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.
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
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
36
Drug
Riley Hospital for Children
Indianapolis, Indiana, United States
University of Michigan Congenital Heart Center
Ann Arbor, Michigan, United States
Cincinnati Children's Hospital Medical Center
Cincinnati, Ohio, United States
Children's Hospital of Philadelphia
Philadelphia, Pennsylvania, United States
Number of Subjects With Serious Adverse Events Possibly or Probably Related to Udenafil
Number of subjects experiencing serious adverse events possibly or probably related to udenafil at doses of 37.5 mg daily, 37.5 mg twice daily, 87.5 mg daily, 87.5 mg twice daily, and 125 mg daily given over a five-day period.
Time frame: 5 days
Evaluate the Pharmacokinetic (PK) Profile of Udenafil: Cmax
Evaluate the pharmacokinetic (PK) profile of udenafil, by weight, age, and gender in adolescents with Fontan physiology at multiple dosing levels.
Time frame: Day 5, zero to 48 hours after the last dose
Evaluate the Effect of Udenafil on Pharmacodynamic (PD) Outcomes: Exercise Capacity
Evaluate the effect of udenafil on pharmacodynamic (PD) outcomes including: exercise capacity, vascular function, and echocardiographic measures of myocardial performance (MPI). The outcome measures (OM) are a difference between baseline (BL) and follow-up (FU) \[OM = FU-BL\].
Time frame: Day 1 (baseline) and Day 5 (follow-up)
Evaluate the Pharmacokinetic (PK) Profile of Metabolite DA-8164: Cmax
Evaluate the pharmacokinetic (PK) profile of metabolite DA-8164, by weight, age, and gender in adolescents with Fontan physiology at multiple dosing levels.
Time frame: Day 5, zero to 48 hours after the last dose
Evaluate the Pharmacokinetic (PK) Profile of Udenafil: Tmax
Evaluate the pharmacokinetic (PK) profile of udenafil, by weight, age, and gender in adolescents with Fontan physiology at multiple dosing levels.
Time frame: Day 5, zero to 48 hours after the last dose
Evaluate the Pharmacokinetic (PK) Profile of Udenafil: T-1/2
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Primary Children's Medical Center
Salt Lake City, Utah, United States
The Hospital for Sick Children
Toronto, Ontario, Canada
Evaluate the pharmacokinetic (PK) profile of udenafil, by weight, age, and gender in adolescents with Fontan physiology at multiple dosing levels.
Time frame: Day 5, zero to 48 hours after the last dose
Evaluate the Pharmacokinetic (PK) Profile of Udenafil: AUC (0-tau)
Evaluate the pharmacokinetic (PK) profile of udenafil, by weight, age, and gender in adolescents with Fontan physiology at multiple dosing levels.
Time frame: Day 5, zero to 48 hours after the last dose
Evaluate the Pharmacokinetic (PK) Profile of Udenafil: CLSS/F
Evaluate the pharmacokinetic (PK) profile of udenafil, by weight, age, and gender in adolescents with Fontan physiology at multiple dosing levels.
Time frame: Day 5, zero to 48 hours after the last dose
Evaluate the Effect of Udenafil on Pharmacodynamic (PD) Outcomes: Vascular Function [Change in Natural Log Transformed Reactive Hyperemia Index (RHI)]
Evaluate the effect of udenafil on pharmacodynamic (PD) outcomes including: exercise capacity, vascular function, and echocardiographic measures of myocardial performance (MPI). The outcome measures (OM) are a difference between baseline (BL) and follow-up (FU, Day-5) \[OM = FU-BL\]. Endothelial pulse amplitude tonometry (Endo-PAT) is a technique for the non-invasive assessment of peripheral vascular function. In adults, Endo-PAT has been demonstrated to identify those with coronary artery dysfunction and to correlate with brachial artery reactivity testing. Endo-PAT use in children has been more limited, but has shown excellent reproducibility. Reactive hyperemia index (RHI), a measure of the hyperemic response adjusted for baseline blood flow, is a measure of vascular function. A higher value denotes better, or more healthy, vascular (endothelial) function. The data represents a change in the index value so there is no minimum or maximum value that can be represented on a scale.
Time frame: Day 1 (baseline) and Day 5 (follow-up)
Absolute Change in Blood Pool Myocardial Performance Index (MPI)
The outcome measures (OM) are a difference between baseline (BL) and follow-up (FU, Day-5). Change in the MPI from baseline to Day 5 is determined by velocities from blood pool Doppler of the inflow and outflow tract of the dominant ventricle. The measure is the ratio of the sum of isovolumetric contraction time and isovolumetric relaxation time, divided by ventricular ejection time. A lower value is consistent with a more efficient ventricle (better function). A value of zero indicates that there is no isovolumetric contraction or relaxation and, while physiologically implausible, would be consistent with a perfectly efficient ventricle. In general, a decrease in the MPI corresponds to more efficient (better) ventricular function, while an increase in MPI corresponds to less efficient (worse) ventricular function. The data represents a change in the index value so there is no minimum or maximum value that can be represented on a scale.
Time frame: Day 1 (baseline) and Day 5 (follow-up)
Evaluate the Pharmacokinetic (PK) Profile of Metabolite DA-8164: Tmax
Evaluate the pharmacokinetic (PK) profile of metabolite DA-8164, by weight, age, and gender in adolescents with Fontan physiology at multiple dosing levels.
Time frame: Day 5, zero to 48 hours after the last dose
Evaluate the Pharmacokinetic (PK) Profile of Metabolite DA-8164: T-1/2
Evaluate the pharmacokinetic (PK) profile of metabolite DA-8164, by weight, age, and gender in adolescents with Fontan physiology at multiple dosing levels.
Time frame: Day 5, zero to 48 hours after the last dose
Evaluate the Pharmacokinetic (PK) Profile of Metabolite DA-8164: AUC(0-tau)
Evaluate the pharmacokinetic (PK) profile of metabolite DA-8164, by weight, age, and gender in adolescents with Fontan physiology at multiple dosing levels.
Time frame: Day 5, zero to 48 hours after the last dose