Clinical Trials Register

Summary
EudraCT Number:	2019-003902-29
Sponsor's Protocol Code Number:	EASI-Child
National Competent Authority:	Italy - Italian Medicines Agency
Clinical Trial Type:	EEA CTA
Trial Status:	Trial now transitioned
Date on which this record was first entered in the EudraCT database:	2021-05-24
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

Italy - Italian Medicines Agency

A.2

EudraCT number

2019-003902-29

A.3

Full title of the trial

Early Administration of Ivabradine in Children with Heart Failure.

“Somministrazione precoce di ivabradina nei bambini ospedalizzati per scompenso cardiaco-EArly adminiStration of Ivabradine in CHILDren with heart failure EASI-Child- studio pilota”

A.3.1

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

Early Administration of Ivabradine in Children with Heart Failure.

“Somministrazione precoce di ivabradina nei bambini ospedalizzati per scompenso cardiaco-EArly adminiStration of Ivabradine in CHILDren with heart failure EASI-Child- studio pilota”

A.3.2

Name or abbreviated title of the trial where available

EASI-Child

A.4.1

Sponsor's protocol code number

EASI-Child

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	IRCCS, OSPEDALE PEDIATRICO BAMBINO GESÙ DI ROMA
B.1.3.4	Country	Italy
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	Ministero della Salute
B.4.2	Country	Italy
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	IRCCS Ospedale Pediatrico Bambino Gesù
B.5.2	Functional name of contact point	Centro Trials
B.5.3	Address:
B.5.3.1	Street Address	Piazza S.Onofrio 4
B.5.3.2	Town/ city	Roma
B.5.3.3	Post code	00165
B.5.3.4	Country	Italy
B.5.4	Telephone number	0668593081
B.5.5	Fax number	0668593914
B.5.6	E-mail	CTC@opbg.net

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	Procoralan
D.2.1.1.2	Name of the Marketing Authorisation holder	Les Laboratoires Servier
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	Procoralan
D.3.2	Product code	[na]
D.3.4	Pharmaceutical form	Tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.9.2	Current sponsor code	na
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	range
D.3.10.3	Concentration number	5 to 8
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	Information not present in EudraCT
D.3.11.3.2	Gene therapy medical product	Information not present in EudraCT
D.3.11.3.3	Tissue Engineered Product	Information not present in EudraCT
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	Information not present in EudraCT
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	Information not present in EudraCT
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.IMP: 2
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	Corlanor
D.2.1.1.2	Name of the Marketing Authorisation holder	Amgen
D.2.1.2	Country which granted the Marketing Authorisation	United States
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	Corlanor
D.3.2	Product code	[na]
D.3.4	Pharmaceutical form	Oral solution
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.9.2	Current sponsor code	na
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	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	Information not present in EudraCT
D.3.11.3.2	Gene therapy medical product	Information not present in EudraCT
D.3.11.3.3	Tissue Engineered Product	Information not present in EudraCT
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	Information not present in EudraCT
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	Information not present in EudraCT
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.IMP: 3
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	Procoralan
D.2.1.1.2	Name of the Marketing Authorisation holder	Les Laboratoires Servier
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	Procoralan
D.3.2	Product code	[NA]
D.3.4	Pharmaceutical form	Tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.9.2	Current sponsor code	na
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	range
D.3.10.3	Concentration number	5 to 8
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	Information not present in EudraCT
D.3.11.3.2	Gene therapy medical product	Information not present in EudraCT
D.3.11.3.3	Tissue Engineered Product	Information not present in EudraCT
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	Information not present in EudraCT
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	Information not present in EudraCT
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

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Acute hearth failure in dilated cardiomyopathy.

Insufficienza cardiaca acuta nella cardiomiopatia dilatativa

E.1.1.1

Medical condition in easily understood language

dilated cardiomyopathy.

cardiomiopatia dilatativa

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	SOC
E.1.2	Classification code	10007541
E.1.2	Term	Cardiac disorders
E.1.2	System Organ Class	10007541 - Cardiac disorders

E.1.3

Condition being studied is a rare disease

Yes

E.2 Objective of the trial

E.2.1

Main objective of the trial

Evaluate the response to ivabradine administration on heart rate after 14 days of stable therapy.

