Clinical Trials Register

Summary
EudraCT Number:	2013-001747-31
Sponsor's Protocol Code Number:	CLCZ696D2301
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:	2014-01-10
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

2013-001747-31

A.3

Full title of the trial

A multicenter, randomized, double-blind, parallel group, active-controlled study to evaluate the efficacy and safety of LCZ696 compared to valsartan, on morbidity and mortality in heart failure patients (NYHA Class II-IV) with preserved ejection fraction.

Estudio multicéntrico, aleatorizado, doble ciego, de grupos paralelos, con control activo, para evaluar la eficacia y seguridad de LCZ696 comparado con valsartan, sobre la morbilidad y mortalidad en pacientes con insuficiencia cardiaca (Clase II-IV NYHA) con fracción de eyección preservada

A.3.1

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

A study to evaluate the efficacy and safety of LCZ969 in heart failure patients with preserved ejection fraction.

Etudio para evaluar la eficacia y seguridad de LCZ696 en pacientes con insuficiencia cardiaca con fracción de eyección preservada

A.3.2

Name or abbreviated title of the trial where available

PARAGON-HF

A.4.1

Sponsor's protocol code number

CLCZ696D2301

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	Novartis Farmacéutica, S.A.
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	Novartis Pharma Services AG
B.4.2	Country	Switzerland
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Novartis Farmacéutica, S.A.
B.5.2	Functional name of contact point	Departamento Médico (ICRO)
B.5.3	Address:
B.5.3.1	Street Address	Gran Via de les corts Catalanes 764
B.5.3.2	Town/ city	Barcelona
B.5.3.3	Post code	08013
B.5.3.4	Country	Spain
B.5.4	Telephone number	+34900353036
B.5.5	Fax number	+34932479903
B.5.6	E-mail	eecc.novartis@novartis.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	No
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	LCZ696 50mg
D.3.2	Product code	LCZ696
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	not available
D.3.9.3	Other descriptive name	LCZ696
D.3.9.4	EV Substance Code	SUB30457
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	50
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	No
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	LCZ696 100mg
D.3.2	Product code	LCZ696
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	not available
D.3.9.3	Other descriptive name	LCZ696
D.3.9.4	EV Substance Code	SUB30457
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	100
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	No
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	LCZ696 200mg
D.3.2	Product code	LCZ696
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	not available
D.3.9.3	Other descriptive name	LCZ696
D.3.9.4	EV Substance Code	SUB30457
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	200
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	Comparator
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	Diovan Cardio 40 mg
D.2.1.1.2	Name of the Marketing Authorisation holder	Novartis Farmacéutica, S.A.
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	Diovan 40mg
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	VALSARTAN
D.3.9.1	CAS number	137862-53-4
D.3.9.4	EV Substance Code	SUB00017MIG
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	40
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	Comparator
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	Diovan 80 mg
D.2.1.1.2	Name of the Marketing Authorisation holder	Novartis Farmacéutica, S.A.
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	Diovan 80mg
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	VALSARTAN
D.3.9.1	CAS number	137862-53-4
D.3.9.4	EV Substance Code	SUB00017MIG
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	80
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	Comparator
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	Diovan 160 mg
D.2.1.1.2	Name of the Marketing Authorisation holder	Novartis Farmacéutica S.A.
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	Diovan 160mg
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	VALSARTAN
D.3.9.1	CAS number	137862-53-4
D.3.9.4	EV Substance Code	SUB00017MIG
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	160
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	Film-coated tablet
D.8.4	Route of administration of the placebo	Oral use
D.8 Placebo: 6
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

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Heart failure with preserved ejection fraction

Insuficiencia cardíaca con fracción de eyección preservada

E.1.1.1

Medical condition in easily understood language

Heart failure

Insuficiencia cardíaca

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	16.1
E.1.2	Level	LLT
E.1.2	Classification code	10069211
E.1.2	Term	Diastolic heart failure
E.1.2	System Organ Class	100000004849

E.1.2 Medical condition or disease under investigation

E.1.2	Version	16.1
E.1.2	Level	LLT
E.1.2	Classification code	10019279
E.1.2	Term	Heart failure
E.1.2	System Organ Class	100000004849

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

The primary objective of this study is to compare LCZ696 to valsartan in reducing the rate of the composite endpoint of cardiovascular death and total (first and recurrent) heart failure (HF) hospitalizations, in HF patients (NYHA Class II-IV) with preserved EF (LVEF ?45%). The treatment arm with the lower rate of events will be deemed as having a successful response.

