作者
Bettina Henzi,Simone Schmidt,Sara Nagy,Daniela Rubino-Nacht,Sabine Schaedelin,Niveditha Putananickal,G. Stimpson,Helge Amthor,Anne‐Marie Childs,Nicolas Deconinck,I. de Groot,Iain Horrocks,S. Houwen-van Opstal,Vincent Laugel,Mercedes López Lobato,M. Madruga Garrido,A. Nascimento Osorio,Ulrike Schara–Schmidt,Stefan Spinty,Arpad von Moers,Fiona Lawrence,Patricia Hafner,O.M. Dorchies,Dirk Fischer,Deborah Ridout,Francesco Muntoni,Adnan Manzur,R. Quinlivan,Giovanni Baranello,Marion Main,Lianne Abbott,N. Burnett,A. Rohwer,Evelin Milev,A. Wolfe,Eileen Mary O'Reilly,Volker Straub,Michela Guglieri,C. Marini Bettolo,Robert Muni-Lofra,M. James,J. Sodhi,Tracey Willis,E. M. Wright,Claire Rylance,Nick Birchall,Anne‐Marie Childs,Karen Pysden,Cristina Martos-Lozano,Lindsey Pallant,S. Wadsworth,Stefan Spinty,R Madhu,Rajesh Karuvattil,Sarah Gregson,Stuart Clark,Elizabeth Wraige,Heinz Jungbluth,Vasantha Gowda,Maria Vanegas,Emma Sheehan,Amy Wolfe,Alex Schofield,Imelda Hughes,Gary McCullagh,Emily J. Whitehouse,Uma Varma,Sinead Warner,Emily Reading,L.C. Benson,Tracey Willis,Jenny Moustoukas,Kate Strachan,Nicholas Emery,Min Ong,Mark Atherton,Sarah D'Urso,Kay White,Neil Hinde,Kate Skone,Silvia Sanchez Marco,Anurag Saxena,Frances Gibbon,Jim teWaterNaude,Hayley L. Belnoue-Davis,Laura Thompson,Anirban Majumdar,Archana Murugan,Mollie Lynch,Emily Milton,Iolanda Guarino,Richard Tomlinson,Heather Jarvis,Jane M. Berry,Lucy Wills,Claire Frimpong‐Ansah,Judith Watson,Gemma Robertson,Gavin Cobb,Julie Burslem,Iain Horrocks,Jerelyn Wong,Andreas Brunklaus,M DiMarco,Sarah M. Brown,Susanne Mckenzie,Krupa Torne,Rana Mohamed,V. Velmurugan,Manish Prasad,Saam Sedehizadeh,Sarah Williamson,Paula Fenty,C DeGoede,Amy Parkes,Marjorie Illingworth,Neeraj Bhangu,Michelle Geary,Jenni Palmer,Catherine Shill,Cathy White,Kathryn Greenfield,Heledd Tomos,Sherry Gates,Sandya Tirupathi,Ayaz Shah,Dara O’Donoghue,JG McVeigh,Jaci .McFetridge,Grainne Nic Fhirleinn,Nahin Hussain,Dhinesh Baskaran,Zubeida Lambat,Gautam Ambegaonkar,Deepa Krishnakumar,Jacqui Taylor,J Moores,Elma Stephen,Jane Tewnion,Sithara Ramdas,Mario Sa,Laurent Servais,C. Lilien,Hayley Ramjattan,Francesca Taylor,Hugh F. English,Deepak Parasuraman,Rosanna Rabb,Heather McMurchie
摘要
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.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.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.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.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.