PMID- 38508835
OWN - NLM
STAT- MEDLINE
DCOM- 20240322
LR  - 20240421
IS  - 1474-4465 (Electronic)
IS  - 1474-4422 (Linking)
VI  - 23
IP  - 4
DP  - 2024 Apr
TI  - Safety and efficacy of givinostat in boys with Duchenne muscular dystrophy 
      (EPIDYS): a multicentre, randomised, double-blind, placebo-controlled, phase 3 
      trial.
PG  - 393-403
LID - S1474-4422(24)00036-X [pii]
LID - 10.1016/S1474-4422(24)00036-X [doi]
AB  - 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.
CI  - Copyright (c) 2024 Elsevier Ltd. All rights reserved.
FAU - Mercuri, Eugenio
AU  - Mercuri E
AD  - 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. Electronic 
      address: eugeniomaria.mercuri@policlinicogemelli.it.
FAU - Vilchez, Juan J
AU  - Vilchez JJ
AD  - Servicio de Neurologia, Neuromuscular Unit, CIBERER, EURO-RN-NMD, Hospital 
      Universitario y Politecnico La Fe Valencia, Valencia, Spain.
FAU - Boespflug-Tanguy, Odile
AU  - Boespflug-Tanguy O
AD  - I-Motion, Institut de Myologie, Hopital Armand-Trousseau, APHP, Sorbonne 
      Universite, Paris, France; Universite Paris Cite UMR INSERM 1141, Hopital Robert 
      Debre, Paris, France.
FAU - Zaidman, Craig M
AU  - Zaidman CM
AD  - Washington University School of Medicine, St Louis, MO, USA.
FAU - Mah, Jean K
AU  - Mah JK
AD  - Division of Pediatric Neurology, Alberta Children's Hospital, Cumming School of 
      Medicine, University of Calgary, Calgary, AB, Canada.
FAU - Goemans, Nathalie
AU  - Goemans N
AD  - Department of Child Neurology, University Hospitals Leuven, Leuven, Belgium.
FAU - Muller-Felber, Wolfgang
AU  - Muller-Felber W
AD  - LMU Munich, University Hospital, Hauner Children's Hospital, Pediatric Neurology 
      and Developmental Medicine, Munich, Germany.
FAU - Niks, Erik H
AU  - Niks EH
AD  - Department of Neurology, Leiden University Medical Center, Leiden, Netherlands; 
      Duchenne Center Netherlands, Netherlands.
FAU - Schara-Schmidt, Ulrike
AU  - Schara-Schmidt U
AD  - Department of Pediatric Neurology, Children's University Hospital Essen, 
      University of Duisburg-Essen, Essen, Germany.
FAU - Bertini, Enrico
AU  - Bertini E
AD  - Research Unit of Neuromuscular and Neurodegenerative Disorders, Bambino Gesu 
      Children's Hospital, IRCCS, Rome, Italy.
FAU - Comi, Giacomo P
AU  - Comi GP
AD  - 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.
FAU - Mathews, Katherine D
AU  - Mathews KD
AD  - 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.
FAU - Servais, Laurent
AU  - Servais L
AD  - 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.
FAU - Vandenborne, Krista
AU  - Vandenborne K
AD  - ImagingDMD, University of Florida, Gainesville, FL, USA; Department of Physical 
      Therapy, University of Florida, Gainesville, FL, USA.
FAU - Johannsen, Jessika
AU  - Johannsen J
AD  - University Medical Center Hamburg-Eppendorf, Department of Pediatrics, Hamburg, 
      Germany.
FAU - Messina, Sonia
AU  - Messina S
AD  - Department of Clinical and Experimental Medicine, Unit of Neurodegenerative 
      Diseases, AOU Policlinico G Martino, University of Mesina, Messina, Italy.
FAU - Spinty, Stefan
AU  - Spinty S
AD  - Department of Paediatric Neurology, Alder Hey Children's Hospital NHS Trust, 
      Liverpool, UK.
