Clinical Trials Register

Summary
EudraCT Number:	2017-002799-18
Sponsor's Protocol Code Number:	ICICOR-2017-01
National Competent Authority:	Spain - AEMPS
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2017-10-20
Trial results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

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A. Protocol Information

A.1

Member State Concerned

Spain - AEMPS

A.2

EudraCT number

2017-002799-18

A.3

Full title of the trial

Renin-angiotensin System Blockade Benefits in Clinical Evolution and Ventricular Remodeling After Transcatheter Aortic Valve Implantation (RASTAVI)

Beneficio del bloqueo del sistema renina-angiotensina sobre la evolución clínica y el remodelado ventricular tras la colocación de una prótesis percutánea aórtica

A.3.1

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

Renin-angiotensin System Blockade Benefits in Clinical Evolution and Ventricular Remodeling After Transcatheter Aortic Valve Implantation (RASTAVI)

Beneficio del bloqueo del sistema renina-angiotensina sobre la evolución clínica y el remodelado ventricular tras la colocación de una prótesis percutánea aórtica

A.3.2

Name or abbreviated title of the trial where available

RASTAVI

A.4.1

Sponsor's protocol code number

ICICOR-2017-01

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	José Alberto San Román Calvar
B.1.3.4	Country	Spain
B.3.1 and B.3.2	Status of the sponsor	Non-Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	FIS (Fondo de Investigación en Salud)
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	ALPHA BIORESEARCH S.L.
B.5.2	Functional name of contact point	Teresa Bricio
B.5.3	Address:
B.5.3.1	Street Address	Pso. de la Castellana, 163
B.5.3.2	Town/ city	Madrid
B.5.3.3	Post code	28046
B.5.3.4	Country	Spain
B.5.4	Telephone number	0034917452520
B.5.5	Fax number	0034917450653
B.5.6	E-mail	teresa.bricio@alphabioresearch.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	RAMIPRIL
D.2.1.1.2	Name of the Marketing Authorisation holder	ALTER
D.2.1.2	Country which granted the Marketing Authorisation	Spain
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	RAMIPRIL
D.3.2	Product code	RAMIPRIL
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	RAMIPRIL
D.3.9.1	CAS number	87333-19-5
D.3.9.2	Current sponsor code	RAMIPRIL
D.3.9.3	Other descriptive name	RAMIPRIL
D.3.9.4	EV Substance Code	SUB10248MIG
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	RAMIPRIL
D.2.1.1.2	Name of the Marketing Authorisation holder	ALTER
D.2.1.2	Country which granted the Marketing Authorisation	Spain
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	RAMIPRIL
D.3.2	Product code	RAMIPRIL
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	RAMIPRIL
D.3.9.1	CAS number	87333-19-5
D.3.9.2	Current sponsor code	RAMIPRIL
D.3.9.3	Other descriptive name	RAMIPRIL
D.3.9.4	EV Substance Code	SUB10248MIG
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	RAMIPRIL
D.2.1.1.2	Name of the Marketing Authorisation holder	ALTER
D.2.1.2	Country which granted the Marketing Authorisation	Spain
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	RAMIPRIL
D.3.2	Product code	RAMIPRIL
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	RAMIPRIL
D.3.9.1	CAS number	87333-19-5
D.3.9.2	Current sponsor code	RAMIPRIL
D.3.9.3	Other descriptive name	RAMIPRIL
D.3.9.4	EV Substance Code	SUB10248MIG
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.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

Severe aortic stenosis

Estenosis aórtica severa

E.1.1.1

Medical condition in easily understood language

Severe aortic stenosis

Estenosis aórtica severa

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	PT
E.1.2	Classification code	10002906
E.1.2	Term	Aortic stenosis
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

To perform a 1: 1 randomized study in patients who underwent a percutaneous aortic prosthesis as treatment for severe degenerative aortic stenosis and to compare the cardiovascular events, in a follow-up of 3 years, including death from cardiac cause, admission for heart failure and stroke, in patients who have received standard treatment plus ramipril versus patients who have received the usual treatment

Realizar un estudio aleatorizado 1:1, abierto en pacientes a los que se ha puesto una prótesis percutánea aórtica como tratamiento de la estenosis aórtica degenerativa severa y comparar los eventos cardiovasculares, que incluye muerte de causa cardíaca, ingreso por insuficiencia cardíaca e ictus, en un seguimiento de 3 años, en pacientes que han recibido tratamiento habitual más ramipril frente a pacientes que han recibido el tratamiento habitual.

E.2.2

Secondary objectives of the trial

As part of the hypothesis of study, the randomized trial will compare the evolution of left ventricular remodeling at the year of follow-up, between the active treatment group and the control group. Specifically, we will evaluate: Ventricular mass, myocardial fibrosis, ventricular dimensions and ejection fraction.
In addition, other aspects will be compared between the two groups:
1) Functional capacity at one-year follow-up
2) Cardiac cause of death (if the cause of death is unknown, it will be considered of cardiac cause) at one year and at three years of follow-up.
3) Revenue from heart failure at one year and at three years of follow-up.
4) Stroke (compatible symptoms and demonstration with imaging technique) at one year and at three years of follow-up.
5) Death of any cause at one year and at three years of follow-up.

