The use of sildenafil in patients with univentricular heart after Fontan operation - a pilot SINFON-POL study.

Overview

Sponsor-declared trial summary

Key facts

Sponsor

National Institute Of Cardiology

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Cardiovascular Diseases [C14], Phenomena and Processes [G] - Physiological processes [G07], Diseases [C] - Congenital, Hereditary, and Neonatal Diseases and Abnormalities [C16], Phenomena and Processes [G] - Circulatory and Respiratory Physiological Phenomena [G09]

Trial duration

27 Jun 2025 → ongoing

Decision date (initial)

2024-09-22

Transition trial

No

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

No

Funding sources

Zakłady Farmaceutyczne "POLPHARMA" Spółka Akcyjna

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Therapy, Efficacy, Safety

The main objective of the study is to determine whether, in adult patients with univentricular heart after Fontan operation, in stable clinical condition, without indication for cardiac catheterization, the addition of sildenafil to their existing therapy will result in improved physical performance.

Secondary objectives 5

1. Improvement in exercise tolerance
2. Improvement in single ventricle mechanics
3. Improvement in cardiac function
4. Improvement or stabilization of liver fibrosis
5. Improvement in quality of life

Conditions and MedDRA coding

Patients with functionally single ventricle (FSV - functionally single ventricle) after Fontan operation. The term "functionally single ventricle" refers to congenital heart defects in which one of the ventricles is not fully developed and/or one of the valves is atresia/hypoplastic as a result, it is not possible to correct the intracardiac defect. Then, there are indications for the Fontan operation, i.e. a palliative procedure - total cavo-pulmonary connection (TCPC). In patients with a functionally single ventricle, more than one operation is necessary to separate the systemic and pulmonary circulation. As a result of these procedures, Fontan circulation is created, which consists in bypassing the right heart chambers and directing the venous blood to the pulmonary artery. This leads to the removal of the right-to-left shunt and improvement of arterial blood saturation and reduction of volume overload of the systemic ventricle. At the same time, there is an increase in systemic venous pressure and a decrease in cardiac output. Low pulmonary resistance in these patients is crucial for maintaining optimal hemodynamic conditions both at rest and especially during exercise. Even a slight increase in pulmonary resistance leads to reduced pulmonary blood flow, reduced initial depression of a single ventricle, and consequently to reduced cardiac output and worsened exercise tolerance. Thus, pulmonary resistance in these patients should be not only normal, but also as low as possible to ensure adequate single ventricular filling and adequate cardiac output. There is evidence that patients with Fontan surgery increase pulmonary resistance over time. The increase in pulmonary resistance in these patients may result from several factors, and above all from the progressive dysfunction of a single systemic ventricle and the lack of a subpulmonary chamber ensuring pulsatile pulmonary flow. Although the Fontan operation in many patients with an univentricular heart is a very good method of palliative treatment, which undoubtedly extends the survival of children born with this heart defect, it also inevitably leads to severe complications developing over the years. Patients after the Fontan operation are also characterized by a significant reduction in exercise capacity, which is observed both in clinical practice in reference centres dealing with patients with congenital heart defects, and in multi-centre studies. Among other things, it was shown that children after the Fontan operation obtained 30% lower values of peak oxygen uptake in the ergospirometric test compared to the control group of healthy children (Amadero P et al., Heart 2018). The reduced exercise capacity of patients and the development of Fontan circulatory complications affect both the quality of life and the prognosis of adult patients with univentricular heart.

Regulatory references

Plan to share IPD

No

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 5

1. Functionally univentricular heart
2. Post-Fontan operation condition with the creation of a total cavo-pulmonary connection (TCPC) either extracardiac [extracardiac conduit] or intracardiac [lateral intra-atrial tunnel]
3. No clinical indications for cardiac catheterization
4. Age > 18 years
5. Informed consent to participate in the study

Exclusion criteria 14

1. Patients with a functionally univentricular heart within 6 months of their last cardiac operation or intravascular procedure
2. Patients who were taking pulmonary arterial dilators (sildenafil, tadalafil, riociguat, bosentan, macitentan, ambrisentan, epoprostenol, iloprost, selixipag) in the 6 month period preceding study entry, regardless of the duration of therapy and route of administration (oral, intravenous, subcutaneous, inhalated)
3. Patients unable to undergo egrospirometric examination
4. Advanced heart failure (NYHA IV)
5. Resting arterial oxygen saturation <85%
6. Chronic kidney disease (creatinine > 150 µmol/l)
7. Liver damage manifested by a twofold increase in transaminases above the norm
8. Uncontrolled hypotension (blood pressure < 90/50 mmHg) or risk of hypotension (dehydration, systemic ventricular outflow tract obstruction, autonomic nervous system dysfunction, patients taking alpha-blockers)
9. Atrial arrhythmia preventing the execution/interpretation of the above-mentioned tests or a life-threatening exercise-induced arrhythmia history
10. Patients with concomitant diagnoses of: a) cardiovascular events within the last 3 months (acute coronary syndrome, sudden cardiac arrest, ventricular arrhythmias, intracranial hemorrhage, stroke), b) pulmonary embolism, c) infections, d) active bleeding complications, e) severe liver failure (Child-Pugh class C), f) active gastric and/or duodenal peptic ulcer disease, g) malignancy, h) primary muscle and nervous system disease, i) systemic connective tissue disease, j) myocarditis and/or pericarditis, k) predisposition to priapism, sclerosis of the corpus cavernosum or Peyronie's disease, l) sickle cell anemia, leukemia, or multiple myeloma, m) loss of vision in one eye due to non-arteritic anterior ischemic optic neuropathy (NAION), n) enteropathy with protein loss
11. Pregnancy (positive pregnancy test result), planning pregnancy, breastfeeding
12. Non-use of contraception during the study - applies to women of reproductive age
13. Severe central nervous system damage
14. Taking products containing nitric oxide or nitrates in any form (e.g., nitroglycerin, isosorbide mononitrate, isosorbide dinitrate, amyl nitrate, pentaerythritol tetranitrate); use in combination with the most potent CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, ritonavir)

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Increase in peak oxygen uptake (V02max) in ergospirometry test after 24 weeks of treatment

Secondary endpoints 6

1. Increase in the amount of exercise performed, measured in metabolic equivalents (METS) during cardiopulmonary exercise testing (CPET) after 24 weeks of treatment
2. Increase in the distance covered in the 6-minute walk test (6MWT)
3. Increase in the absolute value of global longitudinal strain (GLS) in echocardiography after 24 weeks of treatment
4. Reduction in serum Nt-proBNP levels after 24 weeks of treatment
5. Reduction in fibrosis score on elastography (abdominal ultrasound) after 24 weeks of treatment
6. Increase in the quality of life index as assessed by the SF-36 questionnaire after 24 weeks of treatment

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Placebo 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

National Institute Of Cardiology

Sponsor organisation

National Institute Of Cardiology

Address

Ul. Alpejska 42

City

Warsaw

Postcode

04-628

Country

Poland

Scientific contact point

Organisation

National Institute Of Cardiology

Contact name

Clinical Research Support Centre Information Desk

Public contact point

Organisation

National Institute Of Cardiology

Contact name

Clinical Research Support Centre Information Desk

Locations

1 EU/EEA country · 1 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 5 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

4 submissions — initial application plus substantial / non-substantial modifications