Michela Guglieri1, Kate Bushby1, Michael P McDermott2,3, Kimberly A Hart2, Rabi Tawil2, William B Martens2, Barbara E Herr2, Elaine McColl4, Chris Speed4,5, Jennifer Wilkinson4, Janbernd Kirschner6,7, Wendy M King8, Michelle Eagle1, Mary W Brown2, Tracey Willis9, Robert C Griggs2, Volker Straub1, Henriette van Ruiten1, Anne-Marie Childs10, Emma Ciafaloni2, Perry B Shieh11, Stefan Spinty12, Lorenzo Maggi13, Giovanni Baranello13,14, Russell J Butterfield15, I A Horrocks16, Helen Roper17, Zoya Alhaswani17, Kevin M Flanigan18, Nancy L Kuntz19, Adnan Manzur20, Basil T Darras21, Peter B Kang21,22, Leslie Morrison23, Monika Krzesniak-Swinarska23, Jean K Mah24, Tiziana E Mongini25, Federica Ricci25, Maja von der Hagen26, Richard S Finkel27,28, Kathleen O'Reardon27, Matthew Wicklund29,30, Ashutosh Kumar29, Craig M McDonald31, Jay J Han31, Nanette Joyce31, Erik K Henricson31, Ulrike Schara-Schmidt32, Andrea Gangfuss32, Ekkehard Wilichowski33, Richard J Barohn34, Jeffrey M Statland35, Craig Campbell36, Giuseppe Vita37, Gian Luca Vita38, James F Howard39, Imelda Hughes40, Hugh J McMillan41, Elena Pegoraro42, Luca Bello42, W Bryan Burnette43, Mathula Thangarajh44, Taeun Chang45. 1. John Walton Muscular Dystrophy Research Centre, Newcastle University and Newcastle Hospitals NHS Foundation Trust, Newcastle upon Tyne, England. 2. Department of Neurology, University of Rochester Medical Center, Rochester, New York. 3. Department of Biostatistics and Computational Biology, University of Rochester Medical Center, Rochester, New York. 4. Newcastle University, Newcastle upon Tyne, England. 5. NIHR Clinical Research Network North East and North Cumbria, Newcastle upon Tyne, England. 6. Department of Neuropediatrics and Muscle Disorders, Faculty of Medicine, University Hospital Freiburg, Freiburg, Germany. 7. Department of Neuropediatrics, University Hospital Bonn, Bonn, Germany. 8. Ohio State University, Columbus. 9. Robert Jones and Agnes Hunt Orthopaedic Hospital, NHS Foundation Trust, Oswestry, England. 10. Leeds General Infirmary, Leeds, England. 11. David Geffen School of Medicine, University of California, Los Angeles. 12. Alderhey Children's Hospital NHS Foundation Trust, Liverpool, England. 13. Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy. 14. Dubowitz Neuromuscular Centre, UCL NIHR GOSH Biomedical Research Centre, UCL Great Ormond Street Institute of Child Health, London, England. 15. Department of Pediatric Neurology, University of Utah, Salt Lake City. 16. Glasgow Paediatric Neuromuscular Research Centre, Greater Glasgow and Clyde NHS Yorkhill Hospital, Glasgow, Scotland. 17. University Hospitals Birmingham NHS Foundation Trust, Birmingham, England. 18. Center for Gene Therapy, Abigail Wexner Research Institute, Nationwide Children's Hospital, Columbus, Ohio. 19. Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, Illinois. 20. Great Ormond Street Hospital, London, England. 21. Department of Neurology, Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts. 22. Paul and Sheila Wellstone Muscular Dystrophy Center and Department of Neurology, University of Minnesota Medical School, Minneapolis. 23. Health Sciences Center, University of New Mexico, Albuquerque. 24. Cumming School of Medicine, University of Calgary and Alberta Children's Hospital Research Institute, Calgary, Canada. 25. Neuromuscular Center, AOU Città della Salute e della Scienza, University of Turin, Turin, Italy. 26. Abteilung Neuropädiatrie, Medizinische Fakultät Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany. 27. Nemours Children's Hospital, Orlando, Florida. 28. Center for Experimental Neurotherapeutics, St Jude Children's Research Hospital, Memphis, Tennessee. 29. Penn State Health Milton S. Hershey Medical Center, Hershey, Pennsylvania. 30. Department of Neurology, School of Medicine, University of Colorado, Aurora. 31. Department of Physical Medicine and Rehabilitation and Department of Pediatrics, University of California-Davis, Sacramento. 32. Clinic for Pediatrics I, Pediatric Neurology, University Hospital Essen, Essen, Germany. 33. Department of Pediatrics and Adolescent Medicine, Division of Pediatric Neurology, University Medical Center Göttingen, Göttingen, Germany. 34. University of Missouri, Columbia. 35. University of Kansas Medical Center, Kansas City. 36. Departments of Pediatrics, Clinical Neurological Sciences, and Epidemiology, University of Western Ontario, London, Canada. 37. ERN Neuromuscular Unit, Department of Clinical and Experimental Medicine, University of Messina, Messina, Italy. 38. Unit of Neurology, IRCCS Centro Neurolesi Bonino-Pulejo, Messina, Italy. 39. School of Medicine, University of North Carolina, Chapel Hill. 40. Royal Manchester Children's Hospital, Manchester, England. 41. Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, Canada. 42. ERN Neuromuscular Unit, Department of Neuroscience, University of Padova, Padua, Italy. 43. Vanderbilt University Medical Center, Nashville, Tennessee. 44. Department of Neurology, Virginia Commonwealth University, Richmond. 45. Children's National Hospital, George Washington University, Washington, DC.
