Levosimendan Not Superior to Placebo for Patients With Amyotrophic Lateral Sclerosis

When compared to placebo, levosimendan was not superior at maintaining respiratory function for patients with amyotrophic lateral sclerosis, according to a recent study published in The Lancet Neurology.

“There is an urgent unmet need for new therapies in amyotrophic lateral sclerosis,” wrote Merit Cudkowicz, MD, Healey & AMG Center for ALS, Massachusetts General Hospital, Boston, Massachusetts, and co-researchers. “In a clinical study with healthy volunteers, levosimendan, a calcium sensitiser, was shown to improve neuromechanical efficiency and contractile function of the human diaphragm.”

In this randomized, double-blind, placebo-controlled phase 3 trial, researchers focused on respiratory function to evaluate the safety and efficacy of oral levosimendan for patients with amyotrophic lateral sclerosis.

A total of 496 patients with amyotrophic lateral sclerosis from 99 amyotrophic lateral sclerosis specialist centers across 14 countries who were 18 years or older, with a sitting slow vital capacity of 60-90%, were included in this trial. Screenings occurred between June 21, 2018 and June 28, 2019 with a follow up between June 27, 2018 and June 26, 2019 for a median duration of 50 weeks.

Participants were randomized 2:1 to receive placebo or levosimendan using capsules for oral administration that were identical in appearance.

Change in supine SVC from baseline to 12 weeks was the primary endpoint in this study, with the secondary endpoint being a combined assessment of function and survival up to 48 weeks.

Patients receiving levosimendan saw a -6.73% change from baseline to 12 weeks in supine SVC, while patients receiving placebo saw a -6.99% change. There was little difference between treatment groups in the combined assessment of function and survival at week 48.

Common adverse events included increased heart rate, fall, headache, and dyspnea. Though generally well tolerated, increased heart rate and headache were more common in the levosimendan treatment arm when compared to placebo.

“Levosimendan was not superior to placebo in maintaining respiratory function in a broad population with amyotrophic lateral sclerosis,” Dr Cudkowicz et al concluded. “The possibility of a clinically relevant subgroup of responsive individuals requires further evaluation.”

Cudkowicz M, Genge A, Maragakis N, et al. Safety and efficacy of oral levosimendan in people with amyotrophic lateral sclerosis (the REFALS study): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet Neurol. 2021;20(10):821-831. doi:10.1016/S1474-4422(21)00242-8