Clinical Trials Register

Summary
EudraCT Number:	2013-001783-36
Sponsor's Protocol Code Number:	CLCZ696A2318
National Competent Authority:	Spain - AEMPS
Clinical Trial Type:	EEA CTA
Trial Status:	Prematurely Ended
Date on which this record was first entered in the EudraCT database:	2013-07-12
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

2013-001783-36

A.3

Full title of the trial

A randomized 8-week double-blind, parallel-group, active-controlled, multicenter study to evaluate efficacy and safety of LCZ696 200 mg in comparison with olmesartan 20 mg in essential hypertensive patients not responsive to olmesartan

Estudio multicéntrico, aleatorizado, doble ciego, de grupos paralelos, con control activo de 8 semanas de duración para evaluar la eficacia y la seguridad de LCZ696 200 mg en comparación con olmesartán 20 mg en pacientes con hipertensión esencial que no respondan de forma adecuada a un tratamiento con olmesartán 20 mg

A.3.1

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

Study to evaluate the efficacy and safety of LCZ696 compared with olmesartan in hypertensive patients not responsive to olmesartan.

Estudio para evaluar la eficacia y la seguridad de LCZ696 comparado con olmesartán en pacientes con hipertensión no respondedores a olmesartán

A.4.1

Sponsor's protocol code number

CLCZ696A2318

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
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	0034900353036
B.5.5	Fax number	003493932479903
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.3.2	Product code	LCZ696
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.3.8	INN - Proposed INN	Not available
D.3.9.1	CAS number	936623-90-4
D.3.9.2	Current sponsor code	LCZ696
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: 2
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	Olmetec
D.2.1.1.2	Name of the Marketing Authorisation holder	Daichi-Sankyo
D.2.1.2	Country which granted the Marketing Authorisation	Japan
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	Olmetec
D.3.4	Pharmaceutical form
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	OLMESARTAN
D.3.9.4	EV Substance Code	SUB20707
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	20
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	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	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

Hypertension

Hipertensión

E.1.1.1

Medical condition in easily understood language

High blood pressure

Presión sanguínea alta

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	16.0
E.1.2	Level	PT
E.1.2	Classification code	10015488
E.1.2	Term	Essential hypertension
E.1.2	System Organ Class	10047065 - Vascular 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

Change from baseline in 24-hour mean ambulatory systolic blood pressure (maSBP)

Evaluar la eficacia de LCZ696 200 mg en comparación con olmesartán 20 mg en pacientes con hipertensión esencial que no presenten una respuesta satisfactoria a olmesartán 20 mg contrastando la hipótesis de una reducción superior en la presión arterial sistólica media de la MAPA de 24 horas (PASma) después de 8 semanas de tratamiento.

E.2.2

Secondary objectives of the trial

1. Change from baseline in mean 24-hour ambulatory diastolic blood pressure (maDBP)
2. Change from baseline in mean sitting systolic blood pressure (msSBP)
3. Change from baseline in mean sitting diastolic blood pressure (maDBP)
4. Change from baseline in office pulse pressure
5. Percentage of patients achieving successful overall blood pressure control
6. Number of patients with total adverse events, serious adverse events and death
7. Percentage of patients achieving successful mean sitting systolic blood pressure (msSBP) control
8. Percentage of patients achieving successful mean sitting diastolic blood pressure (msDBP) control
9. Percentage of patients achieving successful mean sitting systolic blood pressure (msSBP) response
10. Percentage of patients achieving successful mean sitting diastolic blood pressure (msDBP) response

1. Evaluar la eficacia de LCZ696 200 mg en comparación con olmesartán 20 mg en : :
-la reducción de la PADma de la MAPA de 24 horas después de 8 sem. (semanas) de tto.
-la reducción de la PASms después de 8 sem.tto.
-la reducción de la presión arterial diastólica media en sedestación (PADms) después de 8 sem. de tto.
- la reducción de la presión de pulso después de 8 sem. de tto.
5. Evaluar la proporción de pacientes que alcancen :
-un control de la presión arterial sistólica y diastólica (< 140/90 mmHg) en todos los grupos de tto en la sem. 8 de tto.
- una respuesta satisfactoria en:
- la PASms (<140 mmHg o una reducción ? 20 mmHg respecto a la basal) en todos los grupos de tto en la sem. 8 de tto.
- la PADms (<90 mmHg o una reducción ? 10 mmHg respecto a la basal) en todos los grupos de tratamiento en la semana 8 de tratamiento.
8. seguridad y la tolerabilidad de LCZ696 200 mg en comparación con olmesartán 20 mg en pacientes con hipertensión esencial.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

