Clinical Trials Register

Summary
EudraCT Number:	2011-001292-39
Sponsor's Protocol Code Number:	CL2-16257-090
National Competent Authority:	Spain - AEMPS
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2012-08-07
Trial results	View 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

2011-001292-39

A.3

Full title of the trial

Determination of the efficacious and safe dose of ivabradine in paediatric patients with dilated cardiomyopathy and symptomatic chronic heart failure aged from 6 months to less than 18 years.
A randomised, double-blind, multicentre, placebo controlled, phase II/III dose-finding study with a PK/PD characterisation and a 1 year efficacy/safety evaluation.

Determinación de la dosis de Ivabradina eficaz y segura en pacientes pediátricos con miocardiopatía dilatada e insuficiencia cardíaca crónica sintomática con edades comprendidas entre 6 meses y los 18 años (no incluidos).
Estudio de búsqueda de dosis de fase II/III con caracterización FC/FD y evaluación de eficacia/seguridad a un año, aleatorizado, doble ciego, multicéntrico y controlado frente a placebo.

A.3.1

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

Determination of the efficacious and safe dose of ivabradine in paediatric patients with dilated cardiomyopathy and symptomatic chronic heart failure aged from 6 months to less than 18 years

Determinación de la dosis de Ivabradina eficaz y segura en niños que padezcan una enfermedad cardíaca y con edades comprendidas entre los 6 meses y los 18 años no cumplidos.

A.4.1

Sponsor's protocol code number

CL2-16257-090

A.5.1

ISRCTN (International Standard Randomised Controlled Trial) Number

ISRCTN60567801

A.7

Trial is part of a Paediatric Investigation Plan

Yes

A.8

EMA Decision number of Paediatric Investigation Plan

P/628/2009

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	Lab Servier
B.1.3.4	Country	Spain
B.3.1 and B.3.2	Status of the sponsor	Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Lab Servier
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	Lab Servier
B.5.2	Functional name of contact point	Departamento I+D
B.5.3	Address:
B.5.3.1	Street Address	Avda. de los Madroños, 33
B.5.3.2	Town/ city	Madrid
B.5.3.3	Post code	28043
B.5.3.4	Country	Spain
B.5.4	Telephone number	00+3491 748 9675
B.5.5	Fax number	00+3491 3003249
B.5.6	E-mail	ana.anorbe@netgrs.com

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.2.1.2	Country which granted the Marketing Authorisation	European Union
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	S16257-2
D.3.2	Product code	S16527-2
D.3.4	Pharmaceutical form	Film-coated 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.3.8	INN - Proposed INN	Ivabradine
D.3.9.1	CAS number	155974-00-8
D.3.9.2	Current sponsor code	S16257-2
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	2.5
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.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	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	European Union
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	S16257-2
D.3.2	Product code	S16257-2
D.3.4	Pharmaceutical form	Film-coated 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.3.8	INN - Proposed INN	Ivabradine
D.3.9.1	CAS number	155974-008
D.3.9.2	Current sponsor code	S16257-2
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	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.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	European Union
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	S16257-2
D.3.2	Product code	S16257-2
D.3.4	Pharmaceutical form	Film-coated 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.3.8	INN - Proposed INN	Ivabradine
D.3.9.1	CAS number	155974-00-8
D.3.9.2	Current sponsor code	S16257-2
D.3.9.3	Other descriptive name	SUB08357MIG
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	7.5
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.IMP: 4
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	European Union
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	S16257-2
D.3.2	Product code	S16257-2
D.3.4	Pharmaceutical form	Film-coated 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.3.8	INN - Proposed INN	Ivabradine
D.3.9.1	CAS number	155974-00-8
D.3.9.2	Current sponsor code	S16257-2
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	10
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.IMP: 5
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	European Union
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	S16257-2
D.3.2	Product code	S16257-2
D.3.4	Pharmaceutical form	Oral solution
D.3.4.1	Specific paediatric formulation	Yes
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Ivabradine
D.3.9.1	CAS number	155974-00-8
D.3.9.2	Current sponsor code	S16257-2
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	0.1
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.IMP: 6
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	European Union
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	S16257-2
D.3.2	Product code	S16257-2
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.3.8	INN - Proposed INN	Ivabradine
D.3.9.1	CAS number	155974-00-8
D.3.9.2	Current sponsor code	S16257-2
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	0.5
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.IMP: 7
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	European Union
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	S16257-2
D.3.2	Product code	S16257-2
D.3.4	Pharmaceutical form	Oral solution
D.3.4.1	Specific paediatric formulation	Yes
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Ivabradine
D.3.9.1	CAS number	155974-00-8
D.3.9.2	Current sponsor code	S16257-2
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	1.33
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	Film-coated tablet
D.8.4	Route of administration of the placebo	Oral use
D.8 Placebo: 2
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Film-coated tablet
D.8.4	Route of administration of the placebo	Oral use
D.8 Placebo: 3
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Film-coated tablet
D.8.4	Route of administration of the placebo	Oral use
D.8 Placebo: 4
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Film-coated tablet
D.8.4	Route of administration of the placebo	Oral use
D.8 Placebo: 5
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Oral solution
D.8.4	Route of administration of the placebo	Oral use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Paediatric dilated cardiomyopathy and symptomatic chronic heart failure

