Key Points
Question
What is the difference in clinical outcomes among 3 corticosteroid regimens (0.75 mg/kg of daily prednisone, 0.90 mg/kg of daily deflazacort, or 0.75 mg/kg of intermittent prednisone for 10 days on and then 10 days off) as initial treatment for boys with Duchenne muscular dystrophy?
Findings
This randomized clinical trial included 196 boys with Duchenne muscular dystrophy; the clinical outcome was a global outcome that incorporated a measure of rising from the floor, forced vital capacity, and global satisfaction with treatment assessed over 3 years. Daily prednisone and daily deflazacort resulted in significantly better outcomes compared with intermittent prednisone; there was no significant difference between the 2 daily regimens.
Meaning
The findings support the use of a daily corticosteroid regimen over an intermittent prednisone regimen that alternates dosing for 10 days on and 10 days off as initial treatment for boys with Duchenne muscular dystrophy.
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
This randomized clinical trial compares the efficacy and adverse effects of the 3 most frequently prescribed corticosteroid regimens for boys with Duchenne muscular dystrophy.
Introduction
Duchenne muscular dystrophy (DMD) is caused by variants in the dystrophin gene (MIM*300377) and epidemiological studies in 2012-2013 reported that DMD was the most common childhood neuromuscular disease with a birth incidence of 1 in 5000 to 6000 live male births.1,2,3
Corticosteroids (prednisone and deflazacort) increase muscle strength and function in DMD,4,5,6,7,8,9 and should be considered for all patients with DMD according to the care recommendations10; however, there is uncertainty regarding the optimal regimen and dosage.11 Moreover, there have been no long-term studies on the standardized prevention of adverse effects for corticosteroid dosing regimens in DMD. When planning for this study was initiated in 2004, 3 surveys of US and European specialist clinics documented that 29 different corticosteroid regimens were used for DMD.12
Daily prednisone (0.75 mg/kg), daily deflazacort (0.90 mg/kg), and intermittent prednisone (0.75 mg/kg) for 10 days on and then 10 days off were the most frequently prescribed regimens.12 Other potentially disease-modifying treatments for DMD are in development.13,14 Most of these trials only include participants on stable corticosteroid regimens. The long-term use of corticosteroids as the standard of care for DMD with or without adjuvant therapies is, therefore, likely to continue for the foreseeable future.
An international, double-blind, parallel-group randomized clinical trial was conducted to compare the 3 most frequently prescribed corticosteroid regimens in terms of their long-term efficacy and adverse effects in boys with DMD not previously treated with corticosteroids.15
Methods
The trial protocol and all of the amendments were approved by the institutional review board or research ethics committee at each study site (Supplement 1). Boys with DMD not previously treated with corticosteroids were recruited at 32 clinic sites in 5 countries (Canada, Germany, Italy, the UK, and the US). Boys with genetically confirmed DMD aged 4 years to younger than 8 years at the time of screening were eligible. Complete eligibility criteria appear in §4.1 and §4.2 of the trial protocol (Supplement 1). There was no placebo group because practice guidelines for DMD recommend corticosteroid treatment.
Written consent from the parent or legal guardian and assent from participants were obtained before initiating any study evaluation. Race and ethnicity were collected as reported by the participant’s parent or guardian per funder requirement. Fixed racial and ethnic categories were used according to classification by the US Office of Management and Budget.
Randomization and Enrollment
After confirmation of eligibility, boys were randomized (1:1:1) to receive either daily prednisone (0.75 mg/kg), daily deflazacort (0.90 mg/kg), or intermittent prednisone (0.75 mg/kg) for 10 days on and then 10 days off (referred to hereafter as intermittent prednisone) (Figure 1). The computer-generated randomization plan was stratified by country and included permuted blocks of size 3 within each country. Details regarding the randomization process appear in §3 of the statistical analysis plan (Supplement 1).
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).
Interventions and Blinding
A clinical trial supply company (Catalent Ltd) manufactured identical tablets of prednisone, deflazacort, and placebo (the placebo tablets were used in the intermittent prednisone regimen to maintain blinding during the 10 days off period). The study drugs were provided in 20-day treatment wallets containing 2 to 6 tablets per day, depending on the weight-band dosing for the participant. The dosage could be reduced if warranted because of adverse events according to standardized trial protocol criteria. Weight-band dosing is described in §5.1.1 of the trial protocol (Supplement 1) and in eTable 1 (Supplement 2).
On July 1, 2017, an issue with the supply of study medication necessitated a temporary switch for the remaining participants to open-label daily prednisone (lasted 2-3 weeks for German, UK, and US participants and lasted 4-5 months for Canadian and Italian participants) and an unblinding of the participants in the intermittent prednisone group in Canada and Italy who could not be restarted with the study medication within 21 days. Additional details appear in the eAppendix in Supplement 2.
Evaluation and Follow-up
All boys were to be followed up for a minimum of 3 years while taking the study medications. The baseline visit was performed within 3 months of the screening visit; boys were then evaluated at months 3 and 6 and then every 6 months until the end of the study (month 36). Details regarding the evaluations performed at each study visit appear in the eAppendix in Supplement 2.
Adverse events are reported as recorded by the study investigators. Adverse events of specific interest also were assessed and recorded at each study visit via clinical assessment, active prompting of parents or legal guardians, or both.
