Repurposing Empagliflozin for DMD-associated Cardiomyopathy in Children 6-18 Years of Age

DMD-associated Dilated Cardiomyopathy

This study aims at exploring the use of empagliflozin in children and adolescents 6-18 years old with Duchenne muscular distrophy (DMD) - associated cardiomyopathy. This molecule is effective in reducing hospitalizations and mortality in adults with heart failure and is used in adolescents with type 2 diabetes mellitus, but little is known on children and adolescents with heart failure. Particularly, the best dose to use in this population is currently unknown. This trial aims to: 1. define a dose rationale for this indication and age group (pharmacokinetic study), 2. assess and monitor safety, 3. assess ease-of-swallow, 4. explore middle-term (3-6 months) efficacy and efficacy markers. Participants will be asked to attend 5 study visits over 6 months, and one end-study visit 2-12 weeks thereafter. Visit 1 will entail an 8h day-hospital stay, while Visits 2, 3, 4 and 5, as well as the end-study visit, will be outpatient clinics (approximately 2h). Participants will be asked to take the studied drug once daily during the 6 months of the study period. No comparison group is foreseen for this study.

Cardiac disease represents the main life-limiting condition in Duchenne muscular dystrophy (DMD). It is important to recognize and address this early in the disease course. Because of lack of DMD specific drugs, present attitudes for established DMD-related cardiomyopathy ground on current treatment for heart failure. Unfortunately, however, current heart failure therapy in Paediatrics is still unsatisfactory, with high in-hospital (7-26%), and 5-year mortality (30%-50%). Furthermore, mortality rate for DMD cardiomyopathy is worse than similarly aged idiopathic dilated cardiomyopathy (DCM) patients. Among the recent improvements in adult heart failure management, the sodium glucose transporter type 2 inhibitors (SGLT2i) dapagliflozin and empagliflozin were found to reduce cardiovascular death or worsening heart failure by 25% on top of optimal medical therapy. Indeed, since 2021, they have been recommended as part of standard heart failure therapy. In the past, paediatric heart failure trials often failed, mainly because of suboptimal dose or inappropriate formulations and endpoints. This phase II.a, open-label trial is designed to characterize pharmacokinetics (primary outcome), ease-of-swallow, safety and explore potential efficacy markers (secondary outcomes) of empagliflozin in 12 children and adolescents with DMD-related cardiomyopathy, so to inform the design and performance of subsequent, state-of-the-art, high-quality efficacy trials. Participants will receive empagliflozin during 6 months. They will have 5 visits, one end-study visit and 7 to 8 pharmacokinetic samples. The timing of these samples will be optimized exploiting contemporary modeling and simulation techniques. Safety evaluation will occur throughout the study, while ease-of-swallow will be evaluated at Visit 1, and efficacy markers at Visits 1, 4 and 5. Pharmacokinetic modeling will characterize primary and secondary pharmacokinetic parameters and allow to define the optimal paediatric dose, informing both current compassionate-care use and the design of future efficacy trials.

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