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

Heart Defects, Congenital Clinical Trial

— SERVE  

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03049540
• Other study ID #: V1 2016-10-12
• Status: Completed
• Phase: Phase 3
• Start date: October 25, 2017
• Est. completion date: October 28, 2021

Study information

• Verified date: June 2023
• Source: Insel Gruppe AG, University Hospital Bern
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 100
• Est. completion date: October 28, 2021
• Est. primary completion date: October 28, 2021
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Congenital Abnormalities
• Congenitally Corrected Transposition of the Great Arteries
• Heart Defects, Congenital
• Transposition of Great Vessels
• Transposition of Great Vessels With Ventricular Inversion

Intervention

Drug:
• Tadalafil 20 MG
Multi-center, double-blind, 1:1 randomized, placebo-controlled clinical trial with Tadalafil
• Placebo 20 MG
Multi-center, double-blind, 1:1 randomized, placebo-controlled clinical trial with Tadalafil

Locations

Country	Name	City	State
Austria	Universitätsklinik für Innere Medizin II, Medizinische Universität Wien	Wien
Switzerland	Kardiologie Universitätsspital Basel	Basel
Switzerland	Bern University Hospital	Bern
Switzerland	Hopitaux Universitaires de Geneve	Geneve
Switzerland	Centre Hospitalier Universitaire Vaudois	Lausanne
Switzerland	Kantonsspital St. Gallen	St Gallen
Switzerland	UniversitätsSpital Zürich, Universitäres Herzzentrum	Zurich

Sponsors (2)

Lead Sponsor	Collaborator
Insel Gruppe AG, University Hospital Bern	Swiss National Science Foundation

Countries where clinical trial is conducted

Austria,  Switzerland, 

References & Publications (14)

Cuypers JA, Eindhoven JA, Slager MA, Opic P, Utens EM, Helbing WA, Witsenburg M, van den Bosch AE, Ouhlous M, van Domburg RT, Rizopoulos D, Meijboom FJ, Bogers AJ, Roos-Hesselink JW. The natural and unnatural history of the Mustard procedure: long-term ou — View Citation

Dos L, Pujadas S, Estruch M, Mas A, Ferreira-Gonzalez I, Pijuan A, Serra R, Ordonez-Llanos J, Subirana M, Pons-Llado G, Marsal JR, Garcia-Dorado D, Casaldaliga J. Eplerenone in systemic right ventricle: double blind randomized clinical trial. The evedes s — View Citation

Greutmann M, Tobler D, Engel R, Heg D, Mueller C, Frenk A, Gabriel H, Rutz T, Buechel RR, Willhelm M, Trachsel L, Freese M, Ruperti-Repilado FJ, Valsangiacomo Buechel E, Beitzke D, Haaf P, Wustmann K, Schwitz F, Possner M, Schwitter J, Bouchardy J, Schwer — View Citation

Kloner RA, Jackson G, Hutter AM, Mittleman MA, Chan M, Warner MR, Costigan TM, Vail GM. Cardiovascular safety update of Tadalafil: retrospective analysis of data from placebo-controlled and open-label clinical trials of Tadalafil with as needed, three tim — View Citation

Marelli AJ, Mackie AS, Ionescu-Ittu R, Rahme E, Pilote L. Congenital heart disease in the general population: changing prevalence and age distribution. Circulation. 2007 Jan 16;115(2):163-72. doi: 10.1161/CIRCULATIONAHA.106.627224. Epub 2007 Jan 8. — View Citation

Mylotte D, Pilote L, Ionescu-Ittu R, Abrahamowicz M, Khairy P, Therrien J, Mackie AS, Marelli A. Specialized adult congenital heart disease care: the impact of policy on mortality. Circulation. 2014 May 6;129(18):1804-12. doi: 10.1161/CIRCULATIONAHA.113.0 — View Citation

Nagendran J, Archer SL, Soliman D, Gurtu V, Moudgil R, Haromy A, St Aubin C, Webster L, Rebeyka IM, Ross DB, Light PE, Dyck JR, Michelakis ED. Phosphodiesterase type 5 is highly expressed in the hypertrophied human right ventricle, and acute inhibition of — View Citation

Roche SL, Redington AN. The failing right ventricle in congenital heart disease. Can J Cardiol. 2013 Jul;29(7):768-78. doi: 10.1016/j.cjca.2013.04.018. — View Citation

Roos-Hesselink JW, Meijboom FJ, Spitaels SE, van Domburg R, van Rijen EH, Utens EM, McGhie J, Bos E, Bogers AJ, Simoons ML. Decline in ventricular function and clinical condition after Mustard repair for transposition of the great arteries (a prospective study of 22-29 years). Eur Heart J. 2004 Jul;25(14):1264-70. doi: 10.1016/j.ehj.2004.03.009. — View Citation

Schwartz BG, Levine LA, Comstock G, Stecher VJ, Kloner RA. Cardiac uses of phosphodiesterase-5 inhibitors. J Am Coll Cardiol. 2012 Jan 3;59(1):9-15. doi: 10.1016/j.jacc.2011.07.051. — View Citation

Tobler D, Bouchardy J, Reto E, Heg D, Muller C, Frenk A, Gabriel H, Schwitter J, Rutz T, Buechel RR, Willhelm M, Trachsel L, Freese M, Greutmann M, Schwerzmann M; SERVE trial. Effect of phosphodiesterase-5 inhibition with Tadalafil on SystEmic Right VEntr — View Citation

van der Bom T, Bouma BJ, Meijboom FJ, Zwinderman AH, Mulder BJ. The prevalence of adult congenital heart disease, results from a systematic review and evidence based calculation. Am Heart J. 2012 Oct;164(4):568-75. doi: 10.1016/j.ahj.2012.07.023. — View Citation

van der Bom T, Winter MM, Bouma BJ, Groenink M, Vliegen HW, Pieper PG, van Dijk AP, Sieswerda GT, Roos-Hesselink JW, Zwinderman AH, Mulder BJ. Effect of valsartan on systemic right ventricular function: a double-blind, randomized, placebo-controlled pilot — View Citation

Vejlstrup N, Sorensen K, Mattsson E, Thilen U, Kvidal P, Johansson B, Iversen K, Sondergaard L, Dellborg M, Eriksson P. Long-Term Outcome of Mustard/Senning Correction for Transposition of the Great Arteries in Sweden and Denmark. Circulation. 2015 Aug 25 — View Citation

* Note: There are 14 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	Systemic right ventricle ejection fraction	Systemic right ventricle ejection fraction measured by CMR or CMDCT	3 years
Secondary	Cardiopulmonary exercise capacity	Assess the effects of PDE-5 inhibition on cardiopulmonary exercise capacity	3 years
Secondary	Serum neurohormonal activation	Assess the effects of PDE-5 inhibition on serum neurohormonal activation	3 years