Addressing heterogeneity in amyotrophic lateral sclerosis CLINICAL TRIALS
Goyal, Namita A; Berry, James D; Windebank, Anthony; Nathan, P; Maragakis, Nicholas J; van den Berg, Leonard H; Genge, Angela; Miller, Robert; Baloh, Robert H; Kern, Ralph; Gothelf, Yael; Lebovits, Chaim; Cudkowicz, Merit
(2020) Muscle & Nerve, volume 62, issue 2, pp. 156 - 166
(Article)
Abstract
Amyotrophic lateral sclerosis (ALS) is a debilitating neurodegenerative disorder with complex biology and significant clinical heterogeneity. Many preclinical and early phase ALS clinical trials have yielded promising results that could not be replicated in larger phase 3 confirmatory trials. One reason for the lack of reproducibility may be ALS biological
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and clinical heterogeneity. Therefore, in this review, we explore sources of ALS heterogeneity that may reduce statistical power to evaluate efficacy in ALS trials. We also review efforts to manage clinical heterogeneity, including use of validated disease outcome measures, predictive biomarkers of disease progression, and individual clinical risk stratification. We propose that personalized prognostic models with use of predictive biomarkers may identify patients with ALS for whom a specific therapeutic strategy may be expected to be more successful. Finally, the rapid application of emerging clinical and biomarker strategies may reduce heterogeneity, increase trial efficiency, and, in turn, accelerate ALS drug development.
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Keywords: amyotrophic lateral sclerosis, biomarkers, clinical trials, disease heterogeneity, enrichment strategies, outcome measures, Reproducibility of Results, Prognosis, Risk Assessment, Humans, Amyotrophic Lateral Sclerosis/drug therapy, Biological Variation, Population, Disease Progression, Transcranial Magnetic Stimulation, Biomarkers, Speech, Drug Development, Physical Functional Performance, Respiratory Function Tests, Outcome Assessment, Health Care, Clinical Trials as Topic/methods, Muscle Strength, Precision Medicine, Clinical Neurology, Physiology (medical), Cellular and Molecular Neuroscience, Physiology, Review, Journal Article
ISSN: 0148-639X
Publisher: John Wiley & Sons Inc.
Note: Publisher Copyright: © 2020 The Authors. Muscle & Nerve published by Wiley Periodicals, Inc.
(Peer reviewed)