美国胸部、胸部 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)-出境医

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出境医 / 临床实验 / 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)

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)

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Study Description

Brief Summary:

Cardiogenic shock (CS) mortality remains high (40%). Despite their frequent use, few clinical outcome data are available to guide the initial selection of vasoactive drug therapies in patients with CS. Based on experts' opinions, the combination of norepinephrine-dobutamine is generally recommended as a first line strategy. Inotropic agents increase myocardial contractility, thereby increasing cardiac output. Dobutamine is commonly recommended to be the inotropic agent of choice and levosimendan is generally used following dobutamine failure. It may represent an ideal agent in cardiogenic shock, since it improves myocardial contractility without increasing cAMP or calcium concentration. At present, there are no convincing data to support a specific inotropic agent in patients with cardiogenic shock. Our hypothesis is that the early use of levosimendan, by enabling the discontinuation of dobutamine, would accelerate the resolution of signs of low cardiac output and facilitate myocardial recovery.

Condition or disease	Intervention/treatment	Phase
Cardiogenic Shock	Drug: Levosimendan 2.5 MG/ML Injectable Solution Drug: Placebo	Phase 3

Study Design

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Study Type :	Interventional (Clinical Trial)
Estimated Enrollment :	610 participants
Allocation:	Randomized
Intervention Model:	Parallel Assignment
Intervention Model Description:	The LevoHeartShock trial is a prospective, double-blind, multicenter, randomized controlled trial comparing the early initiation of levosimendan versus placebo in patients with cardiogenic shock treated with vasopressor therapy according to a conventional strategy of inotrope use (dobutamine as first line agent).
Masking:	Triple (Participant, Care Provider, Investigator)
Masking Description:	The study will be double-blinded. Investigator masking to group assignment after randomization will be guaranteed by use of a placebo. The packaging and labeling of placebo and levosimendan vials will be similar to guarantee the double blinded aspect.
Primary Purpose:	Treatment
Official Title:	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
Estimated Study Start Date :	December 1, 2019
Estimated Primary Completion Date :	July 1, 2023
Estimated Study Completion Date :	June 1, 2024

Arms and Interventions

Arm	Intervention/treatment
Experimental: Levosimendan Experimental group: patients with cardiogenic shock treated with levosimendan in addition to the conventional strategy.	Drug: Levosimendan 2.5 MG/ML Injectable Solution Levosimendan will be diluted with Glucose G5%. The reconstitution of levosimendan will be performed, as close as possible to the start of the infusion. A continuous infusion of levosimendan will be administered over 24 h without bolus, started at a rate of 0.1 μg per kilogram of body weight per minute and, in both the persistence of hypoperfusion signs and in the absence of rate-limiting side effects, will be increased after 2 to 4 hours to a maximum of 0.2 μg per kilogram per minute for a further 20 to 22 hours.
Placebo Comparator: Placebo Control group: Patients with cardiogenic shock treated with placebo for levosimendan in addition to the conventional strategy.	Drug: Placebo Placebo will be diluted with Glucose G5%. The reconstitution of Placebo will be performed, as close as possible to the start of the infusion. A continuous infusion of Placebo will be administered over 24 h without bolus, started at a rate of 0.1 μg per kilogram of body weight per minute and, in both the persistence of hypoperfusion signs and in the absence of rate-limiting side effects, will be increased after 2 to 4 hours to a maximum of 0.2 μg per kilogram per minute for a further 20 to 22 hours.

Arm

Intervention/treatment

Experimental: Levosimendan

Experimental group: patients with cardiogenic shock treated with levosimendan in addition to the conventional strategy.

Drug: Levosimendan 2.5 MG/ML Injectable Solution

Levosimendan will be diluted with Glucose G5%. The reconstitution of levosimendan will be performed, as close as possible to the start of the infusion. A continuous infusion of levosimendan will be administered over 24 h without bolus, started at a rate of 0.1 μg per kilogram of body weight per minute and, in both the persistence of hypoperfusion signs and in the absence of rate-limiting side effects, will be increased after 2 to 4 hours to a maximum of 0.2 μg per kilogram per minute for a further 20 to 22 hours.

Placebo Comparator: Placebo

Control group: Patients with cardiogenic shock treated with placebo for levosimendan in addition to the conventional strategy.

