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Heart Defects, CongenitalPhase 3SERVENCT03049540

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

A Phase 3 study testing Tadalafil 20 MG in people with Heart Defects, Congenital and Transposition of Great Vessels With Ventricular Inversion, run by Insel Gruppe AG, University Hospital Bern at 7 sites in 2 countries.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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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… Read more about this study

Who is it for?
Ages 18 years and older
What is being tested?
Tadalafil 20 MG
Could I receive a placebo?
Yes, some participants may receive a placebo
How many people
100 participants
Where
7 sitesin 2 countries
Study dates
25 Oct 2017to 28 Oct 2021
Phase
Phase 3
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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).

Who cannot join

  • 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)
Show all 16Show fewer
  • 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.

Trial locations and contacts

7 sites in 2 countries.

7 sites in 2 countries

Switzerland6 sites

  • Kardiologie Universitätsspital Basel

    Basel, 4031

  • Bern University Hospital

    Bern, 3010

  • Hopitaux Universitaires de Geneve

    Geneva, 1205

  • Centre Hospitalier Universitaire Vaudois

    Lausanne, 1011

  • Kantonsspital St. Gallen

    Sankt Gallen, 9007

  • UniversitätsSpital Zürich, Universitäres Herzzentrum

    Zurich, 8091

Other trials in Switzerland

Austria1 site

  • Universitätsklinik für Innere Medizin II, Medizinische Universität Wien

    Vienna, 1090

Other trials in Austria

About this study

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

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.

Read the 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.

Being tested
Tadalafil 20 MG, Placebo 20 MG
Medical subject headings
Heart Defects, Congenital, Congenitally Corrected Transposition of the Great Arteries

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • Tadalafil 20 MGDrug

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

  • Placebo 20 MGDrug

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

Study groups in NCT03049540
Study groupRoleWhat they receive
TadalafilActive comparatorTadalafil 20 MG, p.o., once per day for 3 years
Receives: Drug: Tadalafil 20 MG
PlaceboPlacebo comparatorPlacebo 20 MG, p.o., once per day for 3 years
Receives: Drug: Placebo 20 MG

What is being measured

The primary outcome is the main question the study is designed to answer.

  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

    Measured: 3 years

Secondary outcomes (3)

  1. Systemic right ventricle ejection fraction

    Systemic right ventricle ejection fraction measured by CMR or CMDCT

    Measured: 3 years

  2. Cardiopulmonary exercise capacity

    Assess the effects of PDE-5 inhibition on cardiopulmonary exercise capacity

    Measured: 3 years

  3. Serum neurohormonal activation

    Assess the effects of PDE-5 inhibition on serum neurohormonal activation

    Measured: 3 years

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted10 Feb 2017
  2. Study start25 Oct 2017
  3. Primary completion28 Oct 2021
  4. Study completion28 Oct 2021

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 3
Primary purpose
Supportive care
Allocation
Randomised
Intervention model
Parallel groups
Masking
Quadruple blind
Who is masked
Participant, Care provider, Investigator, Outcomes assessor
Enrolment
100 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT03049540
Sponsor's protocol ID
V1 2016-10-12
Acronym
SERVE
Status last verified
Jun 2023
First submitted
8 Feb 2017
Last updated
23 Jun 2023
Results posted
No
FDA-regulated drug
No
FDA-regulated device
No
Individual data sharing
Undecided: Undecided

Publications

  • 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.

    PubMed 15246646

  • 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.

    PubMed 23067916

  • 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.

    PubMed 17210844

  • 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.

    PubMed 24589851

  • 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.

    PubMed 24644309

  • 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.

    PubMed 26185211

  • 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.

    PubMed 23790549

  • 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.

    PubMed 23247302

  • 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.

    PubMed 23972966

  • 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.

    PubMed 17606845

  • 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.

    PubMed 22192662

  • 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.

    PubMed 16765134

  • 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.

    PubMed 37264734

  • 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.

    PubMed 28566262

  • 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.

    PubMed 40470125

Questions about this trial

What is this clinical trial studying?

A Phase 3 study testing Tadalafil 20 MG in people with Heart Defects, Congenital and Transposition of Great Vessels With Ventricular Inversion, run by Insel Gruppe AG, University Hospital Bern at 7 sites in 2 countries.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 1 inclusion and 16 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 23 Jun 2023. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 7 sites in Switzerland, Austria. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Systemic right ventricle endsystolic volume (time frame: 3 years). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT03049540, which also lists 16 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 23 Jun 2023.

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