Pharmacokinetics and Safety Profile of Digoxin in Infants With Single Ventricle Congenital Heart Disease

Study Overview
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Brief Summary
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This is a prospective, multi-center, open-label, PK and safety profile study of enteral digoxin in children <6 months old at time of enrollment, post-surgical or hybrid stage 1 palliation, but prior to surgical stage 2 palliation.

Detailed Description
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The Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) funded this protocol titled Pharmacokinetics and Safety Profile of Digoxin in Infants with Single Ventricle Congenital Heart Disease, protocol number NICHD-2018-DGX01. The Investigational New Drug (IND) Sponsor and Principal Investigator for this protocol is Christopher P. Hornik, MD, MPH. The Contracting Officer's Technical Representative (COTR) to represent the Government for this task order is Perdita Taylor-Zapata. The Duke IRB number for this study is Pro00102130. This study employs a central IRB, the WIRB-Copernicus Group (WCG). The c-IRB (WCG) study number is 20190888 / NICHD-2018-DGX01. This is a prospective, multicenter Phase 1 study with a primary objective to characterize the pharmacokinetics of enteral digoxin in infants with single ventricle congenital heart disease. The secondary objective is to determine the safety profile of enteral digoxin in infants with single ventricle congenital heart disease. Digoxin is used for the treatment of heart failure in pediatric patients and acts by controlling numerous functions of the cardiovascular system. Digoxin use in single ventricle congenital heart disease may decrease interstage mortality. The study will be conducted in approximately 48 subjects at approximately 13 investigational centers. The proposed duration of the study is approximately 196 (±) days. Please see the protocol and synopsis for more information.

Official Title
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Pharmacokinetics and Safety Profile of Digoxin in Infants With Single Ventricle Congenital Heart Disease

Conditions
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Congenital Heart Disease

Intervention / Treatment
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* Drug: Digoxin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis of single ventricle congenital heart disease Status post-surgical or hybrid stage 1 palliation but prior to surgical stage 2 palliation Age ≤ 30 days of life at time of stage 1 palliation Age < 6 months at time of enrollment Require treatment with enteral digoxin per their treating medical provider if their planned maintenance treatment dosing regimen is within the labeled dose range of 7.5 - 20 mcg/kg/day divided in 2 or 3 equal doses Informed consent from parent(s) or legal guardian(s) Exclusion Criteria: Serum creatinine > 2 mg/dL at enrollment Diagnosis of second degree or higher atrioventricular conduction block at enrollment Diagnosis of clinically significant sinus bradycardia requiring intervention at enrollment Known hypersensitivity to digoxin or other forms of digitalis Extracorporeal life support (i.e., ECMO, dialysis, ventricular assist device) at enrollment Received digoxin prior to enrollment Received or anticipated to receive a loading dose of digoxin. Any condition that would make the participant, in the opinion of the investigator, unsuitable for the study

Ages Eligible for Study
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Maximum Age: 6 Months

Sexes Eligible for Study
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All

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Children with single ventricle congenital heart disease<br>Receiving digoxin per standard of care during the interstage period | Drug: Digoxin<br>* Drug administered per standard of care, with a dosing regimen within the labeled dose range of 7.5-20 mcg/kg/day divided in 2 or 3 equal doses<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Plasma concentrations of digoxin | The primary outcome measures are plasma concentrations of digoxin measured using a validated bioanalytical assay at a central laboratory. | Approximately 7 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of adverse events related to study procedures and serious, unexpected, suspected adverse reactions related to digoxin | 1. Adverse events (AEs) related to the study procedures (blood draws and outcome assessments), and serious, unexpected, suspected adverse reactions (SUSARs) related to digoxin will be captured. | Approximately 7 months | 
| Tachyarrthmias | Event of special interest will be captured (number of tachyarrythmias) | Approximately 7 months | 
| Number of participants with second and third degree atrioventricular conduction block |  | Approximately 7 months | 
| Number of participants with sinus bradycardia | Number of participants with sinus bradycardia | Approximately 7 months | 
| Number of participants with need for temporary or permanent pacing | Number of participants with need for temporary or permanent pacing | Approximately 7 months | 
| Frequency of death | Frequency of death | Approximately 7 months | 
| PR interval | Derived from electrocardiograms and their reports performed per standard of care | Approximately 7 months | 
| QRS duration | Derived from electrocardiograms and their reports performed per standard of care | Approximately 7 months | 
| QT interval | Derived from electrocardiograms and their reports performed per standard of care | Approximately 7 months | 
| Corrected QT interval using Bazett's formula | Derived from electrocardiograms and their reports performed per standard of care | Approximately 7 months |