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

Primary Purpose

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

Status
Completed
Phase
Phase 3
Locations
International
Study Type
Interventional
Intervention
Tadalafil 20 MG
Placebo 20 MG
Sponsored by
Insel Gruppe AG, University Hospital Bern
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional supportive care trial for Heart Defects, Congenital

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

  • Universitätsklinik für Innere Medizin II, Medizinische Universität Wien
  • Kardiologie Universitätsspital Basel
  • Bern University Hospital
  • Hopitaux Universitaires de Geneve
  • Centre Hospitalier Universitaire Vaudois
  • Kantonsspital St. Gallen
  • UniversitätsSpital Zürich, Universitäres Herzzentrum

Arms of the Study

Arm 1

Arm 2

Arm Type

Active Comparator

Placebo Comparator

Arm Label

Tadalafil

Placebo

Arm Description

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

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

Outcomes

Primary Outcome Measures

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

Secondary Outcome Measures

Systemic right ventricle ejection fraction
Systemic right ventricle ejection fraction measured by CMR or CMDCT
Cardiopulmonary exercise capacity
Assess the effects of PDE-5 inhibition on cardiopulmonary exercise capacity
Serum neurohormonal activation
Assess the effects of PDE-5 inhibition on serum neurohormonal activation

Full Information

First Posted
February 8, 2017
Last Updated
June 21, 2023
Sponsor
Insel Gruppe AG, University Hospital Bern
Collaborators
Swiss National Science Foundation
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1. Study Identification

Unique Protocol Identification Number
NCT03049540
Brief Title
Effect of Phosphodiesterase-5 Inhibition With Tadalafil on SystEmic Right VEntricular Size and Function
Acronym
SERVE
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
Study Type
Interventional

2. Study Status

Record Verification Date
June 2023
Overall Recruitment Status
Completed
Study Start Date
October 25, 2017 (Actual)
Primary Completion Date
October 28, 2021 (Actual)
Study Completion Date
October 28, 2021 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Insel Gruppe AG, University Hospital Bern
Collaborators
Swiss National Science Foundation

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Heart Defects, Congenital, Transposition of Great Vessels With Ventricular Inversion

7. Study Design

Primary Purpose
Supportive Care
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
100 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Tadalafil
Arm Type
Active Comparator
Arm Description
Tadalafil 20 MG, p.o., once per day for 3 years
Arm Title
Placebo
Arm Type
Placebo Comparator
Arm Description
Placebo 20 MG, p.o., once per day for 3 years
Intervention Type
Drug
Intervention Name(s)
Tadalafil 20 MG
Intervention Description
Multi-center, double-blind, 1:1 randomized, placebo-controlled clinical trial with Tadalafil
Intervention Type
Drug
Intervention Name(s)
Placebo 20 MG
Intervention Description
Multi-center, double-blind, 1:1 randomized, placebo-controlled clinical trial with Tadalafil
Primary Outcome Measure Information:
Title
Systemic right ventricle endsystolic volume
Description
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
Time Frame
3 years
Secondary Outcome Measure Information:
Title
Systemic right ventricle ejection fraction
Description
Systemic right ventricle ejection fraction measured by CMR or CMDCT
Time Frame
3 years
Title
Cardiopulmonary exercise capacity
Description
Assess the effects of PDE-5 inhibition on cardiopulmonary exercise capacity
Time Frame
3 years
Title
Serum neurohormonal activation
Description
Assess the effects of PDE-5 inhibition on serum neurohormonal activation
Time Frame
3 years

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
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.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Markus Schwerzmann, MD
Organizational Affiliation
Bern University Hospital, Zentrum fuer angeborene Herzfehler
Official's Role
Principal Investigator
Facility Information:
Facility Name
Universitätsklinik für Innere Medizin II, Medizinische Universität Wien
City
Wien
ZIP/Postal Code
1090
Country
Austria
Facility Name
Kardiologie Universitätsspital Basel
City
Basel
ZIP/Postal Code
4031
Country
Switzerland
Facility Name
Bern University Hospital
City
Bern
ZIP/Postal Code
3010
Country
Switzerland
Facility Name
Hopitaux Universitaires de Geneve
City
Geneve
ZIP/Postal Code
1205
Country
Switzerland
Facility Name
Centre Hospitalier Universitaire Vaudois
City
Lausanne
ZIP/Postal Code
1011
Country
Switzerland
Facility Name
Kantonsspital St. Gallen
City
St Gallen
ZIP/Postal Code
9007
Country
Switzerland
Facility Name
UniversitätsSpital Zürich, Universitäres Herzzentrum
City
Zurich
ZIP/Postal Code
8091
Country
Switzerland

12. IPD Sharing Statement

Plan to Share IPD
Undecided
IPD Sharing Plan Description
Undecided
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Effect of Phosphodiesterase-5 Inhibition With Tadalafil on SystEmic Right VEntricular Size and Function

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