El objetivo principal de este estudio es comparar LCZ696 con valsartan en la reducción de la tasa de la variable compuesta de muerte CV y hospitalizaciones totales (primera y recurrentes) por IC en pacientes con IC (Clase II-IV NYHA) con FE preservada (FE ventricular izquierda [FEVI] ?45%).

E.2.2

Secondary objectives of the trial

- Evaluation of the composite endpoint of CV death, total HF hospitalizations, total strokes, and total MIs. The treatment arm with the lower rate of events will be deemed a successful response.
- Evaluation of change from baseline to Month 8 in NYHA functional class, a well established grading
scale used to classify a HF patients' level of functionality based on the signs and symptoms of HF exhibited by the patient.
- Evaluation of the time to onset of atrial fibrillation (AF) in patients wtihout prior AF (no prior history of AF and no AF at baseline).
- Evaluation of the time to all cause death.

? Comparar LCZ696 con valsartan para reducir la tasa de la variable compuesta de muerte CV, hospitalizaciones totales por IC, ictus totales no mortales, e infartos de miocardio (IMs) totales no mortales. Total se define como primero y todos los acontecimientos recurrentes.
? Comparar LCZ696 con valsartan para mejorar la clasificación funcional NYHA a los 8 meses.
? Comparar LCZ696 con valsartan en retrasar el tiempo hasta un nuevo inicio de FA (FANI) en pacientes sin antecedentes de FA y sin FA en el electrocardiograma (ECG) a nivel basal.
? Comparar LCZ696 a valsartan en retrasar el tiempo hasta mortalidad por cualquier causa.

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

Following substudies are part of main protocol:
- To compare LCZ696 to valsartan on the profile of pre-specified biomarkers from baseline to predefined time points in a subset of patients.
- To characterize LCZ696 and valsartan pharmacokinetics (PK) at steady-state using population modeling and/or non-compartmental based methods in a subset of patients.
- To compare LCZ696 to valsartan in reducing subclinical atrial fibrillation (AF) or AF burden in a subset of patients with no history of AF and without AF on ECG at baseline.

Los siguientes subestudios son aprte del protocolo principal:? Comparar LCZ696 con valsartan en el perfil de biomarcadores pre-especificados desde la basal a tiempos predefinidos en un subgrupo de pacientes.
? Caracterizar la farmacocinética (PK) de LCZ696 y valsartan en la fase de equilibrio utilizando modelos poblacionales y/o métodos no compartimentales en un subgrupo de pacientes.
? Comparar LCZ696 con valsartan en la reducción de la FA subclínica o la carga de FA en un subgrupo de pacientes sin antecedentes de FA y sin FA en el ECG a nivel basal.

E.3

Principal inclusion criteria

- Left ventricular ejection fraction (LVEF) ?45% prior to study entry.
- Symptom(s) of heart failure (HF) and requiring treatment with diuretic(s) for HF ?30 days prior to study entry.
- Current symptom(s) of HF.
- Structural heart disease (left atrial enlargement or left ventricular hypertrophy) documented by
echocardiogram.
- At least one of the following: a HF hospitalization within 9 months prior to study entry and/or an elevated NT-proBNP.
- Other protocol-defined inclusion criteria may apply.

-FEVI ? 45% antes de Visita 1
-Síntoma(s) de IC que precisa(n) tratamiento con diurético(s) para IC ? 30 días antes de la Visita 1
-Síntoma(s) actual(es) de IC
-Enfermedad cardiaca estructural evidenciada por uno o ambos de los siguientes hallazgos de eco .
-Pacientes con al menos uno de los siguientes: una hospitalización por IC ( en los 9 meses previos a la Visita 1 y/o . NT-proBNP elevado en la Visita 1

E.4

Principal exclusion criteria

- Any prior measurement of LVEF < 45%.
- Acute coronary syndrome (including myocardial infarction (MI)), cardiac surgery, other major cardiovascular surgery within 3 months, or urgent percutaneous coronary intervention (PCI) within 30 days of entry.
- Patients who have had an MI, coronary artery bypass graft (CABG) or other event within the 6 months prior to entry unless an echo measurement performed after the event confirms a LVEF
?45%.
- Current acute decompensated HF requiring therapy.
- Patients who require treatment with 2 or more of the following: an angiotensin converting enzyme inhibitor (ACEI), an angiotensin receptor blocker (ARB) or a renin inhibitor.
- Alternative reason for shortness of breath such as: significant pulmonary disease or severe COPD, hemoglobin (Hgb) <10 g/dl, or body mass index (BMI) > 40 kg/m2.
- Systolic blood pressure (SBP) ? 180 mmHg at entry, or SBP >150 mmHg and <180 mmHg at entry unless the patient is receiving 3 or more antihypertensive drugs.
- Other protocol-defined exclusion criteria may apply.

