Clinical Trials Register

Summary
EudraCT Number:	2018-002277-22
Sponsor's Protocol Code Number:	AMYPAD-02
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:	2018-11-23
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

2018-002277-22

A.3

Full title of the trial

AMYPAD Prognostic and Natural History Study (PNHS), an open label, prospective, multicentre, cohort study linked to the European Prevention of Alzheimer's Dementia (EPAD) Longitudinal Cohort Study (LCS) in individuals without dementia to evaluate the additional value of quantitative amyloid imaging in determining Alzheimer's Disease (AD) dementia risk

Estudio de pronóstico e historia natural (PNHS) del AMYPAD, abierto, prospectivo, multicéntrico, cohorte vinculada al Estudio de Cohorte Longitudinal (ECL) del European Prevention of Alzheimer’s Dementia (EPAD) en personas sin demencia para evaluar el valor añadido de la imagen cuantitativa de amiloide en la determinación del riesgo de demencia por enfermedad de Alzheimer (EA)

A.3.1

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

Prognostic and Natural History Study

Estudio de Pronóstico e Historia Natural

A.3.2

Name or abbreviated title of the trial where available

AMYPAD PNHS

A.4.1

Sponsor's protocol code number

AMYPAD-02

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	Stichting VUmc
B.1.3.4	Country	Netherlands
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	Innovative Medicines Initiative 2 Joint Undertaking
B.4.2	Country	Belgium
B.4.1	Name of organisation providing support	EFPIA (from Janssen Pharmaceutical)
B.4.2	Country	Belgium
B.4.1	Name of organisation providing support	EFPIA (from Piramal Imaging)
B.4.2	Country	United Kingdom
B.4.1	Name of organisation providing support	EFPIA (from GE Healthcare)
B.4.2	Country	United Kingdom
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Stichting VUmc
B.5.2	Functional name of contact point	VUmc
B.5.3	Address:
B.5.3.1	Street Address	Boelelaan 1117
B.5.3.2	Town/ city	Amsterdam
B.5.3.3	Post code	1081 HV
B.5.3.4	Country	Netherlands
B.5.6	E-mail	f.barkhof@vumc.nl

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	Neuraceq
D.2.1.1.2	Name of the Marketing Authorisation holder	Piramal Imaging Limited
D.2.1.2	Country which granted the Marketing Authorisation	European Union
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	Neuraceq
D.3.2	Product code	PRD1617296
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	FLORBETABEN (18F)
D.3.9.1	CAS number	902143-01-5
D.3.9.2	Current sponsor code	AMYPAD-02
D.3.9.4	EV Substance Code	SUB119774
D.3.10	Strength
D.3.10.1	Concentration unit	MBq megabecquerel(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	300
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	Yes
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	Vizamyl
D.2.1.1.2	Name of the Marketing Authorisation holder	GE Healthcare Limited
D.2.1.2	Country which granted the Marketing Authorisation	European Union
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	Vizamyl
D.3.2	Product code	V09AX04
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	Flutemetamol (18F)
D.3.9.1	CAS number	765922-62-1
D.3.9.2	Current sponsor code	AMYPAD-02
D.3.9.3	Other descriptive name	FLUTEMETAMOL (18F)
D.3.9.4	EV Substance Code	SUB33652
D.3.10	Strength
D.3.10.1	Concentration unit	MBq megabecquerel(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	185
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	Yes
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

Alzheimer's Disease

Enfermedad de Alzheimer

E.1.1.1

Medical condition in easily understood language

Alzheimer's Disease (AD) is a neurodegenerative condition that represents the most common cause of cognitive impairment and dementia worldwide.

La Enfermedad de Alzheimer (EA) es una condición neurodegenerativa que representa la causa más común de deterioro cognitivo y demencia en el mundo

E.1.1.2

Therapeutic area

Health Care [N] - Population Characteristics [N01]

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 evaluate the value of quantitative PET amyloid imaging measures for predicting progression within an AD risk probability spectrum (derived from four different dimensions: cognition, other biomarkers, traditional genetic and environmental risk factors and temporal changes in these dimensions) based on quantitative PET amyloid imaging measures, with or without other biomarkers.