FAU - McAdam, Laura
AU  - McAdam L
AD  - Holland Bloorview Kids Rehabilitation Hospital, Bloorview Research Institute, 
      Department of Pediatrics, University of Toronto, Toronto, ON, Canada.
FAU - Selby, Kathryn
AU  - Selby K
AD  - The University of British Columbia, Children's and Women's Health Centre, 
      Vancouver, BC, Canada.
FAU - Byrne, Barry
AU  - Byrne B
AD  - Child Health Research Institute, Department of Pediatrics, University of Florida, 
      Gainesville, FL, USA.
FAU - Laverty, Chamindra G
AU  - Laverty CG
AD  - Department of Neuroscience, University of California, San Diego, San Diego, CA, 
      USA.
FAU - Carroll, Kevin
AU  - Carroll K
AD  - KJC Statistics, Cheshire, UK.
FAU - Zardi, Giulia
AU  - Zardi G
AD  - Alira Health, Milan, Italy.
FAU - Cazzaniga, Sara
AU  - Cazzaniga S
AD  - Italfarmaco, Milan, Italy.
FAU - Coceani, Nicoletta
AU  - Coceani N
AD  - Italfarmaco, Milan, Italy.
FAU - Bettica, Paolo
AU  - Bettica P
AD  - Italfarmaco, Milan, Italy.
FAU - McDonald, Craig M
AU  - McDonald CM
AD  - University of California Davis Health, Sacramento, CA, USA.
CN  - EPIDYS Study Group
LA  - eng
SI  - ClinicalTrials.gov/NCT02851797
PT  - Clinical Trial, Phase III
PT  - Journal Article
PT  - Multicenter Study
PT  - Randomized Controlled Trial
PL  - England
TA  - Lancet Neurol
JT  - The Lancet. Neurology
JID - 101139309
RN  - 5P60F84FBH (givinostat)
RN  - 0 (Carbamates)
RN  - 0 (Adrenal Cortex Hormones)
SB  - IM
EIN - Lancet Neurol. 2024 Apr 18;:. PMID: 38643778
MH  - Humans
MH  - Male
MH  - Child
MH  - Female
MH  - *Muscular Dystrophy, Duchenne/drug therapy
MH  - Treatment Outcome
MH  - Carbamates/adverse effects
MH  - Adrenal Cortex Hormones/therapeutic use
MH  - Double-Blind Method
COIS- Declaration of interests EM declares payment or honoraria for lectures and 
      symposia from Sarepta Therapeutics, PTC Therapeutics, and Roche; and 
      participation on advisory boards for Sarepta Therapeutics, NS Pharma, Santhera, 
      PTC Therapeutics, Roche, Pfizer, WAVE Life Sciences, Italfarmaco, and Dyne 
      Therapeutics, all outside the scope of this manuscript. JJV declares grants from 
      PTC Therapeutics; consulting fees from Santhera, Sarepta Therapeutics, and PTC 
      Therapeutics; and payment for lectures, presentations, speakers bureaus, 
      manuscript writing or educational events from PTC Therapeutics, all outside the 
      scope of this manuscript. OB-T declares grants to her institution from Roche, 
      Novartis, Biogen, Genethon, and Metafora Biosystems; payment or honoraria for 
      lectures, presentations, speakers bureaus, manuscript writing or educational 
      events from Novartis; support for attending meetings and/or travel from Novartis; 
      participation on a data safety monitoring board or advisory board for Minoryx 
      Therapeutics; and unpaid leadership roles with AFM-Telethon (scientific board 
      president) and Societe Francophone de Neurogenetique, all outside the scope of 
      this manuscript. CMZ declares grants or contracts from Biogen and Novartis; 
      consulting fees from Sarepta Therapeutics; payment or honoraria for lectures, 
      presentations, speakers bureaus, manuscript writing or educational events from 
      Sarepta Therapeutics and Optum; support for attending meetings and/or travel from 
      Sarepta Therapeutics and Optum; and participation on a data safety monitoring 
      board or advisory board for Sarepta Therapeutics, all outside the scope of this 
      manuscript. JKM declares research grants to her institution from Italfarmaco, 
      Biogen, Novartis, NS Pharma, Pfizer, PTC Therapeutics, ReveraGen Biopharma, 
      Roche, Sarepta Therapeutics, and Alberta Children's Hospital Foundation, all 
