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NCT Number: NCT04020263

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 (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.

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Key information

Conditions

Cardiogenic Shock Cardiovascular Diseases Heart Diseases Heart Failure Infarction Ischemia Myocardial Infarction Myocardial Ischemia Necrosis Pathologic Processes Pathological Conditions, Signs and Symptoms Shock Shock, Cardiogenic Vascular Diseases

Age range

18 year and older

Sex eligibility

All sexes

Study type

Interventional

Phase

Phase 3

Primary location

CHRU Strasbourg -Nouvel Hôpital Civil, Strasbourg, Bas-Rhin, France

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Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

Inclusion criteria

Adult patient ≥ 18 years with cardiogenic shock defined by:

  • Adequate intravascular volume
  • Norepinephrine to maintain MAP at least at 65 mmHg for at least 3 hours and less than 24h. At inclusion the dose must be <1 microgram/kg/min under norepinephrine base or <2 microgram/kg/min under norepinephrine tartrate, OR/AND Dobutamine since at least 3h and less than 24h at inclusion.
  • Tissue hypoperfusion: at least 1 sign within 24h prior to inclusion (lactate ≥ 2 mmol/l; mottling, capillary refeel time > 3 seconds, oliguria <500ml/24h or ≤ 20 ml/h during the last 2 hours, ScVO2 ≤ 60% or veno-arterial PCO2 gap ≥ 5 mmHg);

Exclusion criteria

  • Myocardial sideration after cardiac arrest of non-cardiac etiology
  • Immediate or anticipated (within 6 hours) indication of Extra Corporel Life Support
  • Use of VA-ECMO or IMPELLA or LVAD;
  • Chronic renal failure requiring hemodialysis
  • Cardiotoxic poisoning
  • Septic cardiomyopathy
  • Previous levosimendan administration within 15 days
  • Cardiac arrest with non-shockable rhythm;
  • No flow time higher > 3 minutes;
  • Cardiac arrest with unknown no flow duration;
  • Total duration of cardiac arrest (no flow plus low flow) > 45 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
  • Pregnant woman, birthing or breastfeeding mother
  • Minor (not emancipated)
  • Person deprived of liberty for judicial or administrative decision;
  • Adult subject to a legal protection measure (such as guardianship, conservatorship)

Treatment and study plan

Levosimendan 2.5 MG/ML Injectable Solution

Drug

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

Drug

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.

Primary outcomes

  1. 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)

  2. 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)

  3. 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 outcomes

  1. Time to death

    Time frame: Day 90

    Prioritized composite endpoint with the following priority order: 1/ time to death, 2/ escalation to permanent left ventricular assist device or cardiac transplantation, 3/ dialysis, 4/ ECLS requirement, 5/ number of cardiovascular events (stroke, recurrent myocardial infarction, urgent coronary revascularization, re-hospitalization for heart failure).

  2. Time to escalation to permanent left ventricular assist device or cardiac transplantation

    Time frame: Day 90

    Prioritized composite endpoint with the following priority order: 1/ time to death, 2/ escalation to permanent left ventricular assist device or cardiac transplantation, 3/ dialysis, 4/ ECLS requirement, 5/ number of cardiovascular events (stroke, recurrent myocardial infarction, urgent coronary revascularization, re-hospitalization for heart failure).

  3. Time to dialysis

    Time frame: Day 90

    Prioritized composite endpoint with the following priority order: 1/ time to death, 2/ escalation to permanent left ventricular assist device or cardiac transplantation, 3/ dialysis, 4/ ECLS requirement, 5/ number of cardiovascular events (stroke, recurrent myocardial infarction, urgent coronary revascularization, re-hospitalization for heart failure).

  4. Time to ECLS requirement

    Time frame: Day 90

    Prioritized composite endpoint with the following priority order: 1/ time to death, 2/ escalation to permanent left ventricular assist device or cardiac transplantation, 3/ dialysis, 4/ ECLS requirement, 5/ number of cardiovascular events (stroke, recurrent myocardial infarction, urgent coronary revascularization, re-hospitalization for heart failure).

  5. number of cardiovascular events

    Time frame: Day 90

    Prioritized composite endpoint with the following priority order: 1/ time to death, 2/ escalation to permanent left ventricular assist device or cardiac transplantation, 3/ dialysis, 4/ ECLS requirement, 5/ number of cardiovascular events (stroke, recurrent myocardial infarction, urgent coronary revascularization, re-hospitalization for heart failure).