Valutare la risposta alla somministrazione di ivabradina sulla frequenza cardiaca dopo 14 giorni di terapia stabile.

E.2.2

Secondary objectives of the trial

Evaluate the response to ivabradine administration on heart rate after 4 months of follow up;
Assess the safety of ivabradine treatment, in terms of:
• blood pressure;
• symptomatic bradycardia;
• adverse events deemed to be related to therapy;
Evaluate ivabradine treatment activity in terms of:
• NT Pro BNP;
• left ventricular function, calculated using a 2D echocardiographic technique (calculation of left ventricle volumes and ejection fraction);

• Valutare la risposta alla somministrazione di ivabradina sulla frequenza cardiaca dopo 4 mesi di follow up;
• Valutare la sicurezza del trattamento con ivabradina, in termini di:
• pressione arteriosa sanguigna;
• bradicardia sintomatica;
• eventi avversi ritenuti correlati alla terapia;
• Valutare l’attività del trattamento con ivabradina in termini di:
• NT Pro BNP;
• funzione ventricolare sinistra, calcolata attraverso tecnica ecocardiografica 2D (calcolo dei volumi del ventricolo sinistro e della frazione d’eiezione);
correlate alla riduzione della frequenza cardiaca, o in maniera indipendente.
Queste valutazioni verranno eseguite al momento della sospensione della terapia inotropa (V0), prima di iniziare terapia con ivabradina (V1), a 14 giorni della terapia (V2), e a 4 mesi dalla terapia (V4).

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

Patients > 6 months of age and under 18 years of age;
Dilated cardiomyopathy defined according to the indications of the Cardiomyopathy Task Force (dilation > 2 SD and hypokinesia);
Ejection fraction < 40%;
Patients with episode of acute heart failure (both de novo and relapse) in the last three months;
Systolic blood pressure > 50th percentile per age and height;
Heart rate > 20% of the expected baseline value by age:
• 6-12 months: =105 bpm
• >1 year <3 years: =95 bpm
• 3-5 years: =75 bpm
• 5-18 years: >70 bpm

• Consenso informato scritto dei soggetti legalmente abilitati a dare il consenso o il/i genitore / i / rappresentante legale dei minori secondo la legge nazionale; assenso in prepuberi e adolescenti
• Pazienti di età > 6 mesi di vita e inferiore ai 18 anni
• Cardiomiopatia dilatativa definita secondo le indicazioni della Task force della Cardiomiopatie (dilatazione > 2 DS e ipocinesia).
• Frazione d’eiezione < 40%
• Pazienti con episodio di scompenso cardiaco acuto (sia de novo che riacutizzazione) negli ultimi tre mesi
• pressione arteriosa sistolica > 50° età e altezza
• frequenza cardiaca > 20% rispetto al valore di base atteso per età:
6-12 mesi: =105 bpm
>1 anno <3 anni: =95 bpm
3-5 anni: =75 bpm
5-18 anni: >70 bpm

E.4

Principal exclusion criteria

Cardiogenic shock in the last three months;
Hypertrophic, restrictive or mixed cardiomyopathy;
Acute lymphocytic myocarditis diagnosed by endomyocardial biopsy;
Significant Valvular Pathology;
Sinoatrial block and congenital long QT-syndrome;
Atrial fibrillation;
Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels > 2.5 times above the normal values, bilirubin > 3mg/dL and creatinine > 2.5 mg/dL.

