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

NCT ID: NCT03049540

Last Updated: 2023-06-23

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 100 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2017-10-25
• Study Completion Date: 2021-10-28

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.

Conditions

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

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: SUPPORTIVE_CARE
• Blinding Strategy: QUADRUPLE

Study Groups

Tadalafil

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

Group Type: ACTIVE_COMPARATOR

Tadalafil 20 MG

Intervention Type: DRUG

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

Placebo

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

Group Type: PLACEBO_COMPARATOR

Placebo 20 MG

Intervention Type: DRUG

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

Interventions

Tadalafil 20 MG

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

Intervention Type: DRUG

Placebo 20 MG

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

Intervention Type: DRUG

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.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Swiss National Science Foundation

OTHER

Sponsor Role: collaborator

Insel Gruppe AG, University Hospital Bern

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Markus Schwerzmann, MD

Role: PRINCIPAL_INVESTIGATOR

Bern University Hospital, Zentrum fuer angeborene Herzfehler

Locations

Universitätsklinik für Innere Medizin II, Medizinische Universität Wien

Vienna, , Austria

Kardiologie Universitätsspital Basel

Basel, , Switzerland

Bern University Hospital

Bern, , Switzerland

Hopitaux Universitaires de Geneve

Geneva, , Switzerland

Centre Hospitalier Universitaire Vaudois

Lausanne, , Switzerland

Kantonsspital St. Gallen

Sankt Gallen, , Switzerland

UniversitätsSpital Zürich, Universitäres Herzzentrum

Zurich, , Switzerland

Countries

Austria; Switzerland

References

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.

Reference Type: BACKGROUND

PMID: 15246646 (View on PubMed)

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.

Reference Type: RESULT

PMID: 23067916 (View on PubMed)

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.

Reference Type: RESULT

PMID: 17210844 (View on PubMed)

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.113.005817. Epub 2014 Mar 3.

Reference Type: RESULT

PMID: 24589851 (View on PubMed)

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 outcome up to 40 years. Eur Heart J. 2014 Jul 1;35(25):1666-74. doi: 10.1093/eurheartj/ehu102. Epub 2014 Mar 18.

Reference Type: RESULT

PMID: 24644309 (View on PubMed)

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;132(8):633-8. doi: 10.1161/CIRCULATIONAHA.114.010770. Epub 2015 Jul 16.

Reference Type: RESULT

PMID: 26185211 (View on PubMed)

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.

Reference Type: RESULT

PMID: 23790549 (View on PubMed)

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 trial. Circulation. 2013 Jan 22;127(3):322-30. doi: 10.1161/CIRCULATIONAHA.112.135392. Epub 2012 Dec 17.

Reference Type: RESULT

PMID: 23247302 (View on PubMed)

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 study. Int J Cardiol. 2013 Oct 15;168(6):5167-73. doi: 10.1016/j.ijcard.2013.07.163. Epub 2013 Jul 25.

Reference Type: RESULT

PMID: 23972966 (View on PubMed)

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 phosphodiesterase type 5 improves contractility. Circulation. 2007 Jul 17;116(3):238-48. doi: 10.1161/CIRCULATIONAHA.106.655266. Epub 2007 Jul 2.

Reference Type: RESULT

PMID: 17606845 (View on PubMed)

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.

Reference Type: RESULT

PMID: 22192662 (View on PubMed)

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 times-per-week or once-a-day dosing. Am J Cardiol. 2006 Jun 15;97(12):1778-84. doi: 10.1016/j.amjcard.2005.12.073. Epub 2006 Apr 27.

Reference Type: RESULT

PMID: 16765134 (View on PubMed)

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, Schwerzmann M; SERVE Investigators. Effect of phosphodiesterase-5 inhibition on SystEmic Right VEntricular size and function. A multicentre, double-blind, randomized, placebo-controlled trial: SERVE. Eur J Heart Fail. 2023 Jul;25(7):1105-1114. doi: 10.1002/ejhf.2924. Epub 2023 Jun 13.

Reference Type: RESULT

PMID: 37264734 (View on PubMed)

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 VEntricular size and function - A multi-center, double-blind, randomized, placebo-controlled clinical trial - SERVE trial - Rational and design. Int J Cardiol. 2017 Sep 15;243:354-359. doi: 10.1016/j.ijcard.2017.05.079. Epub 2017 May 23.

Reference Type: RESULT

PMID: 28566262 (View on PubMed)

Castiglione A, Schwerzmann M, Bouchardy J, Buechel RR, Engel R, Freese M, Gabriel H, Greutmann M, Heg D, Mueller C, Possner M, Ruperti-Repilado FJ, Rutz T, Schwitter J, Thomet C, Tobler D, Wilhelm M, Wustmann K, Schwitz F; SERVE trial. Stable Longitudinal Quality of Life in the SERVE Trial Among Adults With Transposition of the Great Arteries and a Systemic Right Ventricle. CJC Pediatr Congenit Heart Dis. 2024 Dec 12;4(2):81-91. doi: 10.1016/j.cjcpc.2024.12.001. eCollection 2025 Apr.

Reference Type: DERIVED

PMID: 40470125 (View on PubMed)

Ruperti-Repilado FJ, Tran F, Haaf P, Lopez-Ayala P, Greutmann M, Schwerzmann M, Bouchardy J, Gabriel H, Stambach D, Rutz T, Schwitter J, Wustmann K, Freese M, Mueller C, Tobler D. Prognostic Value and Determinants of High-Sensitivity Cardiac Troponin T in Patients With a Systemic Right Ventricle: Insights From the SERVE Trial. J Am Heart Assoc. 2024 May 21;13(10):e034776. doi: 10.1161/JAHA.123.034776. Epub 2024 May 10.

Reference Type: DERIVED

PMID: 38726920 (View on PubMed)

Other Identifiers

V1 2016-10-12

Identifier Type: -

Identifier Source: org_study_id