Clinical trial NCT03049540: Effect of Phosphodiesterase-5 Inhibition With Tadalafil on SystEmic Right VEntricular Size and Function
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Heart Defects, Congenital
Transposition of Great Vessels With Ventricular Inversion
Lead sponsor: Insel Gruppe AG, University Hospital Bern
Sponsor class: OTHER
Collaborators: name: Swiss National Science Foundation
First posted: 2017-02-10
Enrollment: 100
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: SUPPORTIVE_CARE

Brief summary: 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: 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.

Eligibility criteria: 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.

Primary outcomes:
measure: Systemic right ventricle endsystolic volume
timeFrame: 3 years
Secondary outcomes:
measure: Systemic right ventricle ejection fraction
timeFrame: 3 years
measure: Cardiopulmonary exercise capacity
timeFrame: 3 years
measure: Serum neurohormonal activation
timeFrame: 3 years
Other outcomes:
Locations:
city: Wien
country: Austria
facility: Universitätsklinik für Innere Medizin II, Medizinische Universität Wien
city: Basel
country: Switzerland
facility: Kardiologie Universitätsspital Basel
city: Bern
country: Switzerland
facility: Bern University Hospital
city: Geneve
country: Switzerland
facility: Hopitaux Universitaires de Geneve
city: Lausanne
country: Switzerland
facility: Centre Hospitalier Universitaire Vaudois
city: St Gallen
country: Switzerland
facility: Kantonsspital St. Gallen
city: Zurich
country: Switzerland
facility: UniversitätsSpital Zürich, Universitäres Herzzentrum
Study officials:
affiliation: Bern University Hospital, Zentrum fuer angeborene Herzfehler
name: Markus Schwerzmann, MD
role: PRINCIPAL_INVESTIGATOR
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