Fontan Udenafil Exercise Longitudinal Assessment Trial
- Registration Number
- NCT02741115
- Lead Sponsor
- Mezzion Pharma Co. Ltd
- Brief Summary
This study will evaluate the clinical efficacy and safety of udenafil, an orally administered, potent and selective inhibitor of PDE5, versus placebo for the treatment of adolescent subjects who have undergone the Fontan procedure.
- Detailed Description
This study is a randomized, double-blinded, efficacy trial of the effects of udenafil vs. placebo on the background of standard therapy on maximal VO2 (ml/kg/min) from baseline to six months in adolescent survivors of the Fontan procedure. . The target sample size is 400 subjects (200 per group).
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 400
- Males and females with Fontan physiology who are 12 to less than 19 years of age at enrollment.
- Participant consent or parental/guardian consent and participant assent
- Participant fluency in primary language of country in which study is being conducted
- Weight < 40 kg
- Height < 132 cm.
- Hospitalization for acute decompensated heart failure within the last 12 months.
- Current intravenous inotropic drugs.
- Undergoing evaluation for heart transplantation or listed for transplantation.
- Diagnosis of active protein losing enteropathy or plastic bronchitis within the last 3 years, or a history of liver cirrhosis.
- 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 as measured by either catheterization or echocardiography, obtained prior to screening for the trial.
- Single lung physiology with greater than 80% flow to one lung.
- VO2 less than 50%
- Severe ventricular dysfunction assessed qualitatively by clinical echocardiography within six months prior to enrollment.
- Severe valvar regurgitation, ventricular outflow obstruction, or aortic arch obstruction assessed by clinical echocardiography within six months prior to enrollment.
- Significant renal (serum creatinine > 2.0), hepatic (serum AST and/or 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 six weeks prior to screening for the trial.
- Inability to complete exercise testing at baseline screening.
- History of PDE-5 inhibitor use within 3 months before study onset.
- History of any other medication for treatment of pulmonary hypertension within 3 months before study onset.
- Known intolerance to oral udenafil.
- Frequent use of medications or other substances that inhibit or induce CYP3A4.
- Current use of alpha-blockers or nitrates.
- Ongoing or planned participation in another research protocol that would either prevent successful completion of planned study testing or invalidate its results.
- Noncardiac medical, psychiatric, and/or social disorder that would prevent successful completion of planned study testing or would invalidate its results.
- Cardiac care, ongoing or planned, at a non-study center that would impede study completion.
- For females: Pregnancy at the time of screening, pregnancy planned before study completion, or refusal to use an acceptable method of contraception for study duration if sexually active.
- Unable to abstain or limit intake of grapefruit juice during the duration of the trial.
- Refusal to provide written informed consent/assent.
- In the opinion of the primary care physician, the subject is likely to be non-compliant with the study protocol.
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Placebo Placebo Placebo. One tablet twice daily for 26 weeks Drug Udenafil Udenafil. One tablet twice daily for 26 weeks
- Primary Outcome Measures
Name Time Method Change in Maximal VO2 From Baseline to Week 26 Using Last Observation Carried Forward (LOCF) Baseline to 26 Weeks The change in exercise capacity (as measured by peak VO2 at maximum exercise effort) from baseline to 26 weeks
- Secondary Outcome Measures
Name Time Method Change in Myocardial Performance Index (MPI) From Baseline to Week 26 Week 26 Change in the myocardial performance index (MPI) from baseline to 26 weeks 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. The mean left ventricular MPI in healthy people without heart disease is approximately 0.35 while the mean right ventricular MPI is approximately 0.1 due to the reduced ventricular afterload of the pulmonary circulation. 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.
Change in Log-transformed Reactive Hyperemia Index (InRH) From Baseline to Week 26 Week 26 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, 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.
Change in Serum Brain-type Natriuretic Peptide (BNP) From Baseline to Week 26. Week 26 BNP is a hormone produced when the heart is enlarged or has to work harder to pump blood to the body. Higher levels of BNP can be a sign of heart failure.
