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    Summary
    EudraCT Number:2019-001563-74
    Sponsor's Protocol Code Number:PHRCN2018/LEVOHEARTSHOCK-LEVY/YB
    National Competent Authority:France - ANSM
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2020-06-16
    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 number2019-001563-74
    A.3Full title of the trial
    Effect of early use of levosimendan versus placebo on top of a conventional strategy of inotrope use on a combined morbidity-mortality endpoint in patients with cardiogenic shock. LevoHeartShock Study.
    Effet de l’utilisation précoce du levosimendan versus placebo en plus d’une stratégie conventionnelle d’utilisation des inotropes sur un
    critère composite de morbidité-mortalité dans le choc cardiogénique. Protocole LEVOHEARTSHOCK.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Evaluation of a new therapeutic strategy with levosimendan use in the treatment of acute and severe heart failure.
    Evaluation d’une nouvelle stratégie thérapeutique utilisant le levosimendan dans le traitement de l’insuffisance cardiaque aiguë et grave.
    A.3.2Name or abbreviated title of the trial where available
    LevoHearShock
    LevoHeartShock
    A.4.1Sponsor's protocol code numberPHRCN2018/LEVOHEARTSHOCK-LEVY/YB
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT04020263
    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 SponsorCHRU de Nancy
    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 supportDGOS
    B.4.2CountryFrance
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationCHRU de Nancy
    B.5.2Functional name of contact pointDirection Recherche et Innovation
    B.5.3 Address:
    B.5.3.1Street AddressBâtiment Recherche - Rue du Morvan
    B.5.3.2Town/ cityVandoeuvre lès Nancy
    B.5.3.3Post code54511
    B.5.3.4CountryFrance
    B.5.4Telephone number33383155285
    B.5.5Fax number33383157451
    B.5.6E-mailrechclin-innov@chru-nancy.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.2.1.1.1Trade name Zimino
    D.2.1.1.2Name of the Marketing Authorisation holderOrion corporation
    D.2.1.2Country which granted the Marketing AuthorisationFrance
    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 nameZIMINO
    D.3.4Pharmaceutical form Concentrate for solution for injection
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous 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 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
    Cardiogenic shock
    Choc cardiogénique
    E.1.1.1Medical condition in easily understood language
    Acute and severe cardiac dysfunction in an emergency context.
    Défaillance aiguë cardiaque sévère en situation d'urgence médicale.
    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 PT
    E.1.2Classification code 10007625
    E.1.2Term Cardiogenic shock
    E.1.2System Organ Class 10007541 - Cardiac disorders
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    The study goal is to evaluate the effect of the early use of levosimendan versus placebo on top of a conventional use of inotrope with regard to a composite endpoint of 30-day mortality and/or ExtraCorporeal Life Support (ECLS) requirement and/or dialysis.
    Evaluer l’effet d’utilisation précoce du levosimendan versus placebo en plus d’une utilisation conventionnelle d’inotrope au regard d’ un critère composite de mortalité à 30 jours et/ou nécessité d’une assistance cardiaque extra corporelle de courte durée (ECLS) et/ ou de dialyse.
    E.2.2Secondary objectives of the trial
    Determine the impact of levosimendan vs placebo with regard to:
    Composite endpoint of all-cause mortality and/or ECLS and/or dialysis on days 7, 30, 60, 90 180
    Occurrence of death, cardiac transplantation, escalation to permanent left ventricular assist device, stroke, recurrent myocardial infarction, urgent coronary revascularization, dialysis, re-hospitalization for heart failure on days 30, 60, 90, 180 and at 12 months
    Duration and amount of dobutamine
    Lactate clearance
    Number of days with organ failure, defined by the SOFA score, and number of days without organ failure between inclusion and D30
    Total duration of catecholamines and duration without catecholamines between inclusion and D30
    Total duration of mechanical ventilation and duration without mechanical ventilation between inclusion and D30
    Duration of ICU stay and hospitalization
    Occurrence of arrhythmias (including atrial fibrillation, ventricular tachycardia, ventricular fibrillation, torsade de pointe)
    Déterminer l’impact du levosimendan contre placebo à partir de:
    Critère composite de mortalité toute cause et/ou nécessité d’une ECLS et/ou de dialyse à 7, 30, 60, 90 et 180 jrs
    Survenue d'EI cardiovasculaires:décès, transplantation cardiaque, recours à un dispositif d’assistance ventriculaire gauche, AVC, récidive d’infarctus du myocarde, revascularisation coronarienne urgente, dialyse, ré-hospitalisation pour insuffisance cardiaque à 30, 60, 90, 180 jrs et à 12mois
    Durée d’administration et quantité de dobutamine administrée
    Clairance du lactate
    Nb de jours avec défaillance d’organes (score SOFA) et le nb de jours sans défaillance d’organe entre l’inclusion et J30
    Durée de catécholamines et durée sans catécholamines entre l’inclusion et J30
    Durée avec ventilation mécanique(VM) et durée sans VM entre l’inclusion et J30
    Durée de séjour en USIC et à l’hôpital
    Survenue d’arythmies (fibrillation atriale, tachycardie ventriculaire, fibrillation ventriculaire, torsade de pointe)
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Adult patient ≥ 18 years with cardiogenic shock defined by :
    -Adequate intravascular volume
    -Norepinephrine infusion <1 microgram/kg/min to maintain MAP at least at 65 mmHg for at least 3 hours and less than 24h or dobutamine ≥ 5 microgram/kg/min since at least 3h and less than 24h
    -Tissue hypoperfusion: at least 2 signs (lactate ≥ 2 mmol/l, mottling, oliguria <500ml/24h, ScVO2 ≤ 60% or veno-arterial PCO2 gap ≥ 5 mmHg)
    -Clinical pulmonary congestion and/or echocardiographic sign of elevated left ventricular pressure and/or elevated right atrial pressure.
