A phase 2, double-blind, placebo-controlled trial of a valproate/lithium combination in ALS patients.

BACKGROUND: Few treatments for amyotrophic lateral sclerosis (ALS) are currently available. A combination of lithium carbonate and valproic acid (VPA-Li) was proved to inhibit motor neuron death and slow down the disease progression.

METHODS: Outpatients with typical ALS picture were enrolled in a randomized, placebo-controlled trial to assess the efficacy of orally administered VPA-Li. Changes in a functional scale score (ALSFRS-R) and survival rate were chosen as primary outcome variables. Secondary outcome variables included BMI, respiratory monitoring, quality of life, and a global impression of the treatment.

RESULTS: Out of 42 enrolled patients, 20 individuals given VPA-Li and 18 under placebo were included in the final analysis. In total, 45% of patients receiving VPA-Li completed the trial, whereas only 22.22% of patients in the placebo group attended the final visit, 18 months later (P =  0.09). Major changes in the ALSFRS-R score were observed, including a decrease of 1.195 points/month in the placebo group (95% CI: 0.7869-1.6031) and of 0.5085 under VPA-Li treatment (95% CI: 0.2288-0.7882) between months 6 and 14. Adverse events included bad mouth taste, constipation, and anorexia. Survival rate, body weight, and quality of life were positive outcomes by the end of the trial despite a high sample reduction, especially in the placebo group. Including 212 subjects in each group would confirm these differences.

CONCLUSIONS: A combined VPA-Li treatment was linked to a slower ALS progression and better primary and secondary outcomes. This dual treatment overcame the futility threshold and merits further investigation in ALS.