Clinical Trials Register

Summary
EudraCT Number:	2019-004319-29
Sponsor's Protocol Code Number:	P170914J
National Competent Authority:	France - ANSM
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2020-10-06
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.1

Member State Concerned

France - ANSM

A.2

EudraCT number

2019-004319-29

A.3

Full title of the trial

" LEVOSIMENDAN to facilitate weaning from ECMO in severe cardiogenic shock patients

LEVOSIMENDAN afin de faciliter le sevrage de l'ECMO chez les patients présentant un choc cardiogénique sévère

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

" LEVOSIMENDAN to facilitate weaning from ECMO in severe cardiogenic shock patients

LEVOSIMENDAN afin de faciliter le sevrage de l'ECMO chez les patients présentant un choc cardiogénique sévère

A.3.2

Name or abbreviated title of the trial where available

LEVOECMO

A.4.1

Sponsor's protocol code number

P170914J

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	ASSISTANCE PUBLIQUE - HÔPITAUX DE PARIS (AP-HP)
B.1.3.4	Country	France
B.3.1 and B.3.2	Status of the sponsor	Non-Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	DGOS
B.4.2	Country	France
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	ASSISTANCE PUBLIQUE - HÔPITAUX DE PARIS (AP-HP)
B.5.2	Functional name of contact point	Pôle Promotion-DRCI
B.5.3	Address:
B.5.3.1	Street Address	DRCI - Hôpital St Louis, 1 av Claude Vellefaux
B.5.3.2	Town/ city	PARIS
B.5.3.3	Post code	75010
B.5.3.4	Country	France
B.5.4	Telephone number	+33 140 27 57 27
B.5.5	Fax number	+33144 84 17 01
B.5.6	E-mail	carla.vandenabele@aphp.fr

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	ZIMINO 12.5 mg (levosimendan) 2,5 mg/ml
D.2.1.1.2	Name of the Marketing Authorisation holder	ORION CORPORATION
D.2.1.2	Country which granted the Marketing Authorisation	France
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	ZIMINO 12.5 mg (levosimendan) 2,5 mg/ml
D.3.4	Pharmaceutical form	Solution for infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Solution for infusion
D.8.4	Route of administration of the placebo	Intravenous use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Adult patients with acute cardiogenic shock refractory to conventional therapy placed on VA-ECMO support and for whom withdrawal from ECMO is possible.

Patients adultes assistés par VA-ECMO pour choc cardiogénique réfractaire au traitement conventionnel et pour lesquels un sevrage de l’ECMO est envisageable.

E.1.1.1

Medical condition in easily understood language

Adult patients with acute cardiogenic shock refractory to conventional therapy placed on VA-ECMO support and for whom withdrawal from ECMO is possible.

Patients adultes assistés par VA-ECMO pour choc cardiogénique réfractaire au traitement conventionnel et pour lesquels un sevrage de l’ECMO est envisageable.

E.1.1.2

Therapeutic area

Diseases [C] - Cardiovascular Diseases [C14]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.0
E.1.2	Level	PT
E.1.2	Classification code	10007625
E.1.2	Term	Cardiogenic shock
E.1.2	System Organ Class	10007541 - Cardiac disorders

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

To assess the efficacy of early administration of Levosimendan on the time to successful ECMO weaning (defined below) within the 30 days following randomization, in patients with VA-ECMO support for acute cardiogenic shock refractory to conventional therapy.

Évaluer l’efficacité d’une administration précoce de levosimendan pour le succès du sevrage de l’ECMO dans les 30 jours suivant la randomisation. L’analyse prendra en compte le risque compétitif de décès, persistance de l’ECMO et sevrage de l’ECMO avec succès (sans nécessité de remise en place dans les 30 jours).

E.2.2

Secondary objectives of the trial

- Mortality on D30 and D60
- Duration of ECMO support between inclusion-D30, and between inclusion-D60; and number of ECMO-free days between inclusion and D30-D60
-Duration of ICU stay-hospitalization
- Major adverse cardiovascular events on days 30 and 60
- Time to improvement in hemodynamics and time to hemodynamic stabilization
- Number of days with organ failure, defined by SOFA score, and number of days without organ failure between inclusion and D30
- Duration of hemodynamic support with catecholamines and number of days alive without hemodynamic support between inclusion and D30
- Duration of mechanical ventilation and number of days alive without mechanical ventilation between inclusion and D30 and D60
- LV function assessed with echocardiography at Day 30 following randomization
- Incidence of drug adverse effects
- Primary and secondary endpoints in predefined subgroups: acute myocardial infarction, myocarditis, post-cardiac surgery and post-cardiac arrest patients.

