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

Al-Chalabi, Ammar, Shaw, Pamela, Leigh, P Nigel, van den Berg, Leonard, Hardiman, Orla, Ludolph, Albert, Aho, Valtteri V, Sarapohja, Toni and Kuoppamäki, Mikko (2019) Oral Levosimendan in amyotrophic lateral sclerosis: a phase II multicentre, randomised, double-blind, placebo-controlled trial. Journal of Neurology, Neurosurgery and Psychiatry. ISSN 0022-3050

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Abstract

Objective To evaluate the efficacy and safety of oral levosimendan in amyotrophic lateral sclerosis (ALS) patients. This phase 2, randomised, double-blind, placebo-controlled, crossover, 3-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 bd 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 (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 bd (p=0.001). Headache occurred in 16.7% of patients during levosimendan 1 mg daily (p=0.030), 28.6% during 1 mg bd (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 3 study to evaluate the longer-term effects of oral levosimendan in ALS is ongoing.

Item Type: Article
Keywords: levosimendan, SVC, respiratory function, amyotrophic lateral sclerosis
Schools and Departments: Brighton and Sussex Medical School > Neuroscience
Subjects: R Medicine > RC Internal medicine > RC0321 Neurosciences. Biological psychiatry. Neuropsychiatry > RC0346 Neurology. Diseases of the nervous system Including speech disorders
Depositing User: Patricia Butler
Date Deposited: 05 Jul 2019 09:16
Last Modified: 24 Jul 2019 11:00
URI: http://sro.sussex.ac.uk/id/eprint/84754

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