Drug: Placebo

Placebo will be diluted with Glucose G5%. The reconstitution of Placebo will be performed, as close as possible to the start of the infusion. A continuous infusion of Placebo will be administered over 24 h without bolus, started at a rate of 0.1 μg per kilogram of body weight per minute and, in both the persistence of hypoperfusion signs and in the absence of rate-limiting side effects, will be increased after 2 to 4 hours to a maximum of 0.2 μg per kilogram per minute for a further 20 to 22 hours.

Outcome Measures

Primary Outcome Measures :

Proportion of All-cause mortality [ Time Frame: Day 30 following randomization ]
Composite endpoint (i.e. All-cause Mortality and/or Extra Corporel Life Support implantation and/or dialysis)
Proportion of Extra Corporel Life Support implantation [ Time Frame: Day 30 following randomization ]
Composite endpoint (i.e. All-cause Mortality and/or Extra Corporel Life Support implantation and/or dialysis)
Proportion of Dialysis [ Time Frame: Day 30 following randomization ]
Composite endpoint (i.e. All-cause Mortality and/or Extra Corporel Life Support implantation and/or dialysis)

Secondary Outcome Measures :

Proportion of All-cause mortality [ Time Frame: Days 7, 30, 60, 90, 180 ]
Composite endpoint (i.e. All-cause Mortality and/or Extra Corporel Life Support implantation and/or dialysis)
Proportion of Extra Corporel Life Support implantation [ Time Frame: Days 7, 30, 60, 90, 180 ]
Composite endpoint (i.e. All-cause Mortality and/or Extra Corporel Life Support implantation and/or dialysis)
Proportion of dialysis [ Time Frame: Days 7, 30, 60, 90, 180 ]
Composite endpoint (i.e. All-cause Mortality and/or Extra Corporel Life Support implantation and/or dialysis)
Proportion of death [ Time Frame: Days 30, 60, 90, 180 and 12 months ]
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
Proportion of cardiac transplantation [ Time Frame: Days 30, 60, 90, 180 and 12 months ]
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
Proportion of escalation to permanent Left Ventricular Assist Device [ Time Frame: Days 30, 60, 90, 180 and 12 months ]
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
Proportion of stroke [ Time Frame: Days 30, 60, 90, 180 and 12 months ]
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
Proportion of recurrent myocardial infarction [ Time Frame: Days 30, 60, 90, 180 and 12 months ]
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
Proportion of urgent coronary revascularization [ Time Frame: Days 30, 60, 90, 180 and 12 months ]
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
Proportion of dialysis [ Time Frame: Days 30, 60, 90, 180 and 12 months ]
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
Proportion of re-hospitalization for heart failure [ Time Frame: Days 30, 60, 90, 180 and 12 months ]
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
Amount of administered dobutamine [ Time Frame: From baseline to Intensive Care Unit discharge (assessed up to 1 month) ]
Duration of administered dobutamine [ Time Frame: From baseline to Intensive Care Unit discharge (assessed up to 1 month) ]
Duration with abnormal lactate value [ Time Frame: From baseline to Intensive Care Unit discharge (assessed up to 1 month) ]
Lactate Clearance
Number of days with organ failure(s) [ Time Frame: From baseline to Intensive Care Unit discharge (assessed up to 1 month) ]
Defined with the SOFA score
The number of days between inclusion and D30, without organ failure [ Time Frame: From baseline to day 30 ]
Defined with the SOFA score
Duration of catecholamine hemodynamic support [ Time Frame: From baseline to Intensive Care Unit discharge (assessed up to 1 month) ]
The number of days between inclusion and D30 without hemodynamic support [ Time Frame: From baseline to day 30 ]
Duration of mechanical ventilation [ Time Frame: From baseline to Intensive Care Unit discharge (assessed up to 1 month) ]
The number of days alive without mechanical ventilation [ Time Frame: From baseline to day 30 ]
Duration of intensive care unit stay [ Time Frame: Up to Intensive Care Unit discharge (assessed up to 1 month) ]
Duration of hospitalization [ Time Frame: Up to hospitalization discharge (assessed up to 1 month) ]
Occurrence of arrhythmias [ Time Frame: From baseline to Intensive Care Unit discharge (assessed up to 1 month) ]
Including atrial fibrillation and other arrhythmias, ventricular tachycardia, ventricular fibrillation, torsade de pointe

