Effect of Phosphodiesterase-5 Inhibition With Tadalafil on SystEmic Right VEntricular Size and Function

Study Overview
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Brief Summary
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This study assesses in a double-blind, randomized, placebo-controlled multi-center pilot trial the effect of PDE-5 inhibition with Tadalafil on right ventricle size and function, exercise capacity and neurohumoral activation in adults with congenital heart disease and a right ventricle in subaortic position over a 3-year follow-up period.

Detailed Description
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Currently, there are an estimated 300-600 adults living in Switzerland with congenital heart disease (CHD) and a right ventricle (RV) in subaortic (systemic) position. This includes adults with prior atrial switch operations for complete transposition of the great arteries (D-TGA) and adults with congenitally corrected transposition of the great arteries (ccTGA). Although midterm survival is favourable, late outcome is compromised by ventricular dysfunction of the systemic RV, end-stage heart failure, and premature death. Medical heart failure therapy (ACE-inhibitors, beta-blockers, aldosterone antagonists) has been shown to improve ventricular function and survival in patients with left heart failure from acquired heart disease. Unfortunately, case-reports and studies failed to show similar clinical benefits of these drugs in adults with a failing systemic RV. Currently, the only established end-stage therapy for a failing systemic RV is heart transplantation. Given the ubiquitous shortage of donor organs and the number of adults at risk, medical options to improve the fate of patients with a systemic RV are urgently needed. The RV and left ventricle (LV) have different embryological origins, myocardial architecture and contractile properties. In response to increased afterload, as in an RV in systemic position, the RV expresses a fetal gene pattern, with an increase in phosphodiesterase (PDE)-5 expression. PDE-5 is not expressed in the normal RV, but is up-regulated in the hypertrophied RV. PDE-5 inhibition increases contractility in experimental models of RV hypertrophy, but not in the normal RV. In clinical practice, the effects of PDE-5 inhibition on systemic RV function and exercise capacity in adults with TGA have not been tested. This study assesses in a double-blind, randomized, placebo-controlled multi-center pilot trial the effect of PDE-5 inhibition with Tadalafil on RV size and function, exercise capacity and neurohumoral activation in adults with a systemic RV over a 3-year follow-up period.

Official Title
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Effect of Phosphodiesterase-5 Inhibition With Tadalafil on SystEmic Right VEntricular Size and Function - a Multi-center, Double-blind, Randomized, Placebo-controlled Clinical Trial - SERVE Trial

Conditions
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Heart Defects, Congenital, Transposition of Great Vessels With Ventricular Inversion

Intervention / Treatment
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* Drug: Tadalafil 20 MG
* Drug: Placebo 20 MG


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Systemic right ventricle due to prior atrial switch operations for complete transposition of the great arteries (D-TGA) due to congenitally corrected transposition of the great arteries (ccTGA). Exclusion Criteria: Incapability of giving informed consent Myocardial infarction, stroke, or open heart surgery within the 3 months prior to baseline visit Expected heart transplant within the next 6 months starting from baseline Pregnant or nursing women (a pregnancy test is mandatory prior to randomization; women of childbearing potential must agree to use reliable contraception from randomization to end of study treatment) Severe renal insufficiency (Creatinine clearance ≤ 30 ml/min) Severe hepatic insufficiency (Child-Pugh-Class C) Hypotension with blood pressures < 90/50 mmHg at the baseline visit Hypersensibility to Tadalafil Allergy to iodinated (in patients undergoing CMDCT) or Gadolinium-based (in patients undergoing CMR) contrast agents. Co-medication with nitrates Regular use of poppers, i.e. alkyl nitrites, that are inhaled for recreational purposes, including as club drugs used at dance clubs. Co-medication with potent CYP3A4 inhibitors: Ketoconazole, Ritonavir, Rifampicin Co-medication with other PDE-5 inhibitors for erectile dysfunction during the last four weeks prior to baseline visit Medical history of Non-Arteritic Anterior Ischemic Optic Neuropathy (NAION) Hereditary Galactose intolerance, Lactase deficiency or Glucose-Galactose-Malabsorption Participation at another clinical trial in which the primary endpoint has not been reached.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Supportive Care
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Tadalafil<br>Tadalafil 20 MG, p.o., once per day for 3 years | Drug: Tadalafil 20 MG<br>* Multi-center, double-blind, 1:1 randomized, placebo-controlled clinical trial with Tadalafil<br>|
| Placebo Comparator: Placebo<br>Placebo 20 MG, p.o., once per day for 3 years | Drug: Placebo 20 MG<br>* Multi-center, double-blind, 1:1 randomized, placebo-controlled clinical trial with Tadalafil<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Systemic right ventricle endsystolic volume | Assess of the improvement of Tadalafil on systemic right ventricle endsystolic volume measured by cardiovascular magnetic resonance imaging (CMR) or cardiac multirow detector computed tomography (CMDCT) in patients with contraindications for cardiac MRI | 3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Systemic right ventricle ejection fraction | Systemic right ventricle ejection fraction measured by CMR or CMDCT | 3 years | 
| Cardiopulmonary exercise capacity | Assess the effects of PDE-5 inhibition on cardiopulmonary exercise capacity | 3 years | 
| Serum neurohormonal activation | Assess the effects of PDE-5 inhibition on serum neurohormonal activation | 3 years |