Effect of Different Corticosteroid Dosing Regimens on Clinical Outcomes in Boys With Duchenne Muscular Dystrophy: A Randomized Clinical Trial

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.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Guglieri reported receiving grants from Duchenne UK, the European Union’s Horizon 2020 program for the Vision-DMD study (in collaboration with ReveraGen BioPharma Inc), and Sarepta Therapeutics; serving as a consultant to Dyne Therapeutics Inc, Pfizer, and NS Pharma Inc; receiving personal fees from Sarepta Therapeutics; and receiving nonfinancial support from Italfarmaco, Pfizer, ReveraGen BioPharma Inc, and Santhera Pharmaceuticals. Dr McDermott reported receiving grant support from PTC Therapeutics and receiving personal fees from Fulcrum Therapeutics, NeuroDerm Ltd, AstraZeneca, Eli Lilly, Catabasis Pharmaceuticals, Vaccinex Inc, Cynapsus Therapeutics, Neurocrine Biosciences, Voyager Therapeutics, Prilenia Therapeutics, ReveraGen BioPharma Inc, and NS Pharma Inc. Ms Hart reported receiving personal fees from Sarepta Therapeutics, Santhera Pharmaceuticals, and PTC Therapeutics. Dr McColl reported receiving grants from the National Institute for Health Research. Dr Kirschner reported receiving personal fees from PTC Therapeutics, Pfizer, Roche, and Sarepta Therapeutics. Dr Eagle reported receiving personal fees from ATOM International Ltd. Dr Willis reported receiving personal fees from Newcastle University, Novartis, Biogen Inc, Sarepta, Santhera, PTC Therapeutics, and Sanofi Genzyme. Dr Straub reported receiving grants from Sarepta Therapeutics and Sanofi Genzyme and serving as a consultant to Sarepta Therapeutics, Edgewise Therapeutics, Sanofi Genzyme, Vertex Pharmaceuticals, Biogen Inc, Roche, Novartis Gene Therapies, Astellas Gene Therapies, Wave Therapeutics, Kate Therapeutics Inc, and Pfizer. Dr Childs reported receiving personal fees from PTC Therapeutics, Sarepta Therapeutics, FibroGen Inc, the University of Basel, and ReveraGen BioPharma Inc. Dr Ciafaloni reported receiving personal fees from Viela Bio, AveXis Inc (now Novartis Gene Therapies), Biogen Inc, Medscape, Pfizer, PTC Therapeutics, Sarepta Therapeutics, Ra Pharmaceuticals, Wave Therapeutics, and Strongbridge Biopharma; receiving grants from the US Centers for Disease Control and Prevention, Cure SMA, the Muscular Dystrophy Association, the National Institutes of Health, Orphazyme, the Patient-Centered Outcomes Research Institute, Parent Project Muscular Dystrophy, PTC Therapeutics, Santhera Pharmaceuticals, Sarepta Therapeutics, and the US Food and Drug Administration; receiving royalties from Oxford University Press; and receiving compensation from MedLink for editorial duties. Dr Shieh reported receiving grants from Catalyst Pharmaceuticals, Sarepta Therapeutics, PTC Therapeutics, Pfizer, Sanofi, AveXis (now Novartis Gene Therapies), Biogen Inc, Santhera Pharmaceuticals, Fulcrum Therapeutics Inc, Astellas Gene Therapies, Solid Biosciences, ReveraGen BioPharma Inc, AMO Pharma, and Zogenix Inc and receiving personal fees from Sarepta Therapeutics, Ra Pharmaceuticals, Argenx, PTC Therapeutics, Pfizer, CSL Behring, Genentech, AveXis, Grifols, Alexion Pharmaceuticals, and Biogen Inc. Mr Spinty reported receiving personal fees from Roche, Sarepta Therapeutics, Pfizer, and Biogen Inc and receiving grants from PTC Therapeutics. Dr Maggi reported receiving personal fees from Biogen Inc, Sanofi-Genzyme, and Roche. Dr Baranello reported receiving personal fees from PTC Therapeutics, Sarepta Therapeutics, ReveraGen BioPharma Inc, NS Pharma Inc, Pfizer, and