Fontan Udenafil Exercise Longitudinal Trial
FUEL Open-Label Extension Study
Fontan-Associated Liver Disease Study
FUEL Perceptions Study
The Fontan operation has been a wonderful success for children born with congenital heart disease, yet it is not a cure. Over time it becomes harder for children and young adults who have had a Fontan operation to exercise. Currently, there are no approved medications that have proven helpful in preventing this decline. In the FUEL study, we investigated whether taking a medication called udenafil for 6 months helps improve heart function in children who had a Fontan operation. The drug works by making it easier for blood to flow through the lungs and back to the heart. Adolescents were randomized to take udenafil vs. placebo.
After taking the medication for 6 months, participants were invited to join the FUEL OLE study and take udenafil (no placebo) for up to 4 additional years.
In FALD, we studied how the liver is affected by taking udenafil. Every person who has had a Fontan operation develops scarring in their liver over time. This scarring can eventually result in liver cirrhosis or liver failure. We believe that congestion of the blood vessels in the liver is part of the cause of this scarring. Udenafil may decrease the congestion in the blood vessels and slow progression of the liver disease.
In FUEL PERCEPTIONS, participants and their families were invited to complete a questionnaire about their experiences being in the FUEL studies.
Between 2017 and 2019, 30 clinical sites in North America and the Republic of Korea randomized 400 participants aged 12-18 years with Fontan physiology.
Treatment with udenafil was not associated with an improvement in oxygen consumption at peak exercise but was associated with improvements in multiple measures of exercise performance at the ventilatory anaerobic threshold.
Perceptions of these research studies were positive for both teens and parents, slightly better for parents. Both reported they would consider future research. Study teams are a key contributor to positive perception.
Male or females ages 12 to 18 who had Fontan surgery.
In the FUEL study, participants were randomly given either udenafil or placebo pills that they took twice a day, every day for six months. We obtained blood, physical measurements, measurements of blood vessel function (EndoPAT), echocardiograms and ECGs, and exercise function tests at the beginning and end of the study.
In the FUEL OLE study, participants took udenafil pills twice a day, every day, for up to 4 additional years. We obtained blood, physical measurements, measurements of vascular function (EndoPAT), echocardiograms and ECGs, and exercise function tests after one year and continued safety assessments throughout.
In the FALD study, participants in FUEL OLE were asked to have an ultrasound and an MRI.
In FUEL Perceptions, participants in the FUEL and FUEL OLE studies and their parents were invited to complete a single questionnaire about their experiences in the studies.
Peak oxygen consumption increased by 44 ±245 mL/min (2.8%) in the udenafil group and declined by 3.7 ±228 mL/min (−0.2%) in the placebo group (p=0.071). Analysis at VAT demonstrated improvements in the udenafil group versus the placebo group in oxygen consumption (+33 ±185 (3.2%) vs −9 ±193 (−0.9%) mL/min, p=0.012), ventilatory equivalents of carbon dioxide (−0.8 vs −0.06, p=0.014), and work rate (+3.8 vs +0.34 Watts, p=0.021). There was no difference in change of MPI, lnRHI, or serum BNP level. In conclusion, treatment with udenafil (87.5 mg twice daily) was not associated with an improvement in oxygen consumption at peak exercise but was associated with improvements in multiple measures of exercise performance at the ventilatory anaerobic threshold.
Both participants and parents had high perceptions of study participation, with slightly higher perceptions for parents. Participants most liked helping others, the compensation, and the study team, and liked least the study tests and study burden. Parents most liked helping others, helping their child’s health, and the study team, and liked least the study burden. The majority of participants and parents (~90%) reported that they would consider being in a future research study.
D.J. Goldberg, Am Heart J. 2018 Jul; 201:1-8.
This manuscript describes the design of the Fontan Udenafil Exercise Longitudinal (FUEL) trial. It is a trial comparing udenafil to placebo in children and adolescents with single ventricle heart disease who have undergone the Fontan operation. This study will examine changes in exercise capacity, heart performance, and vascular function. These outcomes are important in understanding whether udenafil may be a beneficial medication to maintain health for a longer period in this population.
D.J. Goldberg, Circulation. 2020 Feb 25;141(8):641-651.
M. V. DiMara, Circulation. 2022 Nov 15;15(11):e013676.
The FUEL Echo study was an analysis of the echocardiograms (ultrasounds of the heart) that were performed as part of the FUEL trial. Before this study, it was not known how udenafil affected heart function in patients with a history of Fontan surgery. Overall, patients who received udenafil had improvement in some of the measurements of heart function and also heart filling. Because of the unique way that the Fontan operation works and the limits of what can be understood by ultrasound, more information will be needed to determine exactly how udenafil improves these measurements.