Eligibility Criteria

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Ages Eligible for Study:	18 Years and older (Adult, Older Adult)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

Criteria

Inclusion Criteria:

Adult patient 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 12h or dobutamine ≥ 5 microgram/kg/min since at least 3h and less than 12h
Tissue hypoperfusion: at least 2 signs (lactate ≥ 2 mmol/l, mottling, oliguria, ScVO2 ≤ 60% or veno-arterial PCO2 gap ≥ 5 mmHg)
Clinical pulmonary congestion or elevated natriuretic peptides or echocardiographic sign of elevated left ventricular pressure or elevated right atrial pressure.

Exclusion Criteria:

Myocardial sideration after cardiac arrest of non-cardiac etiology
Immediate or anticipated (within 6 hours) indication of Extra Corporel Life Support
Extra Corporel Life Support (Extracorporeal Membrane Oxygenation (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 randomization
Irreversible neurological pathology
Known hypersensitivity to levosimendan or placebo, or one of its excipients
Woman of childbearing age without effective contraception
Persons referred in articles L.1121-5 to L.1121-8 and L.1122-2 of the Public Health Code:
- Pregnant, parturient or breastfeeding woman
- Person deprived of liberty for judicial or administrative decision
- Person under psychiatric care
- Minor person (non-emancipated)
- Adult person under legal protection (any form of public guardianship)

Contacts and Locations

Contacts

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Contact: Bruno LEVY, Pr	+33 3 83 15 40 84	b.levy@chru-nancy.fr

