Repurposing empagliflozin for Duchenne muscular dystrophy-associated cardiomyopathy in children: a pharmacokinetics, safety and proof-of-concept study among children 6-18 years of age
Duchenne muscular dystrophy (DMD) - associated cardiomyopathy
Empagliflozin 10 mg once daily (commercially available tablets: Jardiance 10 mg film-coated tablets) p.o. once daily for 6 months Follow-up visits: visit 1, visit 2 (week 1), visit 3 (week 6), visit 4 (month 3), visit 5 (month 6), end-study visit (2-12 weeks after study end/visit 5).
1. Children or adolescents 6 to 18 years of age with DMD-associated cardiomyopathy, followed either as in- or outpatients at the Heart Failure Unit, Pediatric Cardiology Service, Heart & Lung Directorate, Great Ormond Street Hospital NHS Foundation Trust, London, will be eligible for inclusion. 1.1. Patients with DMD-associated cardiomyopathy, who are currently followed elsewhere, but who, having been made aware of this study (e.g. through other patients they know, parental associations etc) and who would like to participate, may contact the study team with the question of participating. These patients may be considered for eligibility as well. The study team might want, as an additional inclusion/exclusion criterion, to discuss their participation with their treating paediatric cardiologist. 2. Currently on heart failure medication (any drug or any combination). 3. Patients should potentially benefit from adding an SGLT2i (as judged by the treating physician and the local PI or Co-PI). 4. Patients need to be on stable medical treatment, defined as no new heart failure drug started over the preceding 30 days and no major drug dose modification (apart from minor adaptations, like weight adaptations, rounding or formulation changes) during the 2 weeks prior to enrolment. 5. Adolescents, respectively parents or caregivers of children, capable of giving informed consent (including sufficient development and sufficient understanding, as judged by the local investigator). 6. Ability to tolerate a cardiac MRI investigation without the need for general anaesthesia.
1. Inability to understand and go through the informed consent procedure. 2. Inability to receive medications per os or through a nasogastric tube. 3. Type 1 or Type 2 Diabetes mellitus or any underlying metabolic disease associated with hypoglycaemias. 4. Body weight <15 kg (because, basing on pharmacokinetic simulations, available tablets may exceed adult Cmax and/or AUC by >130% (75th percentile of simulated Cmax and/or AUC) in patients below 15 kg weight) 5. Current smokers (defined as >1 cigarette/week). 6. Use of any other nicotine-delivering product (e.g. nicotine patches). 7. Any known illicit drug abuse. 8. Active chronic HBV, HCV or HIV. 9. Any major surgery within 4 weeks of first dose administration. 10. Blood transfusion recipient within 4 weeks of first dose administration. 11. eGFR equal to or less than 45 mL/min/1.73m2 (simplified Schwartz formula, and/or respectively the cystatine C-based Filler equation). 12. K+ >6.5 mmol/L. 13. Blood glucose <4 mmol/L. 14. There are no blood pressure exclusion criteria foreseen, but participants need to be haemodynamically stable, as assessed by the local investigator. 15. Sustained or symptomatic arrhythmia insufficiently controlled with drug and/or device therapy. 16. Cardio-surgical procedure within the 2 months prior to Visit 1, or interventional cardiac catheterization within 2 weeks prior to Visit 1, or is planned to undergo cardiac surgery or an interventional cardiac catheterization during the study period (i.e. in the 6 months following Visit 1). 17. Post-menarchal female patients (for biological reasons inherent to DMD, this only applies to female carriers or to Becker muscular dystrophy patients) of childbearing potential cannot be included. 18. Females must not be breastfeeding (this criterion is just a legal specification, biologically and clinically it is already implicit in the previous exclusion criterion, since DMD-boys and pre-menarchal girls cannot breastfeed). 19. Known lactose intolerance, gal