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

ABSTRACT: 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.

SUBMITTER: Goldberg DJ

PROVIDER: S-EPMC6010060 | biostudies-literature | 2018 Jul

REPOSITORIES: biostudies-literature

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

Goldberg David J DJ Zak Victor V Goldstein Bryan H BH McCrindle Brian W BW Menon Shaji C SC Schumacher Kurt R KR Payne R Mark RM Rhodes Jonathan J McHugh Kimberly E KE Penny Daniel J DJ Trachtenberg Felicia F Hamstra Michelle S MS Richmond Marc E ME Frommelt Peter C PC Files Matthew D MD Yeager James L JL Pemberton Victoria L VL Stylianou Mario P MP Pearson Gail D GD Paridon Stephen M SM

American heart journal 20180403

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 ...[more]

PMID: 29910047

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Project description:INTRODUCTION:Lung cancer is a significant burden on societies worldwide, and the most common cause of death in patients with cancer overall. Exercise intervention studies in patients with lung cancer have consistently shown benefits with respect to physical and emotional functioning. However, to date, exercise training has not been consistently implemented into clinical practice given that interventions have been costly and not aligned with clinical care. METHODS/DESIGN:The Precision-Exercise-Prescription (PEP) study is a prospective randomised controlled trial comparing the effectiveness and feasibility of a personalised intervention exercise programme among patients with lung cancer undergoing surgery. Two-hundred patients who are diagnosed with stage primary or secondary lung cancer and are eligible to undergo surgical treatment at Huntsman Cancer Institute comprise the target population. Patients are randomised to either the (1) outpatient precision-exercise intervention group or (2) delayed intervention group. The intervention approach uses Motivation and Problem Solving, a hybrid behavioural treatment based on motivational interviewing and practical problem solving. The dosage of the exercise intervention is personalised based on the individual's Activity Measure for Post-Acute-Care outpatient basic mobility score, and incorporates four exercise modes: mobility, callisthenics, aerobic and resistance. Exercise is implemented by physical therapists at study visits from presurgery until 6 months postsurgery. The primary endpoint is the level of physical function assessed by 6?min walk distance at 2 months postsurgery. Secondary outcomes include patient-reported outcomes (eg, quality of life, fatigue and self-efficacy) and other clinical outcomes, including length of stay, complications, readmission, pulmonary function and treatment-related costs up to 6 months postsurgery. ETHICS/DISSEMINATION:The PEP study will test the clinical effectiveness and feasibility of a personalised exercise intervention in patients with lung cancer undergoing surgery. Outcomes of this clinical trial will be presented at national and international conferences and symposia and will be published in international, peer-reviewed journals. Ethics approval was obtained at the University of Utah (IRB 00104671). TRIAL REGISTRATION NUMBER:NCT03306992.

Project description:BackgroundThe FUEL trial (Fontan Udenafil Exercise Longitudinal) demonstrated statistical improvements in exercise capacity following 6 months of treatment with udenafil (87.5 mg po BID). The effect of udenafil on echocardiographic measures of single ventricle function in this cohort has not been studied.MethodsThe 400 enrolled participants were randomized 1:1 to udenafil or placebo. Protocol echocardiograms were obtained at baseline and 26 weeks after initiation of udenafil/placebo. Linear regression compared change from baseline indices of single ventricle systolic, diastolic and global function, atrioventricular valve regurgitation, and mean Fontan fenestration gradient in the udenafil cohort versus placebo, controlling for ventricular morphology (left ventricle versus right ventricle/other) and baseline value.ResultsThe udenafil participants (n=191) had significantly improved between baseline and 26 weeks visits compared to placebo participants (n=195) in myocardial performance index (P=0.03, adjusted mean difference [SE] of changes between groups -0.03[0.01]), atrioventricular valve inflow peak E (P=0.009, 3.95 [1.50]), and A velocities (P=0.034, 3.46 [1.62]), and annular Doppler tissue imaging-derived peak e' velocity (P=0.008, 0.60[0.23]). There were no significant differences in change in single ventricle size, systolic function, atrioventricular valve regurgitation severity, or mean fenestration gradient. Participants with a dominant left ventricle had significantly more favorable baseline values of indices of single ventricle size and function (lower volumes and areas, E/e' ratio, systolic:diastolic time and atrioventricular valve regurgitation, and higher annular s' and e' velocity).ConclusionsFUEL participants who received udenafil demonstrated a statistically significant improvement in some global and diastolic echo indices. Although small, the changes in diastolic function suggest improvement in pulmonary venous return and/or augmented ventricular compliance, which may help explain improved exercise performance in that cohort.RegistrationURL: https://clinicaltrials.gov; Unique Identifier: NCT02741115.

Dataset Information

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

Publications

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

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