Patients with mild to moderate hypertension, untreated or currently taking antihypertensive therapy
-treated patients (using antihypertensive drugs for at least 4 weeks prior to first visit) must have an office msSBP ? 150 mmHg and < 180 mmHg at both first and second visits
-untreated patients (either newly diagnosed or those patients with a history of hypertension but have not been taking any antihypertensive drugs for at least 4 weeks prior to first visit) must have an offcie msSBP ? 150 mmHg and < 180 mmHg at both first and second visits
2. Patients must successfully complete ABPM and pass technical requirements to be qualified for randomization

1. El consentimiento informado por escrito se debe obtener antes de realizar cualquier evaluación.
2. Pacientes de ambos sexos ? 18 años de edad.
3. Pacientes con hipertensión esencial de leve a moderada no tratados o que estén recibiendo actualmente tratamiento antihipertensivo.
a. Pacientes no tratados (con diagnóstico reciente de hipertensión esencial o que tengan antecedentes de hipertensión pero no hayan recibido fármacos antihipertensivos durante al menos 4 semanas antes de la visita 1 que tengan una PASms ?150 mmHg y <180 mmHg tanto en la visita 1 como en la visita 201.
b. Pacientes previamente tratados (que hayan recibido tratamiento antihipertensivo durante las 4 semanas anteriores a la visita 1) que tengan una PASms en la consulta ³ 145 mmHg y < 180 mmHg después del lavado en la visita 201.
4. Pacientes que no respondan de forma adecuada al tratamiento con olmesartán: todos los pacientes deben tener una PASms en la consulta ? 145 mmHg y < 180 mmHg cuando finalice la fase de preinclusión activa con olmesartán 20 mg de 4 semanas de duración (en la visita de aleatorización (visita 301)).
5. Pacientes que finalicen la MAPA de forma satisfactoria y cumplan los requisitos técnicos en la visita 301 para ser aptos para la aleatorización.

E.4

Principal exclusion criteria

1. Malignant or severe hypertension (grade 3 of WHO classification; msDBP ?110 mmHg and/or msSBP ? 180 mmHg)
2. History of angioedema, drug-related or otherwise
3. History or evidence of a secondary form of hypertension, including but not limited to any of the following: renal parenchymal hypertension, renovascular hypertension (unilateral or bilateral renal artery stenosis), coarctation of the aorta, primary hyperaldosteronism, Cushing?s disease, pheochromocytoma, polycystic kidney disease (PKD), drug-induced hypertension
4. Patients who previously entered a LCZ696 study and had been randomized or enrolled to receive active drug treatment

? Hipertensión maligna o severa (grado 3 de la clasificación de la OMS; PADms ? 110 mmHg y/o PASms ? 180 mmHg).
? Antecedentes de angioedema, relacionado o no con el fármaco.
? Antecedentes o signos de alguna forma secundaria de hipertensión, incluyendo, entre otros: hipertensión renal parenquimatosa, hipertensión renovascular (estenosis de la arterial renal unilateral o bilateral), coartación aórtica, hiperaldosteronismo primario, enfermedad de Cushing, feocromocitoma, enfermedad renal poliquística (ERP), hipertensión provocada por fármacos, etc.
? Accidente isquémico transitorio (AIT) durante los 12 meses anteriores a la visita 1 o cualquier antecedente de accidente cerebrovascular.
? Antecedentes de infarto de miocardio, cirugía de baipás coronario o cualquier intervención coronaria percutánea (ICP) durante los 12 meses anteriores a la visita 1.
? Pacientes con diabetes mellitus de tipo 1 o tipo 2 que no esté bien controlada según el criterio clínico del investigador. Los pacientes que actualmente estén recibiendo tratamiento para la diabetes mellitus deberán mantener una dosis estable de medicación antidiabética durante al menos 4 semanas antes de la visita 1.

