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Completed

NCT Number: NCT02201342

Pharmacokinetic/Pharmacodynamic Study of Udenafil in Adolescents

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.

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Key information

Conditions

Single Ventricle Heart Disease After Fontan Surgery

Age range

14 year–18 year

Sex eligibility

All sexes

Study type

Interventional

Phase

Phase 1 / Phase 2

Primary location

The Hospital for Sick Children, Toronto, Ontario, Canada

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About this study

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

Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

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

Treatment and study plan

Udenafil

Drug

Drug

Primary outcomes

  1. Number of Subjects With Serious Adverse Events Possibly or Probably Related to Udenafil

    Time frame: 5 days

    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.

Secondary outcomes

  1. Evaluate the Pharmacokinetic (PK) Profile of Udenafil: Cmax

    Time frame: Day 5, zero to 48 hours after the last dose

    Evaluate the pharmacokinetic (PK) profile of udenafil, by weight, age, and gender in adolescents with Fontan physiology at multiple dosing levels.

  2. Evaluate the Effect of Udenafil on Pharmacodynamic (PD) Outcomes: Exercise Capacity

    Time frame: Day 1 (baseline) and Day 5 (follow-up)

    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].

  3. Evaluate the Pharmacokinetic (PK) Profile of Metabolite DA-8164: Cmax

    Time frame: Day 5, zero to 48 hours after the last dose

    Evaluate the pharmacokinetic (PK) profile of metabolite DA-8164, by weight, age, and gender in adolescents with Fontan physiology at multiple dosing levels.

  4. Evaluate the Pharmacokinetic (PK) Profile of Udenafil: Tmax

    Time frame: Day 5, zero to 48 hours after the last dose

    Evaluate the pharmacokinetic (PK) profile of udenafil, by weight, age, and gender in adolescents with Fontan physiology at multiple dosing levels.

  5. Evaluate the Pharmacokinetic (PK) Profile of Udenafil: T-1/2

    Time frame: Day 5, zero to 48 hours after the last dose

    Evaluate the pharmacokinetic (PK) profile of udenafil, by weight, age, and gender in adolescents with Fontan physiology at multiple dosing levels.

  6. Evaluate the Pharmacokinetic (PK) Profile of Udenafil: AUC (0-tau)

    Time frame: Day 5, zero to 48 hours after the last dose

    Evaluate the pharmacokinetic (PK) profile of udenafil, by weight, age, and gender in adolescents with Fontan physiology at multiple dosing levels.

  7. Evaluate the Pharmacokinetic (PK) Profile of Udenafil: CLSS/F

    Time frame: Day 5, zero to 48 hours after the last dose

    Evaluate the pharmacokinetic (PK) profile of udenafil, by weight, age, and gender in adolescents with Fontan physiology at multiple dosing levels.

  8. Evaluate the Effect of Udenafil on Pharmacodynamic (PD) Outcomes: Vascular Function [Change in Natural Log Transformed Reactive Hyperemia Index (RHI)]

    Time frame: Day 1 (baseline) and Day 5 (follow-up)

    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.

  9. Absolute Change in Blood Pool Myocardial Performance Index (MPI)

    Time frame: Day 1 (baseline) and Day 5 (follow-up)

    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.

  10. Evaluate the Pharmacokinetic (PK) Profile of Metabolite DA-8164: Tmax

    Time frame: Day 5, zero to 48 hours after the last dose

    Evaluate the pharmacokinetic (PK) profile of metabolite DA-8164, by weight, age, and gender in adolescents with Fontan physiology at multiple dosing levels.

  11. Evaluate the Pharmacokinetic (PK) Profile of Metabolite DA-8164: T-1/2

    Time frame: Day 5, zero to 48 hours after the last dose

    Evaluate the pharmacokinetic (PK) profile of metabolite DA-8164, by weight, age, and gender in adolescents with Fontan physiology at multiple dosing levels.

  12. Evaluate the Pharmacokinetic (PK) Profile of Metabolite DA-8164: AUC(0-tau)

    Time frame: Day 5, zero to 48 hours after the last dose

    Evaluate the pharmacokinetic (PK) profile of metabolite DA-8164, by weight, age, and gender in adolescents with Fontan physiology at multiple dosing levels.

Sponsors and collaborators

Lead sponsor

Mezzion Pharma Co. Ltd

Industry

Collaborators

  • National Heart, Lung, and Blood Institute (NHLBI)
  • Pediatric Heart Network

Registry information

Official study title

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

Important dates

Study start
2014
Primary completion
2015
Study completion
2015
First posted
Jul 28, 2014
Registry last updated
May 6, 2025

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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