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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03049540
Recruitment Status : Active, not recruiting
First Posted : February 10, 2017
Last Update Posted : August 3, 2020
Sponsor:
Collaborator:
Swiss National Science Foundation
Information provided by (Responsible Party):
University Hospital Inselspital, Berne

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.

Condition or disease Intervention/treatment Phase
Heart Defects, Congenital Transposition of Great Vessels With Ventricular Inversion Drug: Tadalafil 20 MG Drug: Placebo 20 MG Phase 3

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.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 100 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Supportive Care
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
Actual Study Start Date : October 25, 2017
Estimated Primary Completion Date : May 31, 2021
Estimated Study Completion Date : July 31, 2021

Resource links provided by the National Library of Medicine

Drug Information available for: Tadalafil

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




Primary Outcome Measures :
  1. 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


Secondary Outcome Measures :
  1. Systemic right ventricle ejection fraction [ Time Frame: 3 years ]
    Systemic right ventricle ejection fraction measured by CMR or CMDCT

  2. Cardiopulmonary exercise capacity [ Time Frame: 3 years ]
    Assess the effects of PDE-5 inhibition on cardiopulmonary exercise capacity

  3. Serum neurohormonal activation [ Time Frame: 3 years ]
    Assess the effects of PDE-5 inhibition on serum neurohormonal activation



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03049540


Locations
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Austria
Universitätsklinik für Innere Medizin II, Medizinische Universität Wien
Wien, Austria, 1090
Switzerland
Kardiologie Universitätsspital Basel
Basel, Switzerland, 4031
Bern University Hospital
Bern, Switzerland, 3010
Hopitaux Universitaires de Geneve
Geneve, Switzerland, 1205
Centre Hospitalier Universitaire Vaudois
Lausanne, Switzerland, 1011
Kantonsspital St. Gallen
St Gallen, Switzerland, 9007
UniversitätsSpital Zürich, Universitäres Herzzentrum
Zurich, Switzerland, 8091
Sponsors and Collaborators
University Hospital Inselspital, Berne
Swiss National Science Foundation
Investigators
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Principal Investigator: Markus Schwerzmann, MD Bern University Hospital, Zentrum fuer angeborene Herzfehler
Publications of Results:

Other Publications:
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Responsible Party: University Hospital Inselspital, Berne
ClinicalTrials.gov Identifier: NCT03049540    
Other Study ID Numbers: V1 2016-10-12
First Posted: February 10, 2017    Key Record Dates
Last Update Posted: August 3, 2020
Last Verified: July 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided
Plan Description: Undecided

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Heart Defects, Congenital
Transposition of Great Vessels
Congenital Abnormalities
Cardiovascular Abnormalities
Cardiovascular Diseases
Heart Diseases
Tadalafil
Vasodilator Agents
Phosphodiesterase 5 Inhibitors
Phosphodiesterase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Urological Agents