Change in VO2 at VAT 26 Weeks This outcome measures the change in milliliters of oxygen consumption (VO2) per minute at the ventilatory anaerobic threshold (VAT) between Week 26 and Baseline Visits using last observation carried forward (ITT Population). The anaerobic threshold is the period in exercise when metabolism switches from aerobic to anaerobic. This is an useful measure of submaximal exercise capacity particularly in the single ventricle population.
Change in Work Rate at VAT From Baseline to Week 26 With LOCF 26 Weeks This outcome measures the change in work (measured in Watts) at the ventilatory anaerobic threshold (VAT) between Week 26 and Baseline Visits using last observation carried forward (ITT Population). The anaerobic threshold is the period in exercise when metabolism switches from aerobic to anaerobic. This is an useful measure of submaximal exercise capacity particularly in the single ventricle population.
Change in VE/VCO2 at VAT From Baseline to Week 26 26 Weeks This measure is a ratio of the amount of inspired air required to clear a given volume of CO2 from the circulation at the ventilatory anaerobic threshold (VAT). This measurement is made during exercise stress testing. Decreases in this ratio may reflect an improvement in ventilatory efficiency or an improvement in cardiac function.
Change in Respiratory Rate at Maximal Exercise Effort From Baseline to Week 26 Using LOCF Week 26 Change in Minute Oxygen Consumption at Maximal Exercise Effort From Baseline to Week 26 Week 26 The amount of air that enters the lungs per minute at maximal exercise effort.
Change in Work Rate at Maximal Exercise Effort Between Baseline and Week 26 Using LOCF Week 26 Change in power at maximal exercise effort.
Change in Pediatric Quality of Life (PedsQL) Generic Core Scales - Physical Functioning Subscale (Child Reported) 26 weeks The PedsQL is a short questionnaire that has been used in multiple studies, including a previous study of Fontan patients. A 5-point Likert response scale (0-4) is used. This score was linearly transformed on a scale of 0-100 (0 = 100, 1 = 75, 2 = 50, 3 = 25, 4 = 0). For an individual, a higher score is associated with a higher reported healthcare-related quality of life. For each population (treatment and placebo), population means were calculated at baseline and 26 weeks. The outcome measure is the difference between week 26 and baseline (week 26 - baseline).
Change in Pediatric Quality of Life (PedsQL) Generic Core Scales - Physical Functioning Subscale (Parent Reported) 26 weeks The PedsQL is a short questionnaire that has been used in multiple studies, including a previous study of Fontan patients. A 5-point Likert response scale (0-4) is used. This score was linearly transformed on a scale of 0-100 (0 = 100, 1 = 75, 2 = 50, 3 = 25, 4 = 0). For an individual, a higher score is associated with a higher reported healthcare-related quality of life. For each population (treatment and placebo), population means were calculated at baseline and 26 weeks. The outcome measure is the difference between week 26 and baseline (week 26 - baseline).
Change in Pediatric Quality of Life (PedsQL) Generic Core Scales - Psychosocial Health Subscale (Child Reported) 26 weeks The PedsQL is a short questionnaire that has been used in multiple studies, including a previous study of Fontan patients. A 5-point Likert response scale (0-4) is used. This score was linearly transformed on a scale of 0-100 (0 = 100, 1 = 75, 2 = 50, 3 = 25, 4 = 0). For an individual, a higher score is associated with a higher reported healthcare-related quality of life. For each population (treatment and placebo), population means were calculated at baseline and 26 weeks. The outcome measure is the difference between week 26 and baseline (week 26 - baseline).
Change in Pediatric Quality of Life (PedsQL) Generic Core Scales - Psychosocial Health Subscale (Parent Reported) 26 weeks The PedsQL is a short questionnaire that has been used in multiple studies, including a previous study of Fontan patients. A 5-point Likert response scale (0-4) is used. This score was linearly transformed on a scale of 0-100 (0 = 100, 1 = 75, 2 = 50, 3 = 25, 4 = 0). For an individual, a higher score is associated with a higher reported healthcare-related quality of life. For each population (treatment and placebo), population means were calculated at baseline and 26 weeks. The outcome measure is the difference between week 26 and baseline (week 26 - baseline).