1. Cualquier determinación eco previa de FEVI < 45%.
2. Síndrome coronario agudo (incluyendo IM), cirugía cardiaca, otra cirugía CV mayor, o intervención coronaria percutánea (ICP) en los 3 meses previos a la Visita 1 o una ICP de elección en los 30 días antes de la Visita 1.
3. Pacientes que han tenido un IM, derivación aorto coronaria por injerto (CABG) u otro acontecimiento en los 6 meses previos a la Visita 1 que podrían haber reducido su FE a menos que una determinación de eco realizada después del acontecimiento confirme un FEVI ? 45%.
4. IC descompensada aguda actual que precisa terapia aumentada con diuréticos, vasodilatadores y/o fármacos inotrópicos.
5. Pacientes que precisan tratamiento con 2 o más de los siguientes: un IECA, un ARAII o un inhibidor de la renina.
6. Antecedentes de hipersensibilidad a alguno de los fármacos del estudio o a fármacos de clases químicas similares.
7. Pacientes con antecedentes conocidos de angioedema.

10. Pacientes con alguno de los siguientes:
a. presión arterial sistólica (PAS) ? 180 mmHg en la Visita 1, o
b. PAS >150 mmHg y < 180 mmHg en la Visita 1 a menos que el paciente esté recibiendo 3 o más fármacos antihipertensivos. Fármacos antihipertensivos incluyen, pero sin limitarse a, una tiazida u otro diurético, antagonistas mineralocorticosteroides (ARM), IECA, ARAII, beta bloqueantes y bloqueantes del canal del calcio (BCC), o
c. PAS < 110 mmHg en la Visita 1, o
d. PAS < 105 mmHg hipotensión sintomática determinada por el investigador en la Visita 103 o Visita 201
VEr otros criterios en el protocolo

E.5 End points

E.5.1

Primary end point(s)

Cumulative number of primary composite events of cardiovascular (CV) death and total (first and recurrent) HF hospitalizations.

La variable de eficacia principal del estudio consiste en los tiempos hasta hospitalización recurrente por insuficiencia cardiaca y tiempo de muerte por CV durante el seguimiento del paciente

E.5.1.1

Timepoint(s) of evaluation of this end point

Total follow up time (up to 57 months)

hasta 57 meses

E.5.2

Secondary end point(s)

- Cumulative number of events of the extended composite endpoint of CV death, total HF hospitalizations, total non-fatal strokes, and total non-fatal myocardial infarctions (MIs).
- Change from baseline to Month 8 in New York Heart Association (NYHA) functional class.
- Time to new onset of atrial fibrillation (AF).
- Time to all-cause mortality.

? El número acumulativo de acontecimientos de la variable compuesta ampliada de muerte CV, total de hospitalizaciones por IC no mortales, total de ictus no mortales, y total de IMs no mortales, a lo largo del tiempo durante el periodo doble ciego del estudio
? Cambio en la clase NYHA desde la basal al Mes 8
? Tiempo hasta nuevo inicio de FA
? Tiempo hasta mortalidad por cualquier causa

E.5.2.1

Timepoint(s) of evaluation of this end point

- Total follow up time (up to 57 months).
- 8 months for the NYHA functional class.

-Hasta 57 meses
-8 meses para la clase funcional NYHA

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

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

Yes

E.6.11

Pharmacogenomic

Yes

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

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)

Yes

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

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

321

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

Belgium

Bulgaria

Canada

China

Denmark

France

Greece

Italy

Austria

Croatia

Netherlands

Norway

Portugal

Romania

Slovakia

Sweden

Dominican Republic

Argentina

Brazil

Chile

Colombia

Czech Republic

Ecuador

Finland

Germany

Guatemala

Hong Kong

Hungary

Korea, Republic of

Spain

Israel

Mexico

Panama

Peru

Philippines

Russian Federation

Serbia

Singapore

South Africa

Switzerland

Taiwan

Turkey

United Kingdom

United States

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

LVLS (15-Aug-2018)

ültima visita del último paciente incluido (15 Agosto 2013

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

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:

990

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

3310

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

120

F.4.2

For a multinational trial

F.4.2.1

In the EEA

2034

F.4.2.2

In the whole clinical trial

4300

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

Ninguno

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

2013-12-20

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2013-11-20

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2019-06-07

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