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

Pharmacokinetics - apparent clearance (CL/F)

Empagliflozin concentrations at the different time-points (6 samples at Visit 1, 1 opportunistic sample at Visits 2 and 3; the timing of the samples will be optimized with modeling \& simulation techniques). Basing on these concentrations, non-compartmental pharmacokinetic calculations will be performed, allowing to determine pharmacokinetic parameters (including CL/F).

Pharmacokinetics - apparent (central) volume of distribution (Vd/F)

Empagliflozin concentrations at the different time-points (6 samples at Visit 1, 1 opportunistic sample at Visits 2 and 3; the timing of the samples will be optimized with modeling \& simulation techniques). Basing on these concentrations, non-compartmental pharmacokinetic calculations will be performed, allowing to determine pharmacokinetic parameters (including Vd/F).

Pharmacokinetics - half-life

Empagliflozin concentrations at the different time-points (6 samples at Visit 1, 1 opportunistic sample at Visits 2 and 3; the timing of the samples will be optimized with modeling \& simulation techniques). Basing on these concentrations, non-compartmental pharmacokinetic calculations will be performed, allowing to determine pharmacokinetic parameters (including t1/2).

Pharmacokinetics - AUC

Empagliflozin concentrations at the different time-points (6 samples at Visit 1, 1 opportunistic sample at Visits 2 and 3; the timing of the samples will be optimized with modeling \& simulation techniques). Basing on these concentrations, non-compartmental pharmacokinetic calculations will be performed, allowing to determine pharmacokinetic parameters (including AUC).

Safety 1 - eGFR

Creatinine, respectively Cystatin C, will be collected in order to calculate eGFR (bedside Schwartz formula, respectively Filler equation).

Safety 2 - Occurrence of hypoglycemia

Blood glucose will be checked three times at Visit 1 (baseline, at approximately 2-3h post-intake, and before discharge at 8h post-intake), as well as once at Visits 2 to 5. Outcome measure: number of patients experiencing hypoglycemia.

Safety 3 - Occurrence of ketoacidosis

The outcome is presence (or absence) of ketoacidosis. This will be assessed at Visits 1, 2, 3, 4 and 5. Outcome measure: number of patients experiencing ketoacidosis.

Safety 4 - Occurrence of UTI

The outcome is presence (or absence) of UTI diagnosis. This will be assessed at Visits 1, 2, 3, 4 and 5. Outcome measure: number of patients experiencing UTI between Visit 2 and Visit 5.

Efficacy markers (exploratory), Mechanistic insights - 1: body weight (kg)

To explore the effect of SGLT2 inhibitors on fluid status, body weight will be assessed (outcome: change between Visit 1 and Visit 5).

Efficacy markers (exploratory), Mechanistic insights - 2: heart rate (bpm)

To explore the effect of SGLT2 inhibitors on sympathetic activation, heart rate (in bpm) will be assessed (outcome: change between Visit 1 and Visit 5).

Efficacy markers (exploratory), Mechanistic insights - 3: blood pressure (SBP/DBP, mmHg)

To explore the effect of SGLT2 inhibitors on sympathetic activation, blood pressure (SBP and DBP, in mmHg) will be assessed (outcome: change between Visit 1 and Visit 5).

Efficacy markers (exploratory), Mechanistic insights - 4: b-hydroxybutyrate (mmol/L)

To explore the effect of SGLT2 inhibitors on metabolism shift, b-hydroxybutyrate will be assessed (outcome: change between Visit 1 and Visit 5).