Safety and efficacy of oral levosimendan in people with amyotrophic lateral sclerosis (the REFALS study): a randomised, double-blind, placebo-controlled phase 3 trial.

Published on Oct 1, 2021in Lancet Neurology44.182
· DOI :10.1016/S1474-4422(21)00242-8
Merit Cudkowicz80
Estimated H-index: 80
(Harvard University),
Angela Genge22
Estimated H-index: 22
(Montreal Neurological Institute and Hospital)
+ 100 AuthorsAmmar Al-Chalabi92
Estimated H-index: 92
('KCL': King's College London)
Sources
Abstract
Summary null null Background null There is an urgent unmet need for new therapies in amyotrophic lateral sclerosis. In a clinical study with healthy volunteers, levosimendan, a calcium sensitiser, was shown to improve neuromechanical efficiency and contractile function of the human diaphragm. We aimed to evaluate the safety and efficacy of oral levosimendan in people with amyotrophic lateral sclerosis, with a focus on respiratory function. null null null Methods null The REFALS study is a randomised, double-blind, placebo-controlled phase 3 trial at 99 amyotrophic lateral sclerosis specialist centres in 14 countries worldwide. People with amyotrophic lateral sclerosis were eligible for participation if they were at least 18 years of age and had a sitting slow vital capacity (SVC) of 60–90% predicted. Participants were randomly assigned (2:1) by interactive web-response system to receive either levosimendan or placebo. The capsules for oral administration were identical in appearance to maintain blinding of participants and investigators. The primary endpoint was the change from baseline in supine SVC at 12 weeks, assessed as the percentage of predicted normal sitting SVC. The key secondary endpoint was the combined assessment of function and survival (CAFS) up to 48 weeks. Analyses were done in the intention-to-treat population, comprising all participants who were randomly assigned. This trial is registered at null ClinicalTrials.gov null (NCT03505021) and has been completed. An extension study (REFALS-ES; null NCT03948178 ) has also been completed, but will be reported separately. null null null Findings null Between June 21, 2018, and June 28, 2019, 871 people were screened for the study, of whom 496 were randomly assigned either levosimendan (n=329) or placebo (n=167). Participants were followed up between June 27, 2018 and June 26, 2020, for a median duration of 50·1 (IQR 37·5–51·1) weeks. The median duration of treatment was 47·9 (IQR 26·4–48·1) weeks. Change from baseline in supine SVC at 12 weeks was –6·73% with levosimendan and –6·99% with placebo, with no significant difference between the treatments (estimated treatment difference 0·26%, 95% CI –2·03 to 2·55, p=0·83). Similarly, at week 48, CAFS did not differ between treatment groups (least squares mean change from baseline 10·69, 95% CI –15·74 to 37·12; nominal p value=0·43). The most frequent adverse events were increased heart rate (106 [33%] of 326 receiving levosimendan vs 12 [7%] of 166 receiving placebo), fall (85 [26%] vs 48 [29%]), headache (93 [29%] vs 36 [22%]), and dyspnoea (59 [18%] vs 32 [19%]). 33 (10%) participants allocated levosimendan and 20 (12%) assigned placebo died during the trial, mainly due to respiratory failure or progression of amyotrophic lateral sclerosis. null null null Interpretation null Levosimendan was not superior to placebo in maintaining respiratory function in a broad population with amyotrophic lateral sclerosis. Although levosimendan was generally well tolerated, increased heart rate and headache occurred more frequently with levosimendan than with placebo. The possibility of a clinically relevant subgroup of responsive individuals requires further evaluation. null null null Funding null Orion Corporation.
References17
Newest
#1Jeremy M. Shefner (Barrow Neurological Institute)H-Index: 58
To evaluate safety, dose response, and preliminary efficacy of reldesemtiv over 12 weeks in patients with amyotrophic lateral sclerosis (ALS). Methods: Patients (≤2 years since diagnosis) with slow...
Source
Abstract Background Sodium phenylbutyrate and taurursodiol have been found to reduce neuronal death in experimental models. The efficacy and safety of a combination of the two compounds in persons ...
Source
: Levosimendan is a calcium sensitizer that promotes myocyte contractility through its calcium-dependent interaction with cardiac troponin C. Administered intravenously, it has been used for nearly 2 decades to treat acute and advanced heart failure and to support the heart function in various therapy settings characterized by low cardiac output. Effects of levosimendan on noncardiac muscle suggest a possible new application in the treatment of people with amyotrophic lateral sclerosis (ALS), a ...
