Deflazacort dose optimization and safety evaluation in Duchenne muscular dystrophy (DOSE): A randomized, double-blind non-inferiority trial

Background: US food and drug administration has recently approved deflazacort for Duchenne muscular dystrophy (DMD) and recommended the dosage of 0.9 mg/kg/d for patients aged >= 5years. However, data assessing the minimal efficacious dose and need of dose-titration based on age or disease severity is limited. Objective: To determine whether deflazacort 0.45 mg/kg/d (proposed lower dosage) is non-inferior to 0.9 mg/kg/ d among newly diagnosed patients with DMD. Method: A double-blinded, non-inferiority, randomized trial, conducted between December 2018 and July 2020. Newly diagnosed patient aged 5-15 years with genetic or muscle biopsy confirmed DMD and baseline 6-min walk distance (6MWD) > 150 m were screened. Patients were randomly assigned (1:1), stratified to prespecified subgroups by age (<7years and >7years), and baseline 6MWD (<350 m and >350 m), to receive either 0.45 mg/ kg/d or 0.9 mg/kg/d regimens. The primary endpoint was the change in 6MWD, from baseline to week-24 of intervention. The trial was powered with a predefined, non-inferiority margin of 30 m. The analyses were by modified intention-to-treat (mITT). Result: A total of 97 patients were enrolled, 40 receiving 0.45 mg/kg/d and 45 receiving 0.9 mg/kg/d deflazacort comprised of mITT population. For primary endpoint analysis the mean (SD) change in 6MWD from baseline to week-24 was 9.7 m (41.5) in deflazacort 0.45 mg/kg/d, and 34.7 m (43.5) for 0.9 mg/kg/d. The mean difference in change in 6MWD across the group was 24.8 m (95% CI 6.7 to 43, p value 0.008). The mean difference in change in 6MWD in the subgroups of boys <7 years of age was 21.8 m (95% CI -0.82, 44.5, p = 0.059), with baseline 6MWD of >350 m was 19.9 m (95% CI -2.4, 42.4; p = 0.08). The incidence of combined moderate to severe treatment-related adverse events was significant in the 0.9 mg/kg/d group by week 24 (odds ratio 0.36 [95% CI, 0.14 to 0.89], p = 0.03). Discussion: The efficacy of proposed low dose deflazacort in comparison to the standard dose did not meet the prespecified criteria for non-inferiority. The low dose deflazacort was non-inferior in subgroup of patients with age <7 years and baseline 6MWD of >350 m. Trial registration: Clinical Trial Registry-India Identifier: CTRI/2019/02/017388.