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.

Overview

Sponsor-declared trial summary

Key facts

Sponsor

CHRU De Nancy

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Cardiovascular Diseases [C14]

Trial duration

3 Jul 2023 → ongoing

Decision date (initial)

2024-08-01

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

External identifiers

EU CT number

2024-513811-29-00

EudraCT number

2019-001563-74

ClinicalTrials.gov

NCT04020263

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy

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.

Secondary objectives 16

1. Determine the impact of levosimendan vs. placebo on top of a conventional strategy with regard to Prioritized composite endpoint at days 90 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. Determine the impact of levosimendan vs. placebo on top of a conventional strategy with regard to major adverse cardiovascular events: death, ECLS requirement, dialysis, cardiac transplantation, escalation to permanent left ventricular assist device, major cardiovascular events (stroke, recurrent myocardial infarction, urgent coronary revascularization, re-hospitalization for heart failure) on days 90
3. Determine the impact of levosimendan vs. placebo on top of a conventional strategy with regard to the composite endpoint of all-cause mortality and/or ECLS requirement and/or dialysis on day 90;
4. Determine the impact of levosimendan vs. placebo on top of a conventional strategy with regard to the number of dobutamine free days between randomization and D30;
5. Determine the impact of levosimendan vs. placebo on top of a conventional strategy with regard to the number of vasopressors free days between randomization and D30
6. Determine the impact of levosimendan vs. placebo on top of a conventional strategy with regard to the number of ventilatory free days between randomization and D30
7. Determine the impact of levosimendan vs. placebo on top of a conventional strategy with regard to the number of renal replacement free days between randomization and D 90
8. Determine the impact of levosimendan vs. placebo on top of a conventional strategy with regard to the lactate clearance from randomization to D7
9. Determine the impact of levosimendan vs. placebo on top of a conventional strategy with regard to the duration of ICU stay and hospitalization
10. Determine the impact of levosimendan vs. placebo on top of a conventional strategy with regard to the composite endpoint of all-cause mortality and/or ECLS requirement and/or dialysis on days 7, 60, and 180 days and 12 months following randomization
11. Determine the impact of levosimendan vs. placebo on top of a conventional strategy with regard to the number of renal replacement free days between randomization and D 30, 60, 180 and at 12 months;
12. Determine the impact of levosimendan vs. placebo on top of a conventional strategy with regard to the major adverse cardiovascular events: death, ECLS requirement, dialysis, cardiac transplantation, escalation to permanent left ventricular assist device, major cardiovascular events (stroke, recurrent myocardial infarction, urgent coronary revascularization, re-hospitalization for heart failure) on days 180 and at 12 months;
13. Determine the impact of levosimendan vs. placebo on top of a conventional strategy with regard to the occurrence of arrhythmias requiring therapy with anti-arrhythmic drugs or electric cardioversion (including atrial fibrillation, ventricular tachycardia, ventricular fibrillation, torsade de pointe) from randomization to ICU or CCU discharge.
14. 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.
15. 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.
16. From a dedicated biological collection on which we will measure existing and future biological parameters, we will evaluate the ability of biological measure at ICU/CCU discharge to predict subsequent outcome

Conditions and MedDRA coding

Cardiogenic Shock

Study design 1 period

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 5

1. Adult patient ≥ 18 years with cardiogenic shock
2. Adequate intravascular volume
3. 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.
4. Tissue hypoperfusion: at least 1 sign with in 24 hours 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);
5. Patient affiliated to social security plan.

Exclusion criteria 19

1. Myocardial sideration after cardiac arrest of non-cardiac etiology;
2. No flow time higher > 3 minutes
3. Cardiac arrest with unknown no flow duration
4. Total duration of cardiac arrest (no flow plus low flow) > 45 minutes
5. Cerebral deficit with fixed dilated pupils
6. Patient moribund on the day of enrollment
7. Irreversible neurological pathology
8. Known hypersensitivity to levosimendan or placebo, or one of its excipients;
9. Pregnant woman, birthing or breastfeeding mother
10. Person deprived of liberty for judicial or administrative decision
11. Minor (not emancipated)
12. Immediate or anticipated (within 6 hours) indication of ECLS;
13. Adult subject to a legal protection measure (such as guardianship, conservatorship)
14. Use of VA-ECMO or IMPELLA or LVAD
15. Chronic renal failure requiring hemodialysis;
16. Cardiotoxic poisoning
17. Septic cardiomyopathy
18. Previous levosimendan administration within 15 days
19. Cardiac arrest with non-shockable rhythm

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. All-cause mortality and/or ECLS and/or dialysis at day 30 following randomization.

Secondary endpoints 15

1. Prioritized composite endpoint at days 90 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. Major adverse cardiovascular events: death, ECLS requirement, dialysis, cardiac transplantation, escalation to permanent left ventricular assist device, major cardiovascular events (stroke, recurrent myocardial infarction, urgent coronary revascularization, re-hospitalization for heart failure) on days 90
3. Composite endpoint of all-cause mortality and/or ECLS requirement and/or dialysis on day 90;
4. Number of dobutamine free days between randomization and D30
5. Number of vasopressors free days between randomization and D30;
6. Number of ventilatory free days between randomization and D30
7. Number of renal replacement free days between randomization and D 90
8. Lactate clearance from randomization to D7
9. Duration of ICU stay and hospitalization
10. Composite endpoint of all-cause mortality and/or ECLS requirement and/or dialysis on days 7, 60, and 180 days and 12 months following randomization
11. Number of renal replacement free days between randomization and D 30, 60, 180 and at 12 months
12. Major adverse cardiovascular events: death, ECLS requirement, dialysis, cardiac transplantation, escalation to permanent left ventricular assist device, major cardiovascular events (stroke, recurrent myocardial infarction, urgent coronary revascularization, re-hospitalization for heart failure) on days 180 and at 12 months;
13. Occurrence of arrhythmias requiring therapy with anti-arrhythmic drugs or electric cardioversion (including atrial fibrillation, ventricular tachycardia, ventricular fibrillation, torsade de pointe) from randomization to ICU or CCU discharge.
14. Changes in biomarkers between randomization and ICU/CCU discharge
15. For objectives B2 and B3 the primary outcome will be considered

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Placebo 2

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

CHRU De Nancy

Sponsor organisation

CHRU De Nancy

Address

Co N°34, 29 Avenue Du Mal De Lattre De Tassigny, Bp 60034 29 Avenue Du Mal De Lattre De Tassigny Bp 60034

City

Nancy Cedex

Postcode

54035

Country

France

Scientific contact point

Organisation

CHRU De Nancy

Contact name

Pr Bruno LEVY

Public contact point

Organisation

CHRU De Nancy

Contact name

Pr Bruno LEVY

Locations

1 EU/EEA country · 29 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 10 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

3 submissions — initial application plus substantial / non-substantial modifications