Clinical Trials Register

Summary
EudraCT Number:	2011-005784-24
Sponsor's Protocol Code Number:	MEIXO-VALV-001
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:	2012-03-29
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

2011-005784-24

A.3

Full title of the trial

Dual antiplatelet therapy versus oral anticoagulation for a short time to prevent cerebral embolism after percutaneous aortic valve implantation. Multicenter randomized clinical trial.

Doble Antiagregación versUs anticoagulación oRal por corto tiempo para la prevención de tromboembolismo cerebral posterior al implantE percutáneo de válvulas Aórticas. Ensayo clínico multicéntrico aleatorizado.

A.3.1

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

Clinical trial to evaluate treatment after percutaneous aortic valve implantation

Ensayo clinico para evaluar el tratamiento tras el implante de valvulas percutaneas aórticas

A.3.2

Name or abbreviated title of the trial where available

AUREA

A.4.1

Sponsor's protocol code number

MEIXO-VALV-001

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	Andres Iñiguez Romo
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	Ministry of Health, Social Services and Equal
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	Fundación Biomédica del complejo hospitalario de Vigo
B.5.2	Functional name of contact point	cardiovascular clinical trials
B.5.3	Address:
B.5.3.1	Street Address	Hospital meixoeiro. Interventional cardiology.C/meixoeiro sn
B.5.3.2	Town/ city	Vigo
B.5.3.3	Post code	36214
B.5.3.4	Country	Spain
B.5.4	Telephone number	034986811 758
B.5.5	Fax number	034986811 173
B.5.6	E-mail	carlos.maria.diaz.lopez@sergas.es

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	DUOPLAVIN
D.2.1.1.2	Name of the Marketing Authorisation holder	Sanofi Pharma BristolNON-BREAKING HYPHEN (8209)Myers Squibb SNC 174 Avenue de France F-75013 Paris
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.3.4	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	clopidogrel
D.3.9.1	CAS number	113665-84-2
D.3.9.3	Other descriptive name	clopidogrel (as hydrogen sulphate)
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	75
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	acetylsalicylic acid
D.3.9.1	CAS number	80-78-2
D.3.9.3	Other descriptive name	acetylsalicylic acid
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: 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	Sintrom
D.2.1.1.2	Name of the Marketing Authorisation holder	Novartis Farmacéutica S.A. Gran Vía de les Corts Catalanes, 764 08013 Barcelona.
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	acenocumarol
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	acenocumarol
D.3.9.1	CAS number	152-72-7
D.3.9.3	Other descriptive name	acenocumarol
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	range
D.3.10.3	Concentration number	2 to 4
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

Evaluate the efficacy of dual antiplatelet therapy versus oral anticoagulation for primary prevention of cerebral thromboembolism at three months after percutaneous aortic valve implantation (TAVI).

Evaluar la eficacia de la doble antiagregación frente a la anticoagulación oral para la prevención primaria de tromboembolismo cerebral a los tres meses tras el implante percutáneo de válvulas aórticas (TAVI).

E.1.1.1

Medical condition in easily understood language

Comparing two treatments after implantation of a percutaneous aortic valve: Dual antiplatelet therapy versus oral anticoagulation.

Comparar dos tratamientos tras el implante de una válvula aórtica percutanea: La doble antiagregación frente a la anticoagulación oral para la prevención primaria de tromboembolismo cerebral .

E.1.1.2

Therapeutic area

Diseases [C] - Cardiovascular Diseases [C14]

MedDRA Classification

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 incidence of major vascular events ischemic or hemorrhagic, fatal or nonfatal (cerebral or systemic), the third month after initiation of treatment in both arms after percutaneous aortic valve implantation.

? Determinar la incidencia de eventos vasculares mayores isquémicos o hemorrágicos, fatales o no fatales (cerebrales o sistémicos), al tercer mes tras el inicio del tratamiento en ambos brazos posterior al implante valvular aórtico percutáneo.

