Levosimendan, a calcium sensitizer, was not superior to placebo at maintaining respiratory function in patients with amyotrophic lateral sclerosis (ALS), according to study results published in The Lancet Neurology.
Treatment options for ALS are extremely limited and there is a high unmet need for innovative therapies. Available therapeutic drugs for ALS such as ruluzole and edaravon offer only modest clinical benefits, with edaravon only being approved for use in certain countries. Levosimendan has gotten interesting because it works by making the heart and skeletal muscles more sensitive to calcium, which could improve function. In a previous clinical study in healthy volunteers, levosimendan improved neuromechanical efficiency and contraction of the human diaphragm.
The aim of the current study was to investigate the effect of levosimendan on respiratory function and overall functionality in patients with ALS.
The randomized, double-blind, placebo-controlled phase 3 study REFALS was conducted in 99 specialist ALS centers in 14 countries. Eligible participants were at least 18 years old and had a Sedentary Slow Vital Capacity (SVC) between 60% and 90% of the normal value predicted at screening.
Patients were randomized in a 2: 1 ratio to receive levosimendan or placebo. Those who received levosimendan received oral doses (1-2 mg) in capsules daily, starting at 1 mg once daily for 2 weeks and increasing to 1 mg twice daily when judged tolerable. The patients who received placebo followed the same titration schedule.
The treatment period extended from baseline to week 48. The 12 week change in supine SVC from baseline, rated as the percentage of predicted normal sitting SVC, was the primary endpoint.
A total of 496 patients were enrolled from June 21, 2018 to June 28, 2019 – 329 received levosimendan (mean age 59 years; 63% male; 93% white) and 167 received placebo (mean age 59.7 years; 60th). % masculine; 94% white) and were the intention-to-treat population. The median follow-up time was 50.1 weeks (interquartile range 37.5-51.1).
The mean of the least squares change from baseline in predicted normal SVC in the supine position at 12 weeks was -6.73% for levosimendan and -6.99% for placebo, with an estimated treatment difference (ETD) of 0.26% (95% CI, -2.03 to.). 2.55, P = .83), with no significant difference between the groups.
According to the combined assessment of function and survival rank for the levosimendan and placebo groups (ETD, 10.69; 95% CI, -15.74 to 37.12), there was no difference in the change in function from baseline Observed for 48 weeks.
Treatment-related adverse reactions were reported in 312 (96%) of 326 patients who received levosimendan and 157 (95%) of 166 patients who received placebo. Serious adverse events occurred in 89 (27%) patients on levosimendan and 45 (27%) on placebo. A total of 53 participants died during the study – 33 (10%) in the levosimendan group and 20 (12%) in the placebo group.
The most common adverse events were increased heart rate (106 [33%] among 326 participants who received levosimendan vs. 12 [7%] of 166 participants who received placebo), fall (85 [26%] against 48 [29%]), Headache (93 [29%] against 36 [22%]) and dyspnea (59 [18%] against 32 [19%], respectively).
The researchers found that their population may not have been optimally selected to show a treatment effect, particularly in terms of disease duration and rate of progression. In addition, a correct assessment of the ALS progression rate before the study was not possible due to the lack of a run-in phase.
“Although levosimendan does not appear to be useful in a broad population with amyotrophic lateral sclerosis, the possibility of a clinically relevant subset of responding individuals with short disease duration, poorer baseline respiratory function, and faster disease progression should be further evaluated,” the researchers concluded.
Disclosure: This study was funded by Orion Corporation. Some of the study authors stated links with biotech, pharmaceutical, and / or device manufacturers. For a full list of the author’s disclosures, see the original reference.
Cudkowicz M., Genge A., Maragakis N., et al. Safety and efficacy of oral levosimendan in patients with amyotrophic lateral sclerosis (the REFALS study): a phase 3 randomized, double-blind, placebo-controlled study. Lancet Neurol. Published online October 1, 2021. doi: 10.1016 / S1474-4422 (21) 00242-8