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    Summary
    EudraCT Number:2018-004828-11
    Sponsor's Protocol Code Number:RECHMPL18_0038_prom_7574
    National Competent Authority:France - ANSM
    Clinical Trial Type:EEA CTA
    Trial Status:
    Date on which this record was first entered in the EudraCT database:2019-03-29
    Trial results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedFrance - ANSM
    A.2EudraCT number2018-004828-11
    A.3Full title of the trial
    Phosphodiesterase-type 5 inhibitors in adult and adolescent patients with univentricular heart disease: a multi-center, randomized, double blind phase III study
    Intérêt des inhibiteurs de la Phosphodiestérase de type 5 dans les cardiopathies univentriculaires: essai clinique de phase III, multicentrique, randomisé, en double aveugle chez l’adulte et l’adolescent.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Phosphodiesterase-type 5 inhibitors in adult and adolescent patients with univentricular heart disease: a multi-center, randomized, double blind phase III study
    Intérêt des inhibiteurs de la Phosphodiestérase de type 5 dans les cardiopathies univentriculaires: essai clinique de phase III, multicentrique, randomisé, en double aveugle chez l’adulte et l’adolescent.
    A.3.2Name or abbreviated title of the trial where available
    VU-Inhibition
    VU-Inhibition
    A.4.1Sponsor's protocol code numberRECHMPL18_0038_prom_7574
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorUniversity Hospital of Montpellier
    B.1.3.4CountryFrance
    B.3.1 and B.3.2Status of the sponsorNon-Commercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportUniversity Hospital of Montpellier
    B.4.2CountryFrance
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationUniversity Hospital of Montpellier
    B.5.2Functional name of contact pointGuillemette TACONNET DECKER
    B.5.3 Address:
    B.5.3.1Street AddressDRI,Pav 32 - 39 Avenue Charles Flahault
    B.5.3.2Town/ cityMontpellier
    B.5.3.3Post code34295
    B.5.3.4CountryFrance
    B.5.4Telephone number0033467335573
    B.5.5Fax number0033467339172
    B.5.6E-mailg-taconnet_decker@chu-montpellier.fr
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameMysildecard
    D.3.4Pharmaceutical form Capsule
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboCapsule
    D.8.4Route of administration of the placeboOral use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    adult and adolescent patients with univentricular heart diseases and pulmonary arterial pressure
    patients adolescents et adultes avec ventricule unique avec hypertension artérielle pulmonaire
    E.1.1.1Medical condition in easily understood language
    adult and adolescent patients with univentricular heart diseases and pulmonary arterial pressure
    patients adolescents et adultes avec ventricule unique avec hypertension artérielle pulmonaire
    E.1.1.2Therapeutic area Diseases [C] - Cardiovascular Diseases [C14]
    MedDRA Classification
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To compare the tolerance to effort and the adaptation of pulmonary perfusion by measuring the VE/VCO2 slope in a CPET before and after a 6-month treatment period, between the sildenafil group and the placebo group, among adolescents and adult SV patients with pulmonary hypertension.
    Comparaison de la tolérance et de l'adaptation de la perfusion pulmonaire à l'effort en mesurant la pente VE/VCO2 lors d’une épreuve d’effort cardio-respiratoire avant et après une période de traitement de 6 mois, entre le groupe sildénafil comparé au groupe placebo, chez des patients adolescents et adultes avec ventricule unique avec hypertension pulmonaire.

    E.2.2Secondary objectives of the trial
    Comparison before and after a 6-month treatment period, between the Sildenafil group and the placebo group for:
    1. The evolution of the clinical, biological and functional status, the health-related quality of life, the function of the univentricular heart in non-invasive imaging and the degree of pulmonary hypertension in cardiac catheterization
    2. The compliance and the tolerance of the drug
    Comparaison avant et après une période de traitement de 6 mois, entre le groupe sildénafil et le groupe placebo de :
     L'évolution de l’état clinique, biologique et fonctionnel (NYHA, SaO2, NT-ProBNP, autres paramètres d’épreuve d’effort cardio-respiratoire, test de marche 6 minutes).
     L’évolution de la qualité de vie liée à la santé.
     L’évolution de la fonction myocardique du ventricule unique par une imagerie non invasive.
     L’évolution des pressions artérielles pulmonaires mesurées par cathétérisme cardiaque.