Locations

Show 28 study locations

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France
CHRU Strasbourg -Nouvel Hôpital Civil
Strasbourg, Bas-Rhin, France, 67091
Contact: Ferhat Meziani, MD
Principal Investigator: Ferhat Meziani, MD
AP-HM, la Timone Hospital, Marseille
Marseille, Bouches Du Rhône, France, 13005
Contact: Marc Gainnier, MD
Principal Investigator: Marc Gainnier, MD
AP-HM, Nord Hospital, Marseille
Marseille, Bouches Du Rhône, France, 13015
Contact: Laurent Bonello, MD
Principal Investigator: Laurent Bonello, MD
CHU Caen
Caen, Calvados, France, 14000
Contact: Katrien Blanchart, MD
Principal Investigator: Katrien Blanchart, MD
CHU Dijon, BOCAGE Hospital
Dijon, Côte d'Or, France, 21000
Contact: Jean-Pierre Quenot, MD
Principal Investigator: Jean-Pierre Quenot, MD
CHU Besançon Jean Minjoz Hospital
Besançon, Doubs, France, 25000
Contact: Gilles Capellier, MD
Principal Investigator: Gilles Capellier, MD
CHU Nîmes, Carémeau Hospital
Nîmes, Gard, France, 30029
Contact: Benoît Lattuca, MD
Principal Investigator: Benoît Lattuca, MD
CHU Bordeaux - Hopital haut-leveque
Bordeaux, Gironde, France, 33600
Contact: Edouard Gerbaud, MD
Principal Investigator: Edouard Gerbaud, MD
CHU de Toulouse
Toulouse, Haute-Garonne, France, 31059
Contact: Clément Delmas, MD
Principal Investigator: Clément Delmas, MD
CHU Limoges, Dupuytren Hospital
Limoges, Haute-Vienne, France, 87000
Contact: Philippe Vignon, MD
Principal Investigator: Philippe Vignon, MD
CHU Montpellier, Arnaud de Villeneuve Hospital
Montpellier, Hérault, France, 34090
Contact: François Roubille, MD
Principal Investigator: François Roubille, MD
CHU Montpellier, site Lapeyronie
Montpellier, Hérault, France, 34090
Contact: Kada Klouche, MD
Principal Investigator: Kada Klouche, MD
CHU Rennes, Pontchaillou Hospital
Rennes, Ille Et Vilaine, France, 35000
Contact: Guillaume Leurent, MD
Principal Investigator: Guillaume Leurent, MD
CHU Grenoble, Michallon Hospital
La Tronche, Isère, France, 38043
Contact: Nicolas Terzi, MD
Principal Investigator: Nicolas Terzi, MD
CHU Nantes - Hôtel Dieu
Nantes, Loire-Atlantique, France, 44000
Contact: Jean Reignier, MD
Principal Investigator: Jean Reignier, MD
CHR Metz-Thionville, Mercy Hospital
Ars-Laquenexy, Moselle, France, 57245
Contact: Guillaume Louis, MD
Principal Investigator: Guillaume Louise, MD
CHRU Lille, Cœur Poumon Institute
Lille, Nord, France, 59000
Contact: Nicolas Lamblin, MD
Principal Investigator: Nicolas Lamblin, MD
APHP, Raymond Poincaré Hospital
Garches, Paris, France, 92380
Contact: Djillali Annane, MD
Principal Investigator: Djillali Annane, MD
CHRU Clermont- Ferrand Gabriel-Montpied
Clermont- Ferrand, Puy-de-Dôme, France, 63000
Contact: Elisabeth Coupez, MD
Principal Investigator: Elisabeth Coupez, MD
Hospices Civils de Lyon - Louis Pradel Hospital
Bron, Rhône, France, 69500
Contact: Eric Bonnefoy, MD
Principal Investigator: Eric Bonnefoy, MD
CHU Rouen, Charles Nicolle Hospital
Rouen, Seine Maritime, France, 76000
Contact: Fabienne Tamion, MD
Contact: Emmanuel Besnier, MD
Principal Investigator: Fabienne Tamion, MD
APHP, Henri Mondor Hospital
Créteil, Val De Marne, France, 94010
Contact: Pascal Lim, MD
Principal Investigator: Pascal LIM, MD
CH Henri Duffaut, Avignon
Avignon, Vaucluse, France, 84000
Contact: Stéphane Andrieu, MD
Principal Investigator: Stéphane Andrieu, MD
APHP -Lariboisière Hospital (Cardiology department)
Paris, France, 75010
Contact: Stephane Menzo-Silberman
Principal Investigator: Stephane Menzo-Silberman, MD
APHP, Lariboisière Hospital (intensive care unit and toxicology)
Paris, France, 75010
Contact: Bruno Megarbane, MD
Principal Investigator: Bruno Megarbane, MD
APHP, La Pitié Salpêtrière (medical intensive care unit)
Paris, France, 75013
Contact: Alain Combes, MD
Principal Investigator: Alain Combes, MD
APHP- HEGP Paris
Paris, France, 75015
Contact: Nadia Aissaoui Balanant, MD
Principal Investigator: Nadia Aissaoui Balanant, MD
CHRU Nancy
Vandoeuvre les Nancy, France
Contact: Bruno Lévy, Prof
Principal Investigator: Bruno LEVY, Prof

Sponsors and Collaborators

Central Hospital, Nancy, France

Investigators

Layout table for investigator information

Study Chair:	Clément DELMAS, Dr	CHU Toulouse
Study Chair:	Nicolas GIRERD, Pr	CHRU Nancy
Study Chair:	Patrick ROSSIGNOL, Pr	CHRU Nancy

Tracking Information

First Submitted Date ^ICMJE

June 28, 2019

First Posted Date ^ICMJE

July 16, 2019

Last Update Posted Date

July 18, 2019

Estimated Study Start Date ^ICMJE

December 1, 2019

Estimated Primary Completion Date

July 1, 2023 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures ^ICMJE

Proportion of All-cause mortality [ Time Frame: Day 30 following randomization ]
Composite endpoint (i.e. All-cause Mortality and/or Extra Corporel Life Support implantation and/or dialysis)
Proportion of Extra Corporel Life Support implantation [ Time Frame: Day 30 following randomization ]
Composite endpoint (i.e. All-cause Mortality and/or Extra Corporel Life Support implantation and/or dialysis)
Proportion of Dialysis [ Time Frame: Day 30 following randomization ]
Composite endpoint (i.e. All-cause Mortality and/or Extra Corporel Life Support implantation and/or dialysis)