Evaluar el valor de las medidas cuantitativas de las imágenes obtenidas mediante PET de amiloide para predecir la evolución del rango de probabilidad de riesgo de presentar EA (derivado de cuatro dimensiones diferentes: cognición, otros biomarcadores, factores de riesgo genéticos y medioambientales tradicionales y cambios temporales de estas dimensiones) basada en las medidas de imagen cuantitativa obtenida mediante PET de amiloide, con o sin otros biomarcadores.

E.2.2

Secondary objectives of the trial

1. To evaluate the value of quantitative PET amyloid imaging, with or without other biomarkers, to predict a) cognitive decline, b) brain atrophy, and c) functional decline.
2. To compare regional quantitative PET amyloid imaging measures and global quantitative PET and CSF amyloid measures for their ability to identify participants most likely to experience subsequent cognitive decline.
3. To assess the relationship between (a) continuous measures of baseline amyloid and cognitive decline; and (b) these continuous measures and clinical outcomes.
4. To determine the agreement between the classifications of brain amyloid status based on (a) quantitative PET imaging and (b) visual amyloid PET image interpretation, and compare their ability to predict subsequent cognitive decline.
5. To determine the optimal methodology for the quantification of amyloid load by amyloid PET imaging, through analysis of biological and technical factors affecting quantitative PET amyloid imaging.

1. Evaluar el valor de la imagen cuantitativa obtenida de PET de amiloide, con o sin otros biomarcadores, para predecir a) deterioro cognitivo, b) atrofia cerebral, y c) deterioro funcional
2. Comparar medidas de amiloide de imágenes cuantitativas regionales y globales obtenidas mediante PET y CSF para determinar su capacidad de identificar participantes con más probabilidad de experimentar un deterioro cognitivo
3. Evaluar la relación entre (a) medidas continuas de amiloide basales; y (b) estas medidas continuas y las evaluaciones de los resultados clínicos
4. Determinar el acuerdo entre clasificaciones del estado de amiloide cerebral basado en (a) imágenes obtenidas de PET y (b) interpretaciones visuales, y comparar su habilidad para predecir deterioro cognitivo
5. Determinar la metodología óptima para la cuantificación de la carga de las imágenes obtenidas de PET de amiloide, a través del análisis de factores técnicos y biológicos que pueden afectar la imagen amiloide PET

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

Baseline Eligibility Criteria
1. Participants who are currently active in the EPAD LCS and older than 50 years of age will be eligible if they provide separate written informed consent to participate in the AMYPAD PNHS
2. Participants with a suitable baseline biomarker, cognitive and risk factor profile, as determined by the Selection and Feasibility Committee, based on an adaptive selection algorithm that aims to provide optimal representation of the probability spectrum for AD risk; OR participants that have been randomly selected to maintain the mandated
nondisclosure EPAD LCS.
3. Participants who are assessed by the recruiting investigator to be physically fit to undergo PET scanning and able to tolerate the PET scanning procedure for at least the duration of a static scan (20 minutes).

Follow-up Eligibility Criteria
1. Participants who underwent dynamic PET scanning at baseline:
a. Participants who are willing and available to undergo a follow-up
scan. All participants with a dynamic scan at baseline will be invited for
follow-up scans.
2. Participants who underwent static PET scanning at baseline:
a. Participants who are willing and available to undergo a follow-up
scan, and
b. Are selected based on the Selection and Feasibility Committee's
algorithm for follow-up, which in addition to the previous algorithm also
considers baseline composite SUVR values.

Criterios de elegibilidad basales
1. Participantes que son actualmente activos en el ECL del EPAD y mayores de 50 años de edad serán elegibles si proporcionan otro consentimiento informado para participar en el PNHS del AMYPAD.
2. Participantes con un adecuado perfil basal de biomarcadores, cognición y factores de riesgo, determinado por el Comité de Selección y Viabilidad, basado en un algoritmo de selección adaptativo que tiene como objetivo proporcionar la representación óptima del rango de probabilidad del riesgo de EA; O participantes que han sido seleccionados de forma aleatoria para mantener la confidencialidad estipulada en el ECL del EPAD.
3. Participantes que el investigador encargado del reclutamiento determine que presentan las condiciones físicas adecuadas para someterse a la PET y que sean capaces de tolerar el procedimiento de la PET al menos durante el tiempo necesario para la obtención de una imagen estática (20 minutos).

