STUDY SUMMARIES

The following study summaries support information that was not considered or included as part of the approval for EMFLAZA®. Physicians should carefully assess all relevant safety and efficacy data on EMFLAZA before making the decision to prescribe EMFLAZA to a patient. The data presented is not intended to offer an opinion on the safe or effective use of EMFLAZA for any purpose other than its FDA-approved use. Please see the EMFLAZA full Prescribing Information.

 

Griggs 2016 Study Summary

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

A phase III, double-blind, randomized, placebo-controlled, multicenter study of 196 patients with Duchenne muscular dystrophy (DMD) aged 5-15 years.

The primary efficacy endpoint was average change in muscle strength from baseline to Week 12 compared with placebo. At Week 12, all active treatment arms (deflazacort 0.9 and 1.2 mg/kg/day and prednisone 0.75 mg/kg/day) preserved muscle strength in patients with DMD.

In a secondary endpoint analysis, deflazacort 0.9 mg/kg/day demonstrated a significant improvement in muscle strength vs prednisone from Week 12 to 52.

Deflazacort preserved motor function in patients with DMD. From baseline to Week 52, an exploratory endpoint showed that patients receiving deflazacort had significant improvements in the time to climb 4 stairs compared with prednisone. From Week 12 to Week 52, both deflazacort groups demonstrated greater numerical improvements in time from supine to stand, time to climb 4 stairs, and time to run or walk 30 feet compared with the prednisone-treated participants, but these did not reach significance since the trial was not statistically designed to detect this difference.

The 3 most commonly reported treatment-related adverse events (AEs) were Cushingoid appearance, erythema, and hirsutism. Weight gain—related AEs were more likely to be moderate or severe with prednisone compared with deflazacort. There were more AEs, serious AEs, and AEs leading to discontinuation in prednisone-treated patients than in either deflazacort cohort. Overall, psychiatric AEs were more common in the prednisone group than in the deflazacort groups; however, psychotic disorder was reported more frequently in the deflazacort 0.9 mg/kg/day group. Cataract occurred at a higher rate with daily deflazacort than prednisone.

Study Limitations

Comparisons between deflazacort and prednisone are not included in the approved Prescribing Information for deflazacort, as prednisone is not an approved treatment for Duchenne muscular dystrophy. This study examined deflazacort being dosed at the recommended dose of 0.9 mg/kg/day, as well as a dose of 1.2 mg/kg/day. The study had a 52-week duration of treatment, which did not allow for long-term follow-up to observe the effect of steroids over longer periods of time, and was not powered to achieve significance. Deflazacort and prednisone utilized in this study were from various manufacturers in and outside the United States.

Financial Disclosures of Study Sponsors

This study was sponsored with funding provided by Nordic Merrill Dow and the Muscular Dystrophy Association (MDA).

 

McDonald 2018 Study Summary

Long-term effects of glucocorticoids on function, quality of life, and survival in patients with Duchenne muscular dystrophy: a prospective cohort study

A prospective natural history observational cohort study with 440 patients ages 2 to 28 years, which evaluated the long-term effects of glucocorticoids (GC) in Duchenne muscular dystrophy (DMD). Patients were followed up for 10 years. Patients were stratified by duration of GC treatment (<1 month or ≥12 months). Milestones for 9 groups of the Davis Duchenne Functional assessments were recorded and analyzed using Kaplan-Meier to measure disease progression.

The study also compared patients treated with prednisone or prednisolone (PRED) versus those treated with deflazacort (DFZ) for age at loss of milestones. Patients with cumulative GC treatment duration of 1 year or longer had consistently delayed occurrence of ambulatory disease progression milestones by periods of 2.1 to 4.4 years compared with GC-naive patients or those treated for less than 1 month (all log-rank P<0.0001, apart from time to climb four stairs P=0.0023). GC treatment for 1 year or longer was associated with significantly delayed loss of upper limb milestones by 2.8 to 8.0 years compared with treatment for less than 1 month. Deflazacort was associated with increased median age at loss of three milestones (age at: loss of ability to stand from supine, loss of ambulation, loss of hand-to-mouth function with retained hand function) by 2.1 to 2.7 years in comparison with prednisone or prednisolone (log-rank P<0.012). The mean age at loss of the earliest milestones typically reached (ie, supine to stand ≥5 seconds and supine to stand ≥10 seconds) showed trends in delayed loss of function favoring deflazacort, but differences between agents were not significant. Insufficient numbers of milestone transitions were observed to allow a comparison between GC regimens for loss of distal hand function.

The most common side effects of GC treatment were weight gain, Cushingoid features, behavior changes, growth delay, fractures, cataracts, and skin changes.

