A retrospective investigation of the relationship between baseline covariates and rate of ALSFRS-R decline in ALS clinical trials

Abstract

The revised ALS functional rating scale (ALSFRS-R) is a longitudinal measure of global function commonly used to assess progression of amyotrophic lateral sclerosis (ALS), and as an endpoint in ALS clinical trials. Understanding how baseline covariates affect the rate of functional decline in ALS offers valuable information to clinical trialists. We used a mixed modeling approach in a retrospective study of the pooled resource open-Access ALS clinical trials database to elucidate the associations between baseline covariates and the rate of ALSFRS-R decline over time. In a cohort of 3203 patients followed for an average of 337 days, older age at disease onset (p < 0.001), less time since disease onset (p < 0.001), and bulbar site of onset (p < 0.001) were associated with a significantly faster decline of the ALSFRS-R, while sex did not have a statistically significant effect (p = 0.82). Selective inclusion of ‘age at disease onset’ and ‘time since disease onset’ as covariates provided the best tradeoff between model fit and model precision. The effect of bulbar onset on rate of disease progression was primarily due to accelerated decline in the bulbar subscale of the ALSFRS-R. These findings, which are novel in the clinical trial time frame, contribute to the understanding of disease trajectory in ALS and can be used to guide future design and analysis of clinical trials.

Keywords:

• Epidemiology
• ALSFRS-R
• PRO-ACT
• bulbar
• mixed-model

Acknowledgements

In 2011, Prize4Life, in collaboration with the Northeast ALS Consortium, and with funding from the ALS Therapy Alliance, formed the (PRO-ACT) Consortium. The data available in the PRO-ACT Database were volunteered by PRO-ACT Consortium members. As such, the following organizations and individuals within 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: Neurological Clinical Research Institute, MGH; Northeast ALS Consortium; Novartis; Prize4Life Israel; Regeneron Pharmaceuticals, Inc.; Sanofi; Teva Pharmaceutical Industries, Ltd. We thank Dr. Bronfeld, a member of the Prize4Life team, for clarifications regarding the PRO-ACT database.

Declaration of interest

The authors report no conflicts of interest. The authors alone are responsible for the content and writing of this article.

Supplementary material available online