Description

Study design: Multi-center, prospective, open-label, opportunistic PK/PD study of digoxin.

Randomization: none Blinding /Masking: none Study intervention: Each subject will receive population specific PK model-derived digoxin dosing Duration of participant participation: up to 180 days

Table 1. PK sample collection times PK Sample # Sample window for plasma collection

1. 8 - 11.5 hours after dose / trough level on dosing Day 7 (+/- 2 days)
2. 15 minutes - 1 hour after dose on dosing Day ≥14
3. 2 - 5 hours after dose on dosing Day ≥14
4. 8 - 11.5 hours after dose / trough level on dosing Day ≥14
5. - 7* 8 - 11.5 hours after dose / trough level on any dosing Day ≥14 and ≤180 or Day of S2P

PK sampling: digoxin concentrations in plasma will be measured at a central lab using validated bioanalytical assays. Plasma samples for digoxin quantification will be drawn according to Table 1. Initial PK sample will be obtained once on dosing Day 7 (+/- 2 days). PK samples 2-4 will be obtained once on dosing day ≥14. Every effort will be made to collect samples 2-4 after the same digoxin dose. Up to 3 additional samples will be collected 8 - 11.5 hours after dosing on different dosing days ≥14 but ≤180 or day of S2P, whichever occurs first. Samples 5 - 7 will be collected on different days.

Table 2. PD sample collection times PD Sample # Sample window for plasma collection

1. Within 24 hours prior to first digoxin dose
2. Any time on dosing day 28 (+/- 7 days)
3. Any time on dosing day 112 (+/- 7 days)
4. Any time within 7 days prior to S2P

PD sampling: plasma samples for NT-proBNP and MR-proANP quantification will be collected according to Table 2.

Safety: Adverse events related to the study procedure (sample collection, blood draws and outcome assessments), adverse events related to digoxin, select events of special interest (tachyarrythmias, second and third degree atrioventricular conduction block, sinus bradycardia, need for temporary or permanent pacing, death), and serious, unexpected, suspected adverse reactions (SUSARs) related to digoxin will be captured.

Cardiac assessments: records of echocardiograms and cardiac catheterizations performed per standard of care will be collected.

This study will be conducted in accordance with current U.S. Food and Drug Administration regulations and guidelines, (or, as applicable, the European Clinical Trials Directive and associated guidelines), the International Conference on Harmonisation Guidelines on Good Clinical Practice (which incorporate the principles of the Declaration of Helsinki), as well as all other applicable national and local laws and regulations.

Scientific Rationale for Study Design This study is designed to prospectively validate the PK model-derived dosing of digoxin in infants with single ventricle CHD after S1P but before S2P. A validation trial is necessary to confirm that the weight, age, and estimated glomerular filtration rate based dosing regimen is able to achieve digoxin exposures consistent with the package insert recommendations.

Rationale for Dose Selection A population PK model of digoxin was developed in a cohort of 50 infants with single ventricle CHD treated with digoxin after S1P but prior to S2P. A 2 compartment model with transit compartment absorption best described the digoxin disposition in this population. Body weight and estimated glomerular filtration rate were covariates retained in the model, The model was applied to dosing simulations targeting a Cmin,ss of 0.5 - 2 ng/mL, as recommended by the digoxin package insert. Doses recommended by the model are lower than doses recommended by the current digoxin package insert, and lower that the doses received in the PTN DGX01 trial.