Adverse Events: Disease Progression vs Reversible Effects in ALS
Recommended Citation
Berger A, Arcila-Londono X, Sherman AV. Adverse Events: Disease Progression vs Reversible Effects in ALS. Muscle Nerve 2025; 72:S97.
Document Type
Conference Proceeding
Publication Date
10-6-2025
Publication Title
Muscle Nerve
Abstract
Background: Adverse events (AEs) observed during clinical trials may represent either genuine treatment-related side effects or manifestations of underlying disease progression. This analysis examines potential associations between frequently reported in the PRO-ACT database AEs and irreversible functional decline. Methods: We extracted adverse events and ALSFRS-R scores from PRO-ACT's dataset comprising 12,600 longitudinal records and over 5,700 unique AEs. The analysis centered on the 20 most frequent AEs, each affecting at least 150 participants and cumulatively accounting for over 60% of all recorded events in the dataset. ALSFRS-R scores were aligned to the date of AE (day 0), and ALSFRS-R scores were evaluated over the one-year periods preceding and following each event to detect changes in the trajectory of functional decline. Results: Of the 20 most common AEs, 19 were linked to a persistent increase in the rate of functional decline, as measured by ALSFRS-R scores post-event. On average, the rate of functional decline accelerated from -0.68 points/month before the AE to -1.22 points/month after, with no signs of subsequent recovery. Vomiting (n = 312) was the sole exception with affected participants exhibiting a partial rebound. Bulbar subscores (questions 1-3: speech, salivation, swallowing) and dyspnea (question R-1) dropped sharply at the time of the event (mean—0.45 points) but showed measurable recovery (+0.21 points) within 90 days. Conclusion: The most frequently reported AEs in ALS trials appear to signify irreversible disease progression rather than transient, recoverable complications. These findings underscore an importance to distinguish between symptoms attributable to natural disease progression and those arising from genuine treatment-related safety concerns—particularly in early-phase trials, where safety signals determine the advancement to subsequent phases. Attributing disease progression events to investigational treatments may result in the early termination of promising therapies. Reevaluating current safety assessment strategies could provide insights into the persistently high failure rate of ALS trials.
Volume
72
First Page
S97