Standardization of Care and Management of Adverse Events
Consensus-based guidelines4,5 for the treatment of DMD complications and for the prevention of corticosteroid adverse effects included standardized protocols for assessment and advice regarding diet, behavior, physical therapy, and cardiac surveillance. For areas lacking clear recommendations, expert opinion was sought and consensus was reached among the investigators. Interventions and modifications of study medication dosage were provided for the management of adverse events of specific interest16,17 (§7.4 of the trial protocol in Supplement 1).
Outcome Measures
The composite primary outcome comprised 3 end points (each averaged across all follow-up visits after baseline through month 36): (1) rise from the floor velocity (reciprocal of time to rise from the floor in rise/seconds); (2) forced vital capacity (in liters); and (3) participant or parent global satisfaction with treatment measured by the Treatment Satisfaction Questionnaire for Medication (TSQM; score range, 0-100).18 The rise from the floor velocity component was originally specified as time to rise from the floor. This end point was redefined after the conclusion of follow-up but prior to database lock and unblinding to accommodate data from boys who lost the ability to rise from the floor (infinite time but zero velocity).
The secondary efficacy outcomes included 10-m walk or run velocity, North Star Ambulatory Assessment total score,19,20 distance for the 6-minute walk test, TSQM effectiveness subscale score, ankle range of motion, quality-of-life scores, and cardiac function (left ventricular ejection fraction and fractional shortening as measured by echocardiography). These were considered as means across all follow-up visits after baseline and outcomes at the month 36 visit alone. Based on previous studies, the minimal clinically important difference was 0.023 rise/s for rise from the floor velocity,21 0.212 m/s for 10-m walk or run velocity,21 and a distance of 28 m to 36 m for the 6-minute walk test.22 Other secondary efficacy outcomes included time from the baseline visit to disease milestones, including loss of ambulation (scored as unable [item 2] on the North Star Ambulatory Assessment) and loss of ability to rise from the floor.
The secondary safety outcomes included the occurrence and severity of adverse events and vertebral fractures (as detected by radiography of the lateral thoracolumbar spine at 36 months). Additional secondary safety outcomes such as height, weight, vital signs, behavioral rating scale scores,23,24,25,26,27 and TSQM side effects subscale score were considered as means across all follow-up visits after baseline and outcomes at the month 36 visit alone. Laboratory test abnormalities also were collected. Specific information concerning the rating scales used in the trial appear in eTable 2 in Supplement 2. The bone health outcomes that were evaluated using dual-energy x-ray absorptiometry are not reported here.
Sample Size Determination
A sample size of 100 participants per group (300 total) was chosen by simulation to provide greater than 80% power to detect differences of approximately 0.5 SD units for at least 2 components of the primary outcome between any 2 of the 3 treatment groups using the O’Brien ordinary least-squares method28 and a 2-tailed significance level of 1.7%. The simulations were performed assuming various correlations among the 3 components of the primary outcome and a rate of participant withdrawal of 10%.
Due to concerns regarding slow enrollment in the trial, a blinded interim analysis was performed after 90 participants had completed 12 months of follow-up (in July 2015) to determine whether the sample size could be reduced from the originally planned size of 300 to a number that was feasible given the study timeline. This determination was made based on the correlations among the 3 components of the primary outcome variable (averaged across available time points), which were completely unknown for the correlations involving the TSQM global satisfaction subscale score.
The results revealed that the 3 components of the primary outcome variable were at best weakly correlated (0<r<0.25), allowing the target sample size to be reduced to 225 (§9.5 of the trial protocol in Supplement 1). The independent data and safety monitoring board agreed with this proposal. Details of the sample size justification appear in §5 of the statistical analysis plan (Supplement 1).
Statistical Analysis
The primary statistical analyses were performed according to the treatment to which the participants were randomly assigned. The analyses of the efficacy and safety outcomes (other than adverse events) included all available data from all randomized participants who contributed at least 1 value after baseline for the outcome of interest. The data that were obtained after a participant enrolled in another trial of an investigational treatment were excluded from the analyses. However, the participant was included in the analyses if that participant contributed at least 1 value after baseline for the outcome of interest prior to enrolling in another trial.
For the primary outcome, each of the 3 components was analyzed using a repeated-measures analysis of covariance model (mixed-model repeated measures29). This model appropriately accommodates missing data under the missing at random assumption using direct likelihood. For each pairwise comparison of the treatment groups, upper-tailed P values for the 3 components of the primary outcome were combined using the inverse normal combination statistic,30 with the null hypothesis of no overall treatment effect on the multivariate outcome being rejected for either large positive or large negative values of this statistic. Because the P values being combined are dependent, the overall 2-tailed P value for the comparison of the treatment groups was based on the re-randomization distribution of the inverse normal combination statistic, which was estimated using a random sample of 15 000 repetitions of the original randomization (permuted blocks of size 3, stratified by country).31
The adjusted P values for each treatment group comparison of each individual component (rise from the floor velocity, forced vital capacity, TSQM global satisfaction subscale score) were obtained using a closed testing procedure.32 To illustrate this procedure, consider the comparison of daily prednisone vs intermittent prednisone. Using an identical global test (based on the inverse normal combination statistic) as the one used for the primary outcome (rise from the floor velocity, forced vital capacity, and TSQM global satisfaction subscale score), the P values were obtained for each of the 3 possible bivariate outcomes (rise from the floor velocity and forced vital capacity, forced vital capacity and TSQM global satisfaction subscale score, and rise from the floor velocity and TSQM global satisfaction subscale score) and for each of the 3 individual outcomes.
