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Review of disease-modifying drug trials in amyotrophic lateral sclerosis
  1. Paolo Tornese1,
  2. Stefania Lalli1,
  3. Antoniangela Cocco1,
  4. Alberto Albanese1,2
  1. 1 Department of Neurology, IRCCS Humanitas Research Hospital, Rozzano, Italy
  2. 2 Department of Neuroscience, Catholic University, Milan, Italy
  1. Correspondence to Professor Alberto Albanese, Department of Neurology, IRCCS Humanitas Research Hospital, Rozzano, Italy; alberto.albanese{at}


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.

  • motor neuron disease
  • randomised trials

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  • Contributors All the authors have contributed to this manuscript. There are no other contributors. This work was carried out within the frame of an European Horizon 2020 grant to Alberto Albanese. The original idea was developed by Alberto Albanese. Paolo Tornese carried out data collection. Data analysis was jointly performed by Paolo Tornese, Stefania Lalli and Antoniangela Cocco.

  • Funding Funded by the European Union’s Horizon 2020 research and innovation programme (grant agreement 755 094 to AA).

  • Competing interests None declared.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.

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