Determinants of clinical response to levosimendan in the REFALS phase 3 study in people with ALS
Merit Cudkowicz1, Angela Genge2, Nicholas Maragakis3, Susanne Petri4, Leonard van den Berg5, Valtteri Aho6, Chris Garratt6, Toni Sarapohja6, Ammar Al-Chalabi7
1Massachusetts General Hospital, 2Mcgill University, 3Johns Hopkins University School of Medicine, 4Medizinische Hochschule Hannover, 5University Medical Center Utrecht, 6Orion Pharma, 7King'S College London
Objective:

To evaluate whether baseline characteristics determined response to levosimendan in people with amyotrophic lateral sclerosis (ALS) in the REFALS phase 3 trial (NCT03505021).

Background:

Treatments for people with ALS may not work equally for all patients and it may be possible to identify a population more likely to derive a relevant treatment effect. The REFALS study explored the clinical effects of oral levosimendan during prolonged treatment in people with ALS.

Design/Methods:
The REFALS study enrolled 496 adult participants with ALS and some degree of respiratory dysfunction (sitting SVC 60-90%) at 99 clinical sites in 14 countries in EU, North America and Australia. Participants were randomized (2:1 allocation) to oral levosimendan 1-2mg daily or placebo for 48 weeks in a double-blind, parallel-group design. The primary endpoint was supine SVC at 12 weeks and the key secondary endpoint was combined assessment of ALSFRS-R function and survival (CAFS) through 48 weeks. The analysis plan pre-specified a number of baseline characteristics potentially relevant to the outcome of the study. These characteristics were evaluated in pre-specified sub-group analyses of supine SVC and ALSFRS-R, based on which further sub-groups were determined and analyzed post-hoc.
Results:

492 participants with ALS, mean 26 months from symptom onset, were treated with levosimendan or placebo. Treatment groups were balanced at baseline: spinal onset 81%, mean sitting SVC 76.5%, ALSFRS-R 36.0 points. 83% and 17.5% patients were taking riluzole and edaravone, respectively. Neither the primary  nor the key secondary endpoint showed significant difference between oral levosimendan treatment and placebo. The results of the individual pre-specified and post-hoc sub-group analyses of supine SVC and ALSFRS-R will be presented in detail.

Conclusions:
Although the REFALS study of levosimendan was not positive, subgroup analyses may be of value in identifying patient groups with a stronger treatment effect and inform future trial design.