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J Neurol Neurosurg Psychiatry. 2019 Oct;90(10):1165-1170. doi: 10.1136/jnnp-2018-320288. Epub 2019 Jul 17.

Oral levosimendan in amyotrophic lateral sclerosis: a phase II multicentre, randomised, double-blind, placebo-controlled trial.

Author information

Department of Basic and Clinical Neuroscience, King's College London, Maurice Wohl Clinical Neuroscience Institute, London, UK.
Department of Neurology, King's College Hospital, London, UK.
Sheffield Institute for Translational Neuroscience and NIHR Sheffield Biomedical Research Centre, University of Sheffield, Sheffield, UK.
Department of Neuroscience Brighton and Sussex Medical School, Trafford Centre for Biomedical Science, Falmer, Brighton, UK.
Departmentof Neurology, University Medical Center Utrecht, Utrecht, The Netherlands.
Academic Unit of Neurology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland.
Department of Neurology, University of Ulm, Ulm, Germany.
Orion Pharma, Orion Corporation, Turku, Finland
Orion Pharma, Orion Corporation, Espoo, Finland.
Orion Pharma, Orion Corporation, Turku, Finland.
Lundbeck, Copenhagen, Denmark.



To evaluate the efficacy and safety of oral levosimendan in patients with amyotrophic lateral sclerosis (ALS). This phase II, randomised, double-blind, placebo-controlled, crossover, three-period study with 6 months open-label follow-up enrolled adults with ALS and sitting slow vital capacity (SVC) 60%-90 % of predicted from 11 sites in four countries.


Patients received levosimendan 1 mg daily, 1 mg two times a day or placebo during three 14-day crossover periods and levosimendan 1-2 mg daily during open-label follow-up. Primary endpoint was sitting SVC; secondary endpoints included supine SVC, ALS Functional Rating Scale-Revised (ALSFRS-R), tolerability and safety.


Of 66 patients randomised, 59 contributed to the double-blind results and 50 entered open-label follow-up. Sitting SVC was not significantly different between the treatments. In post hoc analysis using period-wise baselines, supine SVC favoured levosimendan over placebo, estimated mean differences from baseline being -3.62% on placebo, +0.77% on levosimendan 1 mg daily (p=0.018) and +2.38% on 1 mg two times a day (p=0.001). Headache occurred in 16.7% of patients during levosimendan 1 mg daily (p=0.030), 28.6% during 1 mg two times a day (p=0.002) and 3.3% during placebo. The respective frequencies for increased heart rate were 5.1% (p=0.337), 18.5% (p=0.018) and 1.7%. No significant differences between the treatments were seen for other adverse events.


Levosimendan did not achieve the primary endpoint of improving sitting SVC in ALS. Headache and increased heart rate were increased on levosimendan, although it was otherwise well tolerated. A phase III study to evaluate the longer term effects of oral levosimendan in ALS is ongoing.


SVC; amyotrophic lateral sclerosis; levosimendan; respiratory function

Conflict of interest statement

Competing interests: VVA and TS are employees of Orion Corporation. Other authors have no conflicts to disclose.

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