Safety and efficacy of lithium in combination with riluzole for treatment of amyotrophic lateral sclerosis: a randomised, double-blind, placebo-controlled trial

Abstract

Background: In a pilot study, lithium treatment slowed progression of amyotrophic lateral sclerosis (ALS). We aimed to confirm or disprove these findings by assessing the safety and efficacy of lithium in combination with riluzole in patients with ALS.

Methods: We did a double-blind, placebo-controlled trial with a time-to-event design. Between January and June, 2009, patients with ALS who were taking a stable dose of riluzole for at least 30 days were randomly assigned (1:1) by a centralised computer to receive either lithium or placebo. Patients, caregivers, investigators, and all site study staff with the exception of site pharmacists were masked to treatment assignment. The primary endpoint was the time to an event, defined as a decrease of at least six points on the revised ALS functional rating scale score or death. Interim analyses were planned for when 84 patients had been allocated treatment, 6 months later or after 55 events, and after 100 events. Analysis was by intention to treat. The stopping boundary for futility at the first interim analysis was a p value of at least 0.68. We used a log-rank test to compare the distributions of the time to an event between the lithium and placebo groups. This trial is registered with ClinicalTrials.gov, NCT00818389.

Findings: At the first interim analysis, 22 of 40 patients in the lithium group had an event compared with 20 of 44 patients in the placebo group (log rank p=0.51). The hazard ratio of reaching the primary endpoint was 1.13 (95% CI 0.61-2.07). The study was stopped at the first interim analysis because criterion for futility was met (p=0.78). The difference in mean decline in the ALS functional rating scale score between the lithium group and the placebo group was 0.15 (95% CI -0.43 to 0.73, p=0.61). There were no major safety concerns. Falls (p=0.04) and back pain (p=0.05) were more common in the lithium group than in the placebo group.

Interpretation: We found no evidence that lithium in combination with riluzole slows progression of ALS more than riluzole alone. The time-to-event endpoint and use of prespecified interim analyses enabled a clear result to be obtained rapidly. This design should be considered for future trials testing the therapeutic efficacy of drugs that are easily accessible to people with ALS.

Funding: National Institute of Neurological Disorders and Stroke, ALS Association, and ALS Society of Canada.

Figure 1. Participant flow chart

The disposition of subjects in study, including the number screened, randomized, failed, early terminated, and completed.

Figure 2. Survival curve for time to failure

Kaplan-Meier survival curve of survival to event (defined as ≥ 6 points drops in ALSFRS-R score or death) of lithium (solid line) versus placebo (dashed line).

Figure 3

Figure 3a: ALSFRS-R Total Change. The ALSFRS-R total change from baseline by visit (in weeks) in the lithium treated subjects (solid line) vs. the placebo group (dashed line). The values plotted are mean difference in scores from baseline value. The bars indicate 1 standard error of the mean. Figure 3b: Change in Vital Capacity. The Vital Capacity change from baseline by visit (in weeks) in the lithium treated subjects (solid line) vs. the placebo group (dashed line). The values plotted are mean difference in scores from baseline value. The bars indicate 1 standard error of the mean.

Figure 4. Lithium levels

Box plots of plasma lithium levels by visit (in weeks). The band represents the median lithium levels; the bottom and the top of the boxes represent the 25^th and 75^th percentiles respectively. The whiskers represent 1.5 times the lower and upper interquartile range.