Levosimendan, a calcium sensitizer, was not superior to placebo for maintaining respiratory function in patients with amyotrophic lateral sclerosis (ALS), according to study findings published in The Lancet Neurology.
Treatment options for ALS are extremely limited with a high unmet need for innovative therapies. Available therapeutic drugs for ALS, like ruluzole and edaravone, only provide a modest clinical benefit, with edaravone only approved for use in certain countries. Levosimendan has become of interest since it works by increasing calcium sensitivity in heart and skeletal muscles, which could improve function. In a previous clinical trial with healthy volunteers, levosimendan improved neuromechnical efficiency and contraction of the human diaphragm.
The objective 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 REFALS trial was conducted at 99 ALS specialist centers in 14 countries. Eligible participants were at least 18 years of age and had a sitting slow vital capacity (SVC) between 60% and 90% of predicted normal at screening.
The patients were randomized 2:1 to receive levosimendan or placebo. Those who received levosimendan were administered daily oral doses (1-2 mg) in capsules, initially with 1 mg once daily for 2 weeks and increasing to 1 mg twice daily if assessed as tolerable. The patients who received placebo followed the same titration schedule.
The treatment period was from baseline to week 48. The change from baseline in supine SVC at 12 weeks, assessed as percentage of predicted normal sitting SVC, was the primary endpoint.
A total of 496 patients were included 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; 60% male; 94% White) and were the intention-to-treat population. The median follow-up was 50.1 weeks (interquartile range, 37.5-51.1).
The least squares mean regarding the change from baseline at 12 weeks in supine SVC of predicted normal was –6.73% with levosimendan and –6.99% with placebo, with an estimated treatment difference (ETD) of 0.26% (95% CI, –2.03 to 2.55, P =.83), with no significant difference occurring between groups.
No difference was observed in the change from baseline in function to 48 weeks according to the combined assessment of function and survival rank score for the levosimendan and placebo groups (ETD, 10.69; 95% CI, –15.74 to 37.12).
Treatment-emergent adverse events were reported in 312 (96%) of 326 patients who received levosimendan and in 157 (95%) of 166 who received placebo. Serious adverse events occurred in 89 (27%) patients who received levosimendan and in 45 (27%) who received placebo. A total of 53 participants died during the trial—33 (10%) in the levosimendan group and 20 (12%) in the placebo group.
The most frequently occurring adverse events were increased heart rate (106 [33%] among 326 participants receiving levosimendan vs 12 [7%] of 166 participants receiving placebo), fall (85 [26%] vs 48 [29%], respectively), headache (93 [29%] vs 36 [22%], respectively), and dyspnea (59 [18%] vs 32 [19%], respectively).
The investigators noted that their population might not have been optimally selected to show any treatment effect, especially regarding disease duration and progression rate. Also, proper assessment of the pre-study ALS progression rate was not possible owing to the lack of a run-in period.
“Although levosimendan does not appear to be useful in a broad population with amyotrophic lateral sclerosis, the possibility of a clinically relevant subgroup of responsive individuals with a short duration of disease, worse respiratory function at baseline, and faster progression of the disease should be further evaluated,” the researchers concluded.
Disclosure: This study was funded by Orion Corporation. Some of the study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of authors’ disclosures.
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. Published online October 1, 2021. doi: 10.1016/S1474-4422(21)00242-8