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    Summary
    EudraCT Number:2018-000680-93
    Sponsor's Protocol Code Number:SMILE
    National Competent Authority:Italy - Italian Medicines Agency
    Clinical Trial Type:EEA CTA
    Trial Status:Prematurely Ended
    Date on which this record was first entered in the EudraCT database:2021-01-07
    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 ConcernedItaly - Italian Medicines Agency
    A.2EudraCT number2018-000680-93
    A.3Full title of the trial
    Postoperative effects of high-dose esmolol during mitral valve surgery for mitral regurgitation.
    ESMOLOLO IN CHIRURGIA MITRALICA
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Esmolol during mitral valve surgery
    ESMOLOLO IN CHIRURGIA MITRALICA
    A.3.2Name or abbreviated title of the trial where available
    n.a.
    n.a.
    A.4.1Sponsor's protocol code numberSMILE
    A.5.4Other Identifiers
    Name:n.a.Number:n.a.
    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 SponsorIRCCS ISTITUTO CLINICO HUMANITAS
    B.1.3.4CountryItaly
    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 supportn.a.
    B.4.2CountryItaly
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationIRCCS Istituto Clinico Humanitas
    B.5.2Functional name of contact pointn.a.
    B.5.3 Address:
    B.5.3.1Street AddressVia Alessandro Manzoni, 56
    B.5.3.2Town/ cityRozzano (MI)
    B.5.3.3Post code20089
    B.5.3.4CountryItaly
    B.5.4Telephone number0282241
    B.5.5Fax number0282241
    B.5.6E-mailluciano.ravera@humanitas.it
    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.2.1.1.1Trade name BREVIBLOC - 10 MG/ML SOLUZIONE PER INFUSIONE SACCA DA 250 ML
    D.2.1.1.2Name of the Marketing Authorisation holderBAXTER S.P.A.
    D.2.1.2Country which granted the Marketing AuthorisationItaly
    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 nameBREVIBLOC
    D.3.2Product code n.a.
    D.3.4Pharmaceutical form Solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNESMOLOLO
    D.3.9.1CAS number 103598-03-4
    D.3.9.2Current sponsor coden.a.
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number10
    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 Information not present in EudraCT
    D.3.11.3.2Gene therapy medical product Information not present in EudraCT
    D.3.11.3.3Tissue Engineered Product Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    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 placeboSolution for infusion
    D.8.4Route of administration of the placeboIntravenous use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Patients undergoing mitral valve surgery.
    Pazienti sottoposti a chirurgia mitralica.
    E.1.1.1Medical condition in easily understood language
    Patients undergoing mitral valve surgery for primary mitral regurgitation.
    Pazienti sottoposti a chirurgia mitralica.
    E.1.1.2Therapeutic area Diseases [C] - Cardiovascular Diseases [C14]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level LLT
    E.1.2Classification code 10027716
    E.1.2Term Mitral insufficiency
    E.1.2System Organ Class 100000004849
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    The aim of this study is to compare the efficacy of a high-dose continuous infusion of esmolol versus placebo on the primary outcomes of improving myocardial protection, weighed through CK-MB and cTnI release, and the incidence of postoperative low cardiac output syndrome.
    Lo scopo di questo studio ¿ di indagare se l'esmololo migliora la protezione miocardica intraoperatoria e se questa migliore protezione influisce sul decorso postoperatorio dei pazienti. E' nostro intento dimostrare che i pazienti trattati con esmololo presentano un picco postoperatorio di marker cardiaci significativamente inferiore, richiedono un minore supporto inotropo e mostrano un decorso postoperatorio migliore con una pi¿ bassa morbidit¿ e una minore degenza ospedaliera.
    E.2.2Secondary objectives of the trial
    To evaluate the impact of esmolol versus placebo on key secondary endpoints including: operative mortality, ICU and hospital stay, and the most important clinical outcomes: stroke, postoperative myocardial infarction, renal failure, and prolonged need for mechanical ventilation.
    a. Confrontare l'efficacia dell' infusione continua di esmololo rispetto al placebo sull¿ outcome primario dello studio che riguarda il miglioramento della protezione miocardica, valutata attraverso il rilascio da parte del miocardio nel torrente circolatorio di CK-MB e cTnI, e l'incidenza di bassa portata cardiaca postoperatoria (LCOS= low cardiac output syndrome).
    b. Valutare l'impatto dell' esmololo rispetto al placebo sugli endpoints secondari che sono la mortalit¿ operatoria, la durata di degenza in terapia intensiva, la durata di degenza ospedaliera e la morbidit¿ (ictus, infarto miocardico postoperatorio, insufficienza renale, insufficienza respiratoria con necessita di ventilazione meccanica prolungata).