Original Primary Outcome Measures ^ICMJE

Same as current

Change History

Current Secondary Outcome Measures ^ICMJE

Proportion of All-cause mortality [ Time Frame: Days 7, 30, 60, 90, 180 ]
Composite endpoint (i.e. All-cause Mortality and/or Extra Corporel Life Support implantation and/or dialysis)
Proportion of Extra Corporel Life Support implantation [ Time Frame: Days 7, 30, 60, 90, 180 ]
Composite endpoint (i.e. All-cause Mortality and/or Extra Corporel Life Support implantation and/or dialysis)
Proportion of dialysis [ Time Frame: Days 7, 30, 60, 90, 180 ]
Composite endpoint (i.e. All-cause Mortality and/or Extra Corporel Life Support implantation and/or dialysis)
Proportion of death [ Time Frame: Days 30, 60, 90, 180 and 12 months ]
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
Proportion of cardiac transplantation [ Time Frame: Days 30, 60, 90, 180 and 12 months ]
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
Proportion of escalation to permanent Left Ventricular Assist Device [ Time Frame: Days 30, 60, 90, 180 and 12 months ]
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
Proportion of stroke [ Time Frame: Days 30, 60, 90, 180 and 12 months ]
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
Proportion of recurrent myocardial infarction [ Time Frame: Days 30, 60, 90, 180 and 12 months ]
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
Proportion of urgent coronary revascularization [ Time Frame: Days 30, 60, 90, 180 and 12 months ]
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
Proportion of dialysis [ Time Frame: Days 30, 60, 90, 180 and 12 months ]
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
Proportion of re-hospitalization for heart failure [ Time Frame: Days 30, 60, 90, 180 and 12 months ]
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
Amount of administered dobutamine [ Time Frame: From baseline to Intensive Care Unit discharge (assessed up to 1 month) ]
Duration of administered dobutamine [ Time Frame: From baseline to Intensive Care Unit discharge (assessed up to 1 month) ]
Duration with abnormal lactate value [ Time Frame: From baseline to Intensive Care Unit discharge (assessed up to 1 month) ]
Lactate Clearance
Number of days with organ failure(s) [ Time Frame: From baseline to Intensive Care Unit discharge (assessed up to 1 month) ]
Defined with the SOFA score
The number of days between inclusion and D30, without organ failure [ Time Frame: From baseline to day 30 ]
Defined with the SOFA score
Duration of catecholamine hemodynamic support [ Time Frame: From baseline to Intensive Care Unit discharge (assessed up to 1 month) ]
The number of days between inclusion and D30 without hemodynamic support [ Time Frame: From baseline to day 30 ]
Duration of mechanical ventilation [ Time Frame: From baseline to Intensive Care Unit discharge (assessed up to 1 month) ]
The number of days alive without mechanical ventilation [ Time Frame: From baseline to day 30 ]
Duration of intensive care unit stay [ Time Frame: Up to Intensive Care Unit discharge (assessed up to 1 month) ]
Duration of hospitalization [ Time Frame: Up to hospitalization discharge (assessed up to 1 month) ]
Occurrence of arrhythmias [ Time Frame: From baseline to Intensive Care Unit discharge (assessed up to 1 month) ]
Including atrial fibrillation and other arrhythmias, ventricular tachycardia, ventricular fibrillation, torsade de pointe

