Clinical Trials Register

Summary
EudraCT Number:	2018-004063-31
Sponsor's Protocol Code Number:	FIM-PRELEVD-2018-01
National Competent Authority:	Spain - AEMPS
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2019-01-22
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

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A. Protocol Information

A.1

Member State Concerned

Spain - AEMPS

A.2

EudraCT number

2018-004063-31

A.3

Full title of the trial

Mechanisms of cardio and nephroprotection in patients who are going on cardiac surgery with right ventricular dysfunction, with preoperative treatment of levosimendan compared with placebo. (PRELEVD-Pilot Study)

Mecanismos de cardio y nefroprotección en pacientes que van a ser intervenidos de cirugía cardiaca con disfunción ventricular derecha, con tratamiento preoperatorio de levosimendán en comparación con placebo. (PRELEVD-Estudio piloto)

A.3.1

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

Use of levosimendan / placebo as cardio and nephroprotection in patients who are going 0n cardiac surgery with right ventricular dysfunction

Uso de levosimendán / placebo como cardio y nefroprotector en pacientes que van a ser operadosde disfunción cardiaca derecha

A.4.1

Sponsor's protocol code number

FIM-PRELEVD-2018-01

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	Fundación Pública Andaluza para la Investigación de Málaga en Biomedicina y Salud (FIMABIS)
B.1.3.4	Country	Spain
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	Anestesioloy and Reanimation Unit
B.4.2	Country	Spain
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	FIMABIS
B.5.2	Functional name of contact point	Clinical Studies Platform
B.5.3	Address:
B.5.3.1	Street Address	Avda Carlos Haya, s/n
B.5.3.2	Town/ city	Málaga
B.5.3.3	Post code	29010
B.5.3.4	Country	Spain
B.5.4	Telephone number	34951291977
B.5.5	Fax number	32629951440263
B.5.6	E-mail	gloria.luque@fimabis.org

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	LEVOSIMENDAN
D.2.1.1.2	Name of the Marketing Authorisation holder	ORION
D.2.1.2	Country which granted the Marketing Authorisation	Spain
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	Levosimendan
D.3.4	Pharmaceutical form	Concentrate and solvent for solution for injection/infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	LEVOSIMENDAN
D.3.9.1	CAS number	141505-33-1
D.3.9.4	EV Substance Code	SUB08493MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	12.5
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	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

Perioperative right ventricle dysfunction

Disfunción de ventrículo derecho perioperatoria

E.1.1.1

Medical condition in easily understood language

Right ventricle dysfunction

Alteración ventrículo derecho

E.1.1.2

Therapeutic area

Analytical, Diagnostic and Therapeutic Techniques and Equipment [E] - Anesthesia and Analgesia [E03]

MedDRA Classification

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

Evaluate the cardiological and renal effects of the preoperative administration of levosimendan in patients with right ventricular dysfunction who are going to undergo cardiac surgery and evaluate enzymatic routes, and of two of the main miRNAs (21 (related to the increase with renal dysfunction and poor evolution in patients with right ventricular dysfunction and pulmonary hypertension) and 133b (related to right ventricular dysfunction and increased stress or suffering in upward regulation), related to the effects of cardioprotection and pharmacological nephropreservation.

Evaluar los efectos a nivel cardiológico y renal de la administración preoperatoria de levosimendán en pacientes con disfunción ventricular derecha que van a ser intervenidos de cirugía cardiaca y evaluar las rutas enzimáticas, y de dos de los principales miRNAs (21 (relacionado al alza con disfunción renal y mala evolución en pacientes con disfunción de ventrículo derecho e hipertensión pulmonar) y 133b (relacionado con disfunción ventricular derecha y aumento de su stress o sufrimiento en la regulación al alza)), relacionados con los efectos de cardioprotección y nefropreservación farmacológico.

E.2.2

Secondary objectives of the trial

To assess whether there are differences between patients in the renal and IRV flows measured by baseline renal ultrasound and at 48 hours in those patients who were given the preoperative levosimendan; and then compare them with those to whom the drug was not administered.
To assess if there are differences in the incidence of arrhythmias in each group.
Evaluate variations in the EUROSCORE II scale after treatment with levosimendan.

Evaluar si existen diferencias entre pacientes en los flujos renales e IRV medidos por ecografía renal basales y a las 48 horas en los pacientes a los que se les administró el levosimendan preoperatorio; y posteriormente compararlos con aquellos a los que no se les administró el fármaco.
Evaluar si existen diferencias en la incidencia de arritmias en cada uno de los grupos.
Evaluar variaciones en la escala EUROSCORE II tras el tratamiento con levosimendan.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

. Patients ≥ 18 years
• Patients with preoperative right ventricular dysfunction (TAPSE <17 mm, RV dilatation> 39 mm, tricuspid annulus dilatation> 40 mm), diagnosed by preoperative transthoracic echocardiography.
• Give informed consent.

• Pacientes ≥ 18 años
• Pacientes con disfunción de ventrículo derecho preoperatoria (TAPSE<17 mm, dilatación VD>39 mm, dilatación de anillo tricuspídeo>40 mm), diagnosticado por ecocardiografía transtorácica reglada preoperatoria.
• Que otorgue el consentimiento informado.

E.4

Principal exclusion criteria

. History of adverse event related to levosimendan.
• Patients in a situation of hemodynamic instability.
• Preoperative renal dysfunction, estimated through the preoperative GFR rate (creatinine clearance <50ml / min).
• Hypersensitivity to levosimendan or to any of the excipients.
• Significant mechanical obstructions affecting ventricular filling or emptying or both.
• History of Torsade de Pointes.
• Cardiogenic shock situation (lactate> 4 mmol / L)
• TAS before the infusion <100 mmHg (recommendation of the Spanish Society of Cardiology)
• Some serious situation at the discretion of the researcher.

• Historia de reacción adversa a levosimendán.
• Pacientes en situación de inestabilidad hemodinámica.
• Disfunción renal preoperatoria, estimada a través de la tasa de FG preoperatoria (aclaramiento de creatinina < 50ml/min).
• Hipersensibilidad a levosimendán o a cualquiera de los excipientes.
• Obstrucciones mecánicas significativas que afecten al llenado o al vaciado ventricular o a ambos.
• Historia de Torsade de Pointes.
• Situación de shock cardiogénico (lactato>4 mmol/L)
• TAS previa a la infusión<100 mmHg (recomendación de la Sociedad Española de Cardiología)
• Alguna situación grave a criterio del investigador.

E.5 End points

E.5.1

Primary end point(s)

. Cardiac function of right ventricle
. miRNAs and cardiac and renal enzymes

. Función cardiaca del ventrículo derecho
. miRNAs y enzimas cardiacas y renales

E.5.1.1

Timepoint(s) of evaluation of this end point

24h
48h

E.5.2

Secondary end point(s)

. Renal IRV
. EUROSCORE II
. Arrhythmias

. IRV renal
. EUROSCORE II
. Arritmias

E.5.2.1

Timepoint(s) of evaluation of this end point

24h
48h

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

Yes

E.6.3

Therapy

E.6.4

Safety

Yes

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

Yes

E.8.4

The trial involves multiple sites in the 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

LVLP

Última visita del último paciente

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)

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

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

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

F.4.2

For a multinational trial

F.4.2.1

In the EEA

F.4.2.2

In the whole clinical trial

F.5

Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)

None

Ninguna

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

2019-04-26

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2019-02-22

P. End of Trial
P.	End of Trial Status	Ongoing

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