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

Status

Completed

Phases

Phase 1Phase 2

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT02201342

Enrollment

Registered

2014-07-28

Start date

2014-07-31

Completion date

2015-04-30

Last updated

2025-05-06

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Single Ventricle Heart Disease After Fontan Surgery

Keywords

Fontan, Pharmacokinetics, Pharmacodynamics, Exercise capacity, Maximal Oxygen Consumption, Vascular function, EndoPAT, Myocardial performance

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

Interventions

DRUGUdenafil

Drug

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

NONE

Eligibility

Sex/Gender

ALL

Age

14 Years to 18 Years

Healthy volunteers

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

Design outcomes

Primary

Measure	Time frame	Description
Number of Subjects With Serious Adverse Events Possibly or Probably Related to Udenafil	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

Measure	Time frame	Description
Evaluate the Pharmacokinetic (PK) Profile of Udenafil: AUC (0-tau)	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.
Evaluate the Effect of Udenafil on Pharmacodynamic (PD) Outcomes: Exercise Capacity	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) \[OM = FU-BL\].
Evaluate the Pharmacokinetic (PK) Profile of Metabolite DA-8164: Cmax	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.
Evaluate the Pharmacokinetic (PK) Profile of Udenafil: Tmax	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.
Evaluate the Pharmacokinetic (PK) Profile of Udenafil: T-1/2	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.
Evaluate the Pharmacokinetic (PK) Profile of Udenafil: Cmax	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.
Evaluate the Pharmacokinetic (PK) Profile of Metabolite DA-8164: T-1/2	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.
Evaluate the Effect of Udenafil on Pharmacodynamic (PD) Outcomes: Vascular Function [Change in Natural Log Transformed Reactive Hyperemia Index (RHI)]	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.
Absolute Change in Blood Pool Myocardial Performance Index (MPI)	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.
Evaluate the Pharmacokinetic (PK) Profile of Metabolite DA-8164: Tmax	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.
Evaluate the Pharmacokinetic (PK) Profile of Metabolite DA-8164: AUC(0-tau)	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.
Evaluate the Pharmacokinetic (PK) Profile of Udenafil: CLSS/F	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.

Countries

Canada, United States

Participant flow

Participants by arm

Arm	Count
Udenafil 37.5 mg QD Udenafil 37.5 mg tablet once daily for 5 days Udenafil: Drug	6
Udenafil 37.5 mg BID Udenafil 37.5 mg tablet twice daily for 5 days Udenafil: Drug	6
Udenafil 87.5 mg QD Udenafil 87.5 mg tablet once daily for 5 days Udenafil: Drug	6
Udenafil 87.5 mg BID Udenafil 87.5 mg tablet twice daily for 5 days Udenafil: Drug	6
Udenafil 125 mg QD Udenafil 125 mg tablet once daily for 5 days Udenafil: Drug	6
No Drug Cohort undergoing exercise test only	6
Total	36