Original Secondary Outcome Measures ^ICMJE

Proportion of All-cause mortality [ Time Frame: Days 7, 30, 60, 90, 180 ]
Composite endpoint (i.e. All-cause Mortality and/or Extra Corporel Life Support implantation and/or dialysis)
Proportion of Extra Corporel Life Support implantation [ Time Frame: Days 7, 30, 60, 90, 180 ]
Composite endpoint (i.e. All-cause Mortality and/or Extra Corporel Life Support implantation and/or dialysis)
Proportion of dialysis [ Time Frame: Days 7, 30, 60, 90, 180 ]
Composite endpoint (i.e. All-cause Mortality and/or Extra Corporel Life Support implantation and/or dialysis)
Proportion of death [ Time Frame: Days 30, 60, 90, 180 and 12 months ]
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
Proportion of cardiac transplantation [ Time Frame: Days 30, 60, 90, 180 and 12 months ]
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
Proportion of escalation to permanent Left Ventricular Assist Device [ Time Frame: Days 30, 60, 90, 180 and 12 months ]
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
Proportion of stroke [ Time Frame: Days 30, 60, 90, 180 and 12 months ]
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
Proportion of recurrent myocardial infarction [ Time Frame: Days 30, 60, 90, 180 and 12 months ]
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
Proportion of urgent coronary revascularization [ Time Frame: Days 30, 60, 90, 180 and 12 months ]
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
Proportion of dialysis [ Time Frame: Days 30, 60, 90, 180 and 12 months ]
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
Proportion of re-hospitalization for heart failure [ Time Frame: Days 30, 60, 90, 180 and 12 months ]
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
Death, cardiac transplantation, escalation to permanent Left Ventricular Assist Device, stroke, recurrent myocardial infarction, urgent coronary revascularization, dialysis, re-hospitalization for heart failure risk [ Time Frame: Days 30, 60, 90, 180 and 12 months ]
Amount of administered dobutamine [ Time Frame: From baseline to Intensive Care Unit discharge (assessed up to 1 month) ]
Duration of administered dobutamine [ Time Frame: From baseline to Intensive Care Unit discharge (assessed up to 1 month) ]
Duration with abnormal lactate value [ Time Frame: From baseline to Intensive Care Unit discharge (assessed up to 1 month) ]
Lactate Clearance
Number of days with organ failure(s) [ Time Frame: From baseline to Intensive Care Unit discharge (assessed up to 1 month) ]
Defined with the SOFA score
The number of days between inclusion and D30, without organ failure [ Time Frame: From baseline to day 30 ]
Defined with the SOFA score
Duration of catecholamine hemodynamic support [ Time Frame: From baseline to Intensive Care Unit discharge (assessed up to 1 month) ]
The number of days between inclusion and D30 without hemodynamic support [ Time Frame: From baseline to day 30 ]
Duration of mechanical ventilation [ Time Frame: From baseline to Intensive Care Unit discharge (assessed up to 1 month) ]
The number of days alive without mechanical ventilation [ Time Frame: From baseline to day 30 ]
Duration of intensive care unit stay [ Time Frame: Up to Intensive Care Unit discharge (assessed up to 1 month) ]
Duration of hospitalization [ Time Frame: Up to hospitalization discharge (assessed up to 1 month) ]
Occurrence of arrhythmias [ Time Frame: From baseline to Intensive Care Unit discharge (assessed up to 1 month) ]
Including atrial fibrillation and other arrhythmias, ventricular tachycardia, ventricular fibrillation, torsade de pointe

Current Other Pre-specified Outcome Measures

Not Provided

Original Other Pre-specified Outcome Measures

Not Provided

Descriptive Information

Brief Title ^ICMJE

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

Official Title ^ICMJE

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

Brief Summary

Detailed Description

Not Provided

Study Type ^ICMJE

Interventional

Study Phase ^ICMJE

Phase 3

Study Design ^ICMJE

Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:

The LevoHeartShock trial is a prospective, double-blind, multicenter, randomized controlled trial comparing the early initiation of levosimendan versus placebo in patients with cardiogenic shock treated with vasopressor therapy according to a conventional strategy of inotrope use (dobutamine as first line agent).

Masking: Triple (Participant, Care Provider, Investigator)
Masking Description:

The study will be double-blinded. Investigator masking to group assignment after randomization will be guaranteed by use of a placebo. The packaging and labeling of placebo and levosimendan vials will be similar to guarantee the double blinded aspect.

Primary Purpose: Treatment

Condition ^ICMJE

Cardiogenic Shock

Intervention ^ICMJE

Drug: Levosimendan 2.5 MG/ML Injectable Solution
Levosimendan will be diluted with Glucose G5%. The reconstitution of levosimendan will be performed, as close as possible to the start of the infusion. A continuous infusion of levosimendan will be administered over 24 h without bolus, started at a rate of 0.1 μg per kilogram of body weight per minute and, in both the persistence of hypoperfusion signs and in the absence of rate-limiting side effects, will be increased after 2 to 4 hours to a maximum of 0.2 μg per kilogram per minute for a further 20 to 22 hours.
Drug: Placebo
Placebo will be diluted with Glucose G5%. The reconstitution of Placebo will be performed, as close as possible to the start of the infusion. A continuous infusion of Placebo will be administered over 24 h without bolus, started at a rate of 0.1 μg per kilogram of body weight per minute and, in both the persistence of hypoperfusion signs and in the absence of rate-limiting side effects, will be increased after 2 to 4 hours to a maximum of 0.2 μg per kilogram per minute for a further 20 to 22 hours.

