ArticleEuropean journal of neurology2026
Multivariate Survival Analysis of a Comprehensive Clinical Trial of Rapamycin in Amyotrophic Lateral Sclerosis Explores Prognostic Factors and Survival Patterns in C9orf72 Carriers.
Article in European journal of neurology, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
backgroundAmyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease marked by considerable variability in survival times. This retrospective study aims to evaluate the prognostic value of a broad range of variables by conducting a comprehensive survival analysis on longitudinal data from RAP-ALS, a clinical trial investigating the effects of rapamycin in ALS patients (n = 63).
methodsCovariates were classified as risk or protective factors according to their hazard ratios. Regularized Cox regression was utilized to select the best-performing multivariate models in cross-validation. Longitudinal measures were incorporated by modeling covariates as time-dependent. Survival times of treated C9orf72 mutation carriers (n = 6) were further investigated through log-rank tests and restricted mean survival time analysis.
resultsUnivariate analyses confirmed several previously established prognostic factors. Multivariate regularized Cox models incorporated neurofilaments, creatinine, clinical scores, and markers of immune activation. Moreover, the inclusion of time-varying covariates allowed us to investigate late-stage risk factors, such as the neutrophil-to-lymphocyte ratio. Additionally, the analysis indicated a protective effect in treated C9orf72 mutation carriers (log-rank test, p = 0.026), which was confirmed after comparing this treatment subgroup with an independent C9orf72+ cohort (n = 40; RMST test, p = 0.04).
conclusionsThe survival analysis confirmed the role of previously identified prognostic factors, while suggesting that high-performing multivariate models should integrate multiple ALS pathological hallmarks. Moreover, the observed longer survival among C9orf72 mutation carriers contrasts with prior reports. Due to the small sample size and potential confounding factors, the observed benefits in treated C9orf72 patients should be considered exploratory, supporting evaluation in a larger, genetically stratified trial.
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