Abstract
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.BackgroundWith 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.A subset of patients with ALS recruited through the multi-center Phenotype-Genotype-Biomarker study (clinicaltrials.gov: NCT02327845 ) was identified as "trial-like" based on meeting common trial eligibility criteria. Clinical phenotyping was performed by evaluators trained in relevant assessments. Serum neurofilament light (NfL) and phosphorylated neurofilament heavy (pNfH), urinary p75 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.MethodsA subset of patients with ALS recruited through the multi-center Phenotype-Genotype-Biomarker study (clinicaltrials.gov: NCT02327845 ) was identified as "trial-like" based on meeting common trial eligibility criteria. Clinical phenotyping was performed by evaluators trained in relevant assessments. Serum neurofilament light (NfL) and phosphorylated neurofilament heavy (pNfH), urinary p75 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.Baseline serum NfL is a powerful prognostic biomarker, predicting survival and ALSFRS-R rate of decline. Serum NfL <40pg/ml and >100pg/ml correspond to future ALSFRS-R slopes of ∼0.5 and 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 ∼25% sample size saving above those achieved by inclusion of either clinical predictors or ENCALS score alone. The prognostic value of serum pNfH, urinary p75 ECD , and plasma miR-181ab is more limited.FindingsBaseline serum NfL is a powerful prognostic biomarker, predicting survival and ALSFRS-R rate of decline. Serum NfL <40pg/ml and >100pg/ml correspond to future ALSFRS-R slopes of ∼0.5 and 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 ∼25% sample size saving above those achieved by inclusion of either clinical predictors or ENCALS score alone. The prognostic value of serum pNfH, urinary p75 ECD , and plasma miR-181ab is more limited.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 thresholds of NfL might also be used in trial design, for enrichment or stratified randomisation, to improve trial efficiency.InterpretationAmong 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 thresholds of NfL might also be used in trial design, for enrichment or stratified randomisation, to improve trial efficiency.NIH (U01-NS107027, U54-NS092091). ALSA (16-TACL-242).FundingNIH (U01-NS107027, U54-NS092091). ALSA (16-TACL-242).Evidence Before This Study: The phenotypic heterogeneity of ALS poses a challenge for clinical trials, making it more difficult to discern therapeutic effects of investigational agents amidst the noise of natural variability. Prognostic markers are important tools to help mitigate this issue. A host of clinical markers and putative biomarkers have been proposed to have prognostic value, but their relative utility, especially when considered jointly, and the practical implications of their use, have not been well defined.Added Value of This Study: Using a trial-like population from a natural history study, in which clinical trial-grade phenotypic data and multi-modal biomarker data were collected, we show that a subset of clinical factors, encapsulated by the ENCALS predictive model score, and serum neurofilament light chain (NfL) are the most powerful prognostic markers when considering either ALSFRS-R functional decline or permanent assisted ventilation (PAV)/tracheostomy-free survival. Importantly, serum NfL adds prognostic value even after adjusting for the ENCALS score, yielding an additional sample size saving of ∼27% in a hypothetical future clinical trial. While serum phosphorylated neurofilament heavy chain (pNfH), urinary p75 ECD , and plasma miR-181ab each holds some prognostic value, when considered together with the ENCALS score and serum NfL, only p75 ECD may yield additional but modest sample size saving. Implication of All Available Evidence: Blood NfL is a validated biomarker for multiple contexts-of-use. As a prognostic marker, it should be used together with clinical predictors, such as the ENCALS predictive model score, in all ongoing and future ALS clinical trials. The utility of urinary p75 ECD and plasma miR-181ab is less clear. Serum pNfH, as well as serum uric acid, albumin, creatinine, and C-reactive protein (CRP), provide no additional prognostic information.Research in ContextEvidence Before This Study: The phenotypic heterogeneity of ALS poses a challenge for clinical trials, making it more difficult to discern therapeutic effects of investigational agents amidst the noise of natural variability. Prognostic markers are important tools to help mitigate this issue. A host of clinical markers and putative biomarkers have been proposed to have prognostic value, but their relative utility, especially when considered jointly, and the practical implications of their use, have not been well defined.Added Value of This Study: Using a trial-like population from a natural history study, in which clinical trial-grade phenotypic data and multi-modal biomarker data were collected, we show that a subset of clinical factors, encapsulated by the ENCALS predictive model score, and serum neurofilament light chain (NfL) are the most powerful prognostic markers when considering either ALSFRS-R functional decline or permanent assisted ventilation (PAV)/tracheostomy-free survival. Importantly, serum NfL adds prognostic value even after adjusting for the ENCALS score, yielding an additional sample size saving of ∼27% in a hypothetical future clinical trial. While serum phosphorylated neurofilament heavy chain (pNfH), urinary p75 ECD , and plasma miR-181ab each holds some prognostic value, when considered together with the ENCALS score and serum NfL, only p75 ECD may yield additional but modest sample size saving. Implication of All Available Evidence: Blood NfL is a validated biomarker for multiple contexts-of-use. As a prognostic marker, it should be used together with clinical predictors, such as the ENCALS predictive model score, in all ongoing and future ALS clinical trials. The utility of urinary p75 ECD and plasma miR-181ab is less clear. Serum pNfH, as well as serum uric acid, albumin, creatinine, and C-reactive protein (CRP), provide no additional prognostic information.