Clinical Trials Register

Summary
EudraCT Number:	2011-000430-11
Sponsor's Protocol Code Number:	RFBU11-I
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:	2014-06-04
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

2011-000430-11

A.3

Full title of the trial

Transradial access versus Femoral and Bivalirudin versus unfractionated heparin with or without glycoprotein IIb/IIIa inhibitors as a global strategy to minimize bleeding complications in patients with acute coronary syndrome subjected to invasive treatment (MATRIX).

Acceso radial frente a acceso femoral y bivalirudina frente a heparina no fraccionada con o sin inhibidores de la glucoproteína IIb/IIIa como estrategia global para minimizar las complicaciones hemorrágicas en pacientes con síndrome coronario agudo sometidos a tratamiento invasivo

A.3.1

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

Transradial access versus Femoral and Bivalirudin versus unfractionated heparin with or without glycoprotein IIb/IIIa inhibitors to verify the bleeding complications in patients with acute coronary syndrome treatment of
coronary angioplasty.

Acceso radial frente a acceso femoral y bivalirudina frente a heparina no fraccionada con o sin inhibidores de la glucoproteína IIb/IIIa para verificar las complicaciones hemorrágicas en pacientes con síndrome coronario agudo el tratamiento de la angioplastia coronaria.

A.3.2

Name or abbreviated title of the trial where available

Matrix

A.4.1

Sponsor's protocol code number

RFBU11-I

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	Società Italian di Cardiologia Invasiva GISE
B.1.3.4	Country	Italy
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	The Medicine Company
B.4.2	Country	Italy
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	TFS Trial Form Support
B.5.2	Functional name of contact point	Maria Salomone
B.5.3	Address:
B.5.3.1	Street Address	Via Leonardo da Vinci 1
B.5.3.2	Town/ city	Segrate
B.5.3.3	Post code	20090
B.5.3.4	Country	Italy
B.5.4	Telephone number	390291762587
B.5.5	Fax number	390689280930
B.5.6	E-mail	maria.salomone@tfscro.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	Angiox
D.2.1.1.2	Name of the Marketing Authorisation holder	The Medicines Company Ltd
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	Concentrate for solution for infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	BIVALIRUDIN
D.3.9.1	CAS number	128270-60-0
D.3.9.2	Current sponsor code	B01AE06
D.3.9.4	EV Substance Code	SUB05862MIG
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	250
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.2.5	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	Solution for injection
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Heparin Sodic
D.3.9.1	CAS number	9005-49-6
D.3.9.3	Other descriptive name	SODIUM IODOHEPARINATE
D.3.9.4	EV Substance Code	SUB30499
D.3.10	Strength
D.3.10.1	Concentration unit	IU/kg international unit(s)/kilogram
D.3.10.2	Concentration type	range
D.3.10.3	Concentration number	70 to 100
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	No
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	Yes
	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

Patients with acute coronary syndrome (ACS) with or without ST-segment elevation who undergo CATH ± PCI

Pacientes con síndrome coronáreo agudo (SCA) con o sin elevación del segmento ST que son sometidos a angiografia coronaria ± angioplasia (ICP).

E.1.1.1

Medical condition in easily understood language

Patients with acute miocardial infarction with or without ST-segment elevation who undergo CATH and if necessary PCI

Pacientes con infarto de miocardio agudo con o sin elevación del segmento ST que son sometidos a una coronografía y, si es el caso, a una angioplastia coronaria.

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	17.0
E.1.2	Level	LLT
E.1.2	Classification code	10071111
E.1.2	Term	Non ST segment elevation acute coronary syndrome
E.1.2	System Organ Class	100000004849

E.1.2 Medical condition or disease under investigation

E.1.2	Version	17.0
E.1.2	Level	LLT
E.1.2	Classification code	10064346
E.1.2	Term	STEMI
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

To demonstrate that the transradial access site or infusion of bivalirudin compared to femoral access or standard therapy consisting of unfractionated heparin and the provisional use of glycoprotein IIb/IIIa inhibitors are associated with a lower incidence of the composite of death, myocardial infarction and stroke within 30 days after randomization in patients with acute coronary syndrome exposed to early invasive treatment.

Demostrar que el acceso radial o infusión de bivalirudina en comparación con el acceso femoral o la terapia estándar que consiste en heparina no fraccionada y uso provisional de inhibidores de la glucoproteína IIb/IIIa, se asocian con una menor incidencia de la combinación de muerte, infarto de miocardio y ictus dentro de los 30 días después de aleatorización en pacientes con síndrome coronario agudo sometidos a tratamiento invasivo temprano.

