Prognostic clinical and biological markers for amyotrophic lateral sclerosis disease progression: validation and implications for clinical trial design and analysisResearch in context
Michael Benatar,
Eric A. Macklin,
Andrea Malaspina,
Mary-Louise Rogers,
Eran Hornstein,
Vittoria Lombardi,
Danielle Renfrey,
Stephanie Shepheard,
Iddo Magen,
Yahel Cohen,
Volkan Granit,
Jeffrey M. Statland,
Jeannine M. Heckmann,
Rosa Rademakers,
Caroline A. McHutchison,
Leonard Petrucelli,
Corey T. McMillan,
Joanne Wuu,
Michael Benatar,
Volkan Granit,
Jeffrey M. Statland,
Jeannine M. Heckmann,
Corey T. McMillan,
Lauren Elman,
John Ravits,
Jonathan Katz,
Jaya Trivedi,
Andrea Swenson,
Ted M. Burns,
James Caress,
Carlayne Jackson,
Samuel Maiser,
Erik P. Pioro,
Yuen So
Affiliations
Michael Benatar
Department of Neurology, University of Miami Miller School of Medicine, Miami, FL, USA; Corresponding author. Department of Neurology, University of Miami Miller School of Medicine, 1120 NW 14 Street, CRB Suite 1300, Miami, FL, 33136, USA.
Eric A. Macklin
Departments of Neurology and Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
Andrea Malaspina
UCL Queen Square Motor Neuron Disease Center, UCL Queen Square Institute of Neurology, University College London, Queen Square, London, UK
Mary-Louise Rogers
Flinders Health and Medical Research Institute, College of Medicine and Public Health, Flinders University, Adelaide, South Australia, Australia
Eran Hornstein
Department of Molecular Genetics and Molecular Neuroscience, Weizmann Institute of Science, Israel
Vittoria Lombardi
UCL Queen Square Motor Neuron Disease Center, UCL Queen Square Institute of Neurology, University College London, Queen Square, London, UK
Danielle Renfrey
Flinders Health and Medical Research Institute, College of Medicine and Public Health, Flinders University, Adelaide, South Australia, Australia
Stephanie Shepheard
Flinders Health and Medical Research Institute, College of Medicine and Public Health, Flinders University, Adelaide, South Australia, Australia
Iddo Magen
Department of Molecular Genetics and Molecular Neuroscience, Weizmann Institute of Science, Israel
Yahel Cohen
Department of Molecular Genetics and Molecular Neuroscience, Weizmann Institute of Science, Israel
Volkan Granit
Department of Neurology, University of Miami Miller School of Medicine, Miami, FL, USA
Jeffrey M. Statland
Department of Neurology, University of Kansas Medical Center, Kansas City, KS, USA
Jeannine M. Heckmann
Division of Neurology, Department of Medicine, University of Cape Town, South Africa
Rosa Rademakers
VIB Center for Molecular Neurology, Department of Biomedical Sciences, University of Antwerp, Antwerp, Belgium; Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA
Caroline A. McHutchison
School of Philosophy, Psychology, and Language Sciences, The University of Edinburgh, Edinburgh, UK; Euan MacDonald Centre for Motor Neuron Disease Research, The University of Edinburgh, Edinburgh, UK
Leonard Petrucelli
Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA
Corey T. McMillan
Department of Neurology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA
Joanne Wuu
Department of Neurology, University of Miami Miller School of Medicine, Miami, FL, USA; Corresponding author. Department of Neurology, University of Miami Miller School of Medicine, 1120 NW 14 Street, CRB Suite 1300, Miami, FL, 33136, USA.
Summary: 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 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).
