Review of disease-modifying drug trials in amyotrophic lateral sclerosis

J Neurol Neurosurg Psychiatry. 2022 May;93(5):521-529. doi: 10.1136/jnnp-2021-328470. Epub 2022 Feb 28.


We analysed clinical trials of pharmacological interventions on patients with amyotrophic lateral sclerosis (ALS), and compared study quality and design features. The systematic review included articles published in PubMed and trials registered in Included studies were randomised double-blind placebo-controlled clinical trials assessing a disease-modifying pharmacological intervention. Studies were excluded if primary end points were safety or dose finding. A total of 28 735 articles and 721 current trials were identified. 76 published articles and 23 ongoing trials met inclusion criteria; they referred to distinct populations comprising 22 817 participants with ALS. Most articles and all current trials had parallel group design; few articles had cross-over design. A run-in observation period was included in about 20% of published studies and ongoing trials. Primary end points included functional assessment, survival, muscle strength, respiratory function, biomarkers and composite measures. Most recent trials had only functional assessment and survival. Risk of bias was high in 23 articles, moderate in 35, low in 18. A disease modification effect was observed for 10 interventions in phase II studies, two of which were confirmed in phase III. Three confirmatory phase III studies are currently underway. The present review provides cues for the design of future trials. Functional decline and survival, as single or composite measures, stand as the reference end points. Post hoc analyses should not be performed, particularly in studies using composite end points. There is a general agreement on diagnostic criteria; but eligibility criteria must be improved. Run-in observations may be used for censoring patients but are discouraged for refining participants' eligibility. The ALS Functional Rating Scale-Revised needs improvement for use as an ordinal measure of functional decline.

Keywords: motor neuron disease; randomised trials.

Publication types

  • Review
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amyotrophic Lateral Sclerosis* / drug therapy
  • Humans
  • Randomized Controlled Trials as Topic