Roche. Dr Butterfield reported receiving personal fees from AavantiBio, Scholar Rock Inc, AveXis (now Novartis Gene Therapies), Pfizer, PTC Therapeutics, Biogen Inc, and Sarepta Therapeutics. Dr Roper reported reported receiving personal fees from GlaxoSmithKline, Prosensa, BioMarin Pharmaceutical Inc, and Biogen Inc and receiving grants from Summit Therapeutics and Roche. Dr Flanigan reported receiving grants and royalty payments from Astellas Gene Therapies and receiving grants from Sarepta Therapeutics. Dr Kuntz reported receiving personal fees from Sarepta Therapeutics, Astellas Gene Therapies, Novartis, and Genentech. Dr Manzur reported receiving grants from Muscular Dystrophy UK. Dr Darras reported receiving personal fees from Amicus Inc, Audentes Therapeutics (now Astellas Gene Therapies), AveXis (now Novartis Gene Therapies), Biogen Inc, Pfizer, Vertex, Roche, and Genentech; receiving research support from the National Institute of Neurological Disorders and Stroke, the Slaney Family Fund, the Spinal Muscular Atrophy Foundation, Cure SMA, and Working on Walking Fund; receiving grants from Ionis Pharmaceuticals Inc, Biogen Inc, AveXis, Sarepta Therapeutics, Novartis, PTC Therapeutics, Roche, Scholar Rock Inc, and FibroGen Inc; and receiving royalties for books and online publications from Elsevier and UpToDate Inc. Dr Kang reported receiving grants from PTC Therapeutics. Dr Mah reported receiving grants from ReveraGen BioPharma Inc, Pfizer, Italfarmaco, Sarepta Therapeutics, Catabasis Pharmaceuticals, NS Pharma, and PTC Therapeutics. Dr Mongini reported receiving personal fees from Sanofi Genzyme, Biogen Inc, Sarepta Therapeutics, Spark, Roche, and Novartis. Dr Ricci reported receiving grants from the University of Rochester. Dr von der Hagen reported receiving personal fees from PTC Therapeutics Germany GmbH and Pfizer Pharma GmbH and receiving grants from Sarepta Therapeutics. Dr Finkel reported receiving grants from ReveraGen BioPharma Inc, the Muscular Dystrophy Association, the National Institutes of Health, Capricor Therapeutics, Catabasis Pharmaceuticals, Eli Lilly, PTC Therapeutics, Santhera Pharmaceuticals, Sarepta Therapeutics, and Summit Therapeutics. Ms O’Reardon reported receiving grants from Nemours Children’s Hospital. Dr Wicklund reported receiving personal fees from Affinia Therapeutics, Amicus Therapeutics, Edgewise Therapeutics, ML Bio Solutions, Sarepta Therapeutics, and Sanofi-Genzyme. Dr Kumar reported receiving grants from PTC Therapeutics, Sarepta Therapeutics, AveXis (now Novartis Gene Therapies), the Muscular Dystrophy Association, and FibroGen Inc and receiving personal fees from Sarepta Therapeutics, Audentes Therapeutics, AveXis, Roche, Genetech, PTC Therapeutics, Biogen Inc, and the American Academy of Pediatrics. Dr McDonald reported receiving grants from Capricor Therapeutics, Catabasis Pharmaceuticals, FibroGen Inc, Pfizer, PTC Therapeutics, ReveraGen BioPharma Inc, Santhera Pharmaceuticals, the University of Rochester, and Sarepta Therapeutics and receiving personal fees from PTC Therapeutics, Sarepta Therapeutics, Astellas, Avidity Biosciences, BioMarin Pharmaceutical Inc, Capricor Therapeutics, Catabasis Pharmaceuticals, Edgewise Therapeutics, Eli Lilly, Entrada Therapeutics, Epirium Bio, FibroGen Inc, Hoffmann-La Roche, Italfarmaco, Marathon Pharmaceuticals, Pfizer, PTC Therapeutics, Sarepta Therapeutics, and Santhera Pharmaceuticals. Dr Henricson reported receiving personal fees from PTC Therapeutics and Santhera Pharmaceuticals. Dr Schara-Schmidt reported receiving personal fees from Sarepta Therapeutics, Santhera