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    xxxxxxxxx
    1) diagnosi ecocardiografica di insufficienza mitralica primaria severa
    2) da sottoporre a chirurgia di riparazione o sostituzione della valvola mitralica in sternotomia o con approccio mini-invasivo.
    3) sia con funzione sistolica conservata (diametro telesistolico del ventricolo sinistro=35 mm e una frazione di eiezione > 60%) che depressa (diametro telesistolico del ventricolo sinistro=35 mm e una frazione di eiezione < 60%).
    E.4Principal exclusion criteria
    xxxxxxxx
    - Eta <18 anni
    - disfunzione epatica (classe Child-Pugh B e C)
    - dipendenza da dialisi preoperatoria
    - insufficienza mitralica funzionale o ischemica (valutata tramite esame ecocardiografico)
    - stenosi mitralica (valutata tramite esame ecocardiografico)
    - anamnesi positiva per complicanze da beta-bloccanti quali ipotensione, bradicardia, blocco atrioventricolare, crisi asmatica.
    -paziente che nega il consenso informato
    -necessità di arresto di circolo in ipotermia profonda per motivi chirurgici (intervento associato interessante l’aorta ascendente o l’arco aortico)
    - donne in stato di gravidanza, in linea con RCP del farmaco, valutato tramite test di gravidanza
    - Grave bradicardia sinusale (<50 battiti/min), in linea con RCP del farmaco, valutato con ECG
    - Disfunzione del nodo del seno; gravi disturbi nella conduzione del nodo atrio-ventricolare (senza pace-maker); blocco atrio-ventricolare di secondo o terzo grado, in linea con RCP del farmaco, valutati tramite esame ECGrafico.
    - shock cardiogenico, in linea con RCP del farmaco, valutato tramite esame clinico
    - grave ipotensione, in linea con RCP del farmaco, valutata tramite misurazione della pressione arteriosa sistemica
    - insufficienza cardiaca congestizia scompensata, in linea con RCP del farmaco, valutata tramite esame clinico
    - ipersensibilità al principio attivo o ad uno qualsiasi degli eccipienti, in linea con RCP del farmaco
    - pazienti con malattie broncospastiche, in linea con RCP del farmaco
    - feocromocitoma non trattato, in linea con RCP del farmaco. A tutti i pazienti in programma per intervento cardiochirurgico viene eseguito di routine esame TAC torace ed addome, in caso di immagini sospette a livello della midollare del surrene viene eseguita la valutazione dell’acido vanilmandelico nelle urine per la diagnosi di feocromocitonma
    -ipertensione polmonare, in linea con RCP del farmaco, valutata tramite esame ecocardiografico
    - attacco asmatico acuto, in linea con RCP del farmaco, valutato tramite esame clinico
    - acidosi metabolica, in linea con RCP del farmaco, valutata tramite esame emogasanalitico.
    E.5 End points
    E.5.1Primary end point(s)
    xxxxxxxx
    L’end-point primario è rappresentato dal miglioramento della protezione miocardica, e verrà valutato attraverso due parametri:
    1) il rilascio nel torrente ematico degli enzimi specifici di danno miocardico e cioè l’isoenzima MB della creatinchinasi (CK-MB) e la troponina I (cTnI) .
    2) l'incidenza di bassa portata postoperatoria (LCOS, low cardiac output syndrome) che si verifica a causa della disfunzione cardiaca per una non adeguata protezione miocardica durante l’intervento chirurgico.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Evaluation durin postoperative course
    Valutazione nel decorso postoperatorio
    E.5.2Secondary end point(s)
    xxxxxxxx
    Gli end-point secondari sono la mortalit¿ operatoria, la degenza in UTI, la degenza ospedaliera, l¿ictus cerebri, l¿insufficienza renale e la necessita di ventilazione meccanica prolungata.
    E.5.2.1Timepoint(s) of evaluation of this end point
    Evaluation durin postoperative course
    Valutazione nel decorso postoperatorio
    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 Yes
    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 Yes
    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 trial2
    E.8.3 The trial involves single site in the Member State concerned Yes
    E.8.4 The trial involves multiple sites in the Member State concerned No
    E.8.4.1Number of sites anticipated in Member State concerned1
    E.8.5The trial involves multiple Member States No
    E.8.5.1Number of sites anticipated in the EEA1
    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 Information not present in EudraCT
    E.8.7Trial has a data monitoring committee No
    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 months0
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years2
    E.8.9.2In all countries concerned by the trial months0
    E.8.9.2In all countries concerned by the trial days0
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    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) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 300
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 250
    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 state550
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 550
    F.4.2.2In the whole clinical trial 550
    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)
    n.a.
    n.a.
    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 Decision2018-06-05
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2018-03-20
    P. End of Trial
    P.End of Trial StatusPrematurely Ended
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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
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