      outside the scope of this manuscript. NG declares payment or honoraria for 
      lectures, presentations, speakers bureaus, manuscript writing or educational 
      events from Biogen; and participation on a data safety monitoring board or 
      advisory board for Pfizer, Biogen, and WAVE Life Sciences, all outside the scope 
      of this manuscript. WM-F declares payment or honoraria for lectures, 
      presentations, speakers bureaus, manuscript writing or educational events from 
      Biogen, Roche, Sarepta Therapeutics, Sanofi-Aventis, and Novartis; payment to his 
      institution for expert testimony from Astellas Pharma; participation on a data 
      safety monitoring board or advisory board with payment to himself from PTC 
      Therapeutics, Roche, and Novartis, and to his institution from Astellas Pharma; 
      and unpaid leadership roles for the Deutsche Gesellschaft fur Muskelkranke and 
      Glykogenose Deutschland, all outside the scope of this manuscript. EHN declares 
      grants to his institution from Pfizer and PTC Therapeutics; and consulting fees 
      to his institution from Pfizer, Edgewise Therapeutics, Sarepta Therapeutics, 
      Epirium Bio, Regenxbio, Janssen Pharmaceuticals, all outside the scope of this 
      manuscript. US-S declares consulting fees from Santhera, PTC Therapeutics, 
      Sarepta Therapeutics, and Pfizer, all outside the scope of this manuscript. EB 
      declares participation on advisory boards for Pfizer, Roche, Biogen, and 
      Novartis, all outside the scope of this manuscript. GPC declares payment for a 
      lecture from Biogen; participation on advisory boards for PTC Therapeutics, 
      Roche, and Sanofi Genzyme; and an unpaid leadership role (president) of the 
      Italian Association of Myology, all outside the scope of this manuscript. KDM 
      declares grants to her institution from Italfarmaco, Sarepta Therapeutics, PTC 
      Therapeutics, FibroGen, Capricor Therapeutics, Pfizer, Edgewise Therapeutics, 
      Biomarin Pharmaceutical, Centers for Disease Control and Prevention, and the 
      National Institutes of Health; an honorarium to cover travel costs from the 
      Muscular Dystrophy Association; reimbursement to her institution of support to 
      attend meetings and/or travel from the Parent Project Muscular Dystrophy; 
      participation on a data safety monitoring board or advisory board for Dyne 
      Therapeutics, NS Pharma, TRiNDS, and Sarepta Therapeutics; and payment to her 
      institution for participation in a grant review board for the Muscular Dystrophy 
      Association, all outside the scope of this manuscript. LS declares grants to his 
      institution from Roche, Novartis, Biogen, Sysnav Healthcare, Zentech, and Perkin 
      Elmer; consulting fees from Pfizer, Santhera, Dynacure, Dyne Therapeutics, 
      Audentes Therapeutics, Zentech, Sarepta Therapeutics, Roche, Novartis, Biohaven, 
      Biogen Digital Health, Scholar Rock, Regenexbio, and Evox Therapeutics; payment 
      or honoraria for lectures, presentations, speakers bureaus, manuscript writing or 
      educational events from Roche, Biogen, and Novartis; payment for expert testimony 
      from Audentes Therapeutics; participation on a data safety monitoring board or 
      advisory board for FibroGen, Lupin Therapeutics, and Illumina; and unpaid 
      leadership roles for the World Muscle Society, SMA Europe, and the Association 
      Belge contre les Maladies neuro-Musculaires , all outside the scope of this 
      manuscript. KV declares a research service agreement for the current clinical 
      trial. Outside of this manuscript, she declares grants from the National 
      Institutes of Health; and research service support from Sarepta Therapeutics, 
