Efficacy and safety of deflazacort vs prednisone and placebo for Duchenne muscular dystrophy

Abstract

Objective: To assess safety and efficacy of deflazacort (DFZ) and prednisone (PRED) vs placebo in Duchenne muscular dystrophy (DMD).

Methods: This phase III, double-blind, randomized, placebo-controlled, multicenter study evaluated muscle strength among 196 boys aged 5-15 years with DMD during a 52-week period. In phase 1, participants were randomly assigned to receive treatment with DFZ 0.9 mg/kg/d, DFZ 1.2 mg/kg/d, PRED 0.75 mg/kg/d, or placebo for 12 weeks. In phase 2, placebo participants were randomly assigned to 1 of the 3 active treatment groups. Participants originally assigned to an active treatment continued that treatment for an additional 40 weeks. The primary efficacy endpoint was average change in muscle strength from baseline to week 12 compared with placebo. The study was completed in 1995.

Results: All treatment groups (DFZ 0.9 mg/kg/d, DFZ 1.2 mg/kg/d, and PRED 0.75 mg/kg/d) demonstrated significant improvement in muscle strength compared with placebo at 12 weeks. Participants taking PRED had significantly more weight gain than placebo or both doses of DFZ at 12 weeks; at 52 weeks, participants taking PRED had significantly more weight gain than both DFZ doses. The most frequent adverse events in all 3 active treatment arms were Cushingoid appearance, erythema, hirsutism, increased weight, headache, and nasopharyngitis.

Conclusions: After 12 weeks of treatment, PRED and both doses of DFZ improved muscle strength compared with placebo. Deflazacort was associated with less weight gain than PRED.

Classification of evidence: This study provides Class I evidence that for boys with DMD, daily use of either DFZ and PRED is effective in preserving muscle strength over a 12-week period.

Figure 1. Study schematic and patient disposition

Participants enrolled were initially allocated to 1 of the 4 treatment groups (study phase 1). Participants were treated for 12 weeks. After 12 weeks, placebo participants were randomly allocated to 1 of the 3 active treatment groups and all participants were treated until week 52. The intention-to-treat (ITT) population included all participants who were randomized and had at least 1 postbaseline assessment. The safety population included all participants who received at least 1 dose of study medication. AE = adverse event; DFZ = deflazacort; PRED = prednisone.

Figure 2. Change in average muscle strength score (intention-to-treat population)

Data are shown as least squares (LS) mean differences (95% confidence intervals [CIs]) for each of the treatment groups in phase 1 of the study. A positive LS mean value indicates an increase in muscle strength. (A) Change from baseline, which was calculated as a mean of measurements from visit 1 and visit 2 to week 12 (primary endpoint). (B) Change from week 12 to week 52 (secondary endpoint). (C) Change from baseline to week 52. Statistical analysis results are from a mixed-effect repeated measure model with a compound symmetry covariance structure and included treatment group, visit, treatment by visit, stratum, and site as fixed effects, with the baseline value as a continuous covariate. p Values are based on the Dunnett test. *p = 0.0173 vs placebo; **p = 0.0003 vs placebo; †p = 0.0002 vs placebo; ‡p = 0.0044 vs prednisone (PRED) 0.75 mg/kg/d. DFZ = deflazacort; MRC = Medical Research Council.

Figure 3. Change in weight (intention-to-treat population)

Data are least squares (LS) mean differences (95% confidence intervals [CIs]) for each of the treatment groups in phase 1 of the study. A positive LS mean value indicates an increase in weight. (A) Change from baseline, which was calculated as a mean of measurements from visit 1 and visit 2 to week 12. (B) Change from week 12 to week 52. (C) Change from baseline to week 52. Statistical analysis results are from a mixed-effect repeated measure model with a compound symmetry covariance structure and included treatment group, visit, treatment by visit, stratum, and site as fixed effects, with the baseline value as a continuous covariate. p Values are based on the Dunnett test. *p = 0.0459 vs placebo; **p = 0.0003 vs prednisone (PRED) 0.75 mg/kg/d; †p = 0.013 vs PRED 0.75 mg/kg/d; ‡p < 0.0001 vs PRED 0.75 mg/kg/d. DFZ = deflazacort; MRC = Medical Research Council.