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

NCT03049540 | Completed Phase 3

• 1 other identifier: V1 2016-10-12
• Study Type: interventional
• Target: 100
• Locations: 2 countries
• Sites: 7

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.

Conditions

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

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (3)

• Systemic right ventricle ejection fraction

  3 years

• Cardiopulmonary exercise capacity

  3 years

• Serum neurohormonal activation

  3 years

Study Arms (2)

Tadalafil

ACTIVE COMPARATOR

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

Drug: Tadalafil 20 MG

Placebo

PLACEBO COMPARATOR

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

Drug: Placebo 20 MG

Interventions

Tadalafil 20 MG DRUG

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

Tadalafil

Placebo 20 MG DRUG

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

Placebo

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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).

You may not qualify if:

• 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

Sponsors & Collaborators

• Insel Gruppe AG, University Hospital Bern: lead
• Swiss National Science Foundation: collaborator

Study Sites (7)

Universitätsklinik für Innere Medizin II, Medizinische Universität Wien

Vienna, 1090, Austria

Location

Kardiologie Universitätsspital Basel

Basel, 4031, Switzerland

Location

Bern University Hospital

Bern, 3010, Switzerland

Location

Hopitaux Universitaires de Geneve

Geneva, 1205, Switzerland

Location

Centre Hospitalier Universitaire Vaudois

Lausanne, 1011, Switzerland

Location

Kantonsspital St. Gallen

Sankt Gallen, 9007, Switzerland

Location

UniversitätsSpital Zürich, Universitäres Herzzentrum

Zurich, 8091, Switzerland

Location

Related Publications (16)

• 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.

  PMID: 15246646 BACKGROUND

• 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.

  PMID: 23067916 RESULT

• 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.

  PMID: 17210844 RESULT

• 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.

  PMID: 24589851 RESULT

• 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.

  PMID: 24644309 RESULT

• 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.

  PMID: 26185211 RESULT

• 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.

  PMID: 23790549 RESULT

• 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.

  PMID: 23247302 RESULT

• 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.

  PMID: 23972966 RESULT

• 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.

  PMID: 17606845 RESULT

• 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.

  PMID: 22192662 RESULT

• 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.

  PMID: 16765134 RESULT

• 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.

  PMID: 37264734 RESULT

• 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.

  PMID: 28566262 RESULT

• 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.

  PMID: 40470125 DERIVED

• 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.

  PMID: 38726920 DERIVED

MeSH Terms

Conditions

Heart Defects, Congenital; Congenitally Corrected Transposition of the Great Arteries

Interventions

Tadalafil

Condition Hierarchy (Ancestors)

Cardiovascular Abnormalities; Cardiovascular Diseases; Heart Diseases; Congenital Abnormalities; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Transposition of Great Vessels

Intervention Hierarchy (Ancestors)

Carbolines; Pyridines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Indole Alkaloids; Indoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds, 3-Ring

Study Officials

• Markus Schwerzmann, MD

  Bern University Hospital, Zentrum fuer angeborene Herzfehler

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: SUPPORTIVE CARE
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: February 8, 2017
• First Posted: February 10, 2017
• Study Start: October 25, 2017
• Primary Completion: October 28, 2021
• Study Completion: October 28, 2021
• Last Updated: June 23, 2023

Record last verified: 2023-06

Locations

AU (1); CH (6)