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.

Arimoclomol is an investigational drug for amyotrophic lateral sclerosis (ALS) that amplifies heat shock protein gene expression during cell stress. The objectives of the present study were to assess the safety, tolerability, and pharmacokinetics of arimoclomol in ALS. Eighty-four participants with ALS received arimoclomol at one of three oral doses (25, 50, or 100 mg three times daily) or placebo. The primary outcome measure was safety and tolerability. A subset of 44 participants provided serum and cerebrospinal fluid (CSF) samples for pharmacokinetic analysis. Participants who completed 12 weeks of treatment could enroll in a 6-month open-label study. Arimoclomol at doses up to 300 mg/day was well tolerated and safe. Arimoclomol resulted in dose-linear pharmacologic exposures and the half-life did not change with continued treatment. Arimoclomol CSF levels increased with dose. Arimoclomol was shown to be safe, and it crosses the blood-brain barrier. Serum pharmacokinetic profiles support dosing of three times per day. An efficacy study in ALS is planned.

Our objective was to survey ALS clinicians and researchers regarding what percentage reduction in the ALSFRS-R (Amyotrophic Lateral Sclerosis Functional Rating Scale - Revised) slope they would consider clinically meaningful. A nine-question survey was provided to 65 members of the Northeast ALS Consortium (NEALS). They were asked to rate the clinical relevance of 10-50% changes in decline of the ALSFRS-R slope on a seven-point scale (1-7), where 1='not at all clinically meaningful', 4='somewhat clinically meaningful', and 7='very clinically meaningful'. Ninety per cent of participants rated a 20% change in the decline of the ALSFRS-R score as the percentage in which a somewhat clinically significant change starts to be noted (i.e. score of 4 or higher). All participants endorsed a 25% or higher change in the ALSFRS-R score as at least somewhat clinically meaningful (score of 4 or higher). Ninety-three per cent of the participants viewed a 50% change in decline as very clinically meaningful (score of 7). This survey demonstrated that the majority of clinicians and clinical researchers surveyed believe that a therapy that resulted in a change of 20% or greater in the slope of the ALSFRS-R would be clinically meaningful.

Objective: To use a historical placebo control design to determine whether lithium carbonate slows progression of amyotrophic lateral sclerosis (ALS).Methods: A phase II trial was conducted at 10 sites in the Western ALS Study Group using similar dosages (300-450 mg/day), target blood levels (0.3-0.8 mEq/L), outcome measures, and trial duration (13 months) as the positive trial. However, taking riluzole was not a requirement for study entry. Placebo outcomes in patients matched for baseline features from a large database of recent clinical trials, showing stable rates of decline over the past 9 years, were used as historical controls. Results:The mean rate of decline of the ALS Functional Rating Scale-Revised was greater in 107 patients taking lithium carbonate (Ϫ1.20/month, 95% confidence interval [CI] Ϫ1.41 to Ϫ0.98) than that in 249 control patients (Ϫ1.01/month, 95% CI Ϫ1.11 to Ϫ0.92, p ϭ 0.04). There were no differences in secondary outcome measures (forced vital capacity, time to failure, and quality of life), but there were more adverse events in the treated group. Conclusions:The lack of therapeutic benefit and safety concerns, taken together with similar results from 2 other recent trials, weighs against the use of lithium carbonate in patients with ALS. The absence of drift over time and the availability of a large database of patients for selecting a matched historical control group suggest that use of historical controls may result in more efficient phase II trials for screening putative ALS therapeutic agents. Classification of evidence:This study provided Class IV evidence that lithium carbonate does not slow the rate of decline of function in patients with ALS over 13 months. Neurology ® 2011;77:973-979 GLOSSARY ALS ϭ amyotrophic lateral sclerosis; ALSFRS-R ϭ ALS Functional Rating Scale-Revised; CI ϭ confidence interval; FVC ϭ forced vital capacity; MINO ϭ minocycline in ALS trial; NSAE ϭ nonserious adverse event; QOL ϭ quality of life; SAE ϭ serious adverse event; WALS ϭ Western ALS Study Group.

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