The treatment group comparison for an individual outcome (eg, rise from the floor velocity) was statistically significant (at the .017 level) only if it was also significant for the primary outcome (global test for all 3 components) as well as for the bivariate outcomes of which the individual outcome is a component (in this case, [1] rise from the floor velocity and forced vital capacity and [2] rise from the floor velocity and TSQM global satisfaction subscale score). The adjusted P value for that individual outcome (rise from the floor velocity) is taken as the maximum of these 4 P values. This procedure was repeated for the other 2 pairwise group comparisons (daily deflazacort vs intermittent prednisone and daily prednisone vs daily deflazacort). Additional details concerning the statistical models and analysis strategy appear in §7.4.1 of the statistical analysis plan (Supplement 1).
The continuous secondary outcomes obtained at each study visit were analyzed using mixed-model repeated measures as with each component of the primary outcome variable. For outcomes that were obtained less frequently than at each study visit, the analyses were performed using analysis of covariance models with missing data accommodated by using regression-based multiple imputation because of the higher frequency of missing baseline values for the outcome. Further details of the modeling and imputation strategies appear in the eAppendix in Supplement 2. Cox proportional hazards regression models were used to compare the treatment groups with respect to the times to disease milestones, adjusting for age and initial weight band. Formal examination of the proportional hazards assumption (treatment group × time interaction and the plots of scaled Schoenfeld residuals vs time) revealed no clear violations.
Comparisons among the treatment groups with respect to each of the motor function outcomes (rise from the floor velocity, 10-m walk or run velocity, North Star Ambulatory Assessment total score, and distance for the 6-minute walk test) were performed by age group (4-5 years vs 6-7 years) using mixed-model repeated measures, with the main effect of age group added to the analysis model as well as the interaction terms of treatment group × age group, age group × time, and treatment group × age group × time.
Two interim analyses were performed during the trial, one for sample size reestimation (described in the sample size determination section) and one for efficacy. In consultation with the data and safety monitoring board, the schedule for the interim analyses for efficacy was modified from that reported in the trial protocol (Supplement 1). A single interim analysis for efficacy was performed after 95 participants (48%) had completed (or were scheduled to have completed) 36 months of follow-up (June 2017). The analysis of the primary outcome variable was performed using an overall significance level of .001 based on a conservative Haybittle-Peto–type strategy. Upon reviewing the results of this analysis, the data and safety monitoring board recommended continuation of the trial.
All hypothesis tests for the primary outcome variable were performed using a 2-sided significance level of .017, incorporating a Bonferroni adjustment for the 3 pairwise group comparisons. Because of the potential for type I error due to multiple comparisons, findings for the analyses of the secondary outcomes should be interpreted as exploratory. All analyses were performed using SAS software version 9.4 (SAS Institute Inc).
Results
Due to delays in recruitment, enrollment was halted after 196 boys were randomized between January 30, 2013, and September 17, 2016 (65 were randomized to daily prednisone, 65 to daily deflazacort, and 66 to intermittent prednisone). The last participant visit was conducted on October 16, 2019. The mean age of participants was 5.8 years (SD, 1.0 years). Baseline characteristics were generally comparable among the treatment groups, with slightly more White participants in the 2 daily regimen groups combined (90%) than in the intermittent prednisone group (74%) (Table 1).22,33,34
Table 1. Baseline Characteristics of Trial Participants.
| Daily prednisone (n = 65) |
Daily deflazacort (n = 65) |
Intermittent prednisone (n = 66) |
|
|---|---|---|---|
| Age, mean (SD), y | 5.8 (1.0) | 5.8 (1.0) | 5.9 (1.1) |
| Country, No. (%) | |||
| Canada | 5 (8) | 4 (6) | 4 (6) |
| Germany | 6 (9) | 7 (11) | 7 (11) |
| Italy | 8 (12) | 7 (11) | 7 (11) |
| UK | 19 (29) | 20 (31) | 20 (30) |
| US | 27 (42) | 27 (42) | 28 (42) |
| Race, No. (%) | |||
| Asian | 1 (2) | 2 (3) | 6 (9) |
| Black | 2 (3) | 0 | 1 (2) |
| White | 59 (91) | 58 (89) | 49 (74) |
| Multiplea | 1 (2) | 1 (2) | 3 (5) |
| Otherb | 1 (2) | 2 (3) | 4 (6) |
| Not reported | 1 (2) | 2 (3) | 3 (5) |
| Hispanic, No. (%) | 9 (14) | 9 (15) | 13 (21) |
| Weight, mean (SD), kg | 20.0 (3.0) | 19.9 (4.3) | 20.2 (3.5) |
| Height, mean (SD), cm | 109.9 (7.0) | 109.5 (7.6) | 110.9 (7.1) |
| Body mass index, mean (SD)c | 16.5 (1.3) | 16.5 (2.0) | 16.4 (1.6) |
| Rise from the floor velocity, mean (SD), rise/sd | 0.19 (0.09) | 0.19 (0.07) | 0.18 (0.08) |
| 10-m walk or run velocity, mean (SD), m/se | 1.67 (0.39) | 1.73 (0.38) | 1.65 (0.38) |
| North Star Ambulatory Assessment total score, mean (SD)f | 22.0 (5.7) | 21.1 (5.7) | 21.1 (4.9) |
| Distance for the 6-min walk test, mean (SD), mg | 342.4 (58.0) | 330.4 (65.1) | 331.6 (63.6) |
| Forced vital capacity | |||
| Mean (SD), L | 1.0 (0.4) | 1.1 (0.4) | 1.1 (0.4) |
| Mean (SD), % predicted | 85.4 (29.8) | 87.2 (36.2) | 88.1 (34.0) |
Includes any combination of 2 or more of the categories listed above.
