Safety and efficacy of givinostat in boys with Duchenne muscular dystrophy (EPIDYS): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial.

Fecha de publicación: 01/04/2024

Autores de IIS La Fe

Juan Jesús Vílchez Padilla

Autor

Participantes ajenos a IIS La Fe

Mercuri E
Boespflug-Tanguy O
Zaidman CM
Mah JK
Goemans N
Müller-Felber W
Niks EH
Schara-Schmidt U
Bertini E
Comi GP
Mathews KD
Servais L
Vandenborne K
Johannsen J
Messina S
Spinty S
McAdam L
Selby K
Byrne B
Laverty CG
Carroll K
Zardi G
Cazzaniga S
Coceani N
Bettica P
McDonald CM
EPIDYS Study Group

Grupos

Patología Neuromuscular y Ataxias

Investigador Principal

Teresa Sevilla Mantecón

Abstract

BACKGROUND: Duchenne muscular dystrophy, the most common childhood muscular dystrophy, is caused by dystrophin deficiency. Preclinical and phase 2 study data have suggested that givinostat, a histone deacetylase inhibitor, might help to counteract the effects of this deficiency. We aimed to evaluate the safety and efficacy of givinostat in the treatment of Duchenne muscular dystrophy. METHODS: This multicentre, randomised, double-blind, placebo-controlled, phase 3 trial was done at 41 tertiary care sites in 11 countries. Eligible participants were ambulant, male, and aged at least 6 years, had a genetically confirmed diagnosis of Duchenne muscular dystrophy, completed two four-stair climb assessments with a mean of 8 s or less (=1 s variance), had a time-to-rise of at least 3 s but less than 10 s, and had received systemic corticosteroids for at least 6 months. Participating boys were randomly assigned (2:1, allocated according to a list generated by the interactive response technology provider) to receive either oral givinostat or matching placebo twice a day for 72 weeks, stratified by concomitant steroid use. Boys, investigators, and site and sponsor staff were masked to treatment assignment. The dose was flexible, based on weight, and was reduced if not tolerated. Boys were divided into two groups on the basis of their baseline vastus lateralis fat fraction (VLFF; measured by magnetic resonance spectroscopy): group A comprised boys with a VLFF of more than 5% but no more than 30%, whereas group B comprised boys with a VLFF of 5% or less, or more than 30%. The primary endpoint compared the effects of givinostat and placebo on the change in results of the four-stair climb assessment between baseline and 72 weeks, in the intention-to-treat, group A population. Safety was assessed in all randomly assigned boys who received at least one dose of study drug. When the first 50 boys in group A completed 12 months of treatment, an interim futility assessment was conducted, after which the sample size was adapted using masked data from the four-stair climb assessments. Furthermore, the starting dose of givinostat was reduced following a protocol amendment. This trial is registered with ClinicalTrials.gov, NCT02851797, and is complete. FINDINGS: Between June 6, 2017, and Feb 22, 2022, 359 boys were assessed for eligibility. Of these, 179 were enrolled into the study (median age 9·8 years [IQR 8·1-11·0]), all of whom were randomly assigned (118 to receive givinostat and 61 to receive placebo); 170 (95%) boys completed the study. Of the 179 boys enrolled, 120 (67%) were in group A (81 givinostat and 39 placebo); of these, 114 (95%) completed the study. For participants in group A, comparing the results of the four-stair climb assessment at 72 weeks and baseline, the geometric least squares mean ratio was 1·27 (95% CI 1·17-1·37) for boys receiving givinostat and 1·48 (1·32-1·66) for those receiving placebo (ratio 0·86, 95% CI 0·745-0·989; p=0·035). The most common adverse events in the givinostat group were diarrhoea (43 [36%] of 118 boys vs 11 [18%] of 61 receiving placebo) and vomiting (34 [29%] vs 8 [13%]); no treatment-related deaths occurred. INTERPRETATION: Among ambulant boys with Duchenne muscular dystrophy, results of the four-stair climb assessment worsened in both groups over the study period; however, the decline was significantly smaller with givinostat than with placebo. The dose of givinostat was reduced after an interim safety analysis, but no new safety signals were reported. An ongoing extension study is evaluating the long-term safety and efficacy of givinostat in patients with Duchenne muscular dystrophy. FUNDING: Italfarmaco.