• Shock cardiogeno negli ultimi tre mesi
• Cardiomiopatia ipertrofica, restrittiva o mista
• Miocardite acuta linfocitaria diagnosticata alla biopsia endomiocardica
• Patologia valvolare significativa
• Blocco senoatriale e sindrome del QT lungo congenito.
• Fibrillazione atriale
• Livello di aminotransferasi aspartato (AST) e alanina (ALT) > 2.5 volte i valori normali, bilirubina > 3 e creatinina > 2.5 mg/dL.
• Pazienti in gravidanza e/o con test di gravidanza positivo

E.5 End points

E.5.1

Primary end point(s)

Heart rate in b.p.m. (mean (±SD) difference from baseline) after 14 days of stable ivabradine therapy.

• Frequenza cardiaca in b.p.m. (media (±DS) differenza dal baseline) dopo 14 giorni di terapia stabile con ivabradina.

E.5.1.1

Timepoint(s) of evaluation of this end point

14 days

14 giorni

E.5.2

Secondary end point(s)

Heart rate b.p.m. (mean (±SD) difference from baseline) after 4 months of follow-up;
Serum NT-proBNP in pg/mL (mean (±SD) difference from baseline) after 14 days of stable ivabradine therapy, after 4 months of follow-up;
Correlation between heart rate and NT-proBNP value (Pearson's test);
Left ventricular function, calculated using 2D echocardiographic technique (calculation of left ventricle volumes and ejection fraction - mean (±SD) difference from baseline).
Systolic pressure in mmHg (mean (±SD) difference from baseline) after 14 days of stable ivabradine therapy and after 4 months of follow-up;
New use of inotropes (n and % of patients who had to use inotropes within 14 days of stable ivabradine therapy and within 4 months of follow-up);
N and % of dropout on total patients within 14 days of stable ivabradine therapy;
Time (days) from the start of ivabradine therapy and any new episode of acute heart failure, and/or mechanical assist device implantation.

• Frequenza cardiaca b.p.m. (media (±DS) differenza dal baseline) dopo 4 mesi di follow-up;
• NT-proBNP sierico in pg/mL (media (±DS) differenza dal baseline) dopo 14 giorni di terapia stabile con ivabradina, dopo 4 mesi di follow up;
• Correlazione tra frequenza cardiaca e valore di NT-proBNP (test di Pearson);
• Funzione ventricolare sinistra, calcolata attraverso tecnica ecocardiografica 2D (calcolo dei volumi del ventricolo sinistro e della frazione d’eiezione - media (±DS) differenza dal baseline).

E.5.2.1

Timepoint(s) of evaluation of this end point

4 months

4 mesi

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

Yes

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)

Yes

E.7.3

Therapeutic confirmatory (Phase III)

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

E.8.1.1

Randomised

E.8.1.2

Open

E.8.1.3

Single blind

E.8.1.4

Double blind

E.8.1.5

Parallel group

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

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.8.4.1

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

Information not present in EudraCT

E.8.7

Trial has a data monitoring committee

Yes

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

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

E.8.9.2

In all countries concerned by the trial years

E.8.9.2

In all countries concerned by the trial months

E.8.9.2

In all countries concerned by the trial days

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

Yes

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)

Yes

F.1.1.4.1

Number of subjects for this age range:

F.1.1.5

Children (2-11years)

Yes

F.1.1.5.1

Number of subjects for this age range:

F.1.1.6

Adolescents (12-17 years)

Yes

F.1.1.6.1

Number of subjects for this age range:

F.1.2

Adults (18-64 years)

F.1.3

Elderly (>=65 years)

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

Yes

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

Yes

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

CHILDREN

MINORI

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)

After the last visit of the trial, patients will have the possibility to continue receiving ivabradine as established by the “ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure” if the Principal Investigator thinks that the patient is benefiting from ivabradine treatment.

Dopo l'ultima visita dello studio, i pazienti avranno la possibilità di continuare a ricevere ivabradina come stabilito dalle "Linee guida ESC per la diagnosi e il trattamento dell'insufficienza cardiaca acuta e cronica" se lo sperimentatore principale ritiene che il paziente stia beneficiando del trattamento con ivabradina.

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

2020-04-03

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2020-04-30

P. End of Trial
P.	End of Trial Status	Trial now transitioned

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