Provided as an option on the case report form; no additional information collected.
Calculated as weight in kilograms divided by height in meters squared.
The reciprocal of the time taken to stand from supine position on the floor to a straight standing position without help. Typically developing children aged 4 to 5 years score between 0.36 rise/s and 0.50 rise/s and performance improves with age.33
Ten times the reciprocal of the time taken to walk or run barefoot as fast as possible and without any help for the marked distance of 10 m. Typically developing children aged 4 to 5 years score between 2.5 m/s and 3.0 m/s and performance improves with age.33
Ranges from 0 to 34. More than 85% of typically developing boys obtain maximum scores by the age of 4 years.34 A total score of 20 to 22 is suggestive of a young ambulant boy with muscle weakness, ankle tightness, or both, resulting in difficulties in rising from the floor, balance, hopping, and running.
Modified for use as an outcome measure in patients with Duchenne muscular dystrophy. Measures the distance that can be covered in 6 minutes by walking as fast as possible (without running) around 2 flagpoles positioned 25 m apart on a flat ground. Normal values for boys aged 4 to 8 years are between 388 m and 488 m.22
A total of 164 participants (84%) completed 36 months of follow-up, and only 1 boy in each treatment group withdrew participation due to an adverse event (Figure 1). Eleven participants, including 6 (9%) in the daily deflazacort group and 5 (8%) in the intermittent prednisone group initiated participation in another clinical trial while remaining in the FOR-DMD study (eTable 3 in Supplement 2). Accounting for exclusion of data obtained after participation in these trials, there were 55 participants (85%) in the daily prednisone group, 52 participants (80%) in the daily deflazacort group, and 57 participants (86%) in the intermittent prednisone group with at least 30 months of follow-up data (eTable 3 in Supplement 2).
As a result of study medication supply issues, 74 participants were temporarily taken off their assigned blinded study drug and prescribed daily prednisone (60 participants in Germany, the UK, and the US for 2-3 weeks and 14 participants in Canada and Italy for 4-5 months) (eAppendix in Supplement 2). Four participants (in Canada and Italy) were unblinded to their assigned intermittent prednisone regimen (eAppendix in Supplement 2).
Primary Outcome
The results for the individual components of the primary outcome appear in Figure 2 and Table 2. Compared with intermittent prednisone, daily prednisone (P < .001) and daily deflazacort (P = .017) were both more effective in terms of the 3-dimensional primary composite outcome, but a statistically significant difference between the 2 daily regimens was not detected (P = .38). The significant differences between the daily regimens and the intermittent prednisone regimen were principally attributable to the rise from the floor velocity component. The between-group difference in rise from the floor velocity was 0.06 rise/s (98.3% CI, 0.03 to 0.08 rise/s) for daily prednisone vs intermittent prednisone (adjusted P = .003), 0.06 rise/s (98.3% CI, 0.03 to 0.09 rise/s) for daily deflazacort vs intermittent prednisone (adjusted P = .017), and −0.004 rise/s (98.3% CI, −0.03 to 0.02 rise/s) for daily prednisone vs daily deflazacort (adjusted P = .75).
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.
Table 2. Treatment Group Differences With Respect to Individual Components of the Composite Primary Outcome.
| Individual components of the composite primary outcomea | Adjusted group mean (95% CI)b | Daily prednisone vs daily deflazacort | Daily prednisone vs intermittent prednisone | Daily deflazacort vs intermittent prednisone | |||||
|---|---|---|---|---|---|---|---|---|---|
| Daily prednisone | Daily deflazacort | Intermittent prednisone | Mean difference (98.3% CI)b |
P valuec | Mean difference (98.3% CI)b |
P valuec | Mean difference (98.3% CI)b |
P valuec | |
| Rise from the floor velocity, rise/s | 0.236 (0.219 to 0.253) | 0.240 (0.223 to 0.258) | 0.180 (0.163 to 0.197) | −0.004 (−0.03 to 0.02) | .75 | 0.06 (0.03 to 0.08) | .003 | 0.06 (0.03 to 0.09) | .017 |
| Forced vital capacity, L | 1.44 (1.38 to 1.50) | 1.40 (1.34 to 1.46) | 1.46 (1.40 to 1.52) | 0.04 (−0.06 to 0.14) | .71 | −0.02 (−0.12 to 0.08) | .56 | −0.06 (−0.16 to 0.04) | .72 |
| TSQM global satisfaction subscale score | 71.2 (66.8 to 75.7) | 67.8 (63.2 to 72.4) | 65.1 (60.6 to 69.5) | 3.5 (−3.7 to 10.6) | .61 | 6.2 (−0.9 to 13.2) | .28 | 2.7 (−4.4 to 9.8) | .72 |
Abbreviation: TSQM, Treatment Satisfaction Questionnaire for Medication.
