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

Study Overview
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Brief Summary
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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: define a dose rationale for this indication and age group (pharmacokinetic study), assess and monitor safety, assess ease-of-swallow, 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
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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.

Official Title
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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

Conditions
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Heart Failure

Intervention / Treatment
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* Drug: Dapagliflozin tablet
* Drug: Empagliflozin Tablets


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Children 6 to 18 years of age, followed either as in- or outpatients at the Heart failure unit, Great Ormond Street Hospital NHS Foundation Trust, London or at the Paediatric Cardiology Unit, Centre Hospitalier Universitaire Vaudois (CHUV), Lausanne University Hospital, Lausanne, Switzerland will be eligible for inclusion. Currently on heart failure medication (any drug or any combination). Patients should potentially benefit from adding a SGLT2i (as judged by the treating physician and the local PI or Co-PI). Patients need to be on stable medical treatment, defined as no new heart failure drug started over the preceding 2 weeks and no major drug dose modification (apart minor adaptations, like weight adaptations, rounding or formulation changes) during the 2 weeks prior to enrolment. Adolescents, respectively parents or caregivers of children, capable of giving informed consent. Exclusion Criteria: Inability to understand and go through the informed consent procedure. Inability to receive medications per os or through a nasogastric tube. Patients on either Insulin or Metformin will be excluded from participation. This implies the exclusion of patients with Diabetes mellitus (either type 1 or type 2 or other rare forms) necessitating either insulin or metformin. Type 1 Diabetes mellitus or any underlying metabolic disease associated with hypoglycaemias. Body weight <13kg. Current smokers (defined as >1 cigarette/week). Use of any other nicotine-delivering product (e.g. nicotine patches). Any known illicit drug abuse. Active chronic HBV, HCV or HIV. Any major surgery within 4 weeks of first dose administration. Blood transfusion recipient within 4 weeks of dose administration. eGFR =<45mL/min/1.73m2 (simplified Schwartz formula). K+ >6.5mmol/L. Blood glucose <4mmol/L. There are no blood pressure exclusion criteria foreseen, but participants need to be haemodynamically stable, as assessed by the local investigator (board-certified paediatric cardiologist). Sustained or symptomatic arrhythmia insufficiently controlled with drug and/or device therapy. Cardio-surgical procedure within the 2 months prior to Visit 1, or interventional cardiac catheterization within 2 weeks prior to Visit 1, or the patient is planned to undergo cardiac surgery or an interventional cardiac catheterization during the study period (i.e. in the 6 weeks following Visit 1). Post-menarchal female patients of childbearing potential cannot be included. Known lactose intolerance, galactose intolerance, total lactase deficiency, or glucose-galactose malabsorption. Known allergies to excipients of either Dapagliflozin or Empagliflozin. Significant medical history of active severe medical disease. Significant liver disease, Child Pugh Class C, or significant laboratory abnormalities at enrolment. Significant gastroenterological or hepatic disease that could significantly impair absorption or metabolism of orally administered drugs. Any medical co-morbidity, which is deemed incompatible (or only with relevant risk) with study participation by the treating clinician and/or the study investigator. Active urinary tract infection (being treated with antibiotics at the moment of Visit 1) or other relevant bacterial infection, as judged by the treating clinician and/or the study investigator. The patient is currently participating in another interventional clinical trial or has participated in such a trial during the <14 days before Visit 1 (or if enrolment in this study is incompatible with the protocol of that preceding trial).

