REFALS was a phase 3 clinical trial that examined whether taking oral levosimendan can improve or preserve respiratory function in patients with MND. The long-term tolerability and safety of levosimendan in MND patients was evaluated as part of this trial, assessing up to 48 weeks of exposure to the drug.
Levosimendan is a small molecule that works by increasing calcium sensitivity in both heart and skeletal muscle fibers, potentially improving their function. The drug has been developed by Orion Corporation.
Originally developed for the treatment of acute heart failure, levosimendan is sold as Simdax in nearly 60 countries as an intravenous (administered into the bloodstream) medicine for that indication.
Since levosimendan also can improve the activity of skeletal muscle cells, such as those responsible for controlling breathing, Orion thought of assessing whether oral levosimendan could help preserve lung function and delay the need for ventilation support in ALS patients.
Data from the previous, placebo-controlled Phase 2 LEVALS trial (NCT02487407) showed that oral levosimendan was safe and resulted in promising benefits in patients’ lung function when in a supine position (lying down with the face and torso facing up).
This potential benefit was relevant since signs of respiratory insufficiency often appear when lying down.
The Phase 3 REFALS trial (NCT03505021) was designed to assess whether oral levosimendan was superior to a placebo in helping maintain lung function and subsequently preserve overall functionality in people with ALS.
Fully enrolled since July 2019, the trial evaluated the safety and effectiveness of oral levosimendan in 496 ALS patients, recruited across 104 sites in the U.S., Canada, Europe, and Australia.
Participants were assigned randomly to receive orally either 1 mg of levosimendan or a placebo once to twice a day, for up to 48 weeks (11 months).
The trial’s main goal was to assess changes in patients’ lung function by measuring their supine slow vital capacity — the maximum volume of air they could slowly inhale or exhale when in a supine position — after 12 weeks of treatment.
Secondary goals included changes in the ALS Functional Rating Scale-Revised — a validated measure to monitor disability progression in ALS patients — combined with survival at 48 weeks.
The results were announced in July 2020 with the findings that “Levosimendan was not superior to placebo in maintaining respiratory function in a broad population with amyotrophic lateral sclerosis. Although levosimendan was generally well tolerated, increased heart rate and headache occurred more frequently with levosimendan than with placebo. The possibility of a clinically relevant subgroup of responsive individuals requires further evaluation.”
The data has been published in The Lancet Neurology.
A possible treatment resulting from this study is years away. This research will provide preliminary data on the long-term tolerability of levosimendan and will also evaluate whether levosimendan is effective in improving supine slow vital capacity in MND patients.