期刊
MUSCLE & NERVE
卷 66, 期 2, 页码 136-141出版社
WILEY
DOI: 10.1002/mus.27569
关键词
amyotrophic lateral sclerosis; clinical trial; crossover trial design; sodium phenylbutyrate and taurursodiol; survival
资金
- ALS Finding a Cure
- ALS Association
- Amylyx Pharmaceuticals, Inc.
This study utilized the RPSFTM survival analysis method to analyze data from the CENTAUR trial in ALS, and the results showed a significant survival benefit of PB and TURSO compared to placebo. The findings of this study may contribute to the clinical application of observed survival outcomes in future ALS crossover trials.
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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