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

Autor:	Henzi BC; Division of Neuropediatrics and Developmental Medicine, University Children's Hospital Basel, University of Basel, Basel, Switzerland; Department of Neuropediatrics and Muscle Disorders, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany., Schmidt S; Division of Neuropediatrics and Developmental Medicine, University Children's Hospital Basel, University of Basel, Basel, Switzerland., Nagy S; Department of Neurology, University Hospital Basel, University of Basel, Basel, Switzerland., Rubino-Nacht D; Division of Neuropediatrics and Developmental Medicine, University Children's Hospital Basel, University of Basel, Basel, Switzerland., Schaedelin S; Department of Clinical Research, University of Basel and University Hospital Basel, Basel, Switzerland., Putananickal N; Division of Neuropediatrics and Developmental Medicine, University Children's Hospital Basel, University of Basel, Basel, Switzerland., Stimpson G; Developmental Neuroscience Research and Teaching Department, Faculty of Population Health Sciences, Dubowitz Neuromuscular Centre, UCL Great Ormond Street Institute of Child Health, London, UK., Amthor H; Service de Neurologie et Réanimation Pédiatriques, APHP Paris Saclay, Hôpital Raymond Poincaré, Garches, France., Childs AM; The Leeds Teaching Hospitals NHS Trust, Leeds, UK., Deconinck N; Department of Paediatric Neurology and Neuromuscular Reference Center, Hôpital Universitaire des Enfants Reine Fabiola, Université Libre de Bruxelles, Brussels, Belgium., de Groot I; Department of Rehabilitation, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, Netherlands., Horrocks I; Royal Hospital for Children, Glasgow, UK., Houwen-van Opstal S; Department of Rehabilitation, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, Netherlands., Laugel V; Department of Pediatric Neurology, Strasbourg University Hospital, Strasbourg, France., Lopez Lobato M; Sección de Neurología Pediátrica, Hospital Universitario Virgen del Rocío, Seville, Spain., Madruga Garrido M; Sección de Neurología Pediátrica, Hospital Universitario Virgen del Rocío, Seville, Spain., Nascimento Osorio A; Neuromuscular Unit, Department of Neurology, Hospital Sant Joan de Déu and Center for Biomedical Research Network on Rare Diseases, ISCIII, Barcelona, Spain., Schara-Schmidt U; Department of Pediatric Neurology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany., Spinty S; Alder Hey Children's Hospital, Liverpool, UK., von Moers A; Department of Pediatrics, DRK Kliniken Berlin Westend, Berlin, Germany., Lawrence F; Duchenne UK, London, UK., Hafner P; Division of Neuropediatrics and Developmental Medicine, University Children's Hospital Basel, University of Basel, Basel, Switzerland., Dorchies OM; School of Pharmaceutical Sciences and Institute of Pharmaceutical Sciences of Western Switzerland, University of Geneva, Geneva, Switzerland., Fischer D; Division of Neuropediatrics and Developmental Medicine, University Children's Hospital Basel, University of Basel, Basel, Switzerland. Electronic address: dirk.fischer@ukbb.ch.
Jazyk:	angličtina
Zdroj:	The Lancet. Neurology [Lancet Neurol] 2023 Oct; Vol. 22 (10), pp. 890-899.
DOI:	10.1016/S1474-4422(23)00285-5
Abstrakt:	Background: Drug repurposing could provide novel treatment options for Duchenne muscular dystrophy. Because tamoxifen-an oestrogen receptor regulator-reduced signs of muscular pathology in a Duchenne muscular dystrophy mouse model, we aimed to assess the safety and efficacy of tamoxifen in humans as an adjunct to corticosteroid therapy over a period of 48 weeks. Methods: We did a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial at 12 study centres in seven European countries. We enrolled ambulant boys aged 6·5-12·0 years with a genetically confirmed diagnosis of Duchenne muscular dystrophy and who were on stable corticosteroid treatment for more than 6 months. Exclusion criteria included ophthalmological disorders, including cataracts, and haematological disorders. We randomly assigned (1:1) participants using an online randomisation tool to either 20 mg tamoxifen orally per day or matched placebo, stratified by centre and corticosteroid intake. Participants, caregivers, and clinical investigators were masked to treatment assignments. Tamoxifen was taken in addition to standard care with corticosteroids, and participants attended study visits for examinations every 12 weeks. The primary efficacy outcome was the change from baseline to week 48 in scores on the D1 domain of the Motor Function Measure in the intention-to-treat population (defined as all patients who fulfilled the inclusion criteria and began treatment). This study is registered with ClinicalTrials.gov (NCT03354039) and is completed. Findings: Between May 24, 2018, and Oct 14, 2020, 95 boys were screened for inclusion, and 82 met inclusion criteria and were initially enrolled into the study. Three boys were excluded after initial screening due to cataract diagnosis or revoked consent directly after screening, but before randomisation. A further boy assigned to the placebo group did not begin treatment. Therefore, 40 individuals assigned tamoxifen and 38 allocated placebo were included in the intention-to-treat population. The primary efficacy outcome did not differ significantly between tamoxifen (-3·05%, 95% CI -7·02 to 0·91) and placebo (-6·15%, -9·19 to -3·11; 2·90% difference, -3·02 to 8·82, p=0·33). Severe adverse events occurred in two participants: one participant who received tamoxifen had a fall, and one who received placebo suffered a panic attack. No deaths or life-threatening serious adverse events occurred. Viral infections were the most common adverse events. Interpretation: Tamoxifen was safe and well tolerated, but no difference between groups was reported for the primary efficacy endpoint. Slower disease progression, defined by loss of motor function over time, was indicated in the tamoxifen group compared with the placebo group, but differences in outcome measures were neither clinically nor statistically significant. Currently, we cannot recommend the use of tamoxifen in daily clinical practice as a treatment option for boys with Duchenne muscular dystrophy due to insufficient clinical evidence. Funding: Thomi Hopf Foundation, ERA-Net, Swiss National Science Foundation, Duchenne UK, Joining Jack, Duchenne Parent Project, Duchenne Parent Project Spain, Fondation Suisse de Recherche sur les Maladies Musculaires, Association Monegasque contre les Myopathies. Competing Interests: Declaration of interests DF is principal investigator for studies on spinal muscular atrophy sponsored by Hofmann–La Roche. US-S is a consultant for Santhera, PTC Therapeutics, Sarepta, and Pfizer. ND is a consultant for Roche and Novartis and received payment for lectures from Roche. ANO received payment for lectures from Sarepta, Novartis, Biogen, PTC Therapeutics, and Roche and support for attending meetings from PTC Therapeutics, Roche, and Biogen. VL is a consultant for Axelys, Roche, Avexis, and Biogen and received payment for lectures from Biogen, Pfizer, Roche, Novartis, PTC Therapeutics, and Sarepta. VL received support of attending meetings from Novartis, Pfizer, and Biogen and participated in advisory boards for Novartis, Roche, Biogen, and PTC Therapeutics. StS is a consultant for Sarepta, PCT, Roche, WAVE, Pfizer, and Avexis and received payment for lectures from Sarepta. All other authors declare no competing interests. All study sites received payment for study set up and study visits. (Copyright © 2023 Elsevier Ltd. All rights reserved.)
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu