NCT06012266

Repurposing Empagliflozin and Dapagliflozin for Paediatric Heart Failure: Translational Approach and Dose Rationale

Dose Rationale for Dapagliflozin and Empagliflozin in Paediatric Heart Failure: a Phase II.a Pharmacokinetics, Ease-of-swallow, Safety and Proof-of-concept Study Among Children 6-18 Years of Age

• Status: Unknown
• Phase: Phase 2
• Study type: Interventional
• Enrollment: 12 (estimated)
• Sponsor: Centre Hospitalier Universitaire Vaudois · Academic / Other
• Sex: All
• Age: 6 Years – 18 Years
• Healthy volunteers: Not accepted

Summary

This study aims at exploring the use of Dapagliflozin and Empagliflozin in children and adolescents 6-18 years old with heart failure. These molecules are effective in reducing hospitalisations and mortality in adults with heart failure and are used in adolescents with type 2 diabetes mellitus, but little is known on children 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 (4-6 weeks) efficacy and efficacy markers. Participants will be asked to attend 4 study visits over 4-6 weeks, and one end-study visit 2-12 weeks thereafter. Visits 1 and 3 will entail an 8h day-hospital stay, while Visits 2, 4 and the end-study visit will be outpatient clinics (approximately 2h). Participants will be asked to take the studied drug once daily during the 4-6 weeks of the study period. All participants will take both Dapagliflozin and Empagliflozin: 6 will start with Dapagliflozin first (Visits 1-2) and then switch to Empagliflozin (Visits 3-4), while 6 will start with Empagliflozin first (Visits 1-2) and then switch to Dapagliflozin (Visits 3-4). No comparison group is foreseen for this study.

Detailed description

Paediatric heart failure is a relevant healthcare issue, with almost 15'000 yearly hospitalizations just in the USA. Sadly, current heart failure therapy in Paediatrics is still unsatisfactory, with high in-hospital (7-26%), and 5-year mortality (30%-50%). Among the recent improvements in adult heart failure management, impressive is the discovery that Dapagliflozin and Empagliflozin are able 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, cross-over, open-label trial is designed to characterize pharmacokinetics (primary outcome), palatability, safety and explore potential efficacy markers (secondary outcomes) of Dapagliflozin and Empagliflozin in 12 heart failure children, so to inform the design and performance of subsequent, state-of-the-art, high-quality efficacy trials. Participants will first receive Drug A (either Dapagliflozin, n=6, or Empagliflozin, n=6) during 3-5 weeks, followed by the other molecule (Drug B) for 2 weeks. They will have 4 visits, one end-study visit and 11-15 pharmacokinetic samples (depending on their weight). The timing of these samples will be optimized exploiting contemporary modeling and simulation techniques. Safety evaluation will occur throughout the study, while palatability will be evaluated at Visits 1 (Drug A) and 3 (Dug B), and efficacy markers at Visits 1, 3 and 4. 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.

Conditions

• Heart Failure

Interventions

Type	Name	Description
DRUG	Dapagliflozin tablet	Patients randomized to Group A will start with Dapagliflozin on Visit 1 and take Dapagliflozin once daily up to the day before Visit 3. Patients randomized to Group B will start Dapagliflozin once daily on the day of Visit 3, to be continued up to the day preceding Visit 4. Dose: * participants ≤12 year old: 5mg once daily p.o. (commercially available tablet) * participants \>12 year old: 10mg once daily p.o. (commercially available tablet)
DRUG	Empagliflozin Tablets	Patients randomized to Group A will start with Empagliflozin on Visit 1 and take Empagliflozin once daily up to the day before Visit 3. Patients randomized to Group B will start Empagliflozin once daily on the day of Visit 3, to be continued up to the day preceding Visit 4. Dose: Empagliflozin 10mg once daily p.o. (commercially available tablet)

Timeline

• Start date: 2024-08-01
• Primary completion: 2025-08-01
• Completion: 2025-08-01
• First posted: 2023-08-25
• Last updated: 2024-02-07

Locations

3 sites across 2 countries: Switzerland, United Kingdom