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

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• Status: Withdrawn
• Conditions: Pulmonary Hypertension; Single-ventricle; Univentricular Heart
• Intervention / Treatment: Drug: Sildenafil; Drug: Placebos

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: Interventional
• Phase: Phase 3

Contacts and Locations

Participation Criteria

Eligibility Criteria

• 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

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / 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 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

Outcome Measure	Measure Description	Time Frame
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
VO2 max M0	maximum oxygen uptake mesured by Cardio-pulmonary exercise test (CPET)	Month 0
VO2 max M6	maximum oxygen uptake mesured by Cardio-pulmonary exercise test (CPET)	Month 6
ventilatory anaerobic threshold M0	VAT using Beaver's method	Month 0
ventilatory anaerobic threshold M6	VAT using Beaver's method	Month 6
oxygen pulse M0	ratio VO2/heart rate M0	Month 0
oxygen pulse M6	ratio VO2/heart rate M6	Month 6
OUES M0	oxygen uptake efficiency slope mesured by CPET	Month 0
OUES M6	oxygen uptake efficiency slope mesured by CPET	Month 6
NYHA functional class M0	Functional class from I to IV (New York Heart Association Functional classification).	Month 0
NYHA functional class M6	Functional class from I to IV (New York Heart Association Functional classification).	Month 6
blood pressure M0	SV function evaluation with non-invasive imaging	Month 0
blood pressure M6	function evaluation with non-invasive imaging	Month 6
oxygen saturation SaO2	oxygen saturation measured using a transcutaneous sensor	Month 0
oxygen saturation SaO2	oxygen saturation measured using a transcutaneous sensor	Month 6
6-minute walk test (6MWT)	6-minute walk test	Month 0
6-minute walk test (6MWT)	6-minute walk test	Month 6
Health-related quality of life	The SF-36 questionnaire	Month 0
Health-related quality of life	The SF-36 questionnaire	Month 6
Systemic blood flow	SV function with echocardiography	Month 0
Systemic blood flow	SV function with echocardiography	Month 6
SV systolic ejection fraction	SV function with echocardiography	Month 0
SV systolic ejection fraction	SV function with echocardiography	Month 6
2D strain SV function	SV function with echocardiography	Month 0
2D strain SV function	SV function with echocardiography	Month 6
Systemic blood flows in phase contrast	SV function evaluation with MRI	Month 0
Systemic blood flows in phase contrast	SV function evaluation with MRI	Month 6
Pulmonary blood flows in phase contrast	SV function evaluation with MRI	Month 0
Pulmonary blood flows in phase contrast	SV function evaluation with MRI	Month 6
SV systolic ejection fraction	SV function evaluation with MRI	Month 0
SV systolic ejection fraction	SV function evaluation with MRI	Month 6
SV systolic ejection volume	SV function evaluation with MRI	Month 0
SV systolic ejection volume	SV function evaluation with MRI	Month 6
NT Pro BNP	blood test checked	Month 0
NT Pro BNP	blood test checked	Month 6
forced expiratory volume in 1 s (FEV1 )	FEV1 spirometry	month 0
forced expiratory volume in 1 s (FEV1 )	FEV1 spirometry	month 6
Forced vital capacity FVC	FVC spirometry	month 0
Forced vital capacity FVC	FVC spirometry	month 6
FEV1%	FEV1/FEVC ratio	month 0
FEV1%	FEV1/FEVC ratio	month 6
DEMM25/75	DEMM25/75 measured by spirometry	month 0
DEMM25/75	DEMM25/75 measured by spirometry	month 6
Capillary lung volume	pulmonary CO/NO transfer (patient seated and lying down)	month 0
Capillary lung volume	pulmonary CO/NO transfer (patient seated and lying down)	month 6
Cardiac catheterization	pulmonary arterial pressure mmHg	month 0
Cardiac catheterization	pulmonary arterial pressure mmHg	month 6
percentage of patients compliant at 6 months of study treatment	percentage of patients compliant	month 6
AE	type of Averse events	month 6
SAE	type of serious Averse events	month 6

Collaborators and Investigators

• Sponsor: University Hospital, Montpellier
• Investigators: Principal Investigator: Pascal AMEDRO, MD, PhD, University Hospital, Montpellier

Publications and helpful links

General Publications

• Efficacy of phosphodiesterase type 5 inhibitors in univentricular congenital heart disease: the SVINHIBITION study design Pascal Amedro1,2*, Arthur Gavotto1, Hamouda Abassi1, Marie-Christine Picot3, Stefan Matecki1,2, Sophie Malekzadeh-Milani4, Marilyne Levy4, Magalie Ladouceur5, Caroline Ovaert6,7, Philippe Aldebert6, Jean-Benoit Thambo8, Alain Fraisse9, Marc Humbert10,11, Sarah Cohen11, Alban-Elouen Baruteau12, Clement Karsenty13, Damien Bonnet4, Sebastien Hascoet11 and on behalf of the SV-INHIBITION study investigators ESC Heart Failure (2020) Published online in Wiley Online Library (wileyonlinelibrary.com) DOI: 10.1002/ehf2.12630
• 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.

Helpful Links

• Related Info

Study record dates

Study Major Dates

• Study Start (Anticipated): June 1, 2023
• Primary Completion (Anticipated): June 1, 2026
• Study Completion (Anticipated): June 1, 2028

Study Registration Dates

• First Submitted: June 18, 2019
• First Submitted That Met QC Criteria: June 24, 2019
• First Posted (Actual): June 25, 2019

Study Record Updates

• Last Update Posted (Actual): May 15, 2023
• Last Update Submitted That Met QC Criteria: May 11, 2023
• Last Verified: May 1, 2023

More Information

Terms related to this study

• Keywords: sildenafil; Pulmonary hypertension; Congenital heart defect; single ventricle; pulmonary vasodilator; Eexercise capacity
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Respiratory Tract Diseases; Lung Diseases; Congenital Abnormalities; Heart Defects, Congenital; Cardiovascular Abnormalities; Heart Diseases; Hypertension; Hypertension, Pulmonary; Univentricular Heart; Molecular Mechanisms of Pharmacological Action; Vasodilator Agents; Urological Agents; Enzyme Inhibitors; Phosphodiesterase Inhibitors; Phosphodiesterase 5 Inhibitors; Sildenafil Citrate
• Other Study ID 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