Pharmaceuticals, Roche, PTC Therapeutics, and Pfizer. Dr Wilichowski reported receiving grants from the University of Rochester. Dr Statland reported receiving grants from the National Institutes of Health, the FSHD Society, the FSHD Canada Foundation, and the Friends of FSH Research and receiving personal fees from Fulcrum Therapeutics, Dyne Therapeutics Inc, Avidity Biosciences, Mitsubishi Tanabe Pharma, ML Bio Solutions, and Amylyx Pharmaceuticals. Dr Campbell reported receiving personal fees from Acceleron Pharma, AMO Pharma, BioMarin Pharmaceutical Inc, Bristol Myers Squibb, Eli Lily, Biogen Inc, Pfizer, Roche, PTC Therapeutics, Sarepta Therapeutics, Cytokinetics, Wave Therapeutics, Catabasis Pharmaceuticals, Edgewise Therapeutics, and Solid Biosciences and receiving grants from PTC Therapeutics, Genzyme, and Biogen Inc. Dr G. Vita reported receiving grants from Sarepta Therapeutics, Santhera Pharmaceuticals, Italfarmaco, and Wave Therapeutics. Dr G. L. Vita reported receiving grants from Sarepta Therapeutics, Santhera Pharmaceuticals, Italfarmaco, and Wave Therapeutics. Dr Howard reported receiving grants from Alexion Pharmaceuticals, Ra Pharmaceuticals (now UCB), Argenx BVBA, and Millennium Pharmaceuticals Inc and receiving personal fees from Alexion Pharmaceuticals, Argenx BVBA, Ra Pharmaceuticals, Immunovant Inc, Regeneron Pharmaceuticals, Toleranzia, and Viela Bio Inc (now Horizon Therapeutics). Dr Hughes reported receiving personal fees from PTC Therapeutics, Novartis, Santhera Pharmaceuticals, Summit Therapeutics, and Roche. Dr Pegoraro reported receiving personal fees from PTC Therapeutics, Sarepta Therapeutics, Epirium Bio, Roche, Biogen Inc, UCB, and Alexion Pharmaceuticals and receiving grants and nonfinancial support from Santhera Pharmaceuticals. Dr Bello reported serving on boards for Edgewise Therapeutics, PTC Therapeutics, and Sarepta Therapeutics; receiving grant support from Santhera Pharmaceuticals; and receiving personal fees from PTC Therapeutics and Epirium Bio. Dr Burnette reported serving on working groups or boards for PTC Therapeutics, Sarepta Therapeutics, and SteroTherapeutics LLC. Dr Thangarajh reported serving as a consultant to Sarepta Therapeutics. Dr Griggs reported serving as a consultant to Strongbridge and Stealth Pharmaceuticals; receiving personal fees from Solid Biosciences and Elsevier; serving as chair of the research advisory committee and is a board member of the American Brain Foundation; and serving on the executive committee of the Muscle Study Group, which receives support for its activities from pharmaceutical companies. No other disclosures were reported.

Figures

Figure 1.. Recruitment, Randomization, and Participant Flow in the FOR-DMD Trial

aThere were 6 boys who withdrew and never had a study visit after the baseline visit (3 in the daily prednisone group, 2 in the daily deflazacort group, and 1 in the intermittent prednisone group).

Figure 2.. Mean Trajectories Over Time by Treatment Group for Individual Components of the Composite Primary Outcome

The ends of the boxes represent the 25th and 75th percentiles of the distribution; the lines extending vertically from the boxes indicate the range of the data, with the exception of outside values (indicated by circles) that are more than 1.5 × interquartile range from the nearest quartile. The boxes are connected by the adjusted group means obtained from a repeated-measures analysis of covariance model. TSQM indicates Treatment Satisfaction Questionnaire for Medication. Additional details appear in the statistical analysis plan in Supplement 1.