Another Negative Lithium Trial in ALS
Therapeutic doses of lithium carbonate are no more effective than subtherapeutic doses in amyotrophic lateral sclerosis (ALS), according to a newly published, multicenter Italian study. The randomized, dose-finding trial, the findings of which are available today in an e-pub version of Neurology, is the second trial to demonstrate no benefit of the compound in ALS.
A total of 171 patients with probable or definite mild-moderate ALS received either therapeutic (blood levels, 0.4-0.8 mEq/L) or subtherapeutic (blood levels, 0.2-0.4 mEq/L) doses of lithium in single-blind fashion.* In the 15-month study, there was no difference between treatment groups in the rate of the composite primary endpoint, tracheostomy-free survival or “severe” loss of autonomy. (At about 1 year, the rate of the primary endpoint was approximately 60% in both treatment groups, by my read of the provided Kaplan-Meier graph.) The rates of secondary endpoints were also not significantly different between therapeutic and subtherapeutic lithium. In addition, a post-hoc analysis of the primary endpoint, which excluded patients who were not taking riluzole (the only FDA-approved treatment for ALS), showed no treatment-related differences.
A high percentage of patients, nearly 70%, discontinued the study because of adverse events (n = 32), perceived lack of efficacy (n = 32), or poor adherence (n = 4); however, there were no significant differences between the treatment groups in rates of study discontinuation. In each treatment group, 25 discontinuing patients reached the primary endpoint, and another 15 patients completed the 15-month study.
The negative outcomes in this limited Italian study support findings from a recently reported, placebo-controlled North American study (N = 84). Both studies were conducted on the basis of the positive results of Fornai et al, who advertised in 2008 the benefits of lithium in an ALS mouse model and a pilot trial of 84 ALS patients. Last year, Gill et al reported that they were unable to reproduce the positive effect of lithium in the mouse model.
* Evaluating physicians were blinded to treatment.