     La compliance et la tolérance du médicament.
    E.2.3Trial contains a sub-study No
    E.3Principal 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 [50].
    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.
    Les patients doivent remplir tous les critères suivants pour être inclus dans l’étude :
    • Patients âgés de 15 ans et plus.
    • Poids > 20 kg.
    • Patients avec cardiopathie congénitale de type ventricule unique définie selon la classification des cardiopathies congénitales ACC-CHD d’Orphanet.
    • HTAP confirmée par cathétérisme cardiaque avec une PAP moyenne > 15 mmHg et un gradient transpulmonaire > 5 mmHg, réalisé dans le cadre du suivi habituel.
    • Consentement libre et éclairé écrit (patients adultes, parents légaux des adolescents) et assentiment des patients adolescents.
    • Bénéficiaire d'une assurance maladie.
    E.4Principal 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 [49], 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.
    • Patient incapable d’effectuer une épreuve d’effort cardio-pulmonaire.
    • Chirurgie cardiaque prévue pendant l'essai.
    • Patient traité par un vasodilatateur artériel pulmonaire, dans les 6 mois précédant l'inclusion, quels que soient la durée et le (s) type (s) d'administration (orale, intraveineuse, sous-cutanée, inhalation).
    • Patient traité par sildenafil ou tout autre inhibiteur de la phosphodiesterase de type 5 (comme le tadalafil), dans les 6 mois précédant l'inclusion, quelle que soit la durée de l'administration.
    • Cathétérisme cardiaque interventionnel prévu au cours de la période de traitement de l’essai (occlusion collatérale, occlusion de la fenestration, stenting, angioplastie, trouble du rythme du rythme cardiaque).
    • Participation à un autre essai clinique ou administration d'un médicament non indiqué dans les 4 semaines précédant le dépistage.
    • Grossesse, désir de grossesse, absence de contraception pendant la période d'étude.
    • Insuffisance hépatique sévère (Child-Pugh C).
    • Hypersensibilité au principe actif ou à l’un des excipients du comprimé.
    • Combinaison avec des dérivés nitrés ou des donneurs de monoxyde d’azote (tels que le nitrite d’amyle) sous n’importe quelle forme, en raison des effets hypotenseurs.
    • Combinaison avec un activateur de la guanylate cyclase, tel que le Riociguat.
    • Association avec des inhibiteurs du CYP3A4 (par exemple, ketoconazole, itraconazole, ritonavir).
    • Disposition au priapisme, sclérose des corps caverneux, maladie de La Peyronie, drépanocytose, myélome multiple, leucémie.
    • Hypotension artérielle (systémique) non contrôlée ou risque d'hypotension : déshydratation, obstruction à l'éjection du ventricule gauche, dysfonctionnement du système nerveux autonome, patient sous alpha-bloquant.
    • Événements cardiovasculaires graves, récents (<3 mois) ou non stabilisés : infarctus du myocarde, angor instable, mort subite du cœur, arythmie ventriculaire, hémorragie cérébrale.
    • Troubles hémorragiques actifs.
    • Ulcère gastroduodénal actif.
    E.5 End points
    E.5.1Primary end point(s)
    - The evolution of the VE/VCO2 slope (ventilation per minute / volume of carbon dioxide released slope) measured with CPET before and after the 6 month-treatment period
    L'évolution de la pente VE/VCO2 ou « efficience ventilatoire » mesurée lors d’une épreuve d’effort cardio-respiratoire avant et après la période de traitement de 6 mois.
    E.5.1.1Timepoint(s) of evaluation of this end point
    after the 6-months treatment period
    avant et après la période de traitement de 6 mois
    E.5.2Secondary end point(s)
    Evolution between inclusion and end of treatment (6 months) for the following criteria:
    - Clinical endpoints:
    o Functional class from I to IV (New York Heart Association Functional classification).
    o Oxygen saturation (SaO2): measured routinely using a transcutaneous sensor in all cyanogen CHD and/or patient with PAH [30].
    o 6-minute walk test (6MWT).
    - Health-related quality of life:
    o The SF-36 questionnaire [33].
    - SV function evaluation with non-invasive imaging:
    o Echocardiography: systemic blood flow, SV systolic ejection fraction, 2D Strain SV function.
    o MRI: systemic and pulmonary blood flows in phase contrast, SV systolic ejection fraction and volumes [34].
