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

June 21, 2023 updated by: Insel Gruppe AG, University Hospital Bern

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.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

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 Type

Interventional

Enrollment (Actual)

100

Phase

  • Phase 3

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Austria
      • Wien, Austria, 1090
        • Universitätsklinik für Innere Medizin II, Medizinische Universität Wien
  • Switzerland
      • Basel, Switzerland, 4031
        • Kardiologie Universitätsspital Basel
      • Bern, Switzerland, 3010
        • Bern University Hospital
      • Geneve, Switzerland, 1205
        • Hôpitaux Universitaires de Genève
      • Lausanne, Switzerland, 1011
        • Centre Hospitalier Universitaire Vaudois
      • St Gallen, Switzerland, 9007
        • Kantonsspital St. Gallen
      • Zurich, Switzerland, 8091
        • UniversitätsSpital Zürich, Universitäres Herzzentrum

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Description

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.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Supportive Care
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Quadruple

Arms and Interventions

Participant Group / 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

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Systemic right ventricle endsystolic volume
Time Frame: 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
3 years

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Systemic right ventricle ejection fraction
Time Frame: 3 years
Systemic right ventricle ejection fraction measured by CMR or CMDCT
3 years
Cardiopulmonary exercise capacity
Time Frame: 3 years
Assess the effects of PDE-5 inhibition on cardiopulmonary exercise capacity
3 years
Serum neurohormonal activation
Time Frame: 3 years
Assess the effects of PDE-5 inhibition on serum neurohormonal activation
3 years

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Insel Gruppe AG, University Hospital Bern

Collaborators

Swiss National Science Foundation

Investigators

  • Principal Investigator: Markus Schwerzmann, MD, Bern University Hospital, Zentrum fuer angeborene Herzfehler

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

October 25, 2017

Primary Completion (Actual)

October 28, 2021

Study Completion (Actual)

October 28, 2021

Study Registration Dates

First Submitted

February 8, 2017

First Submitted That Met QC Criteria

February 9, 2017

First Posted (Actual)

February 10, 2017

Study Record Updates

Last Update Posted (Actual)

June 23, 2023

Last Update Submitted That Met QC Criteria

June 21, 2023

Last Verified

June 1, 2023

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

  • V1 2016-10-12

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

UNDECIDED

IPD Plan Description

Undecided

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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