Safety and efficacy of oral levosimendan in people with amyotrophic lateral sclerosis (the REFALS study): a randomised, double-blind, placebo-controlled phase 3 trial
RCT (n=496) found levosimendan was not superior to placebo in maintaining respiratory function (change from baseline in supine slow vital capacity at 12 weeks: –6·73% vs. –6·99% with placebo); increased heart rate and headache occurred more frequently with levosimendan.
Source:
The Lancet Neurology
SPS commentary:
According to a commentary, levosimendan is approved in the EU to treat severe heart failure by intravenous administration. Its principal pharmacological effect is to increase cardiac contractility by calcium sensitisation of troponin C. In light of positive action of the drug on the neuromechanical efficiency and contractile function of the diaphragm in healthy controls, levosimendan was considered potentially useful for treating amyotrophic lateral sclerosis (ALS), a disease characterised by progressive upper and lower motor neuron deficits. It notes that in their sample size calculation, the researchers proposed a small difference between the study groups as clinically significant (3·6%). It suggests that considering this small effect, and trial not meeting any of the prespecified endpoints, levosimendan is probably ineffective in ALS. It adds that muscle cell physiology is different in skeletal muscles and the myocardium, and although levosimendan had some positive effects in the diaphragm of healthy controls, its effect on partly denervated skeletal muscle is unknown. Therefore, the results of should not necessarily prevent testing of other drugs with a similar mechanism of action, such as reldesemtiv. It commends the researcher on completing this difficult trial and for sharing their results.