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

Abstract

Background We studied the safety and efficacy of lithium in combination with riluzole in ALS. Recently, a pilot study demonstrated a dramatic effect of lithium in slowing ALS progression. To confirm or refute these findings, United States and Canadian funding organizations and investigators collaborated to design and execute a multicenter, double-blind placebo controlled trial in a rapid and efficient manner. Methods Eligible participants had familial or sporadic ALS diagnosed as clinically possible, laboratory supported probable, probable, or definite ALS according to El Escorial criteria and were taking a stable dose of riluzole for at least 30 days. Subjects were equally randomized by a centralized computer to receive either lithium (serum levels maintained between 0.4-0.8 mEq/L) or placebo. Subjects, caregivers and investigators were blinded to treatment assignment throughout the study. The study used a ‘time to an event’ design, novel to ALS trials. An event was defined as ≥ 6 points drop in the ALS Functional Rating Scale-Revised (ALSFRS-R) score or death. The primary efficacy analysis used a log-rank test to compare the distributions of the time to an event between the lithium and placebo groups. The first interim analysis occurred after 84 of 250 participants were randomized. The stopping boundary for futility at first interim analysis was a p-value ≥ 0.68. Findings The study was terminated early at the first intent-to-treat interim analysis as criterion for futility was met. A log-rank statistical analysis testing the superiority of lithium favored placebo (p-value = 0.78). In the final dataset, 22/40 subjects experienced an event in the lithium group compared to 20/44 subjects in the placebo group (p= 0.51). The point estimate (95% CI) for the hazard ratio of reaching the primary endpoint was 1.126 (0.6116 to 2.073). There were no major safety concerns. Fall (p=0.04) and back pain (p=0.05) were significantly more common in the lithium group. Interpretation Based on the standard error around the observed point estimate of effect, lithium in combination with riluzole did not reach the pre-specified threshold of a 43% or greater slowing in ALS disease progression which contradicts the pilot study. The ‘time to an event’ design enhanced enrollment and expeditiously answered an important clinical question while optimizing patient resources and funds.

Strength Testing in Motor Neuron Diseases

“…To address issues of evaluator variability, a rigorous training and evaluation program was implemented, with standard patient and evaluator positions mandated and a prespecified level of test-retest performance required. In ALS, trials of lithium, ceftriaxone, dexpramipexole, and tirasemtiv have been successfully performed, with reliable data acquired that have characteristics suggesting that measurements of muscle strength with HHD is a sensitive measure of disease progression and therapeutic efficacy [29][30][31][32]. For lithium, ceftriaxone, and dexpramipexole, HHD data closely matched other outcomes, including ALSFRS-R and slow vital capacity, and survival.…”

Potential for Electronic Health Records and Online Social Networking to Redefine Medical Research

“…After news spread of the potential benefit of lithium treatments for ALS, one patient gathered 250 PatientsLikeMe ALS volunteers to self-experiment with lithium. Although there are obvious challenges with such studies, it is worth noting that the patients had a larger sample than the original report and, unlike the initial findings, did not appear to demonstrate benefit from lithium (66 ), which was also the conclusion of a traditional follow-up study (67 ).…”

Clinical Trial Designs in Amyotrophic Lateral Sclerosis: Does One Design Fit All?

“…Other design changes might be equally successful, including a time-toevent design, in which trial participants are offered openlabel access to a drug if a certain end point is reached (e.g., a four-point drop in the ALS Functional Rating Scale-Revised or 10% drop in vital capacity). Such designs were successfully used in the ALS trials of lithium, a repurposed drug that generated a great deal of patient interest and demand for off-label prescription [8,9].…”

“…A large, costly efficacy trial may be avoided if this threshold is not met, as seen in the coenzyme Q10 trial in ALS [78]. Futility stopping rules and a time-to-event design in a randomized trial of lithium in ALS ensured speedy enrollment before halting of the trial for futility at the first interim analysis [8].…”