Ages Eligible for Study
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Minimum Age: 6 Years
Maximum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Interventional Model Description: Order of drug intake will be balanced and randomized, with 6 patients starting with Dapagliflozin (Visits 1-2) and subsequently switching to Empagliflozin (Visits 3-4), and 6 patients starting with Empagliflozin (Visits 1-2) and subsequently switching to Dapagliflozin (Visits 3-4).
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Group A: Dapagliflozin first, Empagliflozin second<br>Patients randomized to Group A will start with Dapagliflozin on Visit 1 and take Dapagliflozin once daily up to the day before Visit 3. On the day of Visit 3, they will switch to Empagliflozin once daily, to be continued up to the day preceding Visit 4. | Drug: Dapagliflozin tablet<br>* 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)<br>Drug: Empagliflozin Tablets<br>* 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)<br>|
| Active Comparator: Group B: Empagliflozin first, Dapagliflozin second<br>Patients randomized to Group B will start with Empagliflozin on Visit 1 and take Empagliflozin once daily up to the day before Visit 3. On the day of Visit 3, they will switch to Dapagliflozin once daily, to be continued up to the day preceding Visit 4. | Drug: Dapagliflozin tablet<br>* 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)<br>Drug: Empagliflozin Tablets<br>* 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)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacokinetics 1: Dapagliflozin, respectively Empagliflozin half-life | This will be derived by pharmacokinetic analysis and modeling, basing on Dapagliflozin, respectively Empagliflozin, concentrations at the different time-points (5-6 samples [according to weight] at Visit 1, 1 opportunistic sample at Visits 2 and 3 for Drug A; 5-6 samples [according to weight] at Visit 3 and 1 opportunistic sample at Visit 4 for Drug B; the timing of the samples will be optimized with modeling & simulation techniques). | Visits 1-4 (Visit 1 = day 1, Visit 2 = week 1, Visit 3 = week 3 to 5, Visit 4 = week 4 to 6 after study start) | 
| Pharmacokinetics 2: Dapagliflozin, respectively Empagliflozin Volume of distribution | This will be derived by pharmacokinetic analysis and modeling, basing on Dapagliflozin, respectively Empagliflozin, concentrations at the different time-points (5-6 samples [according to weight] at Visit 1, 1 opportunistic sample at Visits 2 and 3 for Drug A; 5-6 samples [according to weight] at Visit 3 and 1 opportunistic sample at Visit 4 for Drug B; the timing of the samples will be optimized with modeling & simulation techniques). | Visits 1-4 (Visit 1 = day 1, Visit 2 = week 1, Visit 3 = week 3 to 5, Visit 4 = week 4 to 6 after study start) | 
| Pharmacokinetics 3: Dapagliflozin, respectively Empagliflozin AUC | This will be derived by pharmacokinetic analysis and modeling, basing on Dapagliflozin, respectively Empagliflozin, concentrations at the different time-points (5-6 samples [according to weight] at Visit 1, 1 opportunistic sample at Visits 2 and 3 for Drug A; 5-6 samples [according to weight] at Visit 3 and 1 opportunistic sample at Visit 4 for Drug B; the timing of the samples will be optimized with modeling & simulation techniques). | Visits 1-4 (Visit 1 = day 1, Visit 2 = week 1, Visit 3 = week 3 to 5, Visit 4 = week 4 to 6 after study start) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety 1 - eGFR | Creatinine (respectively Cystatin C in DMD participants) will be collected in order to calculate eGFR (bedside Schwartz formula, respectively Filler equation). | Visits 1-4 (Visit 1 = day 1, Visit 2 = week 1, Visit 3 = week 3 to 5, Visit 4 = week 4 to 6 after study start) | 
| Safety 2 - Occurrence of hypoglycemia | Blood glucose will be checked three times at Visit 1 and Visit 3 (baseline, at the time of 2nd PK sampling, which will be individualized but will be at approximately 2-3h post-intake, and before discharge at 8h post-intake), as well as once at Visits 2 and 4 (together with PK sampling). Outcome measure: number of patients experiencing hypoglycemia. | Visits 1-4 (Visit 1 = day 1, Visit 2 = week 1, Visit 3 = week 3 to 5, Visit 4 = week 4 to 6 after study start) | 
| Safety 3 - Occurrence of ketoacidosis | The outcome is presence (or absence) of ketoacidosis. This will be assessed at Visits 1, 2, 3, and 4. Outcome measure: number of patients experiencing ketoacidosis. | Visits 1-4 (Visit 1 = day 1, Visit 2 = week 1, Visit 3 = week 3 to 5, Visit 4 = week 4 to 6 after study start) | 
| Ease-of-swallow | Ease of swallow will be assessed by means of facial hedonic scales, according to our standard procedure, at Visit 1 (Drug A), and Visit 3 (Drug B). (Scale 1 to 4, 1 being the worse and 4 the best score: very difficult - difficult - possible - easy to swallow.) | Visit 1, Visit 3 (Visit 1 = day 1, Visit 3 = week 3 to 5 after study start) | 
| Efficacy and efficacy markers (exploratory) 1 - Heart failure severity class | Symptoms, clinical signs, NYHA (if >8 years of age) / Ross (if <8 years of age) class assignment. NYHA and Ross heart failure classes share the same scale of I (no limitation of physical activity) to IV (symptoms at rest). Analysis will be performed at Visit 1, Visit 3 and Visit 4. Outcome: change between Visit 1 and Visit 4. | Visits 1, 3 and 4 (Visit 1 = day 1, Visit 3 = week 3 to 5, Visit 4 = week 4 to 6 after study start) | 
| Efficacy and efficacy markers (exploratory) 2 - NT-proBNP level | Analysis will be performed at Visits 1, 3 and 4. Outcome: change between Visit 1 and Visit 4. | Visits 1, 3 and 4 (Visit 1 = day 1, Visit 3 = week 3 to 5, Visit 4 = week 4 to 6 after study start) | 
| Efficacy and efficacy markers (exploratory) 3 - Echocardiography 1: Left-ventricular end-diastolic diameter (LVEDd) | LVEDd (mm) will be measured at Visits 1, 3 and 4. Outcome: change between Visit 1 and Visit 4. | Visits 1, 3 and 4 (Visit 1 = day 1, Visit 3 = week 3 to 5, Visit 4 = week 4 to 6 after study start) | 
| Efficacy and efficacy markers (exploratory) 4 - Echocardiography 2: Left-ventricular end-systolic diameter (LVESd) | LVESd (mm) will be measured at Visits 1, 3 and 4. Outcome: change between Visit 1 and Visit 4. | Visits 1, 3 and 4 (Visit 1 = day 1, Visit 3 = week 3 to 5, Visit 4 = week 4 to 6 after study start) | 
| Efficacy and efficacy markers (exploratory) 5 - Echocardiography 3: Fractional shortening (FS) | FS (%) will be measured at Visits 1, 3 and 4. Outcome: change between Visit 1 and Visit 4. | Visits 1, 3 and 4 (Visit 1 = day 1, Visit 3 = week 3 to 5, Visit 4 = week 4 to 6 after study start) | 
| Efficacy and efficacy markers (exploratory) 6 - Echocardiography 4: Left ventricular ejection fraction (LV-EF) | LV-EF (%) will be measured at Visits 1, 3 and 4. Outcome: change between Visit 1 and Visit 4. | Visits 1, 3 and 4 (Visit 1 = day 1, Visit 3 = week 3 to 5, Visit 4 = week 4 to 6 after study start) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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child