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

Insel Gruppe AG, University Hospital Bern

Status and phase

Completed

Phase 3

Conditions

Heart Defects, Congenital

Transposition of Great Vessels With Ventricular Inversion

Treatments

Drug: Tadalafil 20 MG

Drug: Placebo 20 MG

Study type

Interventional

Funder types

Other

Identifiers

NCT03049540

V1 2016-10-12

Details and patient eligibility

About

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.

Full description

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.

Enrollment

100 patients

Sex

All

Ages

18+ years old

Volunteers

No Healthy Volunteers

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.