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

Cardiogenic Shock Clinical Trial

— LevoHeartShock  

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

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT04020263
• Other study ID #: 2019-001563-74
• Status: Not yet recruiting
• Phase: Phase 3
• Start date: December 1, 2019
• Est. completion date: June 1, 2024

Study information

• Verified date: July 2019
• Source: Central Hospital, Nancy, France
• Contact: Bruno LEVY, Pr
• Phone: +33 3 83 15 40 84
• Email: b.levy[@]chru-nancy.fr
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Not yet recruiting
• Enrollment: 610
• Est. completion date: June 1, 2024
• Est. primary completion date: July 1, 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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)

Related Conditions & MeSH terms

• Cardiogenic Shock
• Shock
• Shock, Cardiogenic

Intervention

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
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.

Locations

Country	Name	City	State
France	CHR Metz-Thionville, Mercy Hospital	Ars-Laquenexy	Moselle
France	CH Henri Duffaut, Avignon	Avignon	Vaucluse
France	CHU Besançon Jean Minjoz Hospital	Besançon	Doubs
France	CHU Bordeaux - Hopital haut-leveque	Bordeaux	Gironde
France	Hospices Civils de Lyon - Louis Pradel Hospital	Bron	Rhône
France	CHU Caen	Caen	Calvados
France	CHRU Clermont- Ferrand Gabriel-Montpied	Clermont- Ferrand	Puy-de-Dôme
France	APHP, Henri Mondor Hospital	Créteil	Val De Marne
France	CHU Dijon, BOCAGE Hospital	Dijon	Côte d'Or
France	APHP, Raymond Poincaré Hospital	Garches	Paris
France	CHU Grenoble, Michallon Hospital	La Tronche	Isère
France	CHRU Lille, Cœur Poumon Institute	Lille	Nord
France	CHU Limoges, Dupuytren Hospital	Limoges	Haute-Vienne
France	AP-HM, la Timone Hospital, Marseille	Marseille	Bouches Du Rhône
France	AP-HM, Nord Hospital, Marseille	Marseille	Bouches Du Rhône
France	CHU Montpellier, Arnaud de Villeneuve Hospital	Montpellier	Hérault
France	CHU Montpellier, site Lapeyronie	Montpellier	Hérault
France	CHU Nantes - Hôtel Dieu	Nantes	Loire-Atlantique
France	CHU Nîmes, Carémeau Hospital	Nîmes	Gard
France	APHP -Lariboisière Hospital (Cardiology department)	Paris
France	APHP, La Pitié Salpêtrière (medical intensive care unit)	Paris
France	APHP, Lariboisière Hospital (intensive care unit and toxicology)	Paris
France	APHP- HEGP Paris	Paris
France	CHU Rennes, Pontchaillou Hospital	Rennes	Ille Et Vilaine
France	CHU Rouen, Charles Nicolle Hospital	Rouen	Seine Maritime
France	CHRU Strasbourg -Nouvel Hôpital Civil	Strasbourg	Bas-Rhin
France	CHU de Toulouse	Toulouse	Haute-Garonne
France	CHRU Nancy	Vandoeuvre les Nancy

Sponsors (1)

Lead Sponsor	Collaborator
Central Hospital, Nancy, France

Country where clinical trial is conducted

France, 

Outcome

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