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

Sponsor

University Hospital Inselspital, Berne (Other)

Overall Status

Completed

CT.gov ID

NCT03049540

Collaborator

Swiss National Science Foundation (Other)

100

Enrollment

Locations

Arms

48.1

Actual Duration (Months)

14.3

Patients Per Site

0.3

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Heart Defects, Congenital Transposition of Great Vessels With Ventricular Inversion	Drug: Tadalafil 20 MG Drug: Placebo 20 MG	Phase 3

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.

Study Design

Study Type:

Interventional

Actual Enrollment :

100 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)

Primary Purpose:

Supportive Care

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

Actual Study Start Date :

Oct 25, 2017

Actual Primary Completion Date :

Oct 28, 2021

Actual Study Completion Date :

Oct 28, 2021

Arms and Interventions

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

Arm

Intervention/Treatment

Active Comparator: Tadalafil

Tadalafil 20 MG, p.o., once per day for 3 years

Drug: Tadalafil 20 MG

Multi-center, double-blind, 1:1 randomized, placebo-controlled clinical trial with Tadalafil

Placebo Comparator: Placebo

Placebo 20 MG, p.o., once per day for 3 years

Drug: Placebo 20 MG

Multi-center, double-blind, 1:1 randomized, placebo-controlled clinical trial with Tadalafil

Outcome Measures

Primary Outcome Measures

Systemic right ventricle endsystolic volume [3 years]
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

Secondary Outcome Measures

Systemic right ventricle ejection fraction [3 years]
Systemic right ventricle ejection fraction measured by CMR or CMDCT
Cardiopulmonary exercise capacity [3 years]
Assess the effects of PDE-5 inhibition on cardiopulmonary exercise capacity
Serum neurohormonal activation [3 years]
Assess the effects of PDE-5 inhibition on serum neurohormonal activation

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts 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.

Contacts and Locations

Locations

	Site	City	Country	Postal Code
1	Universitätsklinik für Innere Medizin II, Medizinische Universität Wien	Wien	Austria	1090
2	Kardiologie Universitätsspital Basel	Basel	Switzerland	4031
3	Bern University Hospital	Bern	Switzerland	3010
4	Hopitaux Universitaires de Geneve	Geneve	Switzerland	1205
5	Centre Hospitalier Universitaire Vaudois	Lausanne	Switzerland	1011
6	Kantonsspital St. Gallen	St Gallen	Switzerland	9007
7	UniversitätsSpital Zürich, Universitäres Herzzentrum	Zurich	Switzerland	8091