Baseline characteristics

Characteristic	Udenafil 37.5 mg QD	Total	No Drug	Udenafil 125 mg QD	Udenafil 87.5 mg BID	Udenafil 87.5 mg QD	Udenafil 37.5 mg BID
Age, Continuous	15.5 years STANDARD_DEVIATION 1	15.8 years STANDARD_DEVIATION 1.3	16.2 years STANDARD_DEVIATION 1.2	16.5 years STANDARD_DEVIATION 1.5	15.5 years STANDARD_DEVIATION 1.8	15.0 years STANDARD_DEVIATION 0.9	16.2 years STANDARD_DEVIATION 0.8
Ethnicity (NIH/OMB) Hispanic or Latino	1 Participants	2 Participants	0 Participants	0 Participants	0 Participants	0 Participants	1 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	5 Participants	34 Participants	6 Participants	6 Participants	6 Participants	6 Participants	5 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Asian	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Black or African American	2 Participants	3 Participants	0 Participants	0 Participants	0 Participants	0 Participants	1 Participants
Race (NIH/OMB) More than one race	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Unknown or Not Reported	1 Participants	5 Participants	1 Participants	2 Participants	0 Participants	0 Participants	1 Participants
Race (NIH/OMB) White	3 Participants	28 Participants	5 Participants	4 Participants	6 Participants	6 Participants	4 Participants
Region of Enrollment Canada	0 Participants	7 Participants	4 Participants	3 Participants	0 Participants	0 Participants	0 Participants
Region of Enrollment United States	6 Participants	29 Participants	2 Participants	3 Participants	6 Participants	6 Participants	6 Participants
Sex: Female, Male Female	2 Participants	15 Participants	2 Participants	2 Participants	3 Participants	3 Participants	3 Participants
Sex: Female, Male Male	4 Participants	21 Participants	4 Participants	4 Participants	3 Participants	3 Participants	3 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk	EG002 affected / at risk	EG003 affected / at risk	EG004 affected / at risk	EG005 affected / at risk
deaths Total, all-cause mortality	0 / 6	0 / 6	0 / 6	0 / 6	0 / 6	0 / 6
other Total, other adverse events	5 / 6	6 / 6	6 / 6	5 / 6	6 / 6	0 / 6
serious Total, serious adverse events	1 / 6	0 / 6	0 / 6	0 / 6	0 / 6	0 / 6

Outcome results

Primary

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

Arm	Measure	Value (NUMBER)
Udenafil 37.5 mg QD	Number of Subjects With Serious Adverse Events Possibly or Probably Related to Udenafil	0 participants
Udenafil 37.5 mg BID	Number of Subjects With Serious Adverse Events Possibly or Probably Related to Udenafil	0 participants
Udenafil 87.5 mg QD	Number of Subjects With Serious Adverse Events Possibly or Probably Related to Udenafil	0 participants
Udenafil 87.5 mg BID	Number of Subjects With Serious Adverse Events Possibly or Probably Related to Udenafil	0 participants
Udenafil 125 mg QD	Number of Subjects With Serious Adverse Events Possibly or Probably Related to Udenafil	0 participants
No Drug	Number of Subjects With Serious Adverse Events Possibly or Probably Related to Udenafil	0 participants

Secondary

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)

Population: n= 4 to 5 for some measures

Arm	Measure	Value (MEAN)	Dispersion
Udenafil 37.5 mg QD	Absolute Change in Blood Pool Myocardial Performance Index (MPI)	-0.052 Change in blood pool MPI	Standard Deviation 0.166
Udenafil 37.5 mg BID	Absolute Change in Blood Pool Myocardial Performance Index (MPI)	-0.003 Change in blood pool MPI	Standard Deviation 0.102
Udenafil 87.5 mg QD	Absolute Change in Blood Pool Myocardial Performance Index (MPI)	-0.076 Change in blood pool MPI	Standard Deviation 0.144
Udenafil 87.5 mg BID	Absolute Change in Blood Pool Myocardial Performance Index (MPI)	-0.118 Change in blood pool MPI	Standard Deviation 0.09
Udenafil 125 mg QD	Absolute Change in Blood Pool Myocardial Performance Index (MPI)	-0.054 Change in blood pool MPI	Standard Deviation 0.18