    Patient affiliated to social security plan.
    -Patient majeur ≥ 18 ans en état de choc cardiogénique défini par :
    -Un volume intravasculaire adéquat,
    -Sous norépinephrine < 1microgramme/kg/min pour maintenir la pression artérielle moyenne (MAP) au moins à 65 mmHg, pendant au moins 3 heures et moins de 24 heures ou sous dobutamine ≥ 5 microgramme/kg/min pendant au moins 3 heures et moins de 24 heures,
    -Hypoperfusion tissulaire : au moins 2 signes (lactate ≥ 2mmol/l, marbrures cutanées, oligurie <500ml/24h, ScVO2 ≤ 60% ou gradient veino-artériel de PCO2 ≥ 5 mmHg),
    -Congestion pulmonaire clinique et/ou signe échocardiographique de pression ventriculaire gauche et/ou pression auriculaire droite élevée,
    -Patient affilié ou bénéficiant d’un régime de la sécurité sociale.
    E.4Principal exclusion criteria
    -Myocardial sideration after cardiac arrest of non-cardiac etiology
    -Immediate or anticipated (within 6 hours) indication of ECLS
    -ECLS (ECMO or Impella)
    -Chronic renal failure requiring hemodialysis
    -Cardiotoxic poisoning
    -Septic cardiomyopathy
    -Previous levosimendan administration within 15 days
    -Cardiac arrest resuscitation >30 minutes
    -Cerebral deficit with fixed dilated pupils
    -Patient moribund on the day of enrollment
    -Irreversible neurological pathology
    -Known hypersensitivity to levosimendan or placebo, or one of its excipients
    -Persons referred in articles L.1121-5 to L.1121-8 and L.1122-2 of the french Public Health Code:
    o Pregnant, parturient or breastfeeding woman
    o Person deprived of liberty for judicial or administrative decision
    o Person under psychiatric care
    o Minor person (non-emancipated)
    o Adult person under legal protection (any form of public guardianship)
    -Sidération myocardique après arrêt cardiaque d’étiologie non cardiaque
    -Indication d’utilisation ECLS immédiate ou anticipée (dans les 6 heures)
    -Patient sous ECLS (ECMO ou Impella)
    -Insuffisance rénale chronique requérant une hémodialyse
    -Empoisonnement cardiotoxique
    -Cardiomyopathie septique
    -Administration de levosimendan dans les 15 jours précédents
    -Arrêt cardiaque avec réanimation > 30 minutes
    -Déficit cérébral avec pupilles dilatées fixes
    -Patient moribond le jour de l'inclusion
    -Pathologie neurologique irréversible
    -Hypersensibilité connue au levosimendan ou placebo, ou à l’un des excipients
    -Femme enceinte, parturiente ou allaitante Personnes privée de liberté par une décision judiciaire ou administrative
    -Personne faisant l’objet de soins psychiatriques
    -Personne majeures faisant l’objet d’une mesure de protection légale (tutelle, curatelle, sauvegarde de justice)
    E.5 End points
    E.5.1Primary end point(s)
    All-cause mortality and/or ECLS and/or dialysis at day 30 following randomization.
    Mortalité toute cause et/ou ECLS et/ou dialyse à J30 suivant la randomisation.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Day 30 following randomization.
    J30 suivant la randomisation.
