Addressing heterogeneity in amyotrophic lateral sclerosis CLINICAL TRIALS

Namita A. Goyal, James D. Berry, Anthony Windebank, Nathan P. Staff, Nicholas J. Maragakis, Leonard H. van den Berg, Angela Genge, Robert Miller, Robert H. Baloh, Ralph Kern, Yael Gothelf, Chaim Lebovits, Merit Cudkowicz

Research output: Contribution to journalReview articlepeer-review

4 Scopus citations


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 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.

Original languageEnglish (US)
Pages (from-to)156-166
Number of pages11
JournalMuscle and Nerve
Issue number2
StatePublished - Aug 1 2020


  • amyotrophic lateral sclerosis
  • biomarkers
  • clinical trials
  • disease heterogeneity
  • enrichment strategies
  • outcome measures

ASJC Scopus subject areas

  • Physiology
  • Clinical Neurology
  • Cellular and Molecular Neuroscience
  • Physiology (medical)


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