Clinical Trials Register

Summary
EudraCT Number:	2018-002176-41
Sponsor's Protocol Code Number:	17HH4268
National Competent Authority:	France - ANSM
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2019-10-08
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

France - ANSM

A.2

EudraCT number

2018-002176-41

A.3

Full title of the trial

PREvention of STroke in Intracerebral haemorrhaGE survivors with Atrial Fibrillation (PRESTIGE-AF)

A.3.1

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

Prevention of Stroke in Survivors of Brain Bleeding with Atrial Fibrillation

A.3.2

Name or abbreviated title of the trial where available

PRESTIGE-AF

A.4.1

Sponsor's protocol code number

17HH4268

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	Imperial College of Science, Technology and Medicine
B.1.3.4	Country	United Kingdom
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	European Union
B.4.2	Country	Belgium
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Imperial College of Science, Technology and Medicine
B.5.2	Functional name of contact point	Gisela Pereira Barreto
B.5.3	Address:
B.5.3.1	Street Address	Joint Research Compliance Office, Room 221, Level 2
B.5.3.2	Town/ city	Medical School Building, Norfolk Place, London
B.5.3.3	Post code	W2 1PG
B.5.3.4	Country	United Kingdom
B.5.4	Telephone number	02075949480
B.5.6	E-mail	g.pereira-barreto@imperial.ac.uk

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	Eliquis
D.2.1.1.2	Name of the Marketing Authorisation holder	Bristol-Myers Squibb / Pfizer EEIG
D.2.1.2	Country which granted the Marketing Authorisation	United Kingdom
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	Eliquis
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	APIXABAN
D.3.9.1	CAS number	503612-47-3
D.3.9.2	Current sponsor code	BMS 562247
D.3.9.3	Other descriptive name	Eliquis
D.3.9.4	EV Substance Code	SUB25425
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	2.5 to 5.0
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	Pradaxa
D.2.1.1.2	Name of the Marketing Authorisation holder	Boehringer Ingelheim International GmbH
D.2.1.2	Country which granted the Marketing Authorisation	United Kingdom
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	Pradaxa
D.3.2	Product code	B01AE07
D.3.4	Pharmaceutical form	Capsule, hard
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	DABIGATRAN ETEXILATE
D.3.9.1	CAS number	211915-06-9
D.3.9.2	Current sponsor code	BIBR1048MS
D.3.9.3	Other descriptive name	Pradaxa
D.3.9.4	EV Substance Code	SUB20521
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	110 to 150
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	Lixiana
D.2.1.1.2	Name of the Marketing Authorisation holder	Daiichi Sankyo , Inc.
D.2.1.2	Country which granted the Marketing Authorisation	United Kingdom
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	Lixiana
D.3.2	Product code	B01AF03
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	edoxaban
D.3.9.1	CAS number	480449-70-5
D.3.9.2	Current sponsor code	DU-176b
D.3.9.3	Other descriptive name	EDOXABAN
D.3.9.4	EV Substance Code	SUB32701
D.3.10	Strength
D.3.10.1	Concentration unit	mg/g milligram(s)/gram
D.3.10.2	Concentration type	range
D.3.10.3	Concentration number	30 to 60
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	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	Xarelto
D.2.1.1.2	Name of the Marketing Authorisation holder	Bayer Pharma AG
D.2.1.2	Country which granted the Marketing Authorisation	United Kingdom
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	Xarelto
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	RIVAROXABAN
D.3.9.1	CAS number	366789-02-8
D.3.9.2	Current sponsor code	BAY 59-7939
D.3.9.3	Other descriptive name	Xarelto
D.3.9.4	EV Substance Code	SUB29263
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	15 to 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

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Ischaemic stroke prevention in patients with atrial fibrillation and previous intracerebral haemorrhage

E.1.1.1

Medical condition in easily understood language

Prevention of stroke (caused by a blood clot) in patients with a heart arrhythmia (atrial fibrillation) who have had a
previous brain bleed (intracerebral haemorrhage)

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	10003658
E.1.2	Term	Atrial fibrillation
E.1.2	System Organ Class	10007541 - Cardiac disorders

E.1.2 Medical condition or disease under investigation

E.1.2	Version	21.1
E.1.2	Level	LLT
E.1.2	Classification code	10067816
E.1.2	Term	Cardioembolic stroke
E.1.2	System Organ Class	100000004852

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.1
E.1.2	Level	LLT
E.1.2	Classification code	10055815
E.1.2	Term	Haemorrhage intracerebral
E.1.2	System Organ Class	100000004852

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

Do particular anti-clotting drugs called direct oral anticoagulants reduce the rate of ischaemic stroke, that is strokes
caused by a blood clot blocking a blood vessel, compared to no anticoagulation (control group) without unacceptably
increasing the risk of recurrent brain bleeds in patients with atrial fibrillation and a previous brain bleed within 6
months before enrolment.