Pacientes pediátricos con miocardiopatía dilatada e insuficiencia cardíaca crónica sintomática

E.1.1.1

Medical condition in easily understood language

Paediatric dilated cardiomyopathy and chronic heart failure

Pacientes pediátricos con miocardiopatía dilatada e insuficiencia cardíaca crónica

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	14.1
E.1.2	Level	LLT
E.1.2	Classification code	10008908
E.1.2	Term	Chronic heart failure
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 determine the optimal dose of ivabradine to reach the target heart rate reduction (HRR) of 20% without inducing a bradycardia (i.e. HR should be greater than a predefined HR threshold by age subset) and/or signs or symptoms related to bradycardia,
To assess the pharmacokinetic (PK) parameters of ivabradine and its active metabolite S 18982 after repeated oral administrations,
To assess the PKPD relationship of ivabradine and its active metabolite S 18982 using heart rate as evaluation criterion.

Determinar la dosis óptima de ivabradina para alcanzar la reducción de la frecuencia cardíaca (RFC) deseada del 20% sin inducir bradicardia (es decir, la FC debería estar por encima de un umbral predefinido de FC por sugrupo de edad) y/o signos o síntomas relacionados con la bradicardia,
Evaluar los parámetros farmacocinéticos (PK) de ivabradina y su metabolito activo S 18982 tras la administración oral repetida,
Evaluar la relación PKPD de ivabradina y su metabolito activo S 18982 utilizando la frecuencia cardiaca como criterio de evaluación.

E.2.2

Secondary objectives of the trial

To assess, compared to placebo, the effects of ivabradine at target dose, on:
.left ventricular ejection fraction, measured by echocardiography,
.clinical symptoms by using the NYHA/ROSS classification,
.global clinical status evaluated by the investigator/parents,
.cardiovascular biomarker by measuring NT-proBNP,
To assess, compared to placebo, the long-term safety of ivabradine over 1-year.

Evaluar los efectos de la dosis óptima de ivabradina, comparada con placebo, sobre:
.la fracción de eyección del ventrículo izquierdo, medida por ecocardiografía,
.los síntomas clínicos, utilizando la clasificación NYHA/ROSS,
.el estado clínico global, evaluado por el investigador/padres,
.biomarcadores cardiovasculares midiendo el NT-proBNP,
Evaluar la seguridad a largo plazo de ivabradina, comparada con placebo, durante 1 año.

E.2.3

Trial contains a sub-study

Yes

E.2.3.1

Full title, date and version of each sub-study and their related objectives

Sub-study protocol on QUALITY OF LIFE attached to CL2-16257-090 study.
Final Version 1-8-2011
The objective is to evaluate the effects of ivabradine compared to placebo on the health related quality of life (HRQL)

Protocolo del sub-estudio sobre CALIDAD DE VIDA adjunto al estudio CL2-16257-090
Versión final 1-8-2011
El objetivo es evaluar los efectos de ivabradina comparada con placebo en la calidad de vida relacionada con la salud.

E.3

Principal inclusion criteria

-Patients of both gender aged from 6 months to less than 18 years old
-Patients with dilated cardiomyopathy (DCM) receiving their usual treatment for chronic heart failure (CHF) at the optimal dose
-Patients in sinus rhythm
Resting heart rate (HR) complying with the following criteria:
.HR >= 105 bpm in the age-subset [6-12[ months
.HR >= 95 bpm in the age-subset [1-3[ years
.HR >= 75 bpm in the age-subset [3-5[ years
.HR >= 70 bpm in the age-subset [5-18[ years.
-CHF class II to IV NYHA or Ross classification, stable for at leas 1 month prior to selection
Left ventricular (LV) dysfunction with LVEF <= 45% documented by echocardiography
LV dysfunction consecutive to idiopathic DCM, post-viral myocarditis DCM or ischaemic DCM, left ventricular non compaction with DCM as primary condition or post anthracyclines DCM (provided the treatment by anthracyclines was stopped at least two years prior to the selection into the study)