E.5 End points

E.5.1

Primary end point(s)

Change from baseline in 24-hour mean ambulatory systolic blood pressure (maSBP).

cambio respecto a valora basal de la presión sanguinea sistólica ambulatoria media 24hr

E.5.1.1

Timepoint(s) of evaluation of this end point

baseline, 8 weeks.

basal, 8 semanas

E.5.2

Secondary end point(s)

1. Change from baseline in mean 24-hour ambulatory diastolic blood pressure (maDBP)
2. Change from baseline in mean sitting systolic blood pressure (msSBP)
3. Change from baseline in mean sitting diastolic blood pressure (maDBP)

4. Change from baseline in office pulse pressure

5. Percentage of patients achieving successful overall blood pressure control

6. Number of patients with total adverse events, serious adverse events and death

7. Percentage of patients achieving successful mean sitting systolic blood pressure (msSBP) control

8. Percentage of patients achieving successful mean sitting diastolic blood pressure (msDBP) control

9. Percentage of patients achieving successful mean sitting systolic blood pressure (msSBP) response

10. Percentage of patients achieving successful mean sitting diastolic blood pressure (msDBP) response

La evaluación secundaria de la eficacia incluye las siguientes variables:
1. Cambio en la PADma de la semana 8 respecto a la basal.
2. Cambio en la PASms de la semana 8 respecto a la basal.
3. Cambio en la PADms de la semana 8 respecto a la basal.
4. Cambio en la presión de pulso de la semana 8 respecto a la basal
5. Tasa de control satisfactoria en la PASms/PADms (< 140/90 mmHg) en la semana 8.
6. Tasa de control satisfactoria en la PASms (< 140 mmHg) en la semana 8.
7. Tasa de control satisfactoria en la PADms (< 90 mmHg) en la semana 8.
8. Tasa de respuesta satisfactoria en la PASms (<140 mmHg o una reducción ? 20 mmHg respecto a la basal) en la semana 8.
9. Tasa de respuesta satisfactoria en la PADms (<90 mmHg o una reducción ? 10 mmHg respecto a la basal) en la semana 8.
10. Cambio en la PASma/PADma diurna y nocturna de la semana 8 respecto a la basal.

E.5.2.1

Timepoint(s) of evaluation of this end point

1. Timpoints of evaluation of this endpoint: baseline, 8 weeks
2. Timpoints of evaluation of this endpoint: baseline, 8 weeks
3. Timpoints of evaluation of this endpoint: baseline, 8 weeks
4. Timpoints of evaluation of this endpoint: baseline, 8 weeks
5. Timpoints of evaluation of this endpoint: 8 weeks
6. Timpoints of evaluation of this endpoint: 8 weeks
7. Timpoints of evaluation of this endpoint: 8 weeks
8. Timpoints of evaluation of this endpoint: 8 weeks
9. Timpoints of evaluation of this endpoint: baseline, 8 weeks
10. Timpoints of evaluation of this endpoint: baseline, 8 weeks

1. Cambio en la PADma de sem. 8 respecto a la basal.
2. Cambio en la PASms de sem. 8 respecto a la basal.
3. Cambio en la PADms de sem. 8 respecto a la basal.
4. Cambio en la presión de pulso de sem. 8respecto a la basal
5. Tasa de control satisfactoria en la PASms/PADms (< 140/90 mmHg) en la semana 8.
6. Tasa de control satisfactoria en la PASms (< 140 mmHg) en la semana 8.
7. Tasa de control satisfactoria en la PADms (< 90 mmHg) en la semana 8.
8. Tasa de respuesta satisfactoria en la PASms (<140 mmHg o una reducción ? 20 mmHg respecto a la basal) en la semana 8.
9. Tasa de respuesta satisfactoria en la PADms (<90 mmHg o una reducción ? 10 mmHg respecto a la basal) en la semana 8.
10. Cambio en la PASma/PADma diurna y nocturna de la semana 8 respecto a la basal.

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

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

E.8.2.3

Other

Yes

E.8.2.3.1

Comparator description

Olmesartan

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

E.8.4

The trial involves multiple sites in the Member State concerned

Yes

E.8.4.1

Number of sites anticipated in Member State concerned

E.8.5

The trial involves multiple Member States

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

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

Argentina

China

Dominican Republic

Peru

Philippines

Russian Federation

United States

Venezuela, Bolivarian Republic of

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

LVLS

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

E.8.9.2

In all countries concerned by the trial years

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:

446

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

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

100

F.4.2.2

In the whole clinical trial

446

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.

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

2013-08-27

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2013-07-30

P. End of Trial
P.	End of Trial Status	Prematurely Ended
P.	Date of the global end of the trial	2014-08-14

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