Journal article
Prognostic clinical and biological markers for amyotrophic lateral sclerosis disease progression: validation and implications for clinical trial design and analysis
EBioMedicine, Vol.108, 105323
10/01/2024
DOI: 10.1016/j.ebiom.2024.105323
PMCID: PMC11415817
PMID: 39270623
Abstract
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 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 p75ECD, 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 ∼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 p75ECD, 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 thresholds of NfL might also be used in trial design, for enrichment or stratified randomisation, to improve trial efficiency. Funding: NIH (U01-NS107027, U54-NS092091). ALSA (16-TACL-242).
Details
- Title: Subtitle
- Prognostic clinical and biological markers for amyotrophic lateral sclerosis disease progression: validation and implications for clinical trial design and analysis
- Creators
- Michael BenatarEric A. Macklin - Harvard Medical SchoolAndrea Malaspina - University College LondonMary-Louise Rogers - Flinders UniversityEran Hornstein - Weizmann Institute of ScienceVittoria Lombardi - University College LondonDanielle Renfrey - Flinders UniversityStephanie Shepheard - Flinders UniversityIddo Magen - Weizmann Institute of ScienceYahel Cohen - Weizmann Institute of ScienceVolkan Granit - University of MiamiJeffrey M. Statland - University of Kansas Medical CenterJeannine M. Heckmann - University of Cape TownRosa RademakersCaroline A. McHutchisonLeonard Petrucelli - Mayo ClinicCorey T. McMillan - University of PennsylvaniaJoanne WuuLauren ElmanJohn RavitsJonathan KatzJaya TrivediAndrea SwensonTed M. BurnsJames CaressCarlayne JacksonSamuel MaiserErik P. PioroYuen So
- Resource Type
- Journal article
- Publication Details
- EBioMedicine, Vol.108, 105323
- Publisher
- Elsevier; AMSTERDAM
- DOI
- 10.1016/j.ebiom.2024.105323
- PMID
- 39270623
- PMCID
- PMC11415817
- ISSN
- 2352-3964
- eISSN
- 2352-3964
- Grant note
- NIH: U01-NS107027, U54-NS092091 ALSA: 16-TACL-242
NIH (U01-NS107027, U54-NS092091) . ALSA (16-TACL-242) .
- Language
- English
- Date published
- 10/01/2024
- Academic Unit
- Neurology
- Record Identifier
- 9984736597002771
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