Change in Pediatric Quality of Life (PedsQL) Inventory - Cardiac Module Scale - Treatment II Subscale (Child-reported) 26 weeks The PedsQL is a short questionnaire that has been used in multiple studies, including a previous study of Fontan patients. A 5-point Likert response scale (0-4) is used. This score was linearly transformed on a scale of 0-100 (0 = 100, 1 = 75, 2 = 50, 3 = 25, 4 = 0). For an individual, a higher score is associated with a higher reported healthcare-related quality of life. For each population (treatment and placebo), population means were calculated at baseline and 26 weeks. The outcome measure is the difference between week 26 and baseline (week 26 - baseline).
Change in Pediatric Quality of Life (PedsQL) Inventory - Cardiac Module Scale - Perceived Physical Appearance Subscale 26 weeks The PedsQL is a short questionnaire that has been used in multiple studies, including a previous study of Fontan patients. A 5-point Likert response scale (0-4) is used. This score was linearly transformed on a scale of 0-100 (0 = 100, 1 = 75, 2 = 50, 3 = 25, 4 = 0). For an individual, a higher score is associated with a higher reported healthcare-related quality of life. For each population (treatment and placebo), population means were calculated at baseline and 26 weeks. The outcome measure is the difference between week 26 and baseline (week 26 - baseline).
Change in Pediatric Quality of Life (PedsQL) Inventory - Cardiac Module Scale - Treatment Anxiety Subscale 26 weeks The PedsQL is a short questionnaire that has been used in multiple studies, including a previous study of Fontan patients. A 5-point Likert response scale (0-4) is used. This score was linearly transformed on a scale of 0-100 (0 = 100, 1 = 75, 2 = 50, 3 = 25, 4 = 0). For an individual, a higher score is associated with a higher reported healthcare-related quality of life. For each population (treatment and placebo), population means were calculated at baseline and 26 weeks. The outcome measure is the difference between week 26 and baseline (week 26 - baseline).
Change in Pediatric Quality of Life (PedsQL) Inventory - Cardiac Module Scale - Cognitive Problems Subscale 26 weeks The PedsQL is a short questionnaire that has been used in multiple studies, including a previous study of Fontan patients. A 5-point Likert response scale (0-4) is used. This score was linearly transformed on a scale of 0-100 (0 = 100, 1 = 75, 2 = 50, 3 = 25, 4 = 0). For an individual, a higher score is associated with a higher reported healthcare-related quality of life. For each population (treatment and placebo), population means were calculated at baseline and 26 weeks. The outcome measure is the difference between week 26 and baseline (week 26 - baseline).
Change in Pediatric Quality of Life (PedsQL) Inventory - Cardiac Module Scale - Communication Problems Subscale 26 weeks The PedsQL is a short questionnaire that has been used in multiple studies, including a previous study of Fontan patients. A 5-point Likert response scale (0-4) is used. This score was linearly transformed on a scale of 0-100 (0 = 100, 1 = 75, 2 = 50, 3 = 25, 4 = 0). For an individual, a higher score is associated with a higher reported healthcare-related quality of life. For each population (treatment and placebo), population means were calculated at baseline and 26 week. The outcome measure is the difference between week 26 and baseline (week 26 - baseline).
Change in Pediatric Cardiac Quality of Life Inventory (PCQLI) Total Score-Ages 8 to 12 (Child Reported) 26 weeks The PCLQI is a disease-specific measure of health-related quality of life for children and adolescents with congenital or acquired heart disease. The PCQLI score is calculated by adding together the scores from the two subscales: Disease Impact and Psychosocial Impact. Each subscale can score a maximum of 50 points, resulting in a total score with a maximum of 100. Higher scores indicate better perceived health-related quality of life. For each population (treatment and placebo), population means were calculated at baseline and 26 weeks. The outcome measure is the difference between week 26 and baseline (week 26 - baseline).
Change in Pediatric Cardiac Quality of Life Inventory (PCQLI) Total Score-Ages 8 to 12 (Parent Reported) 26 weeks The PCLQI is a disease-specific measure of health-related quality of life for children and adolescents with congenital or acquired heart disease. The PCQLI score is calculated by adding together the scores from the two subscales: Disease Impact and Psychosocial Impact. Each subscale can score a maximum of 50 points, resulting in a total score with a maximum of 100. Higher scores indicate better perceived health-related quality of life. For each population (treatment and placebo), population means were calculated at baseline and 26 weeks. The outcome measure is the difference between week 26 and baseline (week 26 - baseline).
