Abstract Details

Title Determinants of clinical response to levosimendan in the REFALS phase 3 study in people with ALS

Topic Neuromuscular and Clinical Neurophysiology (EMG)

Presentation(s) S20 - Motor Neuron Disease/Amyotrophic Lateral Sclerosis (2:24 PM-2:32 PM)

Poster/Presentation
Number 003

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.

Authors/Disclosures
Merit E. Cudkowicz, MD, MSC, FAAN (Massachusetts General Hospital) PRESENTER	Dr. Cudkowicz has received personal compensation in the range of $500-$4,999 for serving as a Consultant for biogen. Dr. Cudkowicz has received personal compensation in the range of $0-$499 for serving as a Consultant for cytokinetics. Dr. Cudkowicz has received personal compensation in the range of $0-$499 for serving as a Consultant for immunitypharm. Dr. Cudkowicz has received personal compensation in the range of $500-$4,999 for serving as a Consultant for transposon. Dr. Cudkowicz has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Quralis. Dr. Cudkowicz has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Regeneron. Dr. Cudkowicz has received personal compensation in the range of $500-$4,999 for serving as a Consultant for vectorY. Dr. Cudkowicz has received personal compensation in the range of $500-$4,999 for serving as a Consultant for inflectis. Dr. Cudkowicz has received personal compensation in the range of $500-$4,999 for serving as a Consultant for novartis. Dr. Cudkowicz has received personal compensation in the range of $500-$4,999 for serving as a Consultant for ono. Dr. Cudkowicz has received personal compensation in the range of $500-$4,999 for serving as a Consultant for otsuka. Dr. Cudkowicz has received personal compensation in the range of $500-$4,999 for serving as a Consultant for coya. Dr. Cudkowicz has received personal compensation in the range of $500-$4,999 for serving as a Consultant for ac immune. Dr. Cudkowicz has received personal compensation in the range of $0-$499 for serving as a Consultant for pontifax. Dr. Cudkowicz has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Inflectis. Dr. Cudkowicz has received personal compensation in the range of $0-$499 for serving as a Consultant for ab science. Dr. Cudkowicz has received personal compensation in the range of $500-$4,999 for serving as a Consultant for aclipse. Dr. Cudkowicz has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Locust Walk. Dr. Cudkowicz has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Pasithea. Dr. Cudkowicz has received personal compensation in the range of $50,000-$99,999 for serving as an officer or member of the Board of Directors for Praxis Precision Medicine. Dr. Cudkowicz has received personal compensation in the range of $10,000-$49,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Annals of Neurology . The institution of Dr. Cudkowicz has received research support from NINDS. The institution of Dr. Cudkowicz has received research support from ALSFAC. The institution of Dr. Cudkowicz has received research support from UCB ra. The institution of Dr. Cudkowicz has received research support from Biohaven. The institution of Dr. Cudkowicz has received research support from Clene nanomedicine. The institution of Dr. Cudkowicz has received research support from prilenia. The institution of Dr. Cudkowicz has received research support from ALS one. The institution of Dr. Cudkowicz has received research support from Seelos. The institution of Dr. Cudkowicz has received research support from Calico. The institution of Dr. Cudkowicz has received research support from denali. The institution of Dr. Cudkowicz has received research support from ITB. The institution of Dr. Cudkowicz has received research support from PharmAust. The institution of Dr. Cudkowicz has received research support from woolsley. Dr. Cudkowicz has received research support from lilly. The institution of Dr. Cudkowicz has received research support from J& J. Dr. Cudkowicz has received publishing royalties from a publication relating to health care.
Angela L. Genge, MD (Mcgill University)	Dr. Genge has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for AL-S Pharma. Dr. Genge has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Amylyx. Dr. Genge has received personal compensation in the range of $100,000-$499,999 for serving as a Consultant for Quralis. Dr. Genge has received personal compensation in the range of $500-$4,999 for serving as a Consultant for MTPA. Dr. Genge has received personal compensation in the range of $0-$499 for serving as a Consultant for WAVE. Dr. Genge has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for eikonizo. Dr. Genge has received personal compensation in the range of $0-$499 for serving on a Scientific Advisory or Data Safety Monitoring board for pepgen. Dr. Genge has received personal compensation in the range of $0-$499 for serving on a Scientific Advisory or Data Safety Monitoring board for rapa.
Nicholas J. Maragakis, MD, FAAN (Johns Hopkins University School of Medicine)	Dr. Maragakis has received personal compensation in the range of $500-$4,999 for serving as a Consultant for UptoDate. Dr. Maragakis has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Apellis Pharmaceuticals. Dr. Maragakis has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Amylyx. An immediate family member of Dr. Maragakis has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for National Basketball Association. Dr. Maragakis has received personal compensation in the range of $0-$499 for serving on a Scientific Advisory or Data Safety Monitoring board for Akava. An immediate family member of Dr. Maragakis has received personal compensation in the range of $0-$499 for serving as an officer or member of the Board of Directors for Johns Hopkins Howard County Medical Center. Dr. Maragakis has stock in Akava. The institution of Dr. Maragakis has received research support from NIH/NINDS. The institution of Dr. Maragakis has received research support from Department of Defense. The institution of Dr. Maragakis has received research support from Maryland Stem Cell Research Fund. Dr. Maragakis has received intellectual property interests from a discovery or technology relating to health care.
	No disclosure on file
Leonard H. Van den Berg, MD (University Medical Centre Utrecht)	The institution of Dr. Van den Berg has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Amylyx. The institution of Dr. Van den Berg has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for ferrrer. The institution of Dr. Van den Berg has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Sanofi. The institution of Dr. Van den Berg has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Biogen. The institution of Dr. Van den Berg has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Takeda. The institution of Dr. Van den Berg has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Novartis. The institution of Dr. Van den Berg has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for BMS. The institution of Dr. Van den Berg has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for ArgenX. The institution of Dr. Van den Berg has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Projenx. The institution of Dr. Van den Berg has received research support from Netherlands ALS Foundation.
	No disclosure on file
Chris Garratt	Chris Garratt has received personal compensation for serving as an employee of Orion Pharma.
	No disclosure on file
Ammar Al-Chalabi, PhD, FRCP DipStat (King'S College London)	The institution of Dr. Al-Chalabi has received personal compensation in the range of $500-$4,999 for serving as a Consultant for OrionPharma. The institution of Dr. Al-Chalabi has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Cytokinetics Inc. The institution of Dr. Al-Chalabi has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Mitsubishi Tanabe Pharma. The institution of Dr. Al-Chalabi has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Amylyx. The institution of Dr. Al-Chalabi has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Quralis. Dr. Al-Chalabi has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for My Name'5 Doddie Foundation. The institution of Dr. Al-Chalabi has received research support from Medical Research Council. The institution of Dr. Al-Chalabi has received research support from NIHR. The institution of Dr. Al-Chalabi has received research support from European Commission. The institution of Dr. Al-Chalabi has received research support from MND Association. The institution of Dr. Al-Chalabi has received research support from My Name'5 Doddie Foundation. Dr. Al-Chalabi has received publishing royalties from a publication relating to health care. Dr. Al-Chalabi has received publishing royalties from a publication relating to health care. Dr. Al-Chalabi has a non-compensated relationship as a SAB Member and Executive Member with TRICALS that is relevant to AAN interests or activities.

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