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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

1
Department of Basic and Clinical Neuroscience, King's College London, Maurice Wohl Clinical Neuroscience Institute, London, UK.
2
Department of Neurology, King's College Hospital, London, UK.
3
Sheffield Institute for Translational Neuroscience and NIHR Sheffield Biomedical Research Centre, University of Sheffield, Sheffield, UK.
4
Department of Neuroscience Brighton and Sussex Medical School, Trafford Centre for Biomedical Science, Falmer, Brighton, UK.
5
Departmentof Neurology, University Medical Center Utrecht, Utrecht, The Netherlands.
6
Academic Unit of Neurology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland.
7
Department of Neurology, University of Ulm, Ulm, Germany.
8
Orion Pharma, Orion Corporation, Turku, Finland valtteri.aho@orionpharma.com.
9
Orion Pharma, Orion Corporation, Espoo, Finland.
10
Orion Pharma, Orion Corporation, Turku, Finland.
11
Lundbeck, Copenhagen, Denmark.

Abstract

OBJECTIVE:

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.

METHODS:

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.

RESULTS:

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.

CONCLUSIONS:

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.

KEYWORDS:

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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