Randomized, blinded trial of weekend vs daily prednisone in Duchenne muscular dystrophy

Abstract

Objective: To perform a double-blind, randomized study comparing efficacy and safety of daily and weekend prednisone in boys with Duchenne muscular dystrophy (DMD). Methods:A total of 64 boys with DMD who were between 4 and 10 years of age were randomized at 1 of 12 centers of the Cooperative International Neuromuscular Research Group. Efficacy and safety of 2 prednisone schedules (daily 0.75 mg/kg/day and weekend 10 mg/kg/wk) were evaluated over 12 months.Results: Equivalence was met for weekend and daily dosing of prednisone for the primary outcomes of quantitative muscle testing (QMT) arm score and QMT leg score. Secondary strength scores for QMT elbow flexors also showed equivalence between the 2 treatment groups. Overall side effect profiles of height and weight, bone density, cataract formation, blood pressure, and behavior, analyzed at 12 months, did not differ between weekend and daily dosing of prednisone. Conclusions:Weekend dosing of prednisone is equally beneficial to the standard daily dosing of prednisone. Analysis of side effect profiles demonstrated overall tolerability of both dosing regimens. Classification of evidence:This study provides Class I evidence that weekend prednisone dosing is as safe and effective as daily prednisone in preserving muscle strength and preventing body mass index increases in boys with DMD over a 12-month period. Neurology Duchenne muscular dystrophy (DMD) is a progressive muscle disorder due to mutations in the dystrophin gene.1,2 Current treatments can slow disease progression, prolonging ambulation, and improving quality of life and survival. [3][4][5] Corticosteroid treatment for DMD 6-12 is recommended by an American Academy of Neurology practice parameter.13 Furthermore, a recently published standard of care review emphasized the benefit of corticosteroids for DMD.14,15 In a large DMD natural history study currently run by the Cooperative International Neuromuscular Research Group (CINRG), 85% of participants are steroid-treated. 16,17 We hypothesized that weekend prednisone dosing would provide equally effective treatment for DMD as standard daily dosing. Furthermore, corticosteroids might be more widely used in DMD if a dosing regimen had fewer side effects, including less weight gain, less effect on linear Editorial, page 416Podcast Scan this code with your smartphone to access this feature CME Scan this code with your smartphone to access this feature

Brazilian consensus on Duchenne muscular dystrophy. Part 1: diagnosis, steroid therapy and perspectives

“…Later studies have demonstrated that different drugs with an equivalent dose show similar effects: prednisone or prednisolone 0.75mg/Kg daily (Level of evidence: 1A, Class of Recommendation: A) 35 or deflazacort 0.9 to 1mg/Kg daily (Level of evidence: 3C, Class of Recommendation: C) 44,45 . Several different drug regimens have been evaluated, but not as extensively as the above daily schemes 44,45,46,47,48 . These different regimens aim to minimize side effects and/or improve the treatment adherence.…”

Review of Phase II and Phase III clinical trials for Duchenne muscular dystrophy

“…The first clinical trial in DMD demonstrating efficacy of prednisone occurred in 1974 [30]. Numerous trials that followed have looked for optimal age of initiation, dose and frequency [6][7][8][9][10][11][12]31]. Conclusions, to date, are that prednisone 0.75 mg/kg/day and deflazacort 0.9 mg/kg are equally effective in improving muscle strength and function in the short term (6 months to 2 years), and that prednisone 0.75 mg/kg/day is optimal compared to other class I dosing studies (1.5, 0.3 mg/kg/day and 0.75 mg/kg/q.…”

“…o.d. and 10 mg/kg/week) [6][7][8][9][10][11][12]31]. In these short-term treatment trials, adverse effects (weight gain, cushingoid appearance) were similar between studies.…”

“…While these side effects were more common in the corticosteroid-treated patients compared to the placebo group, they did not prevent continuation of corticosteroid treatment and were not considered clinically severe. An analysis of long-term side effects occurring with treatment > 2 --3 years duration was not possible because of the trial design [6][7][8][9][10][11][12]31]. However, in nonrandomized trials, boys treated longer than 2 years with prednisone or deflazacort showed significant benefits in ambulation, delayed onset of scoliosis and pulmonary dysfunction, preserved cardiac function, survival and quality of life compared to untreated counterparts [13][14][15][16][17]20,21].…”

Δ-9,11 Modification of Glucocorticoids Dissociates Nuclear Factor-κB Inhibitory Efficacy from Glucocorticoid Response Element-Associated Side Effects

“…Chronic administration of glucocorticoids leads to relatively rapid muscle loss via the Forkhead box O (FOXO)/atrogin atrophy signaling pathway, and can cause glucocorticoid myopathy (critical care myopathy) (Di Giovanni et al, 2004;Puthucheary et al, 2010). In contrast, chronic glucocorticoids are used in Duchenne muscular dystrophy to increase muscle strength and prolong ambulation, possibly through their antiinflammatory effect (Bach et al, 2010;Hussein et al, 2010;Escolar et al, 2011). The beneficial properties of steroids are offset partly by side effects, including atrogin-mediated muscle wasting bone fragility, obesity, and short stature (Schara et al, 2001).…”