Efficacy of Phosphodiesterase-type 5 Inhibitors in Patients With Univentricular Congenital Heart Disease (VU-INHIB)

May 11, 2023 updated by: University Hospital, Montpellier

Phosphodiesterase-type 5 Inhibitors in Adult and Adolescent Patients With Univentricular Heart Disease: a Multi-center, Randomized, Double Blind Phase III Study

In univentricular hearts, selective lung vasodilators such as phosphodiesterase type 5 (PDE5) inhibitors would decrease pulmonary resistance and improve exercise tolerance. However, the level of evidence for the use of PDE5 inhibitors in patients with a single ventricle (SV) remains limited. the investigators present the SV-INHIBITION study rationale, design and methods.The SV-INHIBITION trial is a nationwide multicentre, randomised, double blind, placebo-controlled, phase III study, aiming to evaluate the efficacy of sildenafil on the ventilatory efficiency during exercise, in teenagers and adult patients (>15 y.o.) with a SV. Patients with pulmonary arterial hypertension (mean pulmonary arterial pressure (mPAP) > 15 mmHg and trans-pulmonary gradient > 5 mmHg) measured by cardiac catheterisation, will be eligible. The primary outcome is the variation of the VE/VCO2 slope, measured by a cardiopulmonary exercise test, between baseline and 6 months of treatment. A total of 50 patients are required to observe a decrease of 5 ± 5 points in the VE/VCO2 slope, with a power of 90% power and an alpha risk of 5%. The secondary outcomes are: clinical outcomes, 6 minute walk test, SV function, NT Pro BNP, VO2max, stroke volume, mPAP, trans-pulmonary gradient, SF36 quality of life score, safety and acceptability. This study aims to answer the question whether PDE5 inhibitors should be prescribed in patients with a SV. This trial has been built focusing on the 3 levels of research defined by the WHO: disability (exercise tolerance), deficit (SV function), and handicap (quality of life).

Study Overview

Status

Status

Indicates the current recruitment status or the expanded access status.
Withdrawn

Conditions

Conditions

The disease, disorder, syndrome, illness, or injury that is being studied. On ClinicalTrials.gov, conditions may also include other health-related issues, such as lifespan, quality of life, and health risks.

Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.

Detailed Description

50 Patients with a single ventricle (e.g. univentricular heart), as defined by the ACC-CHD classification, with a mean pulmonary arterial pressure (mPAP) > 15 mmHg and a trans-pulmonary gradient (TPG) > 5 mmHg, and aged 15 years old and above, will be prospectively recruited in the participating centres during their regular follow-up.

Patients wil be randomised into 2 groups:

  • Patients randomised in the group 1 will receive sildenafil in 3 oral doses of 20 mg per day (t.i.d.), as defined in the marketing authorization indicated for PAH in adolescent and adult patients, and for a period of 6 months.
  • Patients in the group 2 will receive a placebo (t.i.d.), for the same period of 6 months. To guarantee the double blind, capsules will be similar in size and colour and will be differentiated only by a vial number regarding to the randomization list. The clinical trials unit of the sponsor's pharmacy will centralize treatment allocation and supply to the participating centres. Drug management (reception, storage, delivery and traceability) will be ensured by the pharmacies of the participating centres.

After the 6 month-treatment period, patients will be followed for 3 months, and undergo at least 2 safety visits (1 and 3 months after intervention, and if necessary, any supplementary unscheduled visits). In accordance with the recommendations of the drug notice, the treatment will be suspended progressively over 1 week (20 mg b.i.d for 3 days, then 20 mg q.d. for 4 days, and then stopped) with a reinforcement of the surveillance. Patients will be able to contact an emergency number during this period and the investigator may decide to continue open treatment with sildenafil if clinically justified.

The study will be conducted in compliance with the Good Clinical Practices protocol and Declaration of Helsinki principles. It was approved by a drawn National Ethics Committee (CPP) and by the French National Agency of Medicine and Health Products Safety (ANSM). Informed consent will be obtained from all patients and their parents or legal guardians for minors.

Study Type

Study Type

Describes the nature of a clinical study. Study types include interventional studies (also called clinical trials), observational studies (including patient registries), and expanded access.
Interventional

Phase

Phase

The stage of a clinical trial studying a drug or biological product, based on definitions developed by the U.S. Food and Drug Administration (FDA). The phase is based on the study's objective, the number of participants, and other characteristics. There are five phases: Early Phase 1 (formerly listed as Phase 0), Phase 1, Phase 2, Phase 3, and Phase 4. Not Applicable is used to describe trials without FDA-defined phases, including trials of devices or behavioral interventions.
  • 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 Contact

Study Contact

The name and contact information for the person who can answer enrollment questions for a clinical study. Each location where the study is being conducted may also have a specific contact, who may be better able to answer those questions.