Abstract
Importance: Corticosteroids improve strength and function in boys with Duchenne muscular dystrophy. However, there is uncertainty regarding the optimum regimen and dosage. Objective: To compare efficacy and adverse effects of the 3 most frequently prescribed corticosteroid regimens in boys with Duchenne muscular dystrophy. Design, Setting, and Participants: Double-blind, parallel-group randomized clinical trial including 196 boys aged 4 to 7 years with Duchenne muscular dystrophy who had not previously been treated with corticosteroids; enrollment occurred between January 30, 2013, and September 17, 2016, at 32 clinic sites in 5 countries. The boys were assessed for 3 years (last participant visit on October 16, 2019). Interventions: Participants were randomized to daily prednisone (0.75 mg/kg) (n = 65), daily deflazacort (0.90 mg/kg) (n = 65), or intermittent prednisone (0.75 mg/kg for 10 days on and then 10 days off) (n = 66). Main Outcomes and Measures: The global primary outcome comprised 3 end points: rise from the floor velocity (in rise/seconds), forced vital capacity (in liters), and participant or parent global satisfaction with treatment measured by the Treatment Satisfaction Questionnaire for Medication (TSQM; score range, 0 to 100), each averaged across all study visits after baseline. Pairwise group comparisons used a Bonferroni-adjusted significance level of .017. Results: Among the 196 boys randomized (mean age, 5.8 years [SD, 1.0 years]), 164 (84%) completed the trial. Both daily prednisone and daily deflazacort were more effective than intermittent prednisone for the primary outcome (P < .001 for daily prednisone vs intermittent prednisone using a global test; P = .017 for daily deflazacort vs intermittent prednisone using a global test) and the daily regimens did not differ significantly (P = .38 for daily prednisone vs daily deflazacort using a global test). The between-group differences were principally attributable to rise from the floor velocity (0.06 rise/s [98.3% CI, 0.03 to 0.08 rise/s] for daily prednisone vs intermittent prednisone [P = .003]; 0.06 rise/s [98.3% CI, 0.03 to 0.09 rise/s] for daily deflazacort vs intermittent prednisone [P = .017]; and -0.004 rise/s [98.3% CI, -0.03 to 0.02 rise/s] for daily prednisone vs daily deflazacort [P = .75]). The pairwise comparisons for forced vital capacity and TSQM global satisfaction subscale score were not statistically significant. The most common adverse events were abnormal behavior (22 [34%] in the daily prednisone group, 25 [38%] in the daily deflazacort group, and 24 [36%] in the intermittent prednisone group), upper respiratory tract infection (24 [37%], 19 [29%], and 24 [36%], respectively), and vomiting (19 [29%], 17 [26%], and 15 [23%]). Conclusions and Relevance: Among patients with Duchenne muscular dystrophy, treatment with daily prednisone or daily deflazacort, compared with intermittent prednisone alternating 10 days on and 10 days off, resulted in significant improvement over 3 years in a composite outcome comprising measures of motor function, pulmonary function, and satisfaction with treatment; there was no significant difference between the 2 daily corticosteroid regimens. The findings support the use of a daily corticosteroid regimen over the intermittent prednisone regimen tested in this study as initial treatment for boys with Duchenne muscular dystrophy. Trial Registration: ClinicalTrials.gov Identifier: NCT01603407.