  6. Proportion of death.

    Time frame: Day 90

  7. Proportion of Extra Corporel Life Support implantation

    Time frame: Day 90

  8. Proportion of dialysis

    Time frame: Day 90

  9. Proportion of cardiac transplantation

    Time frame: Day 90

  10. Proportion of escalation to permanent Left Ventricular Assist Device

    Time frame: Day 90

  11. Proportion of stroke

    Time frame: Day 90

  12. Proportion of recurrent myocardial infarction

    Time frame: Day 90

  13. Proportion of urgent coronary revascularization

    Time frame: Day 90

  14. Proportion of re-hospitalization for heart failure

    Time frame: Day 90

  15. Proportion of All-cause mortality

    Time frame: Day 90

    Composite endpoint of all-cause mortality and/or ECLS requirement and/or dialysis on day 90.

  16. Proportion of Extra Corporel Life Support implantation

    Time frame: Day 90

    Composite endpoint of all-cause mortality and/or ECLS requirement and/or dialysis on day 90.

  17. Proportion of Dialysis

    Time frame: Day 90

    Composite endpoint of all-cause mortality and/or ECLS requirement and/or dialysis on day 90.

  18. Number of dobutamine free days

    Time frame: From randomization to day 30

  19. Number of vasopressors free days

    Time frame: From randomization to day 30

  20. Number of ventilatory free days

    Time frame: From randomization to day 30

  21. Number of renal replacement free days

    Time frame: From randomization to day 90

  22. Lactate clearance

    Time frame: from randomization to day 7

  23. Duration of intensive care unit stay

    Time frame: Up to Intensive Care Unit discharge (assessed up to 1 month)

  24. Duration of hospitalization

    Time frame: Up to hospitalization discharge (assessed up to 1 month)

  25. Proportion of All-cause mortality

    Time frame: days 7, 60, and 180 days and 12 months

    Composite endpoint of all-cause mortality and/or ECLS requirement and/or dialysis

  26. Proportion of Extra Corporel Life Support implantation

    Time frame: days 7, 60, and 180 days and 12 months

    Composite endpoint of all-cause mortality and/or ECLS requirement and/or dialysis

  27. Proportion of dialysis

    Time frame: days 7, 60, and 180 days and 12 months

    Composite endpoint of all-cause mortality and/or ECLS requirement and/or dialysis

  28. Number of renal replacement free days

    Time frame: D 30, 60, 180 and at 12 months

  29. Proportion of death

    Time frame: days 180 and at 12 months

  30. Proportion of Extra Corporel Life Support implantation

    Time frame: days 180 and at 12 months

  31. Proportion of dialysis

    Time frame: days 180 and at 12 months

  32. proportion of cardiac transplantation

    Time frame: days 180 and at 12 months

  33. proportion of escalation to permanent left ventricular assist device

    Time frame: days 180 and at 12 months

  34. Proportion of stroke

    Time frame: days 180 and at 12 months

  35. Proportion of recurrent myocardial infarction

    Time frame: days 180 and at 12 months

  36. Proportion urgent coronary revascularization

    Time frame: days 180 and at 12 months

  37. proportion of re-hospitalization for heart failure

    Time frame: days 180 and at 12 months

  38. Occurrence of arrhythmias requiring therapy

    Time frame: from randomization to intensive care unit discharge.

    Occurrence of arrhythmias requiring therapy with anti-arrhythmic drugs or electric cardioversion (including atrial fibrillation, ventricular tachycardia, ventricular fibrillation, torsade de pointe)

  39. the changes in biomarkers

    Time frame: from randomization to intensive care unit discharge.

    From a dedicated biological collection on which we will measure existing and future biological parameters, we will evaluate the effect of Levosimendan on the changes in biomarkers between randomization and ICU/CCU discharge

  40. All-cause mortality and/or ECLS and/or dialysis

    Time frame: Day 30

    From a dedicated biological collection on which we will measure existing and future biological parameters, we will evaluate the ability of clinical and biological measure to predict levosimendan effect for the primary endpoint.

  41. All-cause mortality and/or ECLS and/or dialysis

    Time frame: At intensive care unit discharge

    From a dedicated biological collection on which we will measure existing and future biological parameters, we will evaluate the ability of biological measure to predict subsequent outcome

Study contacts

Contact information is provided by the study sponsor or research team.

Bruno LEVY, Pr

CONTACT

[email protected]

+33 3 83 15 40 84

Sponsors and collaborators

Lead sponsor

Pr Bruno LEVY

Other

Registry information

Acronym: LevoHeartShock

Important dates

Study start
2023
Primary completion
2027
Study completion
2028
First posted
Jul 16, 2019
Registry last updated
Aug 5, 2025

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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