Como parte de la hipótesis de estudio, en el ensayo aleatorizado se comparará la evolución del remodelado ventricular izquierdo al año de seguimiento entre el grupo de tratamiento activo y el grupo control. Concretamente se evaluarán: Masa ventricular, fibrosis miocárdica, dimensiones ventriculares y fracción de eyección.
Además, se compararán otros aspectos entre el grupo de tratamiento activo y el grupo control:
1) Capacidad funcional al año de seguimiento
2) Muerte de causa cardíaca (si la causa de muerte no se conoce se considerará de causa cardíaca) al año y a los tres años del seguimiento.
3) Ingreso por insuficiencia cardíaca al año y a los tres años del seguimiento.
4) Ictus (síntomas compatibles y demostración con técnica de imagen) al año y a los tres años del seguimiento.
5) Muerte de cualquier causa al año y a los tres años.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

- Replacement of the aortic valve with a percutaneous prosthesis decided by the heart team due to severe aortic stenosis.
- Do not have any device not compatible with RM.
- Ability to understand and sign informed consent.
- They do not meet any of the exclusion criteria.

Se incluirán en el estudio, pacientes mayores de 60 años de edad, reclutados en el área de hospitalización, que cumplan los siguientes requisitos: diagnóstico de estenosis aórtica severa por criterios ecocardiográficos.

CRITERIOS DE INCLUSIÓN
- Sustitución de la válvula aórtica con una prótesis percutánea aceptada en una sesión médico-quirúrgica por estenosis aórtica severa.
- No tienen ningún dispositivo no compatible con RM.
- Capacidad de entender y firmar el consentimiento informado.
- No cumplen ninguno de los criterios de exclusión.

E.4

Principal exclusion criteria

- Associated mitral valvulopathy requiring intervention.
- Left ventricular ejection fraction <40% and to have history of myocardial infarction or previous diagnosis of dilated cardiomyopathy.
- Prescription of SRA blockers in the 3 months prior to the start of the study.
- Known allergy or intolerance to IECAs.
- Severe chronic kidney disease (glomerular filtration <30 ml / min). Patients between 30 and 50 ml / min, will participate in the study but they will not be given gadolinium during MRI.
- Systolic arterial pressure less than 100 mmHg or diastolic less than 40 mmHg.
- Pregnancy in second or third trimester.
- Participation in another clinical trial.

CRITERIOS DE EXCLUSIÓN
- Valvulopatía mitral asociada que requiera intervención.
- Fracción de eyección ventricular izquierda menor del 40% y antecedentes de infarto de miocardio o diagnóstico previo de miocardiopatía dilatada.
- Prescripción de bloqueantes del SRA en los 3 meses previos al comienzo del
estudio.
- Alergia o intolerancia conocida a los IECAs.
- Insuficiencia renal significativa (filtrado glomerular < 30 ml/min). Si está entre 30 y 50 ml/min, puede entrar en el estudio pero no se le administrará gadolinio durante la RM.
- Presión sistólica menor de 100 mmHg o diastólica menor de 40 mmHg.
- Embarazo en segundo o tercer trimestre.
- Participación en otro ensayo clínico.

E.5 End points

E.5.1

Primary end point(s)

Cardiovascular events, including death from cardiac cause, admission for heart failure and stroke

Eventos cardiovasculares que incluye muerte de causa cardíaca, ingreso por insuficiencia cardíaca e ictus.

E.5.1.1

Timepoint(s) of evaluation of this end point

At the first year and at a follow-up of 3 years

Al año y en un seguimiento de 3 años.

E.5.2

Secondary end point(s)

Left ventricular remodeling. Specifically: Ventricular mass, myocardial fibrosis, ventricular dimensions and ejection fraction.

Remodelado ventricular izquierdo. Concretamente: masa ventricular, fibrosis miocárdica, dimensiones ventriculares y fracción de eyección.

E.5.2.1

Timepoint(s) of evaluation of this end point

At the first year and at a follow-up of 3 years

Al año y en un seguimiento de 3 años.

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)

E.7.4

Therapeutic use (Phase IV)

Yes

E.8 Design of the trial

E.8.1

Controlled

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

Yes

E.8.1.3

Single blind

E.8.1.4

Double blind

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)

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

Yes

E.8.4

The trial involves multiple sites in the Member State concerned

E.8.5

The trial involves multiple Member States

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.7

Trial has a data monitoring committee

E.8.8

Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial

LVLS

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

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:

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

300

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

336

F.4.2

For a multinational trial

F.4.2.1

In the EEA

336

F.4.2.2

In the whole clinical trial

336

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)

Ninguno. Práctica clínica habitual.

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

2017-12-27

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2017-11-16

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

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