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.
More than 30 phase II or III clinical trials have been carried out in amyotrophic lateral sclerosis (ALS). Only riluzole, however, has been shown to extend survival and/or time to tracheostomy. Many early ALS trials lacked solid pharmacodynamic and pharmacokinetic data for the treatment being tested, challenging the interpretation of the efficacy and pathway relevance. Understanding of the genetics and pathophysiology of ALS has improved considerably in the past decade, but biomarkers of disease activity remain lacking. A more efficient approach to early phase clinical trials is needed to accelerate the identification of useful agents for ALS. Here we summarize our current thinking about phase II design options and the potential benefits of a clinical trial network for phase II trials in ALS.
Preradiotherapy low albumin levels and NLR>5 correlate with decreased survival in patients with locally advanced pancreatic adenocarcinoma treated with SBRT, indicating the prognostic value of systemic inflammatory markers (such as NLR) and a role of nutritional supplementation to improve outcomes in these patients. Further investigation is warranted.
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