Study protocol summary

Study Title : Duchenne muscular dystrophy: double-blind randomized trial to find optimum steroid regimen

Abbreviated title : FOR DMD

EudraCT number : 2010-023744-33

Objective

This is a multi-centre, double-blind, parallel group, 36-60 month study, comparing three corticosteroid regimens in wide use in DMD:

• daily prednisone (0.75 mg/kg/day)
• intermittent prednisone (0.75 mg/kg/day, 10 days on, 10 days off)
• daily deflazacort (0.9 mg/kg/day).

Primary study objective: The proposed randomized controlled trial will compare 3 corticosteroid regimens to address the pragmatic hypothesis that daily corticosteroids (prednisone or deflazacort) will be of greater benefit in terms of function and subject/parent satisfaction than intermittent corticosteroids (prednisone).

Secondary study objectives: A second hypothesis is that daily deflazacort will be associated with a better side effect profile than daily prednisone. The study protocol includes standardized regimens for prevention/ treatment of predictable side effects of corticosteroid medication, as well as standards of care for the general management of DMD. The trial directly addresses the current chaos in prescribed treatment schedules; its results will have direct impact on the current and future management of boys with DMD throughout the world by providing the evidence base for rational clinical practice.

The results of the trial will allow the generation of clear and specific evidence-based guidelines for patient treatment.

Design and Outcomes

The primary outcome variable will be a three-dimensional (multivariate) outcome consisting of the following three components (each averaged over all post-baseline follow-up visits through Month 36): (1) time to stand from lying (log-transformed), (2) forced vital capacity, and (3) subject/parent global satisfaction with treatment, as measured by the Treatment Satisfaction Questionnaire for Medication.

Secondary outcome variables will include regimen tolerance, adverse event profile, secondary functional outcomes including the 6 minute walk test, quality of life, and cardiac function.

The primary statistical analysis will consist of a global test of the null hypothesis that the corticosteroid regimens do not differ with regard to any of the three outcomes against the alternative that they differ (in the same direction) for all three outcome variables. The analyses will involve three separate pair-wise comparisons among the three treatment regimens using O’Brien’s OLS statistics, each performed using a Bonferroni-corrected two-tailed significance level of 0.017. The analyses will be adjusted for covariates, namely country/region, baseline time to stand from lying, baseline FVC and initial weight band. A sample size of 100 subjects per group (300 total) will provide adequate power to detect differences that are thought to be of minimal clinical significance between any two of the three treatment groups, assuming a 10% rate of subject withdrawal.

Interventions and Duration

The trial will randomize 300 boys aged 4-7 years to 0.75 mg/kg/d prednisone; 0.75 mg/kg/d prednisone for 10 days alternating with 10 days off; or 0.9 mg/kg/d deflazacort. All boys will complete a minimum of 3 years (36 months) of treatment period. All boys entering the trial will remain on study drug until the last boy completes the 36 months of treatment. This may be up to 60 months.

Commercial stock prednisone and deflazacort differ from one to another in appearance and their use would prevent blinding of subjects, parents and physicians to the allocated treatment. To achieve double-blinding, a clinical trials supplies company (Catalent) will manufacture identical tablets of prednisone and deflazacort, and matched placebo (to maintain blinding in the 10 days off period, for the intermittent prednisone regimen). This medication will be presented in form of tablets for oral administration. This solution is preferred to over-encapsulation of commercial stock tablets, as the resulting capsules would be quite large, presenting potential difficulties in swallowing for the younger children.

Study drug will be presented in 20 day treatment wallets containing 2-6 tablets per day (i.e. a total of 40 to 120 tablets), depending on the weight band, in a blister pack. Dosage banding for different steroid regimens will be as follows:

Each wallet will be labelled with a multilingual booklet label and a single panel variable label. The wallets will be collated into cartons containing either 7 cards or 12 cards. Each carton will be labelled with a multilingual booklet and a single panel variable label.

Sample Size and Population:

Eligible boys will be those with confirmed DMD (defined as male with clinical signs compatible with DMD AND confirmed DMD mutation in the dystrophin gene (out of frame deletion or duplication or point mutation) or; age at least 4 years and under 8 years; ability to rise independently from floor; willingness and ability of parent or legal guardian to give informed consent; willingness and ability to comply with scheduled visits, drug administration plan and study procedures; and ability to maintain reproducible FVC measurements.

Exclusion criteria: history of major renal or hepatic impairment, immunosuppression or other contraindications to corticosteroid therapy; history of chronic systemic fungal or viral infections; diabetes mellitus; idiopathic hypercalciuria; lack of chicken pox immunity and refusal to undergo immunization; evidence of symptomatic cardiomyopathy; allergy/sensitivity to study drugs or their formulations; current or previous treatment with corticosteroids or other immunosuppressive treatments for DMD or other recurrent indications; inability to take tablets; allergy/sensitivity to study drugs or their formulations; severe behavioral problems, including autism; previous or ongoing medical conditions, medical history, physical findings or laboratory abnormalities that could affect safety or impair the assessment of study results; weight of less than 13 kilograms; exposure to any investigational drug currently or within 3 months prior to start study treatment.

A sample size of 100 subjects per group (300 total) will provide adequate power to detect differences that are thought to be of minimal clinical significance between any two of the three treatment groups, assuming a 10% rate of subject withdrawal.