E.2.2

Secondary objectives of the trial

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

1. PRU Matrix Substudy - Customized Choice of P2Y12 oral receptor blocker based on an integrated algorithm of phenotype assessment via Point of care testing
Version 3 Amendment of 14 April 2013
Objectives:To demonstrate in ACS patients undergoing early percutaneous intervention that an algorithm to select the most proper oral P2Y12 blocker integrating phenotype information will result in a lower composite endpoint of cardiovascular death, myocardial infarction, stroke or BARC defined bleeding type 2 or 3 at 1 year follow-up compared to standard of care.
2. OPTICAL COHERENCE TOMOGRAPHY (OCT) SUB-STUDY
Version 3 Amendment of 14 April 2013
Objectives: The use of long-term bivalirudin infusion, as compared to the intra-procedural only administration, reduces residual thrombosis of stent struts evaluated by OCT at the end of procedure and at 3-5 days follow-up, in patients affected by STEMI, treated by primary PCI and showing multivessel disease suitable for staged PCI.
3. RADIATION DOSE SUB-STUDY
Version 3 Amendment of 14 April 2013
Objectives: Aim of our study is to evaluate the radiation dose adsorbed by operators during percutaneous coronary procedures in the setting of acute coronary syndromes comparing the transradial and the transfemoral approach. Moreover we will also evaluate the radiation dose adsorbed by operators during right or left transradial approach.

1. Subestudio PRU MATRIX: Elección personalizada del bloqueador oral del receptor P2Y12 basada en un algoritmo integrado de valoración del fenotipo (reactividad plaquetaria testada con VerifyNow).
Protocolo versión 3 de 14 de abril de 2013
Objetivos: Demostrar que en pacientes con SCA sometidos a ICP, la elección del bloqueador oral P2Y12 basada en un algoritmo integrado de valoración del fenotipo resultará en una reducción del endpoint compuesto de muerte, re-infarto, ictus y hemorragia de tipo 2 o 3 (clasificación BARC) a un año de la ICP respecto al tratamiento habitual.
2. Subestudio OCT (tomografía de coherencia óptica)
Protocolo versión 3 de 14 de abril de 2013
Objetivos: la infusión prolongada de bivalirudina al final de la ICP comparado con la administración solamente durante la ICP, reduce la trombosis residual del stent, evaluada por OCT al final del procedimiento y a los 3-5 días de seguimiento, en pacientes que sufren STEMI sometidos a ICP primaria y presentando una enfermedad multivaso candidata a una intervención de IPC por etapas.
3. Subestudio de DOSIS DE RADIACIÓN
Protocolo versión 3 de 14 de abril de 2013
Objetivos: Evaluar la dosis de radiación absorbida por los cirujanos durante los procedimientos de ICP en el contexto de SCA, comparando la aproximación transradial versus la transfemoral. Además, se comparará la radiación de dosis absorbida por los cirujanos durante la aproximación transradial derecha e izquierda.

E.3

Principal inclusion criteria

All patients with acute coronary syndrome (ACS) with or without ST-segment elevation who undergo angiography coronary ± angioplasty (PCI) and that eligible for treatment with both access sites trans-radial and trans-femoral will be enrolled on consecutive basic.

Todos los pacientes con Síndrome Coronáreo Agudo (SCA) on o sin elevación del segmento ST que son sometidos a angiografia coronaria ± angioplastia (ICP) y que sean elegibles para el tratamiento con ambas aproximaciones transradial y transfemoral.

E.4

Principal exclusion criteria

1.Patients who can not give informed consent or have a life expectancy of <30 days.
2.Allergy/intolerance to bivalirudin or unfractionated heparin.
3.Stable or silent CAD as indication to coronary angiography.
4.Treatment with LWMH within the past 6 hours.
5.Treatment with any GPI in the previous 3 days.
6.Absolute contraindications or allergy that cannot be pre-medicated to iodinated contrast or to any of the study medications including both aspirin and clopidogrel.
7.Contraindications to angiography, including but not limited to severe peripheral vascular disease.
8.If it is known, pregnant or nursing mothers. Women of child-bearing age will be asked if they are pregnant or think that they may be pregnant.
9.If it is known, a creatinine clearance <30 mL/min or dialysis dependent.
10.Previous enrolment in this study.
11.Treatment with other investigational drugs or devices within the preceding 30 days.
12.Randomisation or planned use of other investigational drugs or devices in this trial.
13.Severe uncontrolled hypertension (defined as persistent systolic blood pressure higher than 220 mmHg despite medical treatment).
14.Subacute bacterial endocarditis.
15.PCI in the previous 30 days.

1. Los pacientes que no pueden dar el consentimiento informado o que tienen una esperanza de vida < 30 días.
2. Alergia/intolerancia a bivalirudina o heparina no fraccionada.
3. AC estable o inactiva como indicación de angiografía coronaria.
4. Tratamiento con HBPM durante las 6 últimas horas.
5. Tratamiento con cualquier IGP en los 3 días previos.
6. Contraindicaciones absolutas o alergia, que no se puede premedicar, al contraste yodado o a cualquiera de las medicaciones del estudio, incluyendo aspirina y clopidogrel.
7. Contraindicaciones para la angiografía que incluyen, aunque sin limitación, la enfermedad vascular periférica grave.
8. Si se conoce, mujeres embarazadas o en período de lactancia. Se preguntará a las mujeres en edad fértil si están embarazadas o si creen que pueden estarlo.
9. Si se conoce, un aclaramiento de creatinina < 30 mL/min o en diálisis.
10. Inclusión previa en este estudio.
11. Tratamiento con otros fármacos o dispositivos en investigación durante los 30 días previos.
12. Aleatorización o uso previsto de otros fármacos o dispositivos en investigación en este ensayo.
13. Hipertensión incontrolada grave (definida como una presión arterial sistólica persistente superior a 220 mmHg a pesar del tratamiento médico).
14. Endocarditis bacteriana subaguda.
15. ICP en los 30 días previos.