E.2.2

Secondary objectives of the trial

? To assess the frequency of new areas of cerebral infarction among the different treatment regimens after percutaneous aortic valve implantation using magnetic resonance imaging.
? To determine the incidence of major vascular events ischemic or hemorrhagic, fatal or nonfatal (cerebral or systemic), the first and sixth month.
? Evaluate changes in the levels of serum markers of cerebral ischemic damage and correlate them with new areas of cerebral infarction by magnetic resonance imaging after percutaneous aortic valve implantation in both treatment arms.
? Detect the presence of cognitive impairment in stroke patients with aortic valve after percutaneous implant and determine their prognostic implications in both treatment arms.

? Evaluar la frecuencia de nuevos zonas de infarto cerebral entre los diferentes esquemas de tratamiento posterior al implante valvular aórtico percutáneo mediante resonancia magnética craneal.
? Determinar la incidencia de eventos vasculares mayores isquémicos o hemorrágicos, fatales o no fatales (cerebrales o sistémicos), al primer y sexto mes.
? Evaluar los cambios en los niveles de los marcadores séricos de daño isquémico cerebral y correlacionarlos con nuevas zonas de infarto cerebral por resonancia magnética craneal posterior al implante valvular aórtico percutáneo en ambos brazos de tratamiento.
? Detectar la presencia de alteraciones cognitivas en los pacientes con infartos cerebrales posterior al implante valvular aórtico percutáneo y determinar su implicación pronóstica en ambos brazos de tratamiento.
? Evaluar la calidad de vida de los pacientes en ambos brazos de tratamiento.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1 .- Adult patients (? 18 years) with ability to understand and accept the participation in the clinical trial.

2 .- Patients with symptomatic degenerative severe aortic stenosis confirmed by imaging studies or invasive method, evaluated by the team of Cardiothoracic Surgery and rejected conventional surgical aortic valve replacement due to unacceptably high risk and accepted for TAVI procedure;

3 .- That they have signed informed consent.

4 .- Patients who are not participating in any clinical trial or research study.

1.- Pacientes adultos (? 18 años) con capacidad para entender y aceptar la participación en el ensayo clínico.

2.- Pacientes con estenosis aórtica severa degenerativa sintomática confirmada por estudios de imagen o método invasivo, evaluados por el equipo de Cirugía Cardiotorácica y rechazados para cirugía convencional de remplazo valvular aórtico debido a riesgo inaceptablemente alto y aceptados para procedimiento de TAVI;

3.- Que hayan firmado del consentimiento informado.

4.- Pacientes que no estén participando en ningún ensayo clínico o estudio de investigación.

E.4

Principal exclusion criteria

1 .- Patients who previously regime are under oral anticoagulation or antiplatelet therapy and post-procedure TAVI have to maintain dual antiplatelet therapy or anticoagulation
2 .- Patients who can not undergo an MRI study for various reasons; 3 .- recent stroke <14 days prior, revascularized coronary artery disease or life expectancy <12 months;
4 .- Patients with proven allergy to aspirin, clopidogrel or acenocoumarol;
5 .- Patients after TAVI procedure can not undergo a regimen of dual antiplatelet therapy or oral anticoagulation for 3 months for any new post-TAVI medical indication;
6 .- Patients who are pregnant or breastfeeding.

1.- Pacientes que previamente estén bajo régimen con anticoagulación oral o doble antiagregación y que posterior al procedimiento de TAVI tengan que mantener tratamiento con doble antiagregación o anticoagulación
2.- Pacientes que no puedan someterse a un estudio de RMC por diversas razones; 3.- Infarto cerebral reciente < 14 días previos, enfermedad arterial coronaria no revascularizada o esperanza de vida < 12 meses;
4.- Pacientes con alergia comprobada al acido acetil salicílico, clopidogrel o acenocumarol;
5.- Pacientes que posterior al procedimiento de TAVI no puedan someterse a un régimen de antiagregación dual o anticoagulación oral durante 3 meses por alguna nueva indicación médica post-TAVI;
6.- Pacientes embarazadas o en período de lactancia.