    E.5.2Secondary end point(s)
    1. Mortality and/or ECLS requirement and/or dialysis on days 7, 30 (main secondary), 60, 90 and 180
    2. Composite endpoint of major adverse cardiovascular events defined as death, cardiac transplantation, escalation to permanent left ventricular assist device, stroke, recurrent myocardial infarction, urgent coronary revascularization, dialysis, re-hospitalization for heart failure at days 30, 60, 90, 180, and at 12 months
    3. Amount and duration of administered dobutamine from baseline to ICU or CCU discharge
    4. Duration with abnormal lactate value from baseline to ICU or CCU discharge
    5. Number of days with organ failure(s), defined with the SOFA score, and the number of days, between inclusion and D30, without organ failure
    6. Duration of catecholamine hemodynamic support and the number of days between inclusion and D30 without hemodynamic support
    7. Duration of mechanical ventilation and the number of days, between inclusion and D30, alive without mechanical ventilation
    8. Duration of ICU stay and of hospitalization
    9. Occurrence of arrhythmias (including atrial fibrillation and other arrhythmias, ventricular tachycardia, ventricular fibrillation, torsade de pointe) from baseline to ICU or CCU discharge
    1. Décès toute cause et/ou ECLS et/ou dialyse à 7, 30, 90 et 180 jours
    2. Critère composite d’événements indésirables cardiovasculaires majeurs définis par : décès, transplantation cardiaque, recours à un dispositif d’assistance ventriculaire gauche, AVC, récidive d’infarctus du myocarde, revascularisation coronarienne urgente, dialyse, ré-hospitalisation pour insuffisance cardiaque à 30, 60, 90, 180 jours et à 12 mois.
    3. Quantité et durée d’administration de dobutamine entre l'inclusion et la sortie d'USIC ou de réanimation
    4. Durée avec taux de lactate anormale entre l'inclusion et la sortie d'USIC ou de réanimation
    5. Nombre de jours avec défaillance d’organes, défini par le score SOFA, et le nombre de jours sans défaillance d’organe, entre l’inclusion et J30.
    6. Durée d’utilisation de catécholamine et le nombre de jours sans catécholamine entre l’inclusion et J30
    7. Durée de ventilation mécanique et le nombre de jours vivant sans ventilation mécanique, entre l’inclusion et J 30
    8. Durée de séjour en Unité de Soins Intensifs ou réanimation et durée de séjour à l’hôpital
    9. Survenue d’arythmies (incluant fibrillation atriale et autres arythmies, tachycardie ventriculaire, fibrillation ventriculaire, torsade de pointe) entre l'inclusion et la sortie d'USIC ou de réanimation
    E.5.2.1Timepoint(s) of evaluation of this end point
    Endpoint 1 : on days 7, 30, 60, 90 and 180
    Endpoint 2 : at days 30, 60, 90, 180, and at 12 months
    Endpoint 3 : from baseline to ICU or CCU discharge
    Endpoint 4: from baseline to ICU or CCU discharge
    Endpoint 5: from baseline to ICU or CCU discharge, and the number of days, between inclusion and D30, without organ failure
    Endpoint 6: from baseline to ICU or CCU discharge and the number of days between inclusion and D30 without hemodynamic support
    Endpoint 7: from baseline to ICU or CCU discharge, and the number of day between inclusion and D30, alive without mechanical ventilation
    Endpoint 8: Duration of ICU stay and of hospitalization
    Endpoint 9: from baseline to ICU or CCU discharge.
    Critère 1: à 7, 30, 90 et 180 jours,
    Critère 2: à 30, 60, 90, 180 jours et à 12 mois,
    Critère 3: entre l'inclusion et la sortie d'USIC ou de réanimation,
    Critère 4: entre l'inclusion et la sortie d'USIC ou de réanimation,
    Critère 5: entre l'inclusion et la sortie d'USIC ou de réanimation, et le nombre de jours sans défaillance d’organe, entre l’inclusion et J30,
    Critère 6: entre l'inclusion et la sortie d'USIC ou de réanimation et le nombre de jours sans catécholamine entre l’inclusion et J30,
    Critère 7: entre l'inclusion et la sortie d'USIC ou de réanimation et le nombre de jours vivant sans ventilation mécanique, entre l’inclusion et J30,
    Critère 8: Durée de séjour en USIC ou en réanimation et à l’hôpital,
    Critère 9: entre l'inclusion et la sortie d'USIC ou de réanimation
    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 No
    E.6.4Safety Yes
    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 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 concerned29
    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
    last visit of last subject
    Dernière visite de suivi du dernier patient
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years
    E.8.9.1In the Member State concerned months54
    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 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: 427
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 183
    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 Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation Yes
    F.3.3.6Subjects incapable of giving consent personally Yes
    F.3.3.6.1Details of subjects incapable of giving consent
    the persons included in this research may not be able to receive information regarding the study and give their consent before the implementation of the protocol due to cardiogenic shock.Patient included in emergency situation
    Compte tenu de la pathologie étudiée (choc cardiogénique) ces patients seront hors d’état d’exprimer leur consentement. De plus le pronostic de survie de ces patients est menacé, inclusion en situation d’urgence vitale immédiate.
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state610
    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
    non applicable, suivi habituel.
    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 Decision2020-07-24
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2020-07-10
    P. End of Trial
    P.End of Trial StatusOngoing
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