Major Finding: ALS patients experienced similar numbers of events (a decline of six or more points on the ALSFRS-R or death) during treatment with lithium plus riluzole or placebo plus riluzole (22 of 40 patients vs. 20 of 44 patients, respectively).
Data Source: Double-blind, randomized, placebo-controlled trial of 84 patients.
Disclosures: The trial was funded by the National Institute for Neurological Disorders and Stroke and the ALS Society of Canada. Mr. Swash and the investigators reported no relevant conflicts of interest.
The addition of lithium to riluzole for the treatment of amyotrophic lateral sclerosis does not substantially slow disease progression compared with riluzole alone, according to data from a double-blind, randomized, phase II study.
The findings contradict those of a small pilot study that was published in 2008 suggesting that the addition of lithium to standard riluzole therapy led to a slower decline in disease-related disability compared with riluzole therapy alone, according to the lead investigator Dr. Swati P. Aggarwal of Massachusetts General Hospital, Boston, and her colleagues.
The investigators stopped the trial on the recommendation of the data and safety monitoring board and the National Institute of Neurological Disorders and Stroke after the first planned interim analysis showed that lithium in combination with riluzole provided no added benefit over placebo plus riluzole (Lancet Neurol. 2010 April 6 [doi:10.1016/S1474-4422(10)70068-5
Although the findings of the phase II study provide “no convincing evidence for the use of lithium as a treatment for patients with ALS,” Dr. Aggarwal and her associates wrote that future studies should assess the possibility of smaller beneficial effects of lithium in ALS and the therapeutic potential of compounds that target the induction of autophagy.
The phase II trial of 84 patients with ALS from the United States and Canada used a time-to-event design to try to validate the promising results of the earlier study (Proc. Natl. Acad. Sci. U.S.A. 2008;105:2052–7).
This design allowed the investigators to compare the distributions of how long it took patients to show a decrease of at least six points on the ALS functional rating scale–revised (ALSFRS-R) or to die. The study was designed to have greater than 80% power to detect a 40% decrease in the rate of ALSFRS-R decline if all of the originally planned 250 patients had completed the study, they noted.
In an accompanying editorial, Michael Swash from Barts and the London School of Medicine and Dentistry, London, praised the novelty of the study's time-to-event design, which was powered specifically to detect a major effect of lithium, because of the potential for a rapid result and the possibility of crossover from placebo to treatment (Lancet Neurol. 2010 April 6 [doi:10.1016/S1474-4422(10)70085-5
“Use of this study design in trials of ALS represents an important advance,” he wrote.
“Now all that is required is a drug that has plausible pharmacology and pharmacokinetics, and has a favorable side effect profile, which has been studied in rigorous experiments using SOD1 mice.” This tall order, he noted, is “worth striving for.”
Of the 40 patients in the lithium group, 1 patient died and 21 had a decrease of at least six points on the ALSFRS-R. In the placebo group, 3 of 44 patients died and 17 had a decrease of six points or more on the ALSFRS-R. In addition to the reported deaths, 18 patients experienced 29 serious events after randomization, with no difference in the rate of occurrence between the two groups, Dr. Aggarwal and her coauthors reported.
The lithium doses in the study ranged from 150 mg to 1,050 mg per day to achieve a serum concentration of 0.4–0.8 mEq/L, which matches the range used in the pilot study, the authors wrote.
Although the investigators could not rule out the possibility of a small positive effect associated with lithium or that other serum concentration ranges could be beneficial, “the lower limit of the 95% CI around the difference in rates of decline of the ALSFRS-R total score was −0.43, suggesting that although a modest benefit of lithium was not ruled out by this study, an effect of 43% or more could be eliminated,” they wrote.