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

Eligibility Criteria

The key requirements that people who want to participate in a clinical study must meet or the characteristics they must have. Eligibility criteria consist of both inclusion criteria (which are required for a person to participate in the study) and exclusion criteria (which prevent a person from participating). Types of eligibility criteria include whether a study accepts healthy volunteers, has age or age group requirements, or is limited by sex.

Ages Eligible for Study

15 years to 80 years (Child, Adult, Older Adult)

Accepts Healthy Volunteers

No

Description

Inclusion Criteria:

  1. 15 years of age and over.
  2. Patient's weight over 20 kg
  3. Patients with CHD with a single ventricular type defined by the classification of congenital heart diseases in Orphanet (53).
  4. PAH defined by diagnostic catheterization with mean PAP > 15 mmHg and a trans-pulmonary gradient > 5 mmHg, performed as part of the usual follow-up. No definition of PAH in SV is available as a result of a particular physiology. Therefore, we chose the 15mmHg cut-off, which is used in clinical routine to allow or contra-indicate the Fontan procedure [50,51].
  5. Appropriate written informed consent (adult patients, legal parents for teenagers), and formal assent (teenagers), should to be provided.
  6. Beneficiary of a health insurance.

Exclusion Criteria:

  1. Patient who is unable to perform a cardio-pulmonary exercise test.
  2. Cardiac surgery planned during the trial.
  3. Patient treated by any pulmonary arterial vasodilator drug, as defined in the 2015 PH guidelines (52), within 6 months before inclusion, regardless the duration and the type(s) (oral, intravenous, subcutaneous, inhaled) of administration.
  4. Patient treated by Sildenafil or any other type of phosphodiesterase-type 5 inhibitor (such as tadalafil) within 6 months before inclusion, regardless the duration of administration.
  5. Interventional cardiac catheterization planned during the trial (collateral occlusion, fenestration occlusion, stenting, angioplasty, ablation of rhythm disorder), other than during the screening.
  6. Participation in another clinical trial or administration of an off-label drug in the 4 weeks preceding the screening.
  7. Pregnancy, desire for pregnancy, absence of contraception during the study period.
  8. Severe hepatic insufficiency (Child-Pugh C class).

  9. Hypersensitivity to the active substance or to any of the excipients of the tablet:

    microcrystalline cellulose, calcium hydrogen phosphate anhydrous, croscarmellose sodium, stearate of magnesium, hypromellose, titanium dioxide (E171), monohydrate lactose, glycerol triacetate.

  10. Combination with products called "nitric oxide donors" (such as amyl nitrite) or with nitrates in any form, due to the hypotensive effects of nitrates.
  11. Concomitant administration of PDE5 inhibitors, such as Sildenafil, with guanylate cyclase stimulators, such as Riociguat.
  12. Combination with the most potent inhibitors of CYP3A4 (eg ketoconazole, itraconazole, ritonavir).
  13. Disposition to priapism, sclerosis of corpora cavernosa, disease of La Peyronie, sickle cell anemia, multiple myeloma, leukemia.
  14. Uncontrolled hypotension or risk of hypotension: water depletion, obstruction to ejection of the left ventricle, dysfunction of the autonomic nervous system, patient under alpha-blocker.
  15. Severe cardiovascular events, recent (<3 months) or not stabilized: myocardial infarction, unstable angina, sudden cardiac death, ventricular arrhythmia, cerebrovascular hemorrhage.
  16. Active hemorrhagic disorders.
  17. Active gastro-duodenal ulcer.
  18. Patients with loss of vision of an eye due to non-arteritic anterior ischemic optic neuropathy (NAION), whether or not this event has been associated with previous exposure to a PDE5 inhibitor.

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: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Triple

Arms and Interventions

Participant Group / Arm

Participant Group / Arm

A group or subgroup of participants in a clinical trial that receives a specific intervention/treatment, or no intervention, according to the trial's protocol.
Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.
Experimental: sildenafil
• Patients randomised in the group 1 will receive sildenafil in 3 oral doses of 20 mg per day (t.i.d.), as defined in the marketing authorization indicated for PAH in adolescent and adult patients, and for a period of 6 months.
Drug: Sildenafil
Patients randomised in the group 1 will receive sildenafil in 3 oral doses of 20 mg per day
Other Names:
  • sildenafil group
Placebo Comparator: placebo
• Patients in the group 2 will receive a placebo (t.i.d.), for the same period of 6 months. To guarantee the double blind, capsules will be similar in size and colour and will be differentiated only by a vial number regarding to the randomization list
Drug: Placebos
Patients randomised in the group placebo in 3 oral doses of per day
Other Names:
  • placebo group

What is the study measuring?

