Relationship between quantitative strength and functional outcomes in the phase 2 FORTITUDE-ALS trial

Abstract

Objective

To assess the relationship among measurements of strength, function, and quality of life in an amyotrophic lateral sclerosis (ALS) clinical trial.

Methods

In the FORTITUDE-ALS clinical trial (NCT03160898), 456 participants in the full-analysis set were treated with either reldesemtiv or placebo for 12 weeks; this post hoc analysis included all participants regardless of treatment assignments. Assessments included slow vital capacity (SVC), the ALS Functional Rating Scale-Revised (ALSFRS-R), and the 5-item ALS Assessment Questionnaire (ALSAQ-5). Muscle strength was measured quantitatively with hand-held dynamometry, and grip strength with a dedicated dynamometer. The relationship between strength and ALSFRS-R fine and gross motor domain scores, or responses to ALSAQ-5 questions on hand function and walking, was assessed with Spearman’s rank correlation. The relationship between mean upper- or lower-extremity muscle strength and specific ALSFRS-R domains was modeled using principal-components analysis.

Results

Upper-extremity muscle strength and hand grip were highly correlated with ALSFRS-R fine motor scores and the ALSAQ-5 hand function question. Similarly, lower-extremity strength correlated well with ALSFRS-R gross motor domain and the ALSAQ-5 walking question. For SVC, correlation was poor with the ALSFRS-R respiratory domain, but stronger with the total score, potentially reflecting the insensitivity of the respiratory questions in the scale. Upper- and lower-extremity strength were both strong predictors of ALSFRS-R domain scores.

Conclusions

In this analysis of data from an ALS clinical trial, muscle strength quantified by dynamometry was strongly correlated with functional capacity. These results suggest that muscle strength directly relates to specific functions of importance to people with ALS.

Keywords:

• Amyotrophic lateral sclerosis
• reldesemtiv
• dynamometry
• ALSAQ-5
• ALSFRS-R
• vital capacity

Declaration of interest

JMS reports compensation received as a consultant from Amylyx, Apic Biosciences, NeuroSense Therapeutics, Cytokinetics, Denali Therapeutics, GSK, Mitsubishi Tanabe Pharma America, Orphazyme, Orthogonal, Pinteon Therapeutics, RRD, SwanBio, Helixmith, Novartis, Sanofi, PTC, and EMD Serono; and research support from Amylyx, Biogen, Biotie Therapies (now Acorda Therapeutics), Cytokinetics, Mitsubishi Tanabe Pharma America, Alexion, MediciNova Inc, Ionis, Alector, and Orphazyme. BJ has no conflicts of interest to declare. SK, FIM, LM, JW, AAW, and SAR are employees and stockholders of Cytokinetics, Incorporated.

Data availability statement

Data reported herein are part of a sponsor-led clinical development programme that is ongoing, and thus complete datasets for the trial will not be made available with this report.