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

2021; Elsevier BV; Volume: 20; Issue: 10 Linguagem: Inglês

10.1016/s1474-4422(21)00242-8

1474-4465

Merit Cudkowicz, Angela Genge, Nicholas J. Maragakis, Susanne Petri, Leonard van den Berg, Valtteri V. Aho, Toni Sarapohja, Mikko Kuoppamäki, Chris Garratt, Ammar Al‐Chalabi, Matthew C. Kiernan, Susan Mathers, Robert D. Henderson, Merrilee Needham, David Schultz, Wolfgang N. Löscher, Nenad Mitrović, Jakob Rath, Philip Van Damme, Jan De Bleecker, Stéphanie Delstanche, Wendy Johnston, Lorne Zinman, Colleen O’Connell, Geneviève Matte, Annie Dionne, Lawrence Korngut, John Turnbull, Hannu Laaksovirta, Manu Jokela, Tero Tapiola, Marie‐Hélène Soriani, Philippe Couratier, William Camu, Philippe Corcia, Albert C. Ludolph, Julian Großkreutz, Thomas Meyer, Matthias Boentert, Berthold Schrank, Johannes Prudlo, Robert Untucht, Orla Hardiman, Gabriele Siciliano, Adriano Chiò, Letizia Mazzini, Maurizio Inghilleri, Claudia Caponnetto, Gabriele Mora, Jesús S. Mora Pardina, Eva Farrero Muñoz, Juan F. Vázquez‐Costa, Eduardo Agüera, Luís Varona, Peter Andersen, Caroline Ingre, Rune Johansson, Aleksandar Radunović, Carolyn Young, Suma Babu, Aziz Shaibani, Nathan P. Staff, Tuan Vu, Michael H. Rivner, Stephen N. Scelsa, Kumaraswamy Sivakumar, Waqar Waheed, Daragh Heitzman, Sandeep Rana, Gary L. Pattee, Senda Ajroud‐Driss, Elham Bayat, Edward J. Kasarskis, Dale J. Lange, Michael A. Elliott, Brent T. Harris, Kevin J. Felice, Michael Pulley, Justin Kwan, M. Brown, John Ravits, Matthew Burford, Chafic Karam, Timothy M. Miller, Jinsy Andrews, Todd Levine, Eduardo Locatelli, James Wymer, Richard Bedlack, Dominic Fee, Namita Goyal, Björn Oskarsson, Leo McCluskey, James B. Caress, Michael D. Weiss, Adam Quick, Mark B. Bromberg, David Lacomis, Stephen A. Goutman, Kourosh Rezania, Gaurav Guliani, Kimberly Goslin, Jonathan Katz,

Parkinson's Disease Mechanisms and Treatments

Background 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. Methods 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 ClinicalTrials.gov (NCT03505021) and has been completed. An extension study (REFALS-ES; NCT03948178) has also been completed, but will be reported separately. Findings 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. Interpretation 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. Funding Orion Corporation.