A global test based on the inverse normal P value combination statistic was used. Each comparison used a 2-tailed significance level of .017. P = .38 for daily prednisone vs daily deflazacort; P<.001 for daily prednisone vs intermittent prednisone; and P = .017 for daily deflazacort vs intermittent prednisone.
Obtained from a repeated-measures analysis of covariance model with terms for treatment group, country, baseline weight-band dosage, the baseline value of the outcome variable, time (treated as a categorical variable), and interaction terms for the baseline value of the outcome variable × time and for treatment group × time. Because the TSQM was not administered at baseline, the model for the TSQM global satisfaction score includes baseline values for rise from the floor velocity and forced vital capacity (with no interactions between these baseline variables and time) instead of the baseline value of the outcome variable.
Adjusted using a closed testing procedure applied to the global test for the composite outcome. Additional information appears in the statistical analysis plan in Supplement 1 and in the eAppendix in Supplement 2.
The between-group differences with respect to forced vital capacity and TSQM global satisfaction subscale score were not significant. For forced vital capacity, the between-group difference was −0.02 L (98.3% CI, −0.12 to 0.08 L) for daily prednisone vs intermittent prednisone (adjusted P = .56), −0.06 L (98.3% CI, −0.16 to 0.04 L) for daily deflazacort vs intermittent prednisone (adjusted P = .72), and 0.04 L (98.3% CI, −0.06 to 0.14 L) for daily prednisone vs daily deflazacort (adjusted P = .71). For the TSQM global satisfaction subscale score, the between-group difference was 6.2 (98.3% CI, −0.9 to 13.2) for daily prednisone vs intermittent prednisone (adjusted P = .28), 2.7 (98.3% CI, −4.4 to 9.8) for daily deflazacort vs intermittent prednisone (adjusted P = .72), and 3.5 (98.3% CI, −3.7 to 10.6) for daily prednisone vs daily deflazacort (adjusted P = .61). Individual changes from baseline for rise from the floor velocity and forced vital capacity appear in eFigure 1 in Supplement 2.
Secondary Efficacy Outcomes
The results for the secondary outcome measures assessing motor function appear in eFigures 2-3 and eTable 4 in Supplement 2. Participants in the daily regimen groups performed significantly better than those in the intermittent prednisone regimen group with respect to all secondary motor function outcomes; there were no significant differences between the 2 daily regimens.
For 10-m walk or run velocity, the between-group difference was 0.32 m/s (98.3% CI, 0.16 to 0.48 m/s) for daily prednisone vs intermittent prednisone (P < .001) and 0.29 m/s (98.3% CI, 0.13 to 0.45 m/s) for daily deflazacort vs intermittent prednisone (P < .001) (eTable 4 in Supplement 2). For North Star Ambulatory Assessment total score, the between-group difference was 3.0 (98.3% CI, 1.0 to 5.0) for daily prednisone vs intermittent prednisone (P < .001) and 3.3 (98.3% CI, 1.3 to 5.3) for daily deflazacort vs intermittent prednisone (P < .001). The between-group difference in distance for the 6-minute walk test was 38.1 m (98.3% CI, 6.7 to 69.6 m) for daily prednisone vs intermittent prednisone (P = .004) and 37.4 m (98.3% CI, 6.0 to 68.7 m) for daily deflazacort vs intermittent prednisone (P = .005).
No significant between-group differences were apparent with respect to forced vital capacity (expressed as a percentage of predicted normal in eFigure 2 in Supplement 2), the TSQM effectiveness subscale score, or quality of life (eTable 4 in Supplement 2). The efficacy results were similar when considering the outcomes at the month 36 visit alone rather than the mean across all follow-up visits after baseline (eTable 5 in Supplement 2). The results concerning the regimen comparisons for rise from the floor velocity and all other motor function outcomes were consistent between age groups (4-5 years vs 6-7 years) (eFigures 4-7 in Supplement 2).
Disease Milestones
During the trial, 15 participants (8%) lost the ability to walk and 28 (14%) lost the ability to rise from the floor. These events occurred more frequently in boys in the intermittent prednisone group but most of the group comparisons were not statistically significant (eTable 6 in Supplement 2). There was a significant between-group difference for time to loss of ability to rise from the floor (hazard ratio, 0.17 [98.3% CI, 0.04 to 0.69]) for daily deflazacort vs intermittent prednisone (P = .002).
Safety Outcomes
The adverse events that occurred in more than 5% of participants appear in Table 3. Most of the adverse events were expected for a pediatric population and for patients receiving corticosteroid treatment and were classified as mild in severity. Some of the events were relatively common, such as those related to abnormal behavior, infections, and gastrointestinal issues, and were distributed similarly among the treatment groups.