Secondary

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

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

Population: n= 4 to 5 for some measures

Arm	Measure	Group	Value (MEAN)	Dispersion
Udenafil 37.5 mg QD	Evaluate the Effect of Udenafil on Pharmacodynamic (PD) Outcomes: Exercise Capacity	Max VO2 at max exercise effort	-0.8 ml/kg/min	Standard Deviation 1.7
Udenafil 37.5 mg QD	Evaluate the Effect of Udenafil on Pharmacodynamic (PD) Outcomes: Exercise Capacity	VO2 at anaerobic threshold	-0.5 ml/kg/min	Standard Deviation 4.1
Udenafil 37.5 mg BID	Evaluate the Effect of Udenafil on Pharmacodynamic (PD) Outcomes: Exercise Capacity	Max VO2 at max exercise effort	-1.6 ml/kg/min	Standard Deviation 5.1
Udenafil 37.5 mg BID	Evaluate the Effect of Udenafil on Pharmacodynamic (PD) Outcomes: Exercise Capacity	VO2 at anaerobic threshold	0.1 ml/kg/min	Standard Deviation 1
Udenafil 87.5 mg QD	Evaluate the Effect of Udenafil on Pharmacodynamic (PD) Outcomes: Exercise Capacity	Max VO2 at max exercise effort	-1.4 ml/kg/min	Standard Deviation 2.5
Udenafil 87.5 mg QD	Evaluate the Effect of Udenafil on Pharmacodynamic (PD) Outcomes: Exercise Capacity	VO2 at anaerobic threshold	-1.1 ml/kg/min	Standard Deviation 1.9
Udenafil 87.5 mg BID	Evaluate the Effect of Udenafil on Pharmacodynamic (PD) Outcomes: Exercise Capacity	Max VO2 at max exercise effort	0.2 ml/kg/min	Standard Deviation 5
Udenafil 87.5 mg BID	Evaluate the Effect of Udenafil on Pharmacodynamic (PD) Outcomes: Exercise Capacity	VO2 at anaerobic threshold	-1.7 ml/kg/min	Standard Deviation 2.1
Udenafil 125 mg QD	Evaluate the Effect of Udenafil on Pharmacodynamic (PD) Outcomes: Exercise Capacity	Max VO2 at max exercise effort	0.9 ml/kg/min	Standard Deviation 2.6
Udenafil 125 mg QD	Evaluate the Effect of Udenafil on Pharmacodynamic (PD) Outcomes: Exercise Capacity	VO2 at anaerobic threshold	1.2 ml/kg/min	Standard Deviation 1.9
No Drug	Evaluate the Effect of Udenafil on Pharmacodynamic (PD) Outcomes: Exercise Capacity	Max VO2 at max exercise effort	-0.3 ml/kg/min	Standard Deviation 1.8
No Drug	Evaluate the Effect of Udenafil on Pharmacodynamic (PD) Outcomes: Exercise Capacity	VO2 at anaerobic threshold	0.1 ml/kg/min	Standard Deviation 3.8

Secondary

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)

Population: n= 4 to 5 for some measures

Arm	Measure	Value (MEAN)	Dispersion
Udenafil 37.5 mg QD	Evaluate the Effect of Udenafil on Pharmacodynamic (PD) Outcomes: Vascular Function [Change in Natural Log Transformed Reactive Hyperemia Index (RHI)]	0.3 Change in natural log Transformed RHI	Standard Deviation 0.47
Udenafil 37.5 mg BID	Evaluate the Effect of Udenafil on Pharmacodynamic (PD) Outcomes: Vascular Function [Change in Natural Log Transformed Reactive Hyperemia Index (RHI)]	-0.07 Change in natural log Transformed RHI	Standard Deviation 0.17
Udenafil 87.5 mg QD	Evaluate the Effect of Udenafil on Pharmacodynamic (PD) Outcomes: Vascular Function [Change in Natural Log Transformed Reactive Hyperemia Index (RHI)]	0.07 Change in natural log Transformed RHI	Standard Deviation 0.22
Udenafil 87.5 mg BID	Evaluate the Effect of Udenafil on Pharmacodynamic (PD) Outcomes: Vascular Function [Change in Natural Log Transformed Reactive Hyperemia Index (RHI)]	-0.03 Change in natural log Transformed RHI	Standard Deviation 0.2
Udenafil 125 mg QD	Evaluate the Effect of Udenafil on Pharmacodynamic (PD) Outcomes: Vascular Function [Change in Natural Log Transformed Reactive Hyperemia Index (RHI)]	-0.10 Change in natural log Transformed RHI	Standard Deviation 0.38

Secondary

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.