-Mortalité à J30 et J60
-Durée totale sous ECMO entre l’inclusion-J30/J60 ; nombre de jours sans ECMO entre l’inclusion et J30/J60
-Durée de séjour en réa-hospitalisation
-Évts cardiovasculaires importants à J30 /J60
-Tps nécessaire à l’amélioration des paramètres et stabilisation hémodynamiques
-Nbr de jours avec une défaillance d’organe définie par le score SOFA et le nbr de jours vivant sans défaillance d’organe entre l’inclusion-J30
-Durée totale du soutien hémodynamique par catécholamines et nbr de jours vivant sans soutien hémodynamique entre l’inclusion-J30
-Durée totale de ventilation mécanique et nbre de jours vivant sans ventilation mécanique entre l’inclusion/ J30/J60
-Fonction du ventricule gauche évaluée par une échocardiographie à 30 jrs
-Incidence des effets indésirables liés au levosimendan
- Critères primaires et secondaires d’évaluation dans les sous-groupes suivant : infarctus du myocarde, myocardite, post-chirurgie cardiaque, et post arrêt cardiaque

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Acute cardiogenic shock patient refractory to conventional therapy placed on VA-ECMO support in the preceding 48h.
2. Obtain informed consent from a close relative or surrogate. According to the urgent inclusion procedure, randomization may take place and the consent of a close relative or surrogate will be sought as soon as possible. The patient's consent to prosecute will be sought as soon as his condition permits.

1) Choc cardiogénique sévère chez des patients réfractaires au traitement conventionnel placés sous ECMO-VA dans les 48h
2) Obtention d’un consentement écrit et éclairé par la personne de confiance/proche/famille. Selon la procédure d’inclusion en urgence, la randomisation pourra avoir lieu et le consentement personne de confiance/proche/famille sera recherché dès que possible. Le consentement de poursuite du patient sera recherché dès que son état le permettra.

E.4

Principal exclusion criteria

1. Age <18
2. Pregnancy
3. Initiation of ECMO >48 h
4. Resuscitation >30 minutes before ECMO
5. Irreversible neurological pathology
6. End-stage cardiomyopathy with no hope of LV function recovery
7. Mechanical complication of myocardial infarction
8. Aortic regurgitation > II
9. VA-ECMO for pulmonary embolism
10. VA-ECMO for cardiotoxic drug intoxication
11. VA-ECMO after left-ventricle assist device implantation
12. VA-ECMO in heart transplant patients
13. Patient moribund on the day of randomization, SAPS II >90
14. Liver cirrhosis (Child B or C) and other severe hepatic insufficiency
15. Chronic renal failure requiring hemodialysis
16. Known hypersensitivity to levosimendan
17. Prior history of “torsades de pointes”
18. History of epilepsy

1) Âge <18
2) Grossesse
3) Initiation de l’ECMO-VA >48 h
4) Resuscitation >30 minutes avant l’ECMO
5) Pathologie neurologique irréversible
6) Cardiomyopathie en phase terminale sans espoir de récupération de la fonction duventricule gauche
7) Complication mécanique de l’infarctus du myocarde
8) Insuffisance aortique > II
9) ECMO-VA pour une embolie pulmonaire
10) ECMO-VA pour une intoxication aux médicaments cardiotoxiques
11) ECMO après mise en place d’une assistance ventriculaire gauche
12) ECMO-VA chez des patients ayant eu une greffe cardiaque
13) Patient moribond le jour de la randomisation avec un score SAPS II > 90
14) Cirrhose hépatique (B ou C)
15) Insuffisance rénale chronique nécessitant une dialyse
16) Allergie connue au levosimendan
17) Antécédents de torsades de pointes
18) Antécédents d’épilepsie

E.5 End points

E.5.1

Primary end point(s)

Time to successful ECMO weaning within the 30 days following randomization. :
- ECMO weaning will be considered successful only if the patient survives without ECMO, other mechanical circulatory support device or heart transplantation 30 days after ECMO removal.
- Thus all ECMO weaning from randomization to 30 days after randomization will be considered, and the qualification for successful ECMO weaning will need 30 days of follow-up after ECMO removal (thus until day 60 after randomization for an ECMO weaning performed on day 30 after randomization).
- Patients still under ECMO 30 days after randomization will be considered as censored.
- The number of days alive without ECMO was not an appropriate primary outcome due to the high proportion of patients dying with ECMO and thus ex-aequo (0 days).
The analysis will therefore model the risk of successful ECMO ablation in the presence of two competing risks (death and weaning failure).

Délai de sevrage de l’ECMO dans les 30 jours suivant la randomisation :
- Un sevrage d’ECMO est considéré comme réussi seulement si le patient survit sans ECMO, sans assistance circulatoire ou transplantation cardiaque dans les 30 jours suivant l’ablation de l’ECMO
- Ainsi tout sevrage d’ECMO de la randomisation à 30 jours après la randomisation sera pris en compte et un sevrage réussi nécessitera 30 jours de suivi après le retrait de l’ECMO (jusqu’au 60ème jour après la randomisation pour un sevrage d’ECMO à 30 jours après la randomisation)
- Les patients encore sous ECMO 30 jours après la randomisation seront censurés
- Le nombre de jours vivant sans ECMO n’est pas un critère principal approprié en raison du taux élevé de décès sous ECMO de ces patients et donc ex-aequo (0 jours).
L’analyse permettra de modéliser le risque de succès d’ablation de l’ECMO en présence de deux risques compétitifs (décès et échec de sevrage)

E.5.1.1

Timepoint(s) of evaluation of this end point

Day 30

Jour 30

E.5.2

Secondary end point(s)

