Efficacy of Phosphodiesterase-type 5 Inhibitors in Patients With Univentricular Congenital Heart Disease

NCT03997097 | Withdrawn Phase 3

• 1 other identifier: 7574
• Study Type: interventional
• Target: N/A
• Locations: 0 countries
• Sites: N/A

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).

Conditions

Single-ventricle; Pulmonary Hypertension; Univentricular Heart

Keywords

Congenital heart defect; single ventricle; Pulmonary hypertension; sildenafil; pulmonary vasodilator; Eexercise capacity

Outcome Measures

Primary Outcomes (2)

• ventilatory efficiency M0

  ventilatory efficiency, e.g. the VE/VCO2 slope, measured by CPET

  Month 0

• ventilatory efficiency M6

  ventilatory efficiency, e.g. the VE/VCO2 slope, measured by

  Month 6

Secondary Outcomes (49)

• VO2 max M0

  Month 0

• VO2 max M6

  Month 6

• ventilatory anaerobic threshold M0

  Month 0

• ventilatory anaerobic threshold M6

  Month 6

• oxygen pulse M0

  Month 0

Study Arms (2)

sildenafil

EXPERIMENTAL

• 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

placebo

PLACEBO COMPARATOR

• 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

Interventions

Sildenafil DRUG

Patients randomised in the group 1 will receive sildenafil in 3 oral doses of 20 mg per day

Also known as: sildenafil group

sildenafil

Placebos DRUG

Patients randomised in the group placebo in 3 oral doses of per day

Also known as: placebo group

placebo

Eligibility Criteria

• Age: 15 Years - 80 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• years of age and over.
• Patient's weight over 20 kg
• Patients with CHD with a single ventricular type defined by the classification of congenital heart diseases in Orphanet (53).
• 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 \[50,51\].
• Appropriate written informed consent (adult patients, legal parents for teenagers), and formal assent (teenagers), should to be provided.
• Beneficiary of a health insurance.

You may not qualify if:

• Patient who is unable to perform a cardio-pulmonary exercise test.
• Cardiac surgery planned during the trial.
• 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.
• Concomitant administration of PDE5 inhibitors, such as Sildenafil, with guanylate cyclase stimulators, such as Riociguat.
• Combination with the most potent inhibitors of CYP3A4 (eg ketoconazole, itraconazole, ritonavir).
• Disposition to priapism, sclerosis of corpora cavernosa, disease of La Peyronie, sickle cell anemia, multiple myeloma, leukemia.
• 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.
• Severe cardiovascular events, recent (\<3 months) or not stabilized: myocardial infarction, unstable angina, sudden cardiac death, ventricular arrhythmia, cerebrovascular hemorrhage.
• Active hemorrhagic disorders.

Sponsors & Collaborators

• University Hospital, Montpellier: lead

Related Publications (1)

• Amedro P, Gavotto A, Abassi H, Picot MC, Matecki S, Malekzadeh-Milani S, Levy M, Ladouceur M, Ovaert C, Aldebert P, Thambo JB, Fraisse A, Humbert M, Cohen S, Baruteau AE, Karsenty C, Bonnet D, Hascoet S; SV-INHIBITION study investigators. Efficacy of phosphodiesterase type 5 inhibitors in univentricular congenital heart disease: the SV-INHIBITION study design. ESC Heart Fail. 2020 Apr;7(2):747-756. doi: 10.1002/ehf2.12630. Epub 2020 Mar 9.

  PMID: 32147955 BACKGROUND

MeSH Terms

Conditions

Univentricular Heart; Hypertension, Pulmonary; Heart Defects, Congenital

Interventions

Sildenafil Citrate

Condition Hierarchy (Ancestors)

Cardiovascular Abnormalities; Cardiovascular Diseases; Heart Diseases; Congenital Abnormalities; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Lung Diseases; Respiratory Tract Diseases; Hypertension; Vascular Diseases

Intervention Hierarchy (Ancestors)

Sulfonamides; Amides; Organic Chemicals; Sulfones; Sulfur Compounds; Piperazines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Purines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring

Study Officials

• Pascal AMEDRO, MD, PhD

  University Hospital, Montpellier

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: June 18, 2019
• First Posted: June 25, 2019
• Study Start: June 1, 2023
• Primary Completion (Estimated): June 1, 2026
• Study Completion (Estimated): June 1, 2028
• Last Updated: May 15, 2023

Record last verified: 2023-05

Data Sharing

• IPD Sharing: Will not share