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: 12 years to 16 years (Child, Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

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 Dose Level 1 qd; Udenafil tablet dose Level 1 daily for 5 days	Drug: Udenafil; Drug
Experimental: Udenafil Dose Level 1 bid; Udenafil Dose Level 1 twice daily for 5 days.	Drug: Udenafil; Drug
Experimental: Udenafil Dose Level 2 qd; Udenafil tablet dose level 2 once daily for 5 days.	Drug: Udenafil; Drug
Experimental: Udenafil Dose Level 2 bid; Udenafil tablet dose level 2 twice daily for 5 days	Drug: Udenafil; Drug
Experimental: Udenafil Dose Level 3 qd; Udenafil tablet dose level 3 daily for 5 days	Drug: Udenafil; Drug
No Intervention: No Drug; 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

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 (Estimate): July 28, 2014

Study Record Updates

• Last Update Posted (Estimate): April 27, 2015
• Last Update Submitted That Met QC Criteria: April 24, 2015
• Last Verified: April 1, 2015

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; Heart Defects, Congenital; Cardiovascular Abnormalities; Heart Diseases; Univentricular Heart; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Phosphodiesterase Inhibitors; Phosphodiesterase 5 Inhibitors; Udenafil
• Other Study ID Numbers: PHN-Udenafil-01; U01HL068270 (U.S. NIH Grant/Contract)