Phase II screening trial of lithium carbonate in amyotrophic lateral sclerosis: examining a more efficient trial design

Neurology. 2011 Sep 6;77(10):973-9. doi: 10.1212/WNL.0b013e31822dc7a5. Epub 2011 Aug 3.


Objective: To use a historical placebo control design to determine whether lithium carbonate slows progression of amyotrophic lateral sclerosis (ALS).

Methods: A phase II trial was conducted at 10 sites in the Western ALS Study Group using similar dosages (300-450 mg/day), target blood levels (0.3-0.8 mEq/L), outcome measures, and trial duration (13 months) as the positive trial. However, taking riluzole was not a requirement for study entry. Placebo outcomes in patients matched for baseline features from a large database of recent clinical trials, showing stable rates of decline over the past 9 years, were used as historical controls.

Results: The mean rate of decline of the ALS Functional Rating Scale-Revised was greater in 107 patients taking lithium carbonate (-1.20/month, 95% confidence interval [CI] -1.41 to -0.98) than that in 249 control patients (-1.01/month, 95% CI -1.11 to -0.92, p = 0.04). There were no differences in secondary outcome measures (forced vital capacity, time to failure, and quality of life), but there were more adverse events in the treated group.

Conclusions: The lack of therapeutic benefit and safety concerns, taken together with similar results from 2 other recent trials, weighs against the use of lithium carbonate in patients with ALS. The absence of drift over time and the availability of a large database of patients for selecting a matched historical control group suggest that use of historical controls may result in more efficient phase II trials for screening putative ALS therapeutic agents.

Classification of evidence: This study provided Class IV evidence that lithium carbonate does not slow the rate of decline of function in patients with ALS over 13 months.

Publication types

  • Clinical Trial, Phase II
  • Comparative Study
  • Multicenter Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Amyotrophic Lateral Sclerosis / drug therapy*
  • Amyotrophic Lateral Sclerosis / pathology*
  • Disease Progression*
  • Female
  • Humans
  • Lithium Carbonate / therapeutic use*
  • Male
  • Mass Screening* / trends
  • Middle Aged
  • Research Design / trends
  • Young Adult


  • Lithium Carbonate