Driving novel endpoints and study designs in amyotrophic lateral sclerosis: closer examination of the ALSFRS-R subdomains and a new definition of fast and slow progressors

Amyotrophic lateral sclerosis (ALS) is a motor neuron disease that leads to significant morbidity and mortality, but with substantial variability in the rate of progression. A common primary outcome measure used in ALS clinical studies is the ALSFRS-R. Change in this measure may also be used to stratify fast and slow progressors, typically with the assumption of linear decline. Reported limitations of the ALSFRS-R and the assumption of linear slope may hinder novel therapy development. Here we use two distinct populations from a clinical trial database (PRO-ACT) and a natural history registry (ALS TDI) to show that ALSFRS-R fine and gross motor subdomains are more sensitive to disease progression than total score and bulbar and respiratory subdomain scores. We also present a novel non-linear method for defining fast and slow progressors. Together these results may improve demonstration of outcomes in ALS interventional studies using the ALSFRS-R.