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

Pulmonary Hypertension Clinical Trial

— VU-INHIB  

Official title:

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

Clinical Trial Details — Status: Withdrawn

Administrative data

• NCT number: NCT03997097
• Other study ID #: 7574
• Status: Withdrawn
• Phase: Phase 3
• Start date: June 1, 2023
• Est. completion date: June 1, 2028

Study information

• Verified date: May 2023
• Source: University Hospital, Montpellier
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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).

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.

Recruitment information / eligibility

• Status: Withdrawn
• Enrollment: 0
• Est. completion date: June 1, 2028
• Est. primary completion date: June 1, 2026
• Accepts healthy volunteers: No
• Gender: All
• Age group: 15 Years to 80 Years

Eligibility

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.

Related Conditions & MeSH terms

• Heart Diseases
• Hypertension
• Hypertension, Pulmonary
• Pulmonary Hypertension
• Single-ventricle
• Univentricular Heart

Intervention

Drug:
• Sildenafil
Patients randomised in the group 1 will receive sildenafil in 3 oral doses of 20 mg per day
• Placebos
Patients randomised in the group placebo in 3 oral doses of per day

Locations

Country	Name	City	State
n/a

Sponsors (1)

Lead Sponsor	Collaborator
University Hospital, Montpellier

References & Publications (2)

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. — View Citation

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

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	ventilatory efficiency M0	ventilatory efficiency, e.g. the VE/VCO2 slope, measured by CPET	Month 0
Primary	ventilatory efficiency M6	ventilatory efficiency, e.g. the VE/VCO2 slope, measured by	Month 6
Secondary	VO2 max M0	maximum oxygen uptake mesured by Cardio-pulmonary exercise test (CPET)	Month 0
Secondary	VO2 max M6	maximum oxygen uptake mesured by Cardio-pulmonary exercise test (CPET)	Month 6
Secondary	ventilatory anaerobic threshold M0	VAT using Beaver's method	Month 0
Secondary	ventilatory anaerobic threshold M6	VAT using Beaver's method	Month 6
Secondary	oxygen pulse M0	ratio VO2/heart rate M0	Month 0
Secondary	oxygen pulse M6	ratio VO2/heart rate M6	Month 6
Secondary	OUES M0	oxygen uptake efficiency slope mesured by CPET	Month 0
Secondary	OUES M6	oxygen uptake efficiency slope mesured by CPET	Month 6
Secondary	NYHA functional class M0	Functional class from I to IV (New York Heart Association Functional classification).	Month 0
Secondary	NYHA functional class M6	Functional class from I to IV (New York Heart Association Functional classification).	Month 6
Secondary	blood pressure M0	SV function evaluation with non-invasive imaging	Month 0
Secondary	blood pressure M6	function evaluation with non-invasive imaging	Month 6
Secondary	oxygen saturation SaO2	oxygen saturation measured using a transcutaneous sensor	Month 0
Secondary	oxygen saturation SaO2	oxygen saturation measured using a transcutaneous sensor	Month 6
Secondary	6-minute walk test (6MWT)	6-minute walk test	Month 0
Secondary	6-minute walk test (6MWT)	6-minute walk test	Month 6
Secondary	Health-related quality of life	The SF-36 questionnaire	Month 0
Secondary	Health-related quality of life	The SF-36 questionnaire	Month 6
Secondary	Systemic blood flow	SV function with echocardiography	Month 0
Secondary	Systemic blood flow	SV function with echocardiography	Month 6
Secondary	SV systolic ejection fraction	SV function with echocardiography	Month 0
Secondary	SV systolic ejection fraction	SV function with echocardiography	Month 6
Secondary	2D strain SV function	SV function with echocardiography	Month 0
Secondary	2D strain SV function	SV function with echocardiography	Month 6
Secondary	Systemic blood flows in phase contrast	SV function evaluation with MRI	Month 0
Secondary	Systemic blood flows in phase contrast	SV function evaluation with MRI	Month 6
Secondary	Pulmonary blood flows in phase contrast	SV function evaluation with MRI	Month 0
Secondary	Pulmonary blood flows in phase contrast	SV function evaluation with MRI	Month 6
Secondary	SV systolic ejection fraction	SV function evaluation with MRI	Month 0
Secondary	SV systolic ejection fraction	SV function evaluation with MRI	Month 6
Secondary	SV systolic ejection volume	SV function evaluation with MRI	Month 0
Secondary	SV systolic ejection volume	SV function evaluation with MRI	Month 6
Secondary	NT Pro BNP	blood test checked	Month 0
Secondary	NT Pro BNP	blood test checked	Month 6
Secondary	forced expiratory volume in 1 s (FEV1 )	FEV1 spirometry	month 0
Secondary	forced expiratory volume in 1 s (FEV1 )	FEV1 spirometry	month 6
Secondary	Forced vital capacity FVC	FVC spirometry	month 0
Secondary	Forced vital capacity FVC	FVC spirometry	month 6
Secondary	FEV1%	FEV1/FEVC ratio	month 0
Secondary	FEV1%	FEV1/FEVC ratio	month 6
Secondary	DEMM25/75	DEMM25/75 measured by spirometry	month 0
Secondary	DEMM25/75	DEMM25/75 measured by spirometry	month 6
Secondary	Capillary lung volume	pulmonary CO/NO transfer (patient seated and lying down)	month 0
Secondary	Capillary lung volume	pulmonary CO/NO transfer (patient seated and lying down)	month 6
Secondary	Cardiac catheterization	pulmonary arterial pressure mmHg	month 0
Secondary	Cardiac catheterization	pulmonary arterial pressure mmHg	month 6
Secondary	percentage of patients compliant at 6 months of study treatment	percentage of patients compliant	month 6
Secondary	AE	type of Averse events	month 6
Secondary	SAE	type of serious Averse events	month 6