- Mortality on Day 30 and Day 60
- Total duration of ECMO support between inclusion and D30 and between inclusion andD60;
- Number of ECMO-free days between inclusion and D30/D60.
- Duration of ICU stay and of hospitalization;
- Major adverse cardiovascular events defined as death, cardiac transplant, escalation to permanent left ventricular assist device, stroke, dialysis, re-hospitalization for heart failure on days 30 and 60
- Time to improvement in hemodynamic parameters (systolic, diastolic, mean blood pressure, heart rate …) and time to hemodynamic stabilization
- Days with organ failure, defined by the SOFA score, and days alive without organ failure between inclusion and D30;
- Duration of hemodynamic support with catecholamines and days alive without hemodynamic support between inclusion and D30;
- Duration of mechanical ventilation and days alive without mechanical ventilation between inclusion and D30 and D60;
- LV function assessed with echocardiography at Day 30 following randomization
- Incidence of adverse drug reactions (including atrial fibrillation and other supraventricular arrhythmias, ventricular arrhythmias including ventricular tachycardia, ventricular fibrillation and torsades de pointes, hypokalemia).
- Primary and secondary endpoints in predefined subgroups: acute myocardial infarction, myocarditis, post-cardiac surgery and post-cardiac arrest patients.

- Mortalité à J30 et J60 ;
- Durée totale sous ECMO entre l’inclusion et J30 et entre l’inclusion et J60 ;
- Nombre de jours sans ECMO entre l’inclusion et J30/J60 ;
- Durée de séjour en réanimation, durée de séjour à l’hôpital ;
- Évènements cardiovasculaires importants comme : décès, transplantation cardiaque, pose de dispositif d’assistance ventriculaire gauche permanent, accident vasculaire cérébral, dialyse, réhospitalisation pour insuffisance cardiaque à J30 et J60 ;
- Temps nécessaire à l’amélioration des paramètres hémodynamiques (pression artérielle systolique, diastolique, pression artérielle moyenne, fréquence cardiaque …) et temps nécessaire à la stabilisation hémodynamique ;
- Nombre de jours avec une défaillance d’organe définie par le score SOFA et le nombre de jours vivant sans défaillance d’organe entre l’inclusion et J30 ;
- Durée totale du soutien hémodynamique par catécholamines et nombre de jours vivant sans soutien hémodynamique entre l’inclusion et J30;
- Durée totale de ventilation mécanique et nombre de jours vivant sans ventilation mécanique entre l’inclusion et J30 et J60;
- Fonction du ventricule gauche évaluée par une échocardiographie à 30 jours suivant la randomisation
- Incidence des effets indésirables liés au levosimendan (fibrillation atriale, arythmie ventriculaire, torsade de pointe, hypokaliémie) ;
- Critères primaires et secondaires d’évaluation dans les sous-groupes suivant : infarctus du myocarde, myocardite, post-chirurgie cardiaque, et post arrêt cardiaque.

E.5.2.1

Timepoint(s) of evaluation of this end point

Day 0 to Day 60

Jour 0 à Jour60

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

E.6.4

Safety

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

E.7.3

Therapeutic confirmatory (Phase III)

Yes

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

E.8.1.3

Single blind

E.8.1.4

Double blind

Yes

E.8.1.5

Parallel group

Yes

E.8.1.6

Cross over

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

Yes

E.8.2.3

Other

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

E.8.4

The trial involves multiple sites in the Member State concerned

Yes

E.8.4.1

Number of sites anticipated in Member State concerned

E.8.5

The trial involves multiple Member States

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.7

Trial has a data monitoring committee

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 the Last Subject

Dernière visite du dernier patient inclus

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

F.1.1.5

Children (2-11years)

F.1.1.6

Adolescents (12-17 years)

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

103

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

103

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

F.3.3.6

Subjects incapable of giving consent personally

Yes

F.3.3.6.1

Details of subjects incapable of giving consent

if the person is unable to express his will and the next-of-kin is
unidentified and/or unreachable at time of inclusion, the investigator
may proceed to the inclusion of the person without any consent

si la personne n'est pas en mesure d'exprimer sa volonté et que le plus
proche parent n'est pas identifié et/ou n'est pas présent au moment de
l'inclusion, l'investigateur peut procéder à l'inclusion de la personne
sans son consentement.

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

206

G. Investigator Networks to be involved in the Trial

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2020-11-30

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2021-10-04

P. End of Trial
P.	End of Trial Status	Completed

Select Country:	Select Age Range:
Select Trial Status:	Select Trial Phase:
Select Gender:
Select Date Range: to
Select Rare Disease:
IMP with orphan designation in the indication
Orphan Designation Number:
Results Status:
Clear advanced search filters

Austria
Belgium
Bulgaria
Croatia
Cyprus
Czechia
Denmark
Estonia
Finland
France
Germany
Greece
Hungary
Iceland
Ireland
Italy
Latvia
Liechtenstein
Lithuania
Luxembourg
Malta
Netherlands
Norway
Poland
Portugal
Romania
Slovakia
Slovenia
Spain
Sweden
United Kingdom
Outside EU/EEA

Clinical trials