Change in Pediatric Cardiac Quality of Life Inventory (PCQLI) Total Score-Ages 13 to 18 (Child Reported) 26 weeks The PCLQI is a disease-specific measure of health-related quality of life for children and adolescents with congenital or acquired heart disease. The PCQLI score is calculated by adding together the scores from the two subscales: Disease Impact and Psychosocial Impact. Each subscale can score a maximum of 50 points, resulting in a total score with a maximum of 100. Higher scores indicate better perceived health-related quality of life. For each population (treatment and placebo), population means were calculated at baseline and 26 weeks. The outcome measure is the difference between week 26 and baseline (week 26 - baseline).
Change in Pediatric Cardiac Quality of Life Inventory (PCQLI) Total Score-Ages 13 to 18 (Parent Reported) 26 weeks The PCLQI is a disease-specific measure of health-related quality of life for children and adolescents with congenital or acquired heart disease. The PCQLI score is calculated by adding together the scores from the two subscales: Disease Impact and Psychosocial Impact. Each subscale can score a maximum of 50 points, resulting in a total score with a maximum of 100. Higher scores indicate better perceived health-related quality of life. For each population (treatment and placebo), population means were calculated at baseline and 26 weeks. The outcome measure is the difference between week 26 and baseline (week 26 - baseline).
Trial Locations
- Locations (30)
Phoenix Children's Hospital/Children's Heart Center at Phoenix Children's Hospital
🇺🇸Phoenix, Arizona, United States
Johns Hopkins All Children's Heart Institute
🇺🇸Saint Petersburg, Florida, United States
Nemours Cardiac Center/Alfred I. duPont Hospital for Children
🇺🇸Wilmington, Delaware, United States
Texas Children's Hospital
🇺🇸Houston, Texas, United States
Rady Children's Hospital
🇺🇸San Diego, California, United States
Boston Children's Hospital
🇺🇸Boston, Massachusetts, United States
Cincinnati Children's Hospital Medical Center
🇺🇸Cincinnati, Ohio, United States
Seattle Children's Hosptial
🇺🇸Seattle, Washington, United States
Cedars/Sinai Heart Institute
🇺🇸Los Angeles, California, United States
Children's National Medical Center
🇺🇸Washington, District of Columbia, United States
Riley Hospital for Children/Herman B. Wells Center for Pediatric Research
🇺🇸Indianapolis, Indiana, United States
University of Michigan Congenital Heart Center/C.S. Mott Children's Hospital
🇺🇸Ann Arbor, Michigan, United States
Children's Hospital Los Angeles
🇺🇸Los Angeles, California, United States
Children's Healthcare of Atlanta
🇺🇸Atlanta, Georgia, United States
Children's Hospital Colorado
🇺🇸Aurora, Colorado, United States
Children's Hospital of New York
🇺🇸New York, New York, United States
Washington University St. Louis/St.Louis Children's Hospital
🇺🇸Saint Louis, Missouri, United States
Nationwide Children's Hosptial
🇺🇸Columbus, Ohio, United States
Sejong General Hospital
🇰🇷Bucheon-si, Gyeonggi-do, Korea, Republic of
University of Nebraska Children's Hospital and Medical Center
🇺🇸Omaha, Nebraska, United States
Children's Hospital of Philadelphia
🇺🇸Philadelphia, Pennsylvania, United States
Children's Mercy Hospital Kansas City
🇺🇸Kansas City, Missouri, United States
Medical University of South Carolina
🇺🇸Charleston, South Carolina, United States
Vanderbilt University Medical Center
🇺🇸Nashville, Tennessee, United States
The Hospital for Sick Children
🇨🇦Toronto, Ontario, Canada
Children's Hospital of Wisconsin
🇺🇸Milwaukee, Wisconsin, United States
Duke University Medical Center
🇺🇸Durham, North Carolina, United States
Stollery Children's Hospital - University of Alberta
🇨🇦Edmonton, Alberta, Canada
Seoul National University Children's Hospital
🇰🇷Seoul, Korea, Republic of
Primary Children's Medical Hospital/Dept. of Pediatric Cardiology
🇺🇸Salt Lake City, Utah, United States