Evaluation of Sildenafil on Exercise Capacity in Adults with Functionally Single Ventricle Post-Fontan Procedure: A Randomized Controlled Trial

The primary objective of this study is to evaluate whether the addition of **sildenafil** to the existing therapy of adult patients with a functionally single ventricle after the Fontan operation, who are in a stable clinical condition and do not require cardiac catheterization, will lead to an improvement in physical performance. This is clinically relevant as patients with a functionally single ventricle often experience reduced exercise capacity and complications related to Fontan circulation, impacting their quality of life and prognosis.

Secondary objectives include assessing the following potential improvements: exercise tolerance, single ventricle mechanics, cardiac function, stabilization or improvement of liver fibrosis, and quality of life. These objectives aim to provide a comprehensive evaluation of the potential benefits of sildenafil in this patient population, addressing various aspects of their health and well-being.

The clinical trial involves **adult patients** with a functionally single ventricle who have undergone the Fontan operation. The study population includes both male and female participants, all over the age of 18, who are in a stable clinical condition and do not require cardiac catheterization. The trial does not involve a vulnerable population. Participants were selected based on their post-Fontan operation status, specifically those with a total cavo-pulmonary connection, either extracardiac or intracardiac. The sponsor has not provided information regarding the total number of participants. The study aims to assess the impact of adding sildenafil to existing therapy on the physical performance of these patients. Lifestyle factors such as diet and physical activity are not specified, but the focus is on individuals who have given informed consent to participate. The trial does not include any specific exclusion criteria beyond those implied by the inclusion criteria.

The clinical trial is designed to evaluate the efficacy and safety of **sildenafil** in adult patients with a functionally single ventricle after the Fontan operation. This study is a randomized, double-blind, placebo-controlled trial, which will span a total duration of 24 weeks. The primary objective is to assess whether the addition of sildenafil to the existing therapy of these patients will enhance their physical performance, specifically by increasing peak oxygen uptake (VO2max) as measured by ergospirometry. Secondary endpoints include improvements in exercise capacity, distance covered in the 6-minute walk test, global longitudinal strain in echocardiography, serum Nt-proBNP levels, fibrosis score on elastography, and quality of life index.

Participants will be required to attend several study visits throughout the trial. The initial visit will be a screening visit to confirm eligibility based on criteria such as age over 18 years, post-Fontan operation status, and absence of clinical indications for cardiac catheterization. Following successful screening, participants will be randomized to receive either sildenafil or a placebo. Subsequent follow-up visits will occur at regular intervals to monitor safety, adherence, and efficacy outcomes. The end-of-study visit will conclude the trial, where final assessments will be conducted to evaluate the primary and secondary endpoints.

The expected length of participant involvement is 24 weeks, aligning with the trial's treatment period. Conditions that may lead to early termination from the study include adverse events, withdrawal of consent, or any clinical indication that necessitates cardiac catheterization. The trial is structured to ensure rigorous monitoring and data collection to support the evaluation of sildenafil's potential benefits in this patient population.

The clinical trial involves the administration of **Sildenafil** in the form of a film-coated tablet, marketed under the name "Remidia, 20 mg, tabletki powlekane." The active substance in this medication is **Sildenafil**, a chemical compound with the ATC code G04BE03. The pharmaceutical form is a film-coated tablet, and the medication is administered orally. The dosage is set at 20 mg per tablet, with a maximum daily dose of 60 mg. The treatment period is limited to a maximum of 24 weeks. The product is manufactured by Zakłady Farmaceutyczne Polpharma S.A. in Poland. Participant compliance with the dosing schedule will be monitored throughout the study to ensure adherence to the prescribed regimen.

In addition to the experimental medication, a **Sildenafil placebo** is used as a comparator in the study. The placebo is designed to mimic the appearance of the active medication but does not contain any active pharmaceutical ingredients. The placebo is administered orally in a similar manner to the active treatment, ensuring that the study remains double-blind. The use of a placebo allows for the assessment of the true efficacy of **Sildenafil** by providing a control group for comparison. Compliance with the administration of the placebo will also be monitored to maintain the integrity of the trial results.

Efficacy in this clinical trial will be assessed through a series of primary and secondary endpoints. The primary endpoint is the increase in peak oxygen uptake (**VO2max**) measured by ergospirometry after 24 weeks of treatment. This parameter is crucial for evaluating the improvement in physical performance in adult patients with a functionally univentricular heart post-Fontan operation.

Secondary endpoints include several measures to provide a comprehensive assessment of efficacy. These are: an increase in the amount of exercise performed, quantified in metabolic equivalents (METS) during cardiopulmonary exercise testing (CPET); an increase in the distance covered in the 6-minute walk test (6MWT); an increase in the absolute value of global longitudinal strain (GLS) in echocardiography; a reduction in serum Nt-proBNP levels; a reduction in fibrosis score on elastography (abdominal ultrasound); and an increase in the quality of life index as assessed by the SF-36 questionnaire. All these secondary endpoints will be evaluated after 24 weeks of treatment.