Table 3. Frequencies of Adverse Events by Treatment Group.
| Adverse eventa | Daily prednisone (n = 65) | Daily deflazacort (n = 65) | Intermittent prednisone (n = 66) | ||||||
|---|---|---|---|---|---|---|---|---|---|
| Total eventsb | Severity of event | Total eventsb | Severity of event | Total eventsb | Severity of event | ||||
| Mild | >Mild | Mild | >Mild | Mild | >Mild | ||||
| Abnormal behaviorc | 22 (34) | 13 | 8 | 25 (38) | 16 | 9 | 24 (36) | 16 | 8 |
| Upper respiratory tract infection | 24 (37) | 23 | 1 | 19 (29) | 17 | 2 | 24 (36) | 19 | 5 |
| Vomiting | 19 (29) | 14 | 5 | 17 (26) | 15 | 2 | 15 (23) | 12 | 3 |
| Abdominal pain | 16 (25) | 12 | 4 | 13 (20) | 13 | 0 | 19 (29) | 17 | 2 |
| Musculoskeletal pain | 12 (18) | 12 | 0 | 15 (23) | 10 | 5 | 16 (24) | 16 | 0 |
| Cough | 13 (20) | 12 | 1 | 12 (18) | 10 | 2 | 11 (17) | 11 | 0 |
| Pyrexia | 12 (18) | 11 | 1 | 12 (18) | 11 | 1 | 10 (15) | 10 | 0 |
| Fall | 10 (15) | 5 | 5 | 7 (11) | 6 | 1 | 12 (18) | 10 | 2 |
| Cushingoid appearance | 11 (17) | 6 | 5 | 11 (17) | 6 | 5 | 5 (8) | 2 | 3 |
| Gastrointestinal infection | 10 (15) | 7 | 3 | 11 (17) | 8 | 3 | 5 (8) | 3 | 2 |
| Diarrhea | 9 (14) | 8 | 1 | 7 (11) | 6 | 1 | 10 (15) | 9 | 1 |
| Skin infection | 8 (12) | 5 | 3 | 8 (12) | 7 | 1 | 9 (14) | 7 | 2 |
| Headache | 9 (14) | 8 | 1 | 9 (14) | 9 | 0 | 6 (9) | 4 | 2 |
| Constipation | 7 (11) | 5 | 2 | 9 (14) | 8 | 1 | 7 (11) | 6 | 1 |
| Ear infection | 5 (8) | 4 | 1 | 8 (12) | 7 | 1 | 9 (14) | 9 | 0 |
| Vitamin D deficiency | 8 (12) | 8 | 0 | 7 (11) | 5 | 2 | 5 (8) | 3 | 2 |
| Weight gain | 10 (15) | 9 | 1 | 4 (6) | 3 | 1 | 5 (8) | 4 | 1 |
| Lower respiratory tract infection | 5 (8) | 3 | 2 | 7 (11) | 5 | 2 | 5 (8) | 1 | 4 |
| Hypertrichosis | 7 (11) | 7 | 0 | 10 (15) | 10 | 0 | 0 | 0 | 0 |
| Bone fracture | 6 (9) | 1 | 5 | 7 (11) | 1 | 6 | 3 (5) | 0 | 3 |
| Rhinitis | 4 (6) | 4 | 0 | 5 (8) | 5 | 0 | 6 (9) | 6 | 0 |
| Sleep disturbance | 4 (6) | 1 | 3 | 7 (11) | 3 | 4 | 4 (6) | 3 | 1 |
| Limb injury | 2 (3) | 2 | 0 | 7 (11) | 3 | 4 | 4 (6) | 4 | 0 |
| Joint pain | 3 (5) | 3 | 0 | 7 (11) | 5 | 2 | 2 (3) | 2 | 0 |
| Influenza | 8 (12) | 6 | 2 | 1 (2) | 0 | 1 | 3 (5) | 1 | 2 |
| Frequent daytime urination | 4 (6) | 3 | 1 | 2 (3) | 2 | 0 | 5 (8) | 5 | 0 |
| High blood pressure | 4 (6) | 4 | 0 | 3 (5) | 2 | 1 | 3 (5) | 2 | 1 |
| Skin papilloma | 7 (11) | 7 | 0 | 3 (5) | 3 | 0 | 0 | 0 | 0 |
| Cataracts | 2 (3) | 2 | 0 | 7 (10) | 6 | 1 | 1 (1) | 1 | 0 |
Listed in order of their total frequency.
No. (%) of participants who experienced the given adverse event at least once during the 36-month follow-up period. For participants who experienced a given adverse event more than once, the event is classified by its maximum severity.
For the daily prednisone group, the description of severity was missing for 1 abnormal behavior event.
Hypertrichosis was reported more commonly in the daily regimen groups than in the intermittent prednisone group (7 boys [11%] in the daily prednisone group; 10 boys [15%] in the daily deflazacort group; and 0 boys in the intermittent prednisone group). Influenza was reported more frequently in the daily prednisone group (8 boys [12%] in the daily prednisone group; 1 boy [2%] in the daily deflazacort group; and 3 boys [5%] in the intermittent prednisone group). Skin papilloma was reported more frequently in the daily prednisone group (7 boys [11%] in the daily prednisone group; 3 boys [5%] in the daily deflazacort group; and 0 boys in the intermittent prednisone group).