Datos de la publicación

ISSN/ISSNe:: 1474-4422, 1474-4465
Tipo:: Article
Páginas:: 393-403
DOI:: 10.1016/S1474-4422(24)00036-X
Factor de Impacto:: 11,674 SCImago ℠
Cuartil:: Q1 SCImago ℠

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Métricas

Filiaciones

Mercuri E:: Pediatric Neurology, Department of Woman and Child Health and Public Health, Child Health Area, Universita Cattolica del Sacro Cuore, Rome, Italy

Centro Clinico Nemo Fondazione Policlinico Gemelli IRCCS, Rome, Italy
Vilchez JJ:: Servicio de Neurología, Neuromuscular Unit, CIBERER, EURO-RN-NMD, Hospital Universitario y Politécnico La Fe Valencia, Valencia, Spain
Boespflug-Tanguy O:: I-Motion, Institut de Myologie, Hôpital Armand-Trousseau, APHP, Sorbonne Université, Paris, France

Université Paris Cité UMR INSERM 1141, Hôpital Robert Debré, Paris, France
Zaidman CM:: Washington University School of Medicine, St Louis, MO, USA
Mah JK:: Division of Pediatric Neurology, Alberta Children's Hospital, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
Goemans N:: Department of Child Neurology, University Hospitals Leuven, Leuven, Belgium
Müller-Felber W:: LMU Munich, University Hospital, Hauner Children's Hospital, Pediatric Neurology and Developmental Medicine, Munich, Germany
Niks EH:: Department of Neurology, Leiden University Medical Center, Leiden, Netherlands

Duchenne Center Netherlands, Netherlands
Schara-Schmidt U:: Department of Pediatric Neurology, Children's University Hospital Essen, University of Duisburg-Essen, Essen, Germany
Bertini E:: Research Unit of Neuromuscular and Neurodegenerative Disorders, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy
Comi GP:: Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Neuromuscular and Rare Diseases Unit, Department of Neuroscience, Milan, Italy

Dino Ferrari Center, Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy
Mathews KD:: Department of Pediatrics, University of Iowa Carver College of Medicine, Iowa City, IA, USA

Department of Neurology, University of Iowa Carver College of Medicine, Iowa City, IA, USA
Servais L:: MDUK Oxford Neuromuscular Centre, University of Oxford, Oxford, UK

NIHR Oxford Biomedical Research Centre, University of Oxford, Oxford, UK

Neuromuscular Reference Center, Department of Paediatrics, University and University Hospital of Liege, Belgium
Vandenborne K:: ImagingDMD, University of Florida, Gainesville, FL, USA

Department of Physical Therapy, University of Florida, Gainesville, FL, USA
Johannsen J:: University Medical Center Hamburg-Eppendorf, Department of Pediatrics, Hamburg, Germany
Messina S:: Department of Clinical and Experimental Medicine, Unit of Neurodegenerative Diseases, AOU Policlinico G Martino, University of Mesina, Messina, Italy
Spinty S:: Department of Paediatric Neurology, Alder Hey Children's Hospital NHS Trust, Liverpool, UK
McAdam L:: Holland Bloorview Kids Rehabilitation Hospital, Bloorview Research Institute, Department of Pediatrics, University of Toronto, Toronto, ON, Canada
Selby K:: The University of British Columbia, Children's and Women's Health Centre, Vancouver, BC, Canada
Byrne B:: Child Health Research Institute, Department of Pediatrics, University of Florida, Gainesville, FL, USA
Laverty CG:: Department of Neuroscience, University of California, San Diego, San Diego, CA, USA
Carroll K:: KJC Statistics, Cheshire, UK
Zardi G:: Alira Health, Milan, Italy
Cazzaniga S:: Italfarmaco, Milan, Italy
Coceani N:: Italfarmaco, Milan, Italy
Bettica P:: Italfarmaco, Milan, Italy
McDonald CM:: University of California Davis Health, Sacramento, CA, USA