E.5 End points

E.5.1

Primary end point(s)

Incidence of major vascular events ischemic or hemorragic, fatal or nonfatal (cerebral or systemic).

Incidencia de eventos vasculares mayores isquémicos o hemorrágicos, fatales o no fatales (cerebrales o sistémicos)

E.5.1.1

Timepoint(s) of evaluation of this end point

3 months after TAVI implantation

3 meses post implantacion TAVI

E.5.2

Secondary end point(s)

? Frequency of new areas of cerebral infarction among the different treatment regimens after percutaneous aortic valve implantation using magnetic resonance imaging.
? Incidence of major vascular events ischemic or hemorrhagic, fatal or nonfatal (cerebral or systemic), the first and sixth month.
? Levels of serum markers of cerebral ischemic damage and correlate them with new areas of cerebral infarction by magnetic resonance imaging after percutaneous aortic valve implantation in both treatment arms.
? Cognitive impairment in stroke patients after implantation and percutaneous aortic valve
? Quality of life of patients in both treatment arms.

Frecuencia de nuevos zonas de infarto cerebral entre los diferentes esquemas de tratamiento posterior al implante valvular aórtico percutáneo mediante resonancia magnética craneal.
? Incidencia de eventos vasculares mayores isquémicos o hemorrágicos, fatales o no fatales (cerebrales o sistémicos), al primer y sexto mes.
? Niveles de los marcadores séricos de daño isquémico cerebral y correlacionarlos con nuevas zonas de infarto cerebral por resonancia magnética craneal posterior al implante valvular aórtico percutáneo en ambos brazos de tratamiento.
? Alteraciones cognitivas en los pacientes con infartos cerebrales posterior al implante valvular aórtico percutáneo y
?Calidad de vida de los pacientes en ambos brazos de tratamiento.

E.5.2.1

Timepoint(s) of evaluation of this end point

? Frequency of new areas of cerebral infarction using magnetic resonance imaging:day 10, day 90.
? Incidence of major vascular events ischemic or hemorrhagic, fatal or nonfatal (cerebral or systemic): 30 and 180 day.
? Levels of serum markers of cerebral ischemic damage: day 10.
? Cognitive impairment in stroke: day 90.
? Quality of life of patients: day 90.

? Frecuencia de las nuevas áreas de infarto cerebral utilizando imágenes de resonancia magnética: el día 10, el día 90.
? Incidencia de eventos vasculares isquémicos o hemorrágicos, fatal o no fatal (cerebral o sistémica): 30 y 180 días.
? Niveles de los marcadores séricos de daño cerebral isquémico: el día 10.
? Deterioro cognitivo en el accidente cerebrovascular: el día 90.
? Calidad de vida de los pacientes: el día 90.

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

Yes

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

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

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

Yes

E.8.1.7.1

Other trial design description

Ciego Terceros (Evaluador)

Evaluator Blinded

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

Yes

E.8.2.3.1

Comparator description

acenocumarol

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

E.8.6.2

Trial being conducted completely outside of the EEA

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

Patients who have completed all testing procedures as defined in the protocol, including post-treatment measurements.Las visit of the last patient and close of the crf.

Pacientes que hayan completado todos los procedimientos del ensayo tal como se definen en el protocolo, incluyendo las determinaciones postratamiento.La ultima visita del ultimo paciente al centro y cierre del crd.

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

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)

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

120

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

120

F.4.2

For a multinational trial

F.4.2.1

In the EEA

120

F.4.2.2

In the whole clinical trial

120

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)

Follow-up by clinical practice.

Seguimiento por practica clinica 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

2012-06-14

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2012-06-12

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

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