Cataracts were reported more frequently in the daily deflazacort group, but none required treatment (2 boys [3%] in the daily prednisone group; 7 boys [10%] in the daily deflazacort group; and 1 boy [1%] in the intermittent prednisone group). Bone fractures (including vertebral fractures) were less common in the intermittent prednisone group (6 boys [9%] in the daily prednisone group; 7 boys [11%] in the daily deflazacort group; and 3 boys [5%] in the intermittent prednisone group) (Table 3 and eTable 7 in Supplement 2). No between-group differences were detected for the TSQM side effects subscale score (eTables 4-5 in Supplement 2).
There was no significant difference in weight gain between participants in the daily prednisone and intermittent prednisone groups, both of which gained more weight than participants in the daily deflazacort group (eFigure 8 and eTables 4-5 in Supplement 2). The between-group difference in weight gain at month 36 was 2.6 kg (98.3% CI, 0.2 to 5.0 kg) for daily prednisone vs daily deflazacort (P = .01) and −3.1 kg (98.3% CI, −5.5 to −0.7 kg) for daily deflazacort vs intermittent prednisone (P = .002). Slowing of growth was significantly less severe with intermittent prednisone than with the daily regimens. Daily deflazacort was associated with the greatest slowing of growth (eFigure 8 and eTables 4-5 in Supplement 2). The between-group difference in height at month 36 was 2.3 cm (98.3% CI, 0.7 to 3.9 cm) for daily prednisone vs daily deflazacort (P < .001), −5.8 cm (98.3% CI, −7.4 to −4.2 cm) for daily prednisone vs intermittent prednisone (P < .001), and −8.1 cm (98.3% CI, −9.7 to −6.4 cm) for daily deflazacort vs intermittent prednisone (P < .001).
The increase in body mass index was significantly greater in the daily prednisone group than in the intermittent prednisone group. The trajectory for body mass index in the deflazacort group fell in between the 2 prednisone regimens (eFigure 8 and eTable 4 in Supplement 2). Cushingoid appearance was commonly observed in all 3 treatment groups (n = 126 [64%]; eTable 8 in Supplement 2), but was reported as an adverse event in only a minority of cases (n = 27 [14%]; Table 3). No treatment group differences were noted for scores on the behavioral rating scales (eFigure 9 and eTables 4-5 in Supplement 2), nor with respect to changes in blood pressure or echocardiographic outcomes (eTables 4-5 in Supplement 2).
There were 45 serious adverse events reported (10 events in 7 participants in the daily prednisone group, 20 events in 10 participants in the daily deflazacort group, and 15 events in 5 participants in the intermittent prednisone group). Only 3 of the serious adverse events were considered attributable to corticosteroids (elevated urinary calcium/creatinine ratio and 2 occurrences of abnormal intervertebral space on spine imaging), all of which were asymptomatic and occurred in the daily prednisone group (eTable 9 in Supplement 2).
Dosage Reductions
Dosage reductions (defined as use of a dosage lower than the participant’s assigned weight-band dosage) were frequent during the trial. These occurred in 32 participants (49%) in the daily prednisone group, 23 participants (35%) in the daily deflazacort group, and 24 participants (36%) in the intermittent prednisone group (eTable 10 in Supplement 2). The predominant reasons for dosage reductions were cushingoid appearance, weight gain, and abnormal behavioral changes. Many of these reductions were temporary, and 87% were decisions to not increase the dosage for weight rather than an absolute reduction in the prescribed number of pills. At month 36, the percentage of participants taking the assigned weight-band dosage was 67% in the daily prednisone group, 75% in the daily deflazacort group, and 73% in the intermittent prednisone group.
The distribution of prescribed medication dosage (accounting for investigator-ordered reductions) as a percentage of the target dosage (0.75 mg/kg/d for prednisone and 0.90 mg/kg/d for deflazacort) at each visit by treatment group appears in eFigure 10 in Supplement 2. Other than slightly lower median percentages in the daily prednisone group during the middle of the follow-up period, the distributions were generally comparable among the treatment groups. Mean adherence with study medication (as determined by counts of dispensed and returned tablets) was greater than 95% in all 3 treatment groups.
Discussion
In this randomized clinical trial of initiation of corticosteroid treatment in young boys with DMD, daily regimens, compared with an intermittent prednisone regimen alternating 10 days on with 10 days off, resulted in significant improvement in a composite outcome that incorporated measures of motor function, pulmonary function, and satisfaction with treatment over a 3-year period. Daily prednisone and daily deflazacort did not differ significantly in their benefits over the first 3 years of treatment. Prednisone (administered daily or intermittently 10 days on and 10 days off) was associated with significantly greater weight gain than daily deflazacort.33 Both daily regimens led to slowing of growth; more so with daily deflazacort.
The benefits of the daily prednisone and daily deflazacort regimens compared with the intermittent prednisone regimen were consistent across measures of motor function. The observed differences in mean response between the daily regimens and the intermittent prednisone regimen exceeded established minimal clinically important differences for rise from floor velocity, 10-m walk or run velocity, and distance for the 6-minute walk test.