Primary Outcome Measures

Primary Outcome Measures

In a clinical study's protocol, the planned outcome measure that is the most important for evaluating the effect of an intervention/treatment. Most clinical studies have one primary outcome measure, but some have more than one.
Outcome Measure
Measure Description
Time Frame
ventilatory efficiency M0
Time Frame: Month 0
ventilatory efficiency, e.g. the VE/VCO2 slope, measured by CPET
Month 0
ventilatory efficiency M6
Time Frame: Month 6
ventilatory efficiency, e.g. the VE/VCO2 slope, measured by
Month 6

Secondary Outcome Measures

Secondary Outcome Measures

In a clinical study's protocol, a planned outcome measure that is not as important as the primary outcome measure for evaluating the effect of an intervention but is still of interest. Most clinical studies have more than one secondary outcome measure.
Outcome Measure
Measure Description
Time Frame
VO2 max M0
Time Frame: Month 0
maximum oxygen uptake mesured by Cardio-pulmonary exercise test (CPET)
Month 0
VO2 max M6
Time Frame: Month 6
maximum oxygen uptake mesured by Cardio-pulmonary exercise test (CPET)
Month 6
ventilatory anaerobic threshold M0
Time Frame: Month 0
VAT using Beaver's method
Month 0
ventilatory anaerobic threshold M6
Time Frame: Month 6
VAT using Beaver's method
Month 6
oxygen pulse M0
Time Frame: Month 0
ratio VO2/heart rate M0
Month 0
oxygen pulse M6
Time Frame: Month 6
ratio VO2/heart rate M6
Month 6
OUES M0
Time Frame: Month 0
oxygen uptake efficiency slope mesured by CPET
Month 0
OUES M6
Time Frame: Month 6
oxygen uptake efficiency slope mesured by CPET
Month 6
NYHA functional class M0
Time Frame: Month 0
Functional class from I to IV (New York Heart Association Functional classification).
Month 0
NYHA functional class M6
Time Frame: Month 6
Functional class from I to IV (New York Heart Association Functional classification).
Month 6
blood pressure M0
Time Frame: Month 0
SV function evaluation with non-invasive imaging
Month 0
blood pressure M6
Time Frame: Month 6
function evaluation with non-invasive imaging
Month 6
oxygen saturation SaO2
Time Frame: Month 0
oxygen saturation measured using a transcutaneous sensor
Month 0
oxygen saturation SaO2
Time Frame: Month 6
oxygen saturation measured using a transcutaneous sensor
Month 6
6-minute walk test (6MWT)
Time Frame: Month 0
6-minute walk test
Month 0
6-minute walk test (6MWT)
Time Frame: Month 6
6-minute walk test
Month 6
Health-related quality of life
Time Frame: Month 0
The SF-36 questionnaire
Month 0
Health-related quality of life
Time Frame: Month 6
The SF-36 questionnaire
Month 6
Systemic blood flow
Time Frame: Month 0
SV function with echocardiography
Month 0
Systemic blood flow
Time Frame: Month 6
SV function with echocardiography
Month 6
SV systolic ejection fraction
Time Frame: Month 0
SV function with echocardiography
Month 0
SV systolic ejection fraction
Time Frame: Month 6
SV function with echocardiography
Month 6
2D strain SV function
Time Frame: Month 0
SV function with echocardiography
Month 0
2D strain SV function
Time Frame: Month 6
SV function with echocardiography
Month 6
Systemic blood flows in phase contrast
Time Frame: Month 0
SV function evaluation with MRI
Month 0
Systemic blood flows in phase contrast
Time Frame: Month 6
SV function evaluation with MRI
Month 6
Pulmonary blood flows in phase contrast
Time Frame: Month 0
SV function evaluation with MRI
Month 0
Pulmonary blood flows in phase contrast
Time Frame: Month 6
SV function evaluation with MRI
Month 6
SV systolic ejection fraction
Time Frame: Month 0
SV function evaluation with MRI
Month 0
SV systolic ejection fraction
Time Frame: Month 6
SV function evaluation with MRI
Month 6
SV systolic ejection volume
Time Frame: Month 0
SV function evaluation with MRI
Month 0
SV systolic ejection volume
Time Frame: Month 6
SV function evaluation with MRI
Month 6
NT Pro BNP
Time Frame: Month 0
blood test checked
Month 0
NT Pro BNP
Time Frame: Month 6
blood test checked
Month 6
forced expiratory volume in 1 s (FEV1 )
Time Frame: month 0
FEV1 spirometry
month 0
forced expiratory volume in 1 s (FEV1 )
Time Frame: month 6
FEV1 spirometry
month 6
Forced vital capacity FVC
Time Frame: month 0
FVC spirometry
month 0
Forced vital capacity FVC
Time Frame: month 6
FVC spirometry
month 6
FEV1%
Time Frame: month 0
FEV1/FEVC ratio
month 0
FEV1%
Time Frame: month 6
FEV1/FEVC ratio
month 6
DEMM25/75
Time Frame: month 0
DEMM25/75 measured by spirometry
month 0
DEMM25/75
Time Frame: month 6
DEMM25/75 measured by spirometry
month 6
Capillary lung volume
Time Frame: month 0
pulmonary CO/NO transfer (patient seated and lying down)
month 0
Capillary lung volume
Time Frame: month 6
pulmonary CO/NO transfer (patient seated and lying down)
month 6
Cardiac catheterization
Time Frame: month 0
pulmonary arterial pressure mmHg
month 0
Cardiac catheterization
Time Frame: month 6
pulmonary arterial pressure mmHg
month 6
percentage of patients compliant at 6 months of study treatment
Time Frame: month 6
percentage of patients compliant
month 6
AE
Time Frame: month 6
type of Averse events
month 6
SAE
Time Frame: month 6
type of serious Averse events
month 6

