Pharmacokinetic/Pharmacodynamic Study of Udenafil in Adolescents

Study Overview
=================
Brief Summary
-----------------
To determine the pharmacokinetic profile and safety of udenafil in adolescents with Fontan physiology and to assess the short-term pharmacodynamic effect of udenafil on pharmacodynamic measures of exercise capacity, ventricular performance, and vascular function.

Detailed Description
-----------------
A dose escalation trial to determine the pharmacokinetics, safety and tolerance of udenafil in male and female adolescent subjects with single ventricle physiology that that have undergone the Fontan surgical procedure. Pharmacodynamic data will also be collected to evaluate the effect of udenafil on acute exercise performance, peripheral vascular function and indices of myocardial performance. Five udenafil cohorts will be evaluated in additional to one drug free cohort

Official Title
-----------------
A Phase I/II Dose Escalation Trial of Udenafil in Adolescents With Single Ventricle Physiology After Fontan Palliation

Conditions
-----------------
Single Ventricle Heart Disease After Fontan Surgery

Intervention / Treatment
-----------------
* Drug: Udenafil


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Males and females with Fontan physiology who are 14-18 years of age. Willingness to return to center to complete blood draws and exercise tests as described in the study protocol. Patients must agree to abstain from alcohol, caffeinated beverages, and grapefruit juice for the duration of the trial. Informed assent from subject informed consent from parent/legal guardian as appropriate. Exclusion Criteria: Non-cardiac medical, psychiatric, and/or social disorder that would prevent successful completion of planned study testing or would invalidate its results. Height <132 cm (minimum height requirement for exercise stress testing). Known Fontan baffle obstruction, branch pulmonary artery stenosis, or pulmonary vein stenosis resulting in a mean gradient of >4 mmHg between the regions proximal and distal to the obstruction. Single lung physiology. Severe ventricular dysfunction or valvular regurgitation (systemic atrioventricular or semilunar valve) determined from review of the echocardiogram performed in closest proximity to study enrollment. Significant renal (serum creatinine > 2.0), hepatic (serum aspartate aminotransferase (AST) and/or alanine aminotransferase ( ALT) > 3 times upper limit of normal), gastrointestinal or biliary disorders that could impair absorption, metabolism or excretion of orally administered medications, based on laboratory assessment at the time of screening visit. Hospitalization for acute decompensated heart failure within the 12 months preceding study enrollment. A diagnosis of active protein losing enteropathy or plastic bronchitis. Active evaluation or listing for heart transplant. History of use of a phosphodiesterase type 5 inhibitor within three months of study enrollment. Concurrent illness that, in the opinion of the investigator, precludes participation. Current therapy with alpha-blockers or nitrates. Pregnancy at the time of enrollment. Latex allergy

Ages Eligible for Study
-----------------
Minimum Age: 14 Years
Maximum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Udenafil Dose Level 1 qd<br>Udenafil tablet dose Level 1 daily for 5 days | Drug: Udenafil<br>* Drug<br>|
| Experimental: Udenafil Dose Level 1 bid<br>Udenafil Dose Level 1 twice daily for 5 days. | Drug: Udenafil<br>* Drug<br>|
| Experimental: Udenafil Dose Level 2 qd<br>Udenafil tablet dose level 2 once daily for 5 days. | Drug: Udenafil<br>* Drug<br>|
| Experimental: Udenafil Dose Level 2 bid<br>Udenafil tablet dose level 2 twice daily for 5 days | Drug: Udenafil<br>* Drug<br>|
| Experimental: Udenafil Dose Level 3 qd<br>Udenafil tablet dose level 3 daily for 5 days | Drug: Udenafil<br>* Drug<br>|
| No Intervention: No Drug<br>No drug | |

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of subjects with Serious Adverse Events | Safety will be measured by the number of subjects experience serious adverse events possibly or probably related to study drug | 5 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Plasma clearance of parent drug and active metabolite | Plasma clearance of parent drug and active metabolite will be determine after the administration of the last dose on day 5. | Day 5, Zero to 48 hours post last dose | 
| Measurement of maximum oxygen consumption (VO2) | Change in maximum oxygen consumption after standard exercise testing. | Day 1 and Day 5 | 
| PAT Index | Measurement of the PAT reactive hyperemia index by the EndoPAT device. | Day 1 and Day 5 | 
| Myocardial Performance Index (MPI) | Myocardial Performance Index determined by echocardiogram. | Day 1 and Day 5 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Fontan, Pharmacokinetics, Pharmacodynamics, Exercise capacity, Maximal Oxygen Consumption, Vascular function, EndoPAT, Myocardial performance