    - NT Pro BNP: this blood test is a biomarker routinely checked in heart failure. It is also a prognostic factor in PAH [35].
    - Cardio-pulmonary exercise test (CPET): The CPET has become the "gold standard" exam in the follow-up of heart failure [25] even in CHD patients [30]. The following values will be measured as detailed in our previous studies [3, 36]:
    o The maximum oxygen consumption (VO2max),
    o The first anaerobic threshold (AT), the ventilatory anaerobic threshold (AT) using Beaver’s method [37],
    o The oxygen pulse (ratio VO2/heart rate) at rest, at AT and at the peak,
    o The OUES (oxygen uptake efficiency slope); VO2 = OUES x log10 VE + b) [38]–[40].
    - Lung function:
    o Spirometry: forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC), FEV1/FVC ratio (FEV1%), DEMM25/75,
    o Capillary lung volume: pulmonary CO/NO transfer (patient seated and lying down) [42,43].
    - Cardiac catheterization: mean pulmonary arterial pressure (mmHg).
    - Percentage of patients compliant at 6 months of study treatment.

    L’évolution entre l’inclusion et la fin du traitement (6 mois) pour les critères suivants:
    - Critères cliniques:
    o Classe fonctionnelle de I à IV (classe fonctionnelle de la New York Heart Association).
    o Saturation en oxygène (SaO2): mesurée régulièrement à l'aide d'un capteur transcutané chez tous les patients avec cardiopathie cyanogène et/ou chez les patients avec d'HTAP.
    o Test de marche de 6 minutes (TM6).
    - Qualité de vie liée à la santé : questionnaire SF36.
    - Fonction du ventricule unique par imagerie non invasive :
    o Échocardiographie: débit sanguin systémique, fraction d'éjection du ventricule systémique, Strain du ventricule unique.
    o IRM: flux sanguins systémiques et pulmonaires en contraste de phase, fraction et volumes d'éjection systolique du ventricule unique.
    - NT Pro-BNP: ce test sanguin est un biomarqueur régulièrement contrôlé en cas d’insuffisance cardiaque. C'est également un facteur pronostique de l'HTAP.
    - Test d'effort cardio-pulmonaire qui est devenu l'examen de référence pour le suivi de l'insuffisance cardiaque, même chez les patients avec cardiopathie congénitale. Les valeurs suivantes seront mesurées comme détaillé dans nos études précédentes :
    o La consommation maximale d'oxygène (VO2max),
    o Le seuil anaérobie ou « premier seuil ventilatoire » (SV1), selon la méthode de Beaver,
    o Le pouls d’oxygène (VO2/fréquence cardiaque) au repos, au SV1 et à la VO2max
    o L’OUES (oxygen uptake efficiency slope) selon la formule : VO2 = OUES x log10 VE + b).
    - Fonction pulmonaire :
    o Spirométrie: volume expiratoire maximal en 1 seconde (VEMS), capacité vitale forcée (CVF), rapport VEMS / CVF, DEMM25 / 75,
    o Volume pulmonaire capillaire: transfert pulmonaire de CO/NO (patient assis et allongé).
    - Cathétérisme cardiaque : pression artérielle pulmonaire moyenne (en mmHg) et gradient transpulmonaire (en mmHg).
    - Pourcentage de patients compliants à 6 mois de traitement.
    E.5.2.1Timepoint(s) of evaluation of this end point
    6 months
    6 mois
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    E.6.4Safety No
    E.6.5Efficacy No
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) No
    E.7.3Therapeutic confirmatory (Phase III) Yes
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo Yes
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial1
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned18
    E.8.5The trial involves multiple Member States No
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA No
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.7Trial has a data monitoring committee Yes
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    LVLS
    LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years2
    E.8.9.1In the Member State concerned months
    E.8.9.1In the Member State concerned days
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 Yes
    F.1.1Number of subjects for this age range: 20
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) Yes
    F.1.1.6.1Number of subjects for this age range: 20
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 30
    F.1.3Elderly (>=65 years) No
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations No
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception No
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state50
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    None
    aucun
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2022-01-10
    N.Ethics Committee Opinion of the trial application
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion
    P. End of Trial
    P.End of Trial Status
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