Corticosteroids are likely to remain the main treatment for boys with DMD for the foreseeable future and worldwide. High-dose prednisone given during the weekend has been proposed as a safe and effective alternative to daily prednisone; however, long-term comparisons have not been reported.35,36 Treatments other than corticosteroids have been approved in recent years for DMD,13 including exon skipping and read-through premature stop variant agents.37,38,39 These treatments are only available for a minority of patients with DMD (<30%) and are prescribed in combination with corticosteroids.
Limitations
This study has several limitations. First, it included only the 3 most frequently prescribed corticosteroid regimens (0.75 mg/kg of daily prednisone, 0.90 mg/kg of daily deflazacort, or 0.75 mg/kg of intermittent prednisone for 10 days on and then 10 days off).
Second, the trial did not achieve its goal to enroll 225 participants; nevertheless, differences in efficacy outcomes between the daily and intermittent corticosteroid regimens were detected, as well as differences among the 3 regimens with respect to height and weight trajectories. Although daily prednisone and daily deflazacort yielded similar trajectories for the motor function outcomes, this study was not designed to establish the equivalence of these 2 regimens.
Third, differences among the regimens with respect to disease milestones and adverse event profiles (eg, fracture risk, cardiomyopathy) might become apparent only with longer-term follow-up (>3 years). Fourth, the existence of competing clinical trials of new putative treatments affected recruitment and retention, though more than 80% of participants completed at least 30 months of follow-up.
Fifth, some participants (74/196) were switched to open-label daily prednisone due to the drug supply issue, though the short duration (<25 days) in the majority (>75%) of the cases is unlikely to have significantly influenced the overall outcomes of the study.
Conclusions
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 protocol and statistical analysis plan
eAppendix. Additional methods and results
eTable 1. Weight bands used to determine the assigned dosage of study medication
eTable 2. Information on rating scales used in the trial
eTable 3. Summary of the timing of final visits included in the statistical analyses
eTable 4. Treatment group differences with respect to secondary outcome variables averaged over all post-baseline visits
eTable 5. Treatment group differences with respect to secondary outcome variables at the Month 36 visit
eTable 6. Times to disease milestones
eTable 7. Lateral spine X-ray results at Month 36
eTable 8. Adverse events of special interest ascertained through active capture
eTable 9. Serious adverse events
eTable 10. Reasons for reductions in the dosage of study medication
eFigure 1. Individual changes from baseline to Month 36 by treatment group for rise from the floor velocity and forced vital capacity
eFigure 2. Mean trajectories over time by treatment group for secondary functional outcome variables
eFigure 3. Individual changes from baseline to Month 36 by treatment group for motor function outcomes
eFigure 4. Mean trajectories over time by treatment group for rise from the floor velocity, separately for each age group (4-5 years, 6-7 years)
eFigure 5. Mean trajectories over time by treatment group for ten-meter walk/run velocity, separately for each age group (4-5 years, 6-7 years)
eFigure 6. Mean trajectories over time by treatment group for NSAA total score, separately for each age group (4-5 years, 6-7 years)
eFigure 7. Mean trajectories over time by treatment group for six-minute walk test distance, separately for each age group (4-5 years, 6-7 years)
eFigure 8. Mean trajectories over time by treatment group for weight, height, and body mass index
eFigure 9. Mean trajectories over time by treatment group for behavioral outcome variables
eFigure 10. Distributions of percentage of target dosage of study medication at each visit, accounting for dosage reductions, by treatment group
eReferences
Additional Contributions
Management of Adverse Events
Data sharing statement
References
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Trial protocol and statistical analysis plan
eAppendix. Additional methods and results
eTable 1. Weight bands used to determine the assigned dosage of study medication
eTable 2. Information on rating scales used in the trial
eTable 3. Summary of the timing of final visits included in the statistical analyses
eTable 4. Treatment group differences with respect to secondary outcome variables averaged over all post-baseline visits
eTable 5. Treatment group differences with respect to secondary outcome variables at the Month 36 visit
eTable 6. Times to disease milestones
eTable 7. Lateral spine X-ray results at Month 36
eTable 8. Adverse events of special interest ascertained through active capture
eTable 9. Serious adverse events
eTable 10. Reasons for reductions in the dosage of study medication
eFigure 1. Individual changes from baseline to Month 36 by treatment group for rise from the floor velocity and forced vital capacity
eFigure 2. Mean trajectories over time by treatment group for secondary functional outcome variables
eFigure 3. Individual changes from baseline to Month 36 by treatment group for motor function outcomes
eFigure 4. Mean trajectories over time by treatment group for rise from the floor velocity, separately for each age group (4-5 years, 6-7 years)
eFigure 5. Mean trajectories over time by treatment group for ten-meter walk/run velocity, separately for each age group (4-5 years, 6-7 years)
eFigure 6. Mean trajectories over time by treatment group for NSAA total score, separately for each age group (4-5 years, 6-7 years)
eFigure 7. Mean trajectories over time by treatment group for six-minute walk test distance, separately for each age group (4-5 years, 6-7 years)
eFigure 8. Mean trajectories over time by treatment group for weight, height, and body mass index
eFigure 9. Mean trajectories over time by treatment group for behavioral outcome variables
eFigure 10. Distributions of percentage of target dosage of study medication at each visit, accounting for dosage reductions, by treatment group
eReferences
Additional Contributions
Management of Adverse Events
Data sharing statement