Prognostic clinical and biological markers for amyotrophic lateral sclerosis disease progression: validation and implications for clinical trial design and analysis

Background With increasing recognition of the value of incorporating prognostic markers into amyotrophic lateral sclerosis (ALS) trial design and analysis plans, there is a pressing need to understand which among the prevailing clinical and biochemical markers have real value, and how they can be optimally used. Methods A subset of patients with ALS recruited through the multi-center Phenotype-Genotype-Biomarker study (clinicaltrials.gov: NCT02327845) was identified fi ed as " trial-like" " based on meeting common trial eligibility criteria. Clinical phenotyping was performed by evaluators trained in relevant assessments. Serum neurofilament fi lament light (NfL) and phosphorylated neurofilament fi lament heavy (pNfH), urinary p75ECD , ECD , plasma microRNA-181, and an array of biochemical and clinical measures were evaluated for their prognostic value. Associations with functional progression were estimated by random-slopes mixed models of ALS functional rating scale-revised (ALSFRS-R) score. Associations with survival were estimated by log-rank test and Cox proportional hazards regression. Potential sample size savings from adjusting for given biomarkers in a hypothetical trial were estimated. Findings Baseline serum NfL is a powerful prognostic biomarker, predicting survival and ALSFRS-R rate of decline. Serum NfL <40 pg/mL and >100 pg/mL correspond to future ALSFRS-R slopes of similar to 0.5 and similar to 1.5 points/month, respectively. Serum NfL also adds value to the best available clinical predictors, encapsulated by the European Network to Cure ALS (ENCALS) predictor score. In models of functional decline, the addition of NfL yields similar to 25% sample size saving above those achieved by inclusion of either clinical predictors or ENCALS score alone. The prognostic value of serum pNfH, urinary p75ECD , ECD , and plasma miR-181ab is more limited. Interpretation Among the multitude of biomarkers considered, only blood NfL adds value to the ENCALS prediction model and should be incorporated into analysis plans for all ongoing and future ALS trials. Defined fi ned thresholds of NfL might also be used in trial design, for enrichment or stratified fi ed randomisation, to improve trial efficiency. fi ciency. Funding NIH (U01-NS107027, U54-NS092091). ALSA (16-TACL-242). Copyright (c) 2024 The Author(s). Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).