Study Arms ^ICMJE

Experimental: Levosimendan
Experimental group: patients with cardiogenic shock treated with levosimendan in addition to the conventional strategy.

Intervention: Drug: Levosimendan 2.5 MG/ML Injectable Solution
Placebo Comparator: Placebo
Control group: Patients with cardiogenic shock treated with placebo for levosimendan in addition to the conventional strategy.

Intervention: Drug: Placebo

Publications *

Not Provided

* Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.

Recruitment Information

Recruitment Status ^ICMJE

Not yet recruiting

Estimated Enrollment ^ICMJE

610

Original Estimated Enrollment ^ICMJE

Same as current

Estimated Study Completion Date ^ICMJE

June 1, 2024

Estimated Primary Completion Date

July 1, 2023 (Final data collection date for primary outcome measure)

Eligibility Criteria ^ICMJE

Inclusion Criteria:

Adult patient 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 12h or dobutamine ≥ 5 microgram/kg/min since at least 3h and less than 12h
Tissue hypoperfusion: at least 2 signs (lactate ≥ 2 mmol/l, mottling, oliguria, ScVO2 ≤ 60% or veno-arterial PCO2 gap ≥ 5 mmHg)
Clinical pulmonary congestion or elevated natriuretic peptides or echocardiographic sign of elevated left ventricular pressure or elevated right atrial pressure.

Exclusion Criteria:

Myocardial sideration after cardiac arrest of non-cardiac etiology
Immediate or anticipated (within 6 hours) indication of Extra Corporel Life Support
Extra Corporel Life Support (Extracorporeal Membrane Oxygenation (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 randomization
Irreversible neurological pathology
Known hypersensitivity to levosimendan or placebo, or one of its excipients
Woman of childbearing age without effective contraception
Persons referred in articles L.1121-5 to L.1121-8 and L.1122-2 of the Public Health Code:
- Pregnant, parturient or breastfeeding woman
- Person deprived of liberty for judicial or administrative decision
- Person under psychiatric care
- Minor person (non-emancipated)
- Adult person under legal protection (any form of public guardianship)

Sex/Gender ^ICMJE

Sexes Eligible for Study:

All

Ages ^ICMJE

18 Years and older (Adult, Older Adult)

Accepts Healthy Volunteers ^ICMJE

Contacts ^ICMJE

Contact: Bruno LEVY, Pr

+33 3 83 15 40 84

b.levy@chru-nancy.fr

Listed Location Countries ^ICMJE

France

Removed Location Countries

Administrative Information

NCT Number ^ICMJE

NCT04020263

Other Study ID Numbers ^ICMJE

2019-001563-74

Has Data Monitoring Committee

Yes

U.S. FDA-regulated Product

Studies a U.S. FDA-regulated Drug Product:	No
Studies a U.S. FDA-regulated Device Product:	No
Product Manufactured in and Exported from the U.S.:	No

IPD Sharing Statement ^ICMJE

Plan to Share IPD:

Undecided

Responsible Party

Central Hospital, Nancy, France

Study Sponsor ^ICMJE

Central Hospital, Nancy, France

Collaborators ^ICMJE

Not Provided

Investigators ^ICMJE

Study Chair:	Clément DELMAS, Dr	CHU Toulouse
Study Chair:	Nicolas GIRERD, Pr	CHRU Nancy
Study Chair:	Patrick ROSSIGNOL, Pr	CHRU Nancy

PRS Account

Central Hospital, Nancy, France

Verification Date

July 2019

^ICMJE Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP

治疗医院

梅奥诊所
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克利夫兰诊所
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约翰霍普金斯医院
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麻省总医院
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密歇根大学医院
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倉敷中央医院
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順天堂医院
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藤田医科大学医院（原藤田保健大学医院)
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北里大学医院
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東京医科大学医院
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4006 776 356

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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)

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