- Pacientes de ambos sexos con edades comprendidas entre los 6 meses y los 18 años no cumplidos
-Pacientes con miocardiopatía dilatada(MCD) que reciben el tratamiento habitual para su ICC a dosis óptima
-Pacientes en ritmo sinusal
Frecuencia cardíaca en reposo (FC) que cumpla los siguientes criterios:
.FC >= 105 lpm en el subgrupo de edad [6-12[ meses
.FC >= 95 lpm en el subgrupo de edad [1-3[ años
.FC >= 75 lpm en el subgrupo de edad [3-5[ años
.FC >= 70 lpm en el subgrupo de edad [5-18[ años.
-ICC clase II a IV de la clasificación NYHA or Ross, estable desde al menos un mes antes de la selección
Disfunción ventricular izquierda con fracción de eyección del ventrículo izquierdo (LVEF) <= 45% documentada por ecocardiografía
Disfunción ventricular izquierda secundaria a MCD idiopática, MCD tras miocarditis viral o MCD isquémica, no compactación de ventrículo izquierdo con MCD como primera causa o MCD post-antracilcinas (siempre que el tratamiento con antraciclinas haya sido interrumpido al menos 2 años antes de la selección en el estudio)

E.4

Principal exclusion criteria

?Class I NYHA or Ross Classification (asymptomatic patients),
History of symptomatic or sustained (? 30 sec) ventricular arrhythmia unless a cardioverter defibrillator was implanted,
?Patients with structural valvular disease or severe functional valvular disease requiring surgery,
?Significant systemic ventricular outflow obstruction,
?DCM secondary to muscular dystrophies, hemoglobinopathies, HIV, carnitine deficiency,
?Patients requiring unauthorised concomitant treatment
?Serum creatinine >2.0 mg/dL or >180 ?mol/L (blood sample performed at ASSE visit),
?AST and/or ALT > 3 upper normal limits (blood sample performed at ASSE visit),
?Unstable cardiovascular conditionat selection or inclusion.
A girl having childbearing potential and sexually active not having contraception.

Clase I de la clasificación NYHA o Ross (pacientes asintomáticos),
?Antecedentes de arritmia ventricular sintomática o mantenida (? 30 segundos) salvo que tenga implantado un desfibrilador cardioversor,
?Pacientes con enfermedad valvular estructural o enfermedad valvular funcional grave que requiera cirugía
?Obsturcción significativa al flujo de salida ventricular sistémico,
?MCD secundaria a distrofias musculares, hemogloginopatías, VIH, deficiencia de carnitina, ?Pacientes que requieran tratamientos concomitantes no autorizados
?Creatinina sérica>2.0 mg/dL o >180 ?mol/L (muestra de sangre tomada en la visita ASSE),
?AST y/o ALT > 3 veces el límite superior de normalidad (muestra de sangre tomada en la visita ASSE),
?Enfermedad cardiovascular inestable desde la visita de selección.
Niñas en edad fértil y con activiad sexual que no utilizan la contracepción.

E.5 End points

E.5.1

Primary end point(s)

-Characterization PK and PKPD
-Target HR achievement

- Caracterización PK y PKPD
- Obtención de la FC deseada

E.5.1.1

Timepoint(s) of evaluation of this end point

PK measurements: at D014 and M000
Heart rate reduction (HRR): HR measurements during titration period (D000, D014, D028, D042, D056, M000)

Medidas PK: en D014 y M000
Reducción de la frecuencia cardíaca (RFC): medidas de FC durante el periodo de titulación (D000, D014, D028, D042, D056, M000)

E.5.2

Secondary end point(s)

-Echocardiographic parameters
-Heart failure symptoms severity
-Cardiovascular biomarker NT- proBNP.
-Safety

- Parámetros ecocardiográficos
- Gravedad de los síntomas de insuficiencia cardíaca
- Marcador cardiovascular NT- proBNP.
- Seguridad

E.5.2.1

Timepoint(s) of evaluation of this end point

over the study

durante el estudio

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

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

Yes

E.6.7

Pharmacodynamic

Yes

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

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

Yes

E.8.5.1

Number of sites anticipated in the EEA

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

Yes

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.6.3

If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned

Australia

Brazil

Mexico

Russian Federation

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

Last visit last subject as stated in the protocol

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

Number of subjects for this age range:

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

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 discontinuation of the study treatment, the participant will receive appropriate care by his/her doctor

Tras la interrupción del tratamiento del estudio, el investigador recibirá los cuidados apropiados de su médico.

G. Investigator Networks to be involved in the Trial
G.4 Investigator Network to be involved in the Trial: 1
G.4.1	Name of Organisation	NA
G.4.3.4	Network Country	Spain

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

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2011-11-22

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2011-11-11

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2014-02-26

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Orphan Designation Number:
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