Importance: Corticosteroids improve strength and function in boys with Duchenne muscular dystrophy. However, there is uncertainty regarding the optimum regimen and dosage. Objective: To compare efficacy and adverse effects of the 3 most frequently prescribed corticosteroid regimens in boys with Duchenne muscular dystrophy. Design, Setting, and Participants: Double-blind, parallel-group randomized clinical trial including 196 boys aged 4 to 7 years with Duchenne muscular dystrophy who had not previously been treated with corticosteroids; enrollment occurred between January 30, 2013, and September 17, 2016, at 32 clinic sites in 5 countries. The boys were assessed for 3 years (last participant visit on October 16, 2019). Interventions: Participants were randomized to daily prednisone (0.75 mg/kg) (n = 65), daily deflazacort (0.90 mg/kg) (n = 65), or intermittent prednisone (0.75 mg/kg for 10 days on and then 10 days off) (n = 66). Main Outcomes and Measures: The global primary outcome comprised 3 end points: rise from the floor velocity (in rise/seconds), forced vital capacity (in liters), and participant or parent global satisfaction with treatment measured by the Treatment Satisfaction Questionnaire for Medication (TSQM; score range, 0 to 100), each averaged across all study visits after baseline. Pairwise group comparisons used a Bonferroni-adjusted significance level of .017. Results: Among the 196 boys randomized (mean age, 5.8 years [SD, 1.0 years]), 164 (84%) completed the trial. Both daily prednisone and daily deflazacort were more effective than intermittent prednisone for the primary outcome (P < .001 for daily prednisone vs intermittent prednisone using a global test; P = .017 for daily deflazacort vs intermittent prednisone using a global test) and the daily regimens did not differ significantly (P = .38 for daily prednisone vs daily deflazacort using a global test). The between-group differences were principally attributable to rise from the floor velocity (0.06 rise/s [98.3% CI, 0.03 to 0.08 rise/s] for daily prednisone vs intermittent prednisone [P = .003]; 0.06 rise/s [98.3% CI, 0.03 to 0.09 rise/s] for daily deflazacort vs intermittent prednisone [P = .017]; and -0.004 rise/s [98.3% CI, -0.03 to 0.02 rise/s] for daily prednisone vs daily deflazacort [P = .75]). The pairwise comparisons for forced vital capacity and TSQM global satisfaction subscale score were not statistically significant. The most common adverse events were abnormal behavior (22 [34%] in the daily prednisone group, 25 [38%] in the daily deflazacort group, and 24 [36%] in the intermittent prednisone group), upper respiratory tract infection (24 [37%], 19 [29%], and 24 [36%], respectively), and vomiting (19 [29%], 17 [26%], and 15 [23%]). Conclusions and Relevance: Among patients with Duchenne muscular dystrophy, treatment with daily prednisone or daily deflazacort, compared with intermittent prednisone alternating 10 days on and 10 days off, resulted in significant improvement over 3 years in a composite outcome comprising measures of motor function, pulmonary function, and satisfaction with treatment; there was no significant difference between the 2 daily corticosteroid regimens. The findings support the use of a daily corticosteroid regimen over the intermittent prednisone regimen tested in this study as initial treatment for boys with Duchenne muscular dystrophy. Trial Registration: ClinicalTrials.gov Identifier: NCT01603407.
Authors: Michelle Eagle; Simon V Baudouin; Colin Chandler; David R Giddings; Robert Bullock; Kate Bushby Journal: Neuromuscul Disord Date: 2002-12 Impact factor: 4.296
Authors: David J Birnkrant; Katharine Bushby; Carla M Bann; Susan D Apkon; Angela Blackwell; David Brumbaugh; Laura E Case; Paula R Clemens; Stasia Hadjiyannakis; Shree Pandya; Natalie Street; Jean Tomezsko; Kathryn R Wagner; Leanne M Ward; David R Weber Journal: Lancet Neurol Date: 2018-02-03 Impact factor: 44.182
Authors: Michela Guglieri; Kate Bushby; Michael P McDermott; Kimberly A Hart; Rabi Tawil; William B Martens; Barbara E Herr; Elaine McColl; Jennifer Wilkinson; Janbernd Kirschner; Wendy M King; Michele Eagle; Mary W Brown; Tracey Willis; Deborah Hirtz; Perry B Shieh; Volker Straub; Anne-Marie Childs; Emma Ciafaloni; Russell J Butterfield; Iain Horrocks; Stefan Spinty; Kevin M Flanigan; Nancy L Kuntz; Giovanni Baranello; Helen Roper; Leslie Morrison; Jean K Mah; Adnan Y Manzur; Craig M McDonald; Ulrike Schara; Maja von der Hagen; Richard J Barohn; Craig Campbell; Basil T Darras; Richard S Finkel; Giuseppe Vita; Imelda Hughes; Tiziana Mongini; Elena Pegoraro; Matthew Wicklund; Ekkehard Wilichowski; W Bryan Burnette; James F Howard; Hugh J McMillan; Mathula Thangarajh; Robert C Griggs Journal: Contemp Clin Trials Date: 2017-04-24 Impact factor: 2.226
Authors: Katharine Bushby; Richard Finkel; David J Birnkrant; Laura E Case; Paula R Clemens; Linda Cripe; Ajay Kaul; Kathi Kinnett; Craig McDonald; Shree Pandya; James Poysky; Frederic Shapiro; Jean Tomezsko; Carolyn Constantin Journal: Lancet Neurol Date: 2009-11-27 Impact factor: 44.182
Authors: Erik Henricson; Richard Abresch; Jay J Han; Alina Nicorici; Erica Goude Keller; Evan de Bie; Craig M McDonald Journal: PLoS Curr Date: 2013-07-08
Authors: Jerry R Mendell; Zarife Sahenk; Kelly Lehman; Carrie Nease; Linda P Lowes; Natalie F Miller; Megan A Iammarino; Lindsay N Alfano; Amanda Nicholl; Samiah Al-Zaidy; Sarah Lewis; Kathleen Church; Richard Shell; Linda H Cripe; Rachael A Potter; Danielle A Griffin; Eric Pozsgai; Ashish Dugar; Mark Hogan; Louise R Rodino-Klapac Journal: JAMA Neurol Date: 2020-09-01 Impact factor: 18.302