Collaborators and Investigators

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

Sponsor

Sponsor

The organization or person who initiates the study and who has authority and control over the study.
University Hospital, Montpellier

Investigators

Investigators

A researcher involved in a clinical study. Related terms include site principal investigator, site sub-investigator, study chair, study director, and study principal investigator.
  • Principal Investigator: Pascal AMEDRO, MD, PhD, University Hospital, Montpellier

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

Helpful Links

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 (Anticipated)

Study Start

The actual date on which the first participant was enrolled in a clinical study. The "anticipated" study start date is the date that the researchers think will be the study start date.
June 1, 2023

Primary Completion (Anticipated)

Primary Completion

The date on which the last participant in a clinical study was examined or received an intervention to collect final data for the primary outcome measure. Whether the clinical study ended according to the protocol or was terminated does not affect this date. For clinical studies with more than one primary outcome measure with different completion dates, this term refers to the date on which data collection is completed for all the primary outcome measures. The "anticipated" primary completion date is the date that the researchers think will be the primary completion date for the study.
June 1, 2026

Study Completion (Anticipated)

Study Completion

The date on which the last participant in a clinical study was examined or received an intervention/treatment to collect final data for the primary outcome measures, secondary outcome measures, and adverse events (that is, the last participant's last visit). The "anticipated" study completion date is the date that the researchers think will be the study completion date.
June 1, 2028

Study Registration Dates

First Submitted

First Submitted

The date on which the study sponsor or investigator first submitted a study record to ClinicalTrials.gov. There is typically a delay of a few days between the first submitted date and the record's availability on ClinicalTrials.gov (the first posted date).
June 18, 2019

First Submitted That Met QC Criteria

First Submitted That Met QC Criteria

The date on which the study sponsor or investigator first submits a study record that is consistent with National Library of Medicine (NLM) quality control (QC) review criteria. The sponsor or investigator may need to revise and submit a study record one or more times before NLM's QC review criteria are met. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
June 24, 2019

First Posted (Actual)

First Posted

The date on which the study record was first available on ClinicalTrials.gov after National Library of Medicine (NLM) quality control (QC) review has concluded. There is typically a delay of a few days between the date the study sponsor or investigator submitted the study record and the first posted date.
June 25, 2019

Study Record Updates

Last Update Posted (Actual)

Last Update Posted

The most recent date on which changes to a study record were made available on ClinicalTrials.gov. There may be a delay between when the changes were submitted to ClinicalTrials.gov by the study's sponsor or investigator (the last update submitted date) and the last update posted date.
May 15, 2023

Last Update Submitted That Met QC Criteria

Last Update Submitted That Met QC Criteria

The most recent date on which the study sponsor or investigator submitted changes to a study record that are consistent with National Library of Medicine (NLM) quality control (QC) review criteria. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
May 11, 2023

Last Verified

Last Verified

The most recent date on which the study sponsor or investigator confirmed the information about a clinical study on ClinicalTrials.gov as accurate and current. If a study with a recruitment status of recruiting; not yet recruiting; or active, not recruiting has not been confirmed within the past 2 years, the study's recruitment status is shown as unknown.
May 1, 2023

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

Other Study ID Numbers

Identifiers or ID numbers other than the NCT number that are assigned to a clinical study by the study's sponsor, funders, or others. These numbers may include unique identifiers from other trial registries and National Institutes of Health grant numbers.
  • 7574

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

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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