Source
#1Ammar Al-ChalabiH-Index: 92
#2Pamela J. Shaw (University of Sheffield)H-Index: 112
Last. Mikko Kuoppamäki (Orion Corporation)H-Index: 24
view all 9 authors...
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 levosimend...
Source
#1Capucine Morélot-Panzini (University of Paris)H-Index: 26
#2Gaëlle Bruneteau (University of Paris)H-Index: 24
Last. Jésus Gonzalez-Bermejo (University of Paris)H-Index: 23
view all 3 authors...
: Non-invasive ventilation (NIV) has become an essential part of the treatment of amyotrophic lateral sclerosis (ALS) since 2006. NIV very significantly improves survival, quality of life and cognitive performances. The initial NIV settings are simple, but progression of the disease, ventilator dependence and upper airway involvement sometimes make long-term adjustment of NIV more difficult, with a major impact on survival. Unique data concerning the long-term adjustment of NIV in ALS show that ...
Source
#1Jeremy M. Shefner (Barrow Neurological Institute)H-Index: 58
AbstractObjective: To assess the efficacy of tirasemtiv, a fast skeletal muscle troponin activator, vs. placebo in patients with amyotrophic lateral sclerosis. Methods: VITALITY-ALS (NCT02496767) w...
Source
#1Ton Fang ('KCL': King's College London)H-Index: 7
#2Ahmad Al Khleifat ('KCL': King's College London)H-Index: 11
Last. Ammar Al-Chalabi (University of Cambridge)H-Index: 92
view all 7 authors...
Summary Background Riluzole is the only drug to prolong survival for amyotrophic lateral sclerosis (ALS) and, at a dose of 100 mg, was associated with a 35% reduction in mortality in a clinical trial. A key question is whether the survival benefit occurs at an early stage of disease, late stage, or is spread throughout the course of the disease. To address this question, we used the King's clinical staging system to do a retrospective analysis of data from the original dose-ranging clinical tria...
Source
#1Koji AbeH-Index: 81
#2Masashi AokiH-Index: 61
Last. Tomohisa IwasakiH-Index: 1
view all 64 authors...
Summary Background In a previous phase 3 study in patients with amyotrophic lateral sclerosis (ALS), edaravone did not show a significant difference in the Revised ALS Functional Rating Scale (ALSFRS-R) score compared with placebo. Post-hoc analysis of these data revealed that patients in an early stage with definite or probable diagnosis of ALS, defined by the revised El Escorial criteria, who met a select set of inclusion criteria showed a greater magnitude of effect than did the full study po...
Source
#1Jeremy M. Shefner (Barrow Neurological Institute)H-Index: 58
#2Andrew A. WolffH-Index: 22
Last. Jinsy A. AndrewsH-Index: 14
view all 7 authors...
AbstractOur objectives were to evaluate the safety and tolerability of tirasemtiv over 12 weeks and its effect on the revised ALS Functional Rating Scale (ALSFRS-R) and other secondary functional measures. This randomized, double-blind, placebo-controlled trial enrolled adults with ALS and slow vital capacity (SVC) > 50% from 73 centers in eight countries. Patients who tolerated open-label tirasemtiv 125 mg b.i.d. for one week were randomized to double-blind treatment either to placebo or tirase...
Source
#1James D. Berry (Harvard University)H-Index: 29
#2Robert G. Miller (CPMC: California Pacific Medical Center)H-Index: 76
Last. Donald ArchibaldH-Index: 6
view all 9 authors...
AbstractOur objective was to describe a new endpoint for amyotrophic lateral sclerosis (ALS), the Combined Assessment of Function and Survival (CAFS). CAFS ranks patients’ clinical outcomes based on survival time and change in the ALS Functional Rating Scale–Revised (ALSFRS-R) score. Each patient's outcome is compared to every other patient's outcome, assigned a score, and the summed scores are ranked. The mean rank score for each treatment group can then be calculated. A higher mean CAFS score ...
Source
Cited By2
Newest
#1Mamede de Carvalho (IMM: Instituto de Medicina Molecular)H-Index: 57
#2Michael Swash (QMUL: Queen Mary University of London)H-Index: 93
Source
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