Clinical trial NCT02201342: Pharmacokinetic/Pharmacodynamic Study of Udenafil in Adolescents
Official title: A Phase I/II Dose Escalation Trial of Udenafil in Adolescents With Single Ventricle Physiology After Fontan Palliation
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Single Ventricle Heart Disease After Fontan Surgery
Keywords: Fontan
Pharmacokinetics
Pharmacodynamics
Exercise capacity
Maximal Oxygen Consumption
Vascular function
EndoPAT
Myocardial performance
Lead sponsor: Mezzion Pharma Co. Ltd
Sponsor class: INDUSTRY
Collaborators: name: National Heart, Lung, and Blood Institute (NHLBI)
name: Pediatric Heart Network
First posted: 2014-07-28
Enrollment: 36
Sex: ALL
Minimum age (years): 14
Maximum age (years): 18
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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

Eligibility criteria: 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

Primary outcomes:
measure: Number of Subjects With Serious Adverse Events Possibly or Probably Related to Udenafil
timeFrame: 5 days
Secondary outcomes:
measure: Evaluate the Pharmacokinetic (PK) Profile of Udenafil: Cmax
timeFrame: Day 5, zero to 48 hours after the last dose
measure: Evaluate the Effect of Udenafil on Pharmacodynamic (PD) Outcomes: Exercise Capacity
timeFrame: Day 1 (baseline) and Day 5 (follow-up)
measure: Evaluate the Pharmacokinetic (PK) Profile of Metabolite DA-8164: Cmax
timeFrame: Day 5, zero to 48 hours after the last dose
measure: Evaluate the Pharmacokinetic (PK) Profile of Udenafil: Tmax
timeFrame: Day 5, zero to 48 hours after the last dose
measure: Evaluate the Pharmacokinetic (PK) Profile of Udenafil: T-1/2
timeFrame: Day 5, zero to 48 hours after the last dose
measure: Evaluate the Pharmacokinetic (PK) Profile of Udenafil: AUC (0-tau)
timeFrame: Day 5, zero to 48 hours after the last dose
measure: Evaluate the Pharmacokinetic (PK) Profile of Udenafil: CLSS/F
timeFrame: Day 5, zero to 48 hours after the last dose
measure: Evaluate the Effect of Udenafil on Pharmacodynamic (PD) Outcomes: Vascular Function [Change in Natural Log Transformed Reactive Hyperemia Index (RHI)]
timeFrame: Day 1 (baseline) and Day 5 (follow-up)
measure: Absolute Change in Blood Pool Myocardial Performance Index (MPI)
timeFrame: Day 1 (baseline) and Day 5 (follow-up)
measure: Evaluate the Pharmacokinetic (PK) Profile of Metabolite DA-8164: Tmax
timeFrame: Day 5, zero to 48 hours after the last dose
measure: Evaluate the Pharmacokinetic (PK) Profile of Metabolite DA-8164: T-1/2
timeFrame: Day 5, zero to 48 hours after the last dose
measure: Evaluate the Pharmacokinetic (PK) Profile of Metabolite DA-8164: AUC(0-tau)
timeFrame: Day 5, zero to 48 hours after the last dose
Other outcomes:
Locations:
city: Indianapolis
country: United States
facility: Riley Hospital for Children
state: Indiana
city: Ann Arbor
country: United States
facility: University of Michigan Congenital Heart Center
state: Michigan
city: Cincinnati
country: United States
facility: Cincinnati Children's Hospital Medical Center
state: Ohio
city: Philadelphia
country: United States
facility: Children's Hospital of Philadelphia
state: Pennsylvania
city: Salt Lake City
country: United States
facility: Primary Children's Medical Center
state: Utah
city: Toronto
country: Canada
facility: The Hospital for Sick Children
state: Ontario
Study officials:
affiliation: Children's Hospital of Philadelphia
name: David Goldberg, MD
role: PRINCIPAL_INVESTIGATOR
References: