Muscle strength correlated with functional outcomes in Phase 2 analysis
The findings support continued use of muscle strength measurements, scientists say
Direct measures of muscle strength were correlated with functional abilities among amyotrophic lateral sclerosis (ALS) patients in a Phase 2 clinical trial.
Measures of arm and hand muscle strength aligned well with functional domains related to fine motor skills (e.g., handwriting, grasping), whereas leg and foot strength were related to gross motor skills (e.g., walking, climbing stairs).
Scientists believe this direct relationship supports the continued use of muscle strength measurements in ALS clinical trials, where functional capacity measures are typically of primary interest.
In ALS, degeneration of the nerve cells needed for muscle control leads to progressive symptoms of muscle weakness. This can affect not only the limbs, but also the muscles needed for speaking, swallowing, head control, and breathing.
A range of different outcome measures are used in ALS clinical trials to evaluate the efficacy of potential new therapies at slowing the progression of these symptoms.
Using the ALS Functional Rating Scale – Revised
The most common is the ALS Functional Rating Scale – Revised (ALSFRS-R), a measure of overall functional capacity with 12 domains that account for various aspects of physical function such as speech, swallowing, breathing, and walking, among others.
Higher ALSFRS-R scores — or slower score declines — during clinical testing generally indicate a slowing of disease progression. This scale meets guidelines in the U.S. that say primary outcome measures in Phase 3 trials must be clinically relevant, or related to how patients feel, function, or survive.
Evaluations of muscle strength are sometimes also included in clinical testing, but only as supportive, or secondary outcomes. That’s because it is not well established to what degree declines in muscle strength correlate with clinically-meaningful changes in functional capacity.
“It seems intuitive that quantitative measurements of muscle strength should reflect clinically important symptoms of ALS, yet there are no published datasets definitively confirming this relationship,” the researchers wrote.
“If the relationship was established, muscle strength could provide an objective, quantitative measure of disease progression that would complement outcomes such as ALSFRS-R scores,” they added.
Data from the FORTITUDE-ALS Phase 2 clinical trial
In their study, the scientists sought to more closely examine the relationships between different clinical trial outcome measures using data from the previous FORTITUDE-ALS Phase 2 clinical trial (NCT03160898).
The trial was designed to investigate the safety and efficacy of the experimental therapy reldesemtiv against a placebo among 458 adults with early ALS, all of whom had been diagnosed within two years prior to enrollment.
Throughout a treatment period of three months and one-month follow-up, data were collected related to lung function, functional capacity, muscle strength, and life quality.
While clinical testing of reldesemtiv in ALS has been stopped due to lack of effectiveness, the scientists were able to leverage data from the trial to examine the relationship between muscle strength and functionality in ALS patients.
As such, their analysis included 456 FORTITUDE-ALS participants, regardless of their treatment assignment in the trial.
ALSAQ-5 used to assess life quality
In addition to the clinician-rated ALSFRS-R, the patient-reported five-item Amyotrophic Lateral Sclerosis Assessment Questionnaire (ALSAQ-5) was used to assess life quality associated with various functional domains.
Slow vital capacity (SVC) was used as a measure of respiratory function, while quantitative muscle and grip strength testing were used to measure strength in the extremities.
Results showed that overall strength across muscles in the upper extremities (arms/hands) and hand grip strength were each correlated significantly with scores on the ALSFRS-R fine motor skills section, as well as the ALSAQ-5 hand function question.
Fine motor skills refer to those that involve small muscles, usually in the hands and fingers, that are involved in precise movements such as handwriting or grasping.
Meanwhile, lower extremity strength (legs/feet) was correlated significantly with the ALSFRS-R gross motor domain and the ALSAQ-5 walking/standing-up question.
Gross motor skills encompass movements that involve larger muscle groups and whole body movements, like walking or climbing.
SVC values correlated significantly with scores on the ALSFRS-R respiratory domain, but the relationship was weaker than those observed for other muscle groups and their corresponding domains. It also was weaker than the link between SVC and total ALSFRS-R scores.
This could mean that the respiratory domain of ALSFRS-R is less sensitive than its other domains, according to the scientists.
In final models, grip strength, and both upper and lower extremity strength, were found to be significant predictors of ALSFRS-R scores in the corresponding domains.
Continuing to use strength as an ALS outcome measure
“These findings support the continued use of strength … as an ALS outcome measure,” the researchers wrote, although they added that “a longer study may provide additional insights into the relationship between strength and function as ALS continues to progress.”
Six of the study’s authors are employees of Cytokinetics, the sponsor of the FORTITUDE-ALS trial.