Pharmacokinetic/Pharmacodynamic Study of Udenafil in Adolescents

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

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.

Study Overview

• Status: Completed
• Conditions: Single Ventricle Heart Disease After Fontan Surgery
• Intervention / Treatment: Drug: Udenafil

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

• Study Type: Interventional
• Enrollment (Actual): 36
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• Canada
  • Ontario
    • Toronto, Ontario, Canada, M5G1X8
      • The Hospital for Sick Children
• United States
  • Indiana
    • Indianapolis, Indiana, United States, 46201
      • Riley Hospital for Children
  • Michigan
    • Ann Arbor, Michigan, United States, 48109-4204
      • University of Michigan Congenital Heart Center
  • Ohio
    • Cincinnati, Ohio, United States, 45229
      • Cincinnati Children's Hospital Medical Center
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • Children's Hospital of Philadelphia
  • Utah
    • Salt Lake City, Utah, United States, 84113
      • Primary Children's Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 10 years to 14 years (Child, Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Males and females with Fontan physiology who are 14-18 years of age.
2. Willingness to return to center to complete blood draws and exercise tests as described in the study protocol.
3. Patients must agree to abstain from alcohol, caffeinated beverages, and grapefruit juice for the duration of the trial.
4. Informed assent from subject informed consent from parent/legal guardian as appropriate.

Exclusion Criteria:

1. Non-cardiac medical, psychiatric, and/or social disorder that would prevent successful completion of planned study testing or would invalidate its results.
2. Height <132 cm (minimum height requirement for exercise stress testing).
3. 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.
4. Single lung physiology.
5. Severe ventricular dysfunction or valvular regurgitation (systemic atrioventricular or semilunar valve) determined from review of the echocardiogram performed in closest proximity to study enrollment.
6. 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.
7. Hospitalization for acute decompensated heart failure within the 12 months preceding study enrollment.
8. A diagnosis of active protein losing enteropathy or plastic bronchitis.
9. Active evaluation or listing for heart transplant.
10. History of use of a phosphodiesterase type 5 inhibitor within three months of study enrollment.
11. Concurrent illness that, in the opinion of the investigator, precludes participation.
12. Current therapy with alpha-blockers or nitrates.
13. Pregnancy at the time of enrollment.
14. Latex allergy

Study Plan

How is the study designed?

Design Details

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

Number of Arms

6

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Udenafil 37.5 mg QD; Udenafil 37.5 mg tablet once daily for 5 days	Drug: Udenafil; Drug
Experimental: Udenafil 37.5 mg BID; Udenafil 37.5 mg tablet twice daily for 5 days	Drug: Udenafil; Drug
Experimental: Udenafil 87.5 mg QD; Udenafil 87.5 mg tablet once daily for 5 days	Drug: Udenafil; Drug
Experimental: Udenafil 87.5 mg BID; Udenafil 87.5 mg tablet twice daily for 5 days	Drug: Udenafil; Drug
Experimental: Udenafil 125 mg QD; Udenafil 125 mg tablet once daily for 5 days	Drug: Udenafil; Drug
No Intervention: No Drug; Cohort undergoing exercise test only

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	5 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	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].	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.	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.	Day 5, zero to 48 hours after the last dose
Evaluate the Pharmacokinetic (PK) Profile of Udenafil: T-1/2	Evaluate the pharmacokinetic (PK) profile of udenafil, by weight, age, and gender in adolescents with Fontan physiology at multiple dosing levels.	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.	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.	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.	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.	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.	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.	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.	Day 5, zero to 48 hours after the last dose

Collaborators and Investigators

• Sponsor: Mezzion Pharma Co. Ltd
• Collaborators: National Heart, Lung, and Blood Institute (NHLBI); Pediatric Heart Network
• Investigators: Principal Investigator: David Goldberg, MD, Children's Hospital of Philadelphia

Study record dates

Study Major Dates

• Study Start: July 1, 2014
• Primary Completion (Actual): April 1, 2015
• Study Completion (Actual): April 1, 2015

Study Registration Dates

• First Submitted: July 24, 2014
• First Submitted That Met QC Criteria: July 24, 2014
• First Posted (Estimated): July 28, 2014

Study Record Updates

• Last Update Posted (Actual): May 6, 2025
• Last Update Submitted That Met QC Criteria: April 18, 2025
• Last Verified: April 1, 2025

More Information

Terms related to this study

• Keywords: Pharmacokinetics; Fontan; Pharmacodynamics; Vascular function; Exercise capacity; Maximal Oxygen Consumption; EndoPAT; Myocardial performance
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Congenital Abnormalities; Cardiovascular Abnormalities; Heart Defects, Congenital; Univentricular Heart; Heart Diseases; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Phosphodiesterase 5 Inhibitors; Phosphodiesterase Inhibitors; Udenafil
• Other Study ID Numbers: PHN-Udenafil-01; U01HL068270 (U.S. NIH Grant/Contract)