Driving Novel Endpoints and Study Designs In Amyotrophic Lateral Sclerosis

ALSFRS-R Subdomains in Amyotrophic Lateral Sclerosis Clinical Studies

This pre-print examines how ALSFRS-R subdomains may better support endpoint selection and study design in Amyotrophic Lateral Sclerosis (ALS) clinical studies. The Revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R) is a common primary outcome measure used to assess functional change in ALS, but reported limitations of the scale and the typical assumption of linear decline may hinder novel therapy development.

Using two distinct populations from the Pooled Resource Open-Access ALS Clinical Trials database (PRO-ACT) and the ALS Therapy Development Institute (ALS TDI) natural history registry, the authors evaluated ALSFRS-R total scores and subdomains to better understand patterns of ALS disease progression.

Examining ALSFRS-R Subdomains and Disease Progression

The analysis found that the ALSFRS-R fine motor and gross motor subdomains are more sensitive to ALS disease progression than the total score and the bulbar and respiratory subdomain scores. These findings suggest that examining ALSFRS-R subdomains may provide additional insight into functional decline and help inform how outcomes are measured in ALS interventional studies.

A Non-Linear Method for Defining Fast and Slow Progressors

The authors also present a novel non-linear method for defining fast and slow progressors, moving beyond the typical assumption of linear decline. This approach may help researchers better account for variability in ALS progression and support more informative patient stratification in clinical study design.

Together, these findings may help improve how outcomes are demonstrated in ALS interventional studies using the ALSFRS-R.

Pre-print: This manuscript has not yet been peer reviewed.

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