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

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. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03997097
Recruitment Status : Not yet recruiting
First Posted : June 25, 2019
Last Update Posted : March 12, 2020
Sponsor:
Information provided by (Responsible Party):
University Hospital, Montpellier

Brief Summary:
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).

Condition or disease Intervention/treatment Phase
Single-ventricle Pulmonary Hypertension Univentricular Heart Drug: Sildenafil Drug: Placebos Phase 3

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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 50 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary Purpose: Treatment
Official Title: Phosphodiesterase-type 5 Inhibitors in Adult and Adolescent Patients With Univentricular Heart Disease: a Multi-center, Randomized, Double Blind Phase III Study
Estimated Study Start Date : July 1, 2020
Estimated Primary Completion Date : July 1, 2023
Estimated Study Completion Date : July 1, 2025


Arm Intervention/treatment
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 Name: 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 Name: placebo group




Primary Outcome Measures :
  1. ventilatory efficiency M0 [ Time Frame: Month 0 ]
    ventilatory efficiency, e.g. the VE/VCO2 slope, measured by CPET

  2. ventilatory efficiency M6 [ Time Frame: Month 6 ]
    ventilatory efficiency, e.g. the VE/VCO2 slope, measured by


Secondary Outcome Measures :
  1. VO2 max M0 [ Time Frame: Month 0 ]
    maximum oxygen uptake mesured by Cardio-pulmonary exercise test (CPET)

  2. VO2 max M6 [ Time Frame: Month 6 ]
    maximum oxygen uptake mesured by Cardio-pulmonary exercise test (CPET)

  3. ventilatory anaerobic threshold M0 [ Time Frame: Month 0 ]
    VAT using Beaver's method

  4. ventilatory anaerobic threshold M6 [ Time Frame: Month 6 ]
    VAT using Beaver's method

  5. oxygen pulse M0 [ Time Frame: Month 0 ]
    ratio VO2/heart rate M0

  6. oxygen pulse M6 [ Time Frame: Month 6 ]
    ratio VO2/heart rate M6

  7. OUES M0 [ Time Frame: Month 0 ]
    oxygen uptake efficiency slope mesured by CPET

  8. OUES M6 [ Time Frame: Month 6 ]
    oxygen uptake efficiency slope mesured by CPET

  9. NYHA functional class M0 [ Time Frame: Month 0 ]
    o Functional class from I to IV (New York Heart Association Functional classification).

  10. NYHA functional class M6 [ Time Frame: Month 6 ]
    o Functional class from I to IV (New York Heart Association Functional classification).

  11. blood pressure M0 [ Time Frame: Month 0 ]
    SV function evaluation with non-invasive imaging

  12. blood pressure M6 [ Time Frame: Month 6 ]
    function evaluation with non-invasive imaging

  13. oxygen saturation [ Time Frame: Month 0 ]
    oxygen saturation measured using a transcutaneous sensor

  14. oxygen saturation [ Time Frame: Month 6 ]
    oxygen saturation measured using a transcutaneous sensor

  15. SV function M0 [ Time Frame: Month 0 ]
    echocardiography

  16. SV function M6 [ Time Frame: Month 6 ]
    echocardiography



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Ages Eligible for Study:   15 Years to 80 Years   (Child, Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

1• 15 years of age and over.

  • Patients weight over 20 kg.
  • Patients with a single ventricle (e.g. univentricular heart) as defined by the ACC-CHD classification.
  • PAH defined by diagnostic catheterization with mPAP > 15 mmHg and TPG > 5 mmHg, performed as part of the usual follow-up.
  • Written informed consent for adult patients, or legal guardians for teenagers, and formal assent for teenagers.

Exclusion Criteria:

  • • Patient who is unable to perform a CPET.
  • Absolute contraindications for CPET: fever, uncontrolled asthma, respiratory failure, acute myocarditis or pericarditis, uncontrolled arrhythmias causing symptoms or haemodynamic compromise, uncontrolled heart failure, acute pulmonary embolus or pulmonary infarction, and patients with mental impairment leading to inability to cooperate.
  • Cardiac surgery planned during the study.
  • Patient treated by any pulmonary arterial vasodilator drug, within 6 months before inclusion, regardless the duration and the type(s) (oral, intravenous, subcutaneous, inhaled) of administration, such as sildenafil, tadalafil, riociguat, bosentan, macitentan, ambrisentan, epoprostenol, iloprost, treprostinil.
  • Patient treated by sildenafil within 6 months before inclusion, regardless the duration of administration.
  • Interventional cardiac catheterization planned during the trial (collateral occlusion, fenestration occlusion, stenting, angioplasty, ablation of rhythm disorder), other than during the screening (*).
  • Participation in another clinical trial or administration of an off-label drug in the 4 weeks preceding the screening.
  • Pregnancy, desire for pregnancy, absence of contraception during the study period.
  • Severe hepatic insufficiency (Child-Pugh C class).
  • 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.
  • Combination with products called "nitric oxide donors" (such as amyl nitrite) or with nitrates in any form, due to the hypotensive effects of nitrates.
  • Disposition to priapism, sclerosis of corpora cavernosa, disease of La Peyronie, sickle cell anaemia, multiple myeloma, leukaemia.
  • Uncontrolled hypotension or risk of hypotension: water depletion, obstruction to ejection of the left ventricle, dysfunction of the autonomic nervous system, and patient under alpha-blocker.
  • Severe cardiovascular events, recent (<3 months) or not stabilized: myocardial infarction, unstable angina, sudden cardiac death, ventricular arrhythmia, and cerebrovascular haemorrhage.
  • Active haemorrhagic disorders.
  • Active gastro-duodenal ulcer.
  • 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.

    • If a patient requires an interventional catheterisation (fenestration occlusion, stenting of Fontan circulation obstacle, collaterals embolization, etc.), a new hemodynamic catheterisation will be required at least 3 months after procedure to confirm patient's eligibility (mPAP >15mmHg and TPG >5 mmHg).

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): NCT03997097


Contacts
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Contact: Pascal AMEDRO, MD, PhD 00 33 4 67 33 66 32 p-amedro@chu-montpellier.fr

Sponsors and Collaborators
University Hospital, Montpellier
Investigators
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Principal Investigator: Pascal AMEDRO, MD, PhD University Hospital, Montpellier
Additional Information:
Publications:
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Responsible Party: University Hospital, Montpellier
ClinicalTrials.gov Identifier: NCT03997097    
Other Study ID Numbers: 7574
First Posted: June 25, 2019    Key Record Dates
Last Update Posted: March 12, 2020
Last Verified: March 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by University Hospital, Montpellier:
Congenital heart defect
single ventricle
Pulmonary hypertension
sildenafil
pulmonary vasodilator
Eexercise capacity
Additional relevant MeSH terms:
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Hypertension, Pulmonary
Hypertension
Heart Diseases
Vascular Diseases
Cardiovascular Diseases
Lung Diseases
Respiratory Tract Diseases
Sildenafil Citrate
Vasodilator Agents
Phosphodiesterase 5 Inhibitors
Phosphodiesterase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Urological Agents