E.2.2

Secondary objectives of the trial

1. To examine the effect of anticoagulation with DOAC versus no anticoagulation on major cardiovascular outcomes and mortality in ICH patient with AF. Cardiovasular outcomes include stroke, embolism attributed to blood clot formation, death of any cause or attributed to cardiovascular causes and major adverse cardiac events such as death, cardiac stent thrombosis, recurrent heart attacks.
2.To compare the effect of DOACs versus no anticoagulation on major systemic and intracranial bleeding in this Study population (safety)
3. To examine the effect of DOACs versus no anticoagulation on net clinical benefit in ICH patients with AF. Net clinical benefit is defined as composite of all stroke, embolic events attributed to blood clots, heart attack, death attributed to
cardiovascular causes, and massive bleeding.
4. To explore the impact of DOAC vs. no anticoagulation on quality of life, cognition and psychological morbidity in patients with ICH and AF over time

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

There are 3 substudies that are described in detail in the appendix of the main study protocol (section 14).
The first substudy called “Predictive Modelling of Risk” (Version 1.0 Section 14.1 of PRESTIGE-AF Study Protocol) aims to
develop tools for prediction of individual risk of subsequent ischaemic or haemorrhagic strokes in ICH patients with
concomitant AF. For this purpose, observational information on clinical characteristics, biological material for genetic
analysis and determination of proteins in the blood and brain images will be analysed in parallel to data collection in the main PRESTIGE-AF Study.
The second substudy called “longitudinal magnetic resonance imaging (MRI) Substudy” will enroll 200 PRESTIGEAF
participants. Participants of the substudy must have had a brain MRI after their intracerebral haemorrhage (ICH)
before study enrolment. Participants of the MRI Substudy will undergo a second brain MRI at their 12-month visit.
The aim of this observational prospective Substudy is to clarify the amount of subclinical progression of
haemorrhagic and ischaemic damage in ICH patients and test if such dynamics are possibly further predictors of
ICH or ischaemic infarction.
The third substudy called “Pharmacology Substudy” is exploring adherence to direct anticoagulants and exposure
levels in the patient group. Using an innovative technique called the dried blood spot (DBS) sampling technique,
single or multiple venous or capillary whole blood samples can be easily collected by Participants or caregivers at
various time points within the dosing interval, thus providing objective evidence for DOAC adherence and exposure.
Dried blood samples on a paper card will be shipped to a specialised central laboratory which can measure the
blood concentrations of DOACs and correlate the findings with patient characteristics at the end of the study.

E.3

Principal inclusion criteria

1. Age ≥ 18 years
2. Written informed consent
3. Recent history of a non-traumatic spontaneous ICH during the 6 months before enrolment
4. Documented evidence of AF (paroxysmal, persistent or permanent)
CHA2DS2-VASc score≥2 for male, and CHA2DS2-VASc score≥ 3 for female patients
5. Availability of brain imaging following the index Intracerebral Haemorrhage (ICH)

E.4

Principal exclusion criteria

• Patient lacks the capacity to consent
• Fully dependent (modified Rankin scale >4)
• Women who are pregnant, breastfeeding or planning on becoming pregnant
• Women of childbearing potential (WOCBP 12.1) who are unable or unwilling to take measures for effective contraception (4.8)
• ICH occurring within the last 14 days before enrolment
• ICH occurring longer than 6 months before enrolment
• ICH resulting from trauma or vascular malformation
• Indication for long-term anticoagulation other than AF
• Patient has hypertension, which in the opinion of the investigator, is uncontrollable with medication
• Any contraindication (except intracerebral haemorrhage) to treatment with apixaban, dabigatran, edoxaban, rivaroxaban as per Summary of Product Charasteristics (SmPC). Special warnings and precautions for use for apixaban, dabigatran, edoxaban, rivaroxaban as per SmPC should also be taken into account at randomization.”
• Absolute need for antiplatelet therapy at enrolment except aspirin or clopidogrel
• Presence of a left atrial appendage occlusion device (LAAO) or plan to implant an LAAO
• Presence of any medical, psychological, or psychiatric condition which in the opinion of the Principal or Co-Investigator would cause participation in the Study to be unwise
• Participation in any clinical study with an Investigational Medicinal Product within the past 30 days (observational studies are permitted)

E.5 End points

E.5.1

Primary end point(s)

There are two co-primary binary endpoints in the Study (evaluated by time-to-event analysis): Ischaemic stroke and
recurrent intracerebral haemorrhage. The Study will perform hierarchical testing of the two co-primary endpoints in a
parallel group design.

E.5.1.1

Timepoint(s) of evaluation of this end point

Anytime during follow-up period the end points will be evaluated and adjudicated.

E.5.2

Secondary end point(s)

Secondary efficacy endpoints are
1. all stroke and systemic embolism
2. all-cause mortality
3. cardiovascular mortality
4. major adverse cardiac events
5. net clinical benefit defined as composite endpoint of all stroke, systemic embolic event, myocardial infarction,
cardiovascular mortality, and major bleeding [14].

E.5.2.1

Timepoint(s) of evaluation of this end point

Anytime during follow-up period the end points will be evaluated and adjudicated

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

Yes

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

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)

E.8.2.2

Placebo

E.8.2.3

Other

Yes

E.8.2.3.1

Comparator description

No anticoagulation

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

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

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:

100

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

554

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

654

F.4.2.2

In the whole clinical trial

654

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)

The investigational medicinal products (IMPs) used in this study are marketed for stroke prevention in patients with atrial fibrillation. They are sometimes prescribed off label to patients with intracerebral haemorrhage and atrial fibrillation in clinical practice. The IMPs in the study are open label. Each participant will have a final consultation with a study doctor (PI or CO-I) to discuss whether they wish to continue on their current course of treatment.

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

2019-10-03

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2020-01-16

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

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