Stage-specific riluzole effect in amyotrophic lateral sclerosis: a retrospective study

Abstract

Objectives: To estimate the effect of riluzole on the stage-specific risk of progression of ALS. Methods: Patients from the PRO-ACT dataset were staged employing two methods (King's and FT9). Hazard ratios associated with riluzole treatment were estimated for forward transition between stages, using unadjusted and adjusted Markov multistate models. Results: Of 1903 patients, 1587 had received riluzole. Riluzole-treated patients survived non-significantly longer than those who did not (median 22.9 months vs. 18.3 months from time of initial observation, log rank p = 0.16). After adjusting for age and ALSFRS-R slope at first visit, riluzole significantly reduced risk of the following transitions: (1) King's stages: 1->2 (hazard ratio (HR) = 0.81), and 2->3 (HR = 0.82), 4->death (HR = 0.57), and (2) FT9 stages: 1->2 (HR = 0.84), 3->4 (HR = 0.71), and 4->death (HR = 0.67). In contrast, the beneficial effect of riluzole in bulbar-onset patients was in early rather than late King’s stages. Conclusions: This examination of cohorts closely followed in clinical trials finds a beneficial effect of riluzole that is predominantly but not exclusively in later stages of ALS. This analytic framework has utility to discern stage-specific treatment effects, and for refined health economic analyses.

Keywords:

• Survival
• prognostic
• therapy
• clinical trials

Acknowledgements

We are indebted to the PRO-ACT Consortium for providing the data for these analyses, especially to Dr. Alex Sherman for clarifications and suggestions. We would also like to thank the Neurological Institute Center for Outcomes, Research and Evaluation (NI-CORE) and Quantitative Health Sciences (QHS) at Cleveland Clinic for supporting this effort.

Author contributions

NJT conceptualized the study, conducted the statistical analysis, interpreted the data, and prepared the initial manuscript. EPP and BRL interpreted the data and critically revised the manuscript for important intellectual content. All authors contributed equally to the approval of the final manuscript. Members of the PRO-ACT Consortium contributed to the design and implementation of the PRO-ACT Database and/or provided data, but did not participate in the analysis of the data or the writing of this report.

Declaration of interest

This study was not supported by any external or internal grant. There are no competing interests. Dr. Thakore reports grants from Novartis Pharmaceuticals Corporation, outside the submitted work. Dr. Lapin has nothing to disclose. Dr. Pioro reports grants from ALS Association and CDC/NIH, as well as personal fees from Avanir Pharmaceuticals, Inc., Biohaven Pharmaceuticals, Cytokinetics, Inc., ITF Pharma, Inc., MT Pharma America, Inc., and Otsuka America, Inc., outside the submitted work.