      Catabasis Pharmaceuticals, PTC Therapeutics, Summit Therapeutics, Astellas 
      Pharma, ML Bio/VCU, and Edgewise Therapeutics, all directed to the University of 
      Florida, Gainesville, FL, USA. JJ declares consulting fees from Biogen, AveXis, 
      Sarepta Therapeutics, and Roche; and receipt of travel and speaker fees from PTC 
      Therapeutics, all outside the scope of this manuscript. SM declares payment or 
      honoraria for lectures, presentations, speakers bureaus, manuscript writing or 
      educational events from Roche, Biogen, and Novartis, all outside the scope of 
      this manuscript. SS declares payments for participation in ad-hoc advisory boards 
      for PTC Medical, Sarepta Therapeutics, Pfizer, and Roche; and payment for 
      chairing a symposium sponsored by Sarepta Therapeutics at the British 
      Neuropsychiatry Association 2019 annual meeting, all outside the scope of this 
      manuscript. LM declares study funding and payments to her institution for 
      provision of study materials in the current clinical trial. Outside the current 
      manuscript she declares grants to her institution from Anavex Life Sciences. KS 
      declares grants or contracts from Biogen (principal investigator and clinical 
      trial site for a nusinersen study), ReveraGen-Santhera (principal investigator 
      for a vamorolone study), and PTC Therapeutics (principal investigator for an 
      ataluren study); payment to her institution from Roche for a teaching and 
      educational seminar on spinal muscular atrophy; an honorarium from Novartis for a 
      TREAT NMD talk on spinal muscular atrophy; and attendance at advisory boards for 
      Biogen and Roche (including travel), all outside the scope of this manuscript. 
      CGL declares contracts (as principal investigator) from Sarepta Therapeutics, 
      Dyne Therapeutics, Avidity Biosciences, FibroGen, Scholar Rock, and Biohaven; 
      consulting fees from Sarepta Therapeutics (payments to her institution), NS 
      Pharma (payments to herself), and Avidity (payments to her institution and to 
      herself); payments for participation in a speakers bureau from Biogen; and 
      support for attending meetings and/or travel from the Muscular Dystrophy 
      Association, CureCMD, and CureSMA, all outside the scope of this manuscript. KC 
      declares payments directly to KJC Statistics for statistical support of the 
      current trial. SC, NC, and PB are employees of Italfarmaco, the sponsor of the 
      current trial. CMM reports receiving grants or research support from Astellas 
      Pharma, BioMarin Pharmaceutical, Capricor Therapeutics, Catabasis 
      Pharmaceuticals, Edgewise Therapeutics, Italfarmaco, Pfizer, PTC Therapeutics, 
      and Santhera Pharmaceuticals; and consulting fees from Sarepta Therapeutics, 
      Astellas Pharma, Avidity Biosciences, BioMarin Pharmaceutical, Bristol Myers 
      Squib, Capricor Therapeutics, Catabasis Pharmaceuticals, Edgewise Therapeutics, 
      Eli Lilly, Epirium Bio, Entrada Therapeutics, Gilead Sciences, Halo Therapeutics, 
      Italfarmaco, Novartis, PepGen, Pfizer, PTC Therapeutics, Prosensa, and Santhera 
      Pharmaceuticals, all outside the scope of this manuscript. BB and GZ declare no 
      competing interests.
EDAT- 2024/03/21 00:43
MHDA- 2024/03/22 06:44
CRDT- 2024/03/20 21:58
PHST- 2023/09/25 00:00 [received]
PHST- 2024/01/24 00:00 [revised]
PHST- 2024/01/24 00:00 [accepted]
PHST- 2024/03/22 06:44 [medline]
PHST- 2024/03/21 00:43 [pubmed]
PHST- 2024/03/20 21:58 [entrez]
AID - S1474-4422(24)00036-X [pii]
AID - 10.1016/S1474-4422(24)00036-X [doi]
PST - ppublish
SO  - Lancet Neurol. 2024 Apr;23(4):393-403. doi: 10.1016/S1474-4422(24)00036-X.