSO) in ALS incorporating both randomized placebo‐controlled and open‐label extension (OLE) phases. Methods: Intent‐to‐treat (ITT) and RPSFTM survival analyses were performed with final data at a July 2020 cutoff date. Analyses of subgroups based on randomized treatment and OLE phase participation were also performed. Results: Hazard ratios (95% confidence intervals) of death for PB and TURSO versus participants initially on placebo were 0.57 (0.35–0.92) on ITT analysis and 0.39 (0.17–0.88) in the primary on‐treatment RPSFTM analysis (p = .023). Median ITT survival duration for PB and TURSO (25.8 mo) was 6.9 mo longer than placebo (18.9 mo) on ITT analysis and 10.6 mo longer than the median RPSFTM‐adjusted survival duration for placebo (15.2 mo). Median survival duration was 18.8 mo longer in the PB and TURSO–randomized subgroup who continued into the OLE phase versus the placebo‐randomized subgroup who did not continue into the OLE phase (p < .0001), although OLE phase selection bias may have potentially confounded these results. Discussion: Similar to the prespecified ITT analysis, post hoc analyses adjusting for treatment crossover in CENTAUR showed a significant survival benefit for PB and TURSO. Such methods may provide clinical context for observed survival outcomes in future ALS crossover trials.
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Oral combination of TUDCA and sodium phenylbutyrate (AMX0035) slows functional decline and prolongs overall survival in amyotrophic lateral sclerosis patients.
“Notably, an oral combination of TUDCA and sodium phenylbutyrate (AMX0035) is effective in slowing functional decline and prolonging the overall survival of ALS patients.400–402”
From Microbiota–gut–brain axis and its therapeutic applications in neurodegenerative diseases (2024) · cites this paper as [402]
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Trial of Sodium Phenylbutyrate–Taurursodiol for Amyotrophic Lateral Sclerosis
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Self-citationReal-world evidence of riluzole effectiveness in treating amyotrophic lateral sclerosis
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Methods for Adjusting for Bias Due to Crossover in Oncology Trials
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Microbiota–gut–brain axis and its therapeutic applications in neurodegenerative diseases
Loh, J. S., Mak, W. Q., Tan, L. K. S., Ng, C. X., Chan, H. H., Yeow, S. H., Foo, J. B., Ong, Y. S., How, C. W., & Khaw, K. Y. (2024) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-024-01743-1 · Cited by 1,193 · see citing works
- Authors
- Paganoni, S., Watkins, C., Cawson, M., Hendrix, S., Dickson, S. P., Knowlton, N., Timmons, J., Manuel, M., & Cudkowicz, M.
- Affiliations
- Harvard University (US)
- Maple Health Group New York New York USA
- Formerly with Maple Health Group New York New York USA
- Pentara Corporation Millcreek Utah USA
- Amylyx Pharmaceuticals, Inc. (United States) (US)
- Corresponding author
- Paganoni, Sabrina
- ORCID
- Venue
- Muscle & Nerve
- Publisher
- Wiley
- Published
- 2022-05-31
- Volume
- 66
- Issue
- 2
- Pages
- 136-141
- ISSN
- 0148-639X (ISSN-L)
- 1097-4598
- PMC
- PMC9540225
- OpenAlex
- W4229000223
- Cited by
- 48
- References
- 10
- Citations by year
- 2026: 4 · 2025: 2 · 2024: 11 · 2023: 24 · 2022: 6 · 2019: 1
- FWCI
- 5.66
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Muscle & Nerve (publishedVersion, cc-by-nc)
- PubMed Central (publishedVersion, cc-by-nc)
- PubMed (publishedVersion)
- Funders
- ALS Association
- Topics
- Health Sciences › Medicine › Neurology › Amyotrophic Lateral Sclerosis Research
- Physical Sciences › Mathematics › Statistics and Probability › Statistical Methods in Clinical Trials
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Keywords
- amyotrophic lateral sclerosis, 4-phenylbutyric acid, treatment crossover, rank-preserving structural failure time model, open-label extension, survival analysis, selection bias, survival benefit
- MeSH terms
- Amyotrophic Lateral Sclerosis, Double-Blind Method, Humans, Survival Analysis, Cross-Over Studies
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