Study Limitations

Based upon the study design and enrollment, the following limitations should be considered:

  • Steroid use was not randomized as might be in a controlled clinical trial
  • Comparisons between deflazacort (DFZ) and prednisone (PRED) are not included in the approved Prescribing Information for DFZ, as PRED is not an approved treatment for Duchenne muscular dystrophy
  • The analyses included a comparison of multiple glucocorticoid agents and regimens (such as daily vs intermittent dosing)
  • An in-depth analysis of specific doses or schedules was not feasible in a long-term, prospective, observational, natural history study
  • DFZ and PRED utilized in this study were from various manufacturers in and outside the United States
  • Potential differences were noted in socioeconomic status of patients and caregivers—DFZ was not commercially available in the United States at the time of the study
  • DFZ may have been used more frequently in a daily dosing regimen
  • The daily doses of DFZ used in the population were closer to that of the benchmarked FDA-approved labeled dose of 0.90 mg/kg/day

Financial Disclosures of Study Sponsors

This study was supported by US Department of Education/NIDRR (#H133B031118, #H133B090001); US Department of Defense (#W81XWH-12-1-0417); National Institutes of Health/NIAMS (#R01AR061875); and Parent Project Muscular Dystrophy.

 

Bello 2015 Study Summary

Prednisone/prednisolone and deflazacort regimens in CINRG Duchenne Natural History Study

A natural history observational prospective study evaluating age at loss of independent ambulation (LoA) and side-effect profiles associated with different glucocorticoid corticosteroid (GC) regimens in Duchenne muscular dystrophy (DMD). The study included 340 DMD participants, aged 2-28 years, who were enrolled in the Cooperative International Neuromuscular Research Group Duchenne Natural History Study (CINRG-DNHS). LoA was defined as continuous wheelchair use, confirmed by inability to walk 10 minutes unaided. Effects of prednisone or prednisolone (PRED)/deflazacort (DFZ), administration frequency, and dose were analyzed by time-varying Cox regression. Side-effect frequencies were compared using the chi-square test. Average dose of daily PRED administered while ambulatory (n=94) was 75% ± 17% of recommended, which was lower than daily DFZ (83% ± 15%, n=80, P=0.002).

Participants treated ≥1 year while ambulatory (n=252/340) showed a 3-year median delay in LoA (P<0.001). Fourteen different regimens were observed. Nondaily treatment was common for PRED (37%) and rare for DFZ (3%). DFZ was associated with later LoA than PRED (hazard ratio 0.294 ± 0.053 vs 0.490 ± 0.08, P=0.003; 2-year difference in median LoA with daily administration, P<0.001). Average dose was lower for daily PRED (0.56 mg/kg/d, 75% of recommended) than daily DFZ (0.75 mg/kg/d, 83% of recommended, P<0.001). DFZ showed higher frequencies of growth delay (P<0.001), Cushingoid appearance (P=0.002), and cataracts (P<0.001), but not weight gain.

For comparisons of median LoA between GC-treated and untreated participants, “GC-treated” only included those patients who had been administered GCs for ≥1 year, starting 1≥ year before LoA. Side-effect frequency was calculated in 277 participants (86.2%) with any treatment duration while ambulatory. Weight gain (65%), Cushingoid appearance (55%), growth delay (37%), behavior changes (37%), low bone mass density and/or fracture (22%), cataracts (15%), and skin abnormalities (13%) were most frequently reported. Some frequencies might be underestimated because side effects were recorded for only the 3 most recent GC regimens before study baseline. Weight gain frequency was similar for daily DFZ and daily PRED, but daily DFZ showed higher incidence of Cushingoid appearance (72% vs 50%, P=0.002), growth delay (60% vs 27%, P<0.0001), and cataracts (29% vs 5%, P<0.0001).

Study Limitations

Based upon the study design and enrollment, the following limitations should be considered:

  • Steroid use was not randomized as might be in a controlled clinical trial
  • Comparisons between deflazacort (DFZ) and prednisone (PRED) are not included in the approved Prescribing Information for DFZ, as PRED is not an approved treatment for Duchenne muscular dystrophy (DMD)
  • The analyses included a comparison of multiple glucocorticoid (GC) agents and regimens (such as daily vs intermittent dosing)
    • Fourteen distinct regimens of PRED or DFZ were observed
    • An in-depth analysis of specific doses or schedules was not feasible in a long-term, prospective, observational study
  • A “historical” improvement in care was noted, showing a parallel increase in the frequency of GC prescriptions for DMD and implementation of other standards of care such as physical therapy, management of joint contractures, and bone fracture prevention
  • DFZ and PRED utilized in this study were from various manufacturers in and outside the United States
  • Potential differences were noted in socioeconomic status of patients and caregivers—DFZ was not commercially available in the United States at the time of the study

Financial Disclosures of Study Sponsors

This project was funded through the Italian Ministry of Education PhD grant awarded to L.B. for the 28th Cycle of the Doctorate School of Medical, Clinical, and Experimental Science at the University of Padova, Italy; and grants from the NIH (U54HD053177, R24HD050846, UL1RR031988, UL1RR024992, U54RR026139, G12RR003051, 1R01AR061875, RO1AR062380), the US Department of Education/NIDRR (H133B031118, H133B090001), the US Department of Defense (W81XWH-09-1-0592).