E.5 End points

E.5.1

Primary end point(s)

Primary Endpoint at 30 days:
A composite of death, re-infarction (MI) or stroke

Endpoint primario a 30 días:
Endpoint compuesto de muerte, re-infarto (IM) o ictus.

E.5.1.1

Timepoint(s) of evaluation of this end point

30 Days

30 Días

E.5.2

Secondary end point(s)

Key Secondary Endpoints: A composite of death, non-fatal MI, stroke or BARC-defined type 3 and 5 major bleeding complications at 30 days.

Main Secondary Endpoints:
1)The rate of each component of the composite endpoint of the primary or the key secondary endpoint at 30 days and 1 year analyzed in various study populations including the ITT and PP access site group both in the whole recruited patient population (i.e. including patients who underwent angiography only) and in those who finally underwent PCI and in the ITT and PP pharmacology arm both in the whole recruited patient population (i.e. including patients who underwent angiography only) and in those who finally underwent PCI, stratified based on actual use of GPI in the reference group.
2)The rate of stent thrombosis at any time during follow-up and the rate of urgent target vessel revascularization up to 30 days.
3)The rate of procedural success defined as final TIMI 3 flow and a residual coronary stenosis of less than 30% at visual estimation.
4)TIMI major or minor bleeding events and net clinical outcomes (defined as the composite of death, MI, stroke and TIMI minor or major bleedings according to TIMI) and the rate of thrombocytopenia.
5)The length and costs of hospitalization as well as cost-effectiveness of transradial intervention versus transfemoral and bivalirudin versus UFH±GPI.
6)The need for surgical access site repair/intervention and/or blood products transfusion
7)The prognostic impact of bleeding complications on 30 days death, MI or stroke rate as assessed based on various bleeding classifications including BARC, TIMI and GUSTO as well as the prognostic role of thrombocytopenia.
8)The prognostic value of on-treatment P2Y12 platelet residual activity measured via a point-of-care instruments at the time or immediately after PCI

Enpoint secundario clave: Compuesto de muerte, IM no fatal, icuts o complicación hemorrágica tipo 3 y 5 (definición BARC).

Endpoints secundarios más importantes:
1) Tasa de cada componente del endpoint compuesto del endpoint principal o del endpoint secundario clave a los 30 días y al año después de la ICP incluyendo los análisis ITT y PP de los dos lugares de acceso en el total de los pacientes reclutados (es decir, incluyendo los pacientes sometidos sólo a angiografia) y en aquellas poblaciones que finalmente se sometieron a IPC; y incluyendo análisis ITT y PP de los dos brazos farmacológicos en el total de los pacientes reclutados (es decir, incluyendo los pacientes sometidos sólo a angiografía) y en aquellos que finalmente se sometieron a ICP, estratificados según el uso de IGP en el grupo control.

2). Tasa de trombosis del stent en cualquier momento durante el seguimiento y la tasa de revascularización urgente del vaso diana a los 30 días.

3). Tasa de éxito en el proceso definida como flujo TIMI 3 final y estenosis residual inferior al 30% en la estimación visual.

4). Eventos hemorrágicos mayores o menores según la clasificación TIMI y outcome clínico neto (definido como el compuesto de muerte, IM, ictus o hemorragias menores o mayores según la clasificación TIMI) y la tasa de incidencia de trombocitopenia.

5) Tiempo y coste de la hospitalización así como coste-eficacia de la intervención transradial versus transfemoral y bivalirudina versus HNF±IGP.

6) Necesidad de intervención quirúrgico focalizada en el sitio de acceso para la reparación/intervención y/o transfusión de sangre.

7) El impacto pronóstico de complicaciones por sangrado en la tasa de mortalidad a los 30 días, un IM o un ictus, en base a diferentes clasificaciones de sangrado (BARC, TIMI y GUSTO), así como el papel pronóstico de la trombocitopenia.

8) El valor pronóstico de la actividad plaquetaria residual (PRU) bajo tratamiento con bloqueante oral del receptor P2Y12, medido vía VerifyNow durante o inmediatamente después de la ICP.

E.5.2.1

Timepoint(s) of evaluation of this end point

30 days and 1 year

30 días y 1 año

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)

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

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

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

100

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

LVLS

Última visita del último sujeto

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:

6800

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

6800

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

Yes

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

400

F.4.2

For a multinational trial

F.4.2.1

In the EEA

6400

F.4.2.2

In the whole clinical trial

6800

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

2014-04-25

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2014-04-16

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2015-10-16

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