Results of the FUEL Trial.

BACKGROUND: The Fontan operation creates a total cavopulmonary connection, a circulation in which the importance of pulmonary vascular resistance is magnified. Over time, this circulation leads to deterioration of cardiovascular efficiency associated with a decline in exercise performance. Rigorous clinical trials aimed at improving physiology and guiding pharmacotherapy are lacking. METHODS: The FUEL trial (Fontan Udenafil Exercise Longitudinal) was a phase III clinical trial conducted at 30 centers. Participants were randomly assigned udenafil, 87.5 mg twice daily, or placebo in a 1:1 ratio. The primary outcome was the between-group difference in change in oxygen consumption at peak exercise. Secondary outcomes included between-group differences in changes in submaximal exercise at the ventilatory anaerobic threshold, the myocardial performance index, the natural log of the reactive hyperemia index, and serum brain-type natriuretic peptide. RESULTS: Between 2017 and 2019, 30 clinical sites in North America and the Republic of Korea randomly assigned 400 participants with Fontan physiology. The mean age at randomization was 15.5±2 years; 60% of participants were male, and 81% were white. All 400 participants were included in the primary analysis with imputation of the 26-week end point for 21 participants with missing data (11 randomly assigned to udenafil and 10 to placebo). Among randomly assigned participants, 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 ventilatory anaerobic threshold demonstrated improvements in the udenafil group versus the placebo group in oxygen consumption (+33±185 [3.2%] versus -9±193 [-0.9%] mL/min, P=0.012), ventilatory equivalents of carbon dioxide (-0.8 versus -0.06, P=0.014), and work rate (+3.8 versus +0.34 W, P=0.021). There was no difference in change of myocardial performance index, the natural log of the reactive hyperemia index, or serum brain-type natriuretic peptide level. CONCLUSIONS: In the FUEL trial, 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. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT02741115.

Design and rationale of the Fontan Udenafil Exercise Longitudinal (FUEL) trial.

The Fontan operation creates a circulation characterized by elevated central venous pressure and low cardiac output. Over time, these characteristics result in a predictable and persistent decline in exercise performance that is associated with an increase in morbidity and mortality. A medical therapy that targets the abnormalities of the Fontan circulation might, therefore, be associated with improved outcomes. Udenafil, a phosphodiesterase type 5 inhibitor, has undergone phase I/II testing in adolescents who have had the Fontan operation and has been shown to be safe and well tolerated in the short term. However, there are no data regarding the long-term efficacy of udenafil in this population. The Fontan Udenafil Exercise Longitudinal (FUEL) Trial is a randomized, double-blind, placebo-controlled phase III clinical trial being conducted by the Pediatric Heart Network in collaboration with Mezzion Pharma Co, Ltd. This trial is designed to test the hypothesis that treatment with udenafil will lead to an improvement in exercise capacity in adolescents who have undergone the Fontan operation. A safety extension trial, the FUEL Open-Label Extension Trial (FUEL OLE), offers the opportunity for all FUEL subjects to obtain open-label udenafil for an additional 12 months following completion of FUEL, and evaluates the long-term safety and tolerability of this medication. This manuscript describes the rationale and study design for FUEL and FUEL OLE. Together, these trials provide an opportunity to better understand the role of medical management in the care of those who have undergone the Fontan operation.

Results of a phase I/II multi-center investigation of udenafil in adolescents after fontan palliation.

BACKGROUND: The Fontan operation results in a circulation that is dependent on low pulmonary vascular resistance to maintain an adequate cardiac output. Medical therapies that lower pulmonary vascular resistance may augment cardiac output and improve long-term outcomes. OBJECTIVES: This phase I/II clinical trial conducted by the Pediatric Heart Network was designed to evaluate short-term safety, pharmacokinetics (PK), and preliminary efficacy of udenafil in adolescents following Fontan. METHODS: A 5-day dose-escalation trial was conducted in five study cohorts of six subjects each (37.5, 87.5, and 125 mg daily, 37.5 and 87.5 mg by mouth twice daily). A control cohort with 6 subjects underwent exercise testing only. Adverse events (AEs) were recorded, PK samples were collected on study days six through eight, and clinical testing was performed at baseline and day five. RESULTS: The trial enrolled 36 subjects; mean age 15.8 years (58% male). There were no significant differences in subject characteristics between cohorts. No drug-related serious AEs were reported during the study period; 24 subjects had AEs possibly or probably related to study drug. Headache was the most common AE, occurring in 20 of 30 subjects. The 87.5 mg bid cohort was well tolerated, achieved the highest maximal concentration (506 ng/mL) and the highest average concentration over the dosing interval (279 ng/mL), and was associated with a suggestion of improvement in myocardial performance. Exercise performance did not improve in any of the dosing cohorts. CONCLUSIONS: Udenafil was well-tolerated at all dosing levels. The 87.5 mg bid cohort achieved the highest plasma drug level and was associated with a suggestion of improvement in myocardial performance. These data suggest that the 87.5 mg bid regimen may be the most appropriate for a Phase III clinical trial.

An integrated analysis of alprostadil topical cream for the treatment of erectile dysfunction in 1732 patients.

OBJECTIVE: To assess the safety and efficacy of topical alprostadil cream for erectile dysfunction (ED). METHODS: Patients with an ED score of 25 or less on the erectile function domain of the International Index of Erectile Function (IIEF) were randomly assigned to placebo or topical alprostadil cream (100, 200, or 300 microg) for at-home use for 12 weeks in two multicenter, double-blind, parallel-group studies. Patients receiving organic nitrates and patients with diabetes were included. Primary end points included the change in score for the erectile function domain of the IIEF and the change from baseline for the Sexual Encounter Profile (SEP) questions 2 (vaginal penetration success) and 3 (maintenance of erection to ejaculation). Safety was based on observed and reported adverse events and clinical laboratory results. Data from each study were pooled into a single integrated analysis. RESULTS: A total of 1732 patients received placebo (n = 434) or topical alprostadil cream at 100 microg (n = 434), 200 microg (n = 430), or 300 microg (n = 434). The mean changes from baseline to end point in IIEF erectile function (EF) domain scores were -0.7, 1.6, 2.5, and 2.4 points for each group, respectively (P <0.001). Scores on SEP questions 2 and 3 improved slightly but significantly for all drug treatment groups compared with placebo (P <0.001). Most adverse events were localized to the application site and resolved within 2 hours. CONCLUSIONS: Topical alprostadil cream significantly improves ED in a broad range of patients. Most adverse events were limited to the application site and were generally well tolerated.