Criterios de elegibilidad de seguimiento
1. Aquellos participantes que se hayan sometido a una PET dinámica en la basal:
a. Aquellos participantes que estén dispuestos y disponibles para someterse a una imagen de seguimiento. Se invitará a todos los participantes con una imagen dinámica en la basal a someterse a imágenes de seguimiento.
2. Aquellos participantes que se hayan sometido a una PET estática en la basal:
a. Aquellos participantes que estén dispuestos y disponibles para someterse a una imagen de seguimiento y
b. Sean seleccionados de acuerdo con el algoritmo de seguimiento del Comité de Selección y Viabilidad, que además del algoritmo previo también contempla los valores de SUVR integrados en la basal.

E.4

Principal exclusion criteria

1. Participants who are not currently active in the EPAD LCS.
2. Participants in whom PET scanning or magnetic resonance imaging (MRI) are contraindicated.
3. Participants who are not able to complete the study procedures as judged by the investigator.
4. Participants who have known hypersensitivities to the active ingredients of [18F]flutemetamol and [18F]florbetaben, or the excipients for both products (listed in section 6.1 of the respective Summary of Product Characteristics [SPC]).
5. Women who are pregnant, planning to become pregnant, or lactating.

1. Participantes que en la actualidad no sean activos en el ECL del EPAD.
2. Participantes para los que la PET o la resonancia magnética (RM) estén contraindicadas.
3. Participantes que sean incapaces de completar los procedimientos del estudio a criterio del investigador.
4. Aquellos participantes que hayan experimentado hipersensibilidad a los principios activos de [18F]flutemetamol y [18F]florbetaben o a los excipientes de los dos productos (se encuentran en el apartado 6.1 de la ficha técnica [FT] correspondiente).
5. Aquellas mujeres que estén embarazadas, que planeen quedarse embarazadas o que se encuentren en el periodo de lactancia.

E.5 End points

E.5.1

Primary end point(s)

Primary Variables:
1. Composite Centiloid, SUVR and/or BPND values measured from [18F]flutemetamol or [18F]florbetaben PET images
2. Change from baseline in measures of cognitive status and daily functioning, modifiable risk factors, and MRI measures of brain atrophy

1. Valores compuestos de Centiloid, SUVR o de BPND medidos a partir de las imágenes PET con [18F]flutemetamol o [18F]florbetaben.
2. Cambio respecto a la visita basal en una puntuación compuesta de medidas del estado cognitivo y actividades cotidianas, factores de riesgo modificables y medidas de atrofia cerebral obtenidas mediante RM.

E.5.1.1

Timepoint(s) of evaluation of this end point

Cross-sectionally at baseline visit of all subjects;
Longitudinally at the end of the trial.

Corte transversal en la visita basal de todos los sujetos;
Longitudinalmente al final del ensayo.

E.5.2

Secondary end point(s)

Secondary Variables:
1. Change from baseline in measures of cognitive status (e.g. RBANS Total Scale Index Score)
2. Change from baseline in MRI measures of brain atrophy
3. Change from baseline in measures of daily functioning
4. Change from baseline in measures of modifiable risk factors
5. Regional SUVR and/or BPND values at baseline
6. Change from baseline in Centiloid, SUVR and BPND values (global
and/or regional)
7. Baseline R1 values from dynamic scans
8. Change from baseline in R1 values from dynamic scans
9. Threshold values of Centiloid, SUVR and/or BPND for negative/positive amyloid status that produce the greatest agreement with visual interpretation by a trained nuclear physician or radiologist
10. Threshold values of Centiloid, SUVR and/or BPND for negative/positive/grey-zone amyloid status that produce the highest accuracy with respect to predicting cognitive decline (and/or brain atrophy as measured by MRI)

1. Cambio respecto la visita basal en medidas del estado cognitivo (p. ej., la puntuación total de la escala de RBANS).
2. Cambio respecto a la visita basal en medidas de atrofia cerebral por RM.
3. Cambio respecto a la visita basal en medidas de las actividades cotidianas.
4. Cambio respecto a la visita basal en medidas de los factores de riesgo modificables
5. Valores regionales de SUVR o BPND en la visita basal.
6. Cambio respecto a la visita basal en los valores de Centiloid, SUVR y BPND (globales o regionales).
7. Valores basales de R1 de imágenes dinámicas.
8. Cambio respecto a la basal en los valores de R1 de imágenes dinámicas.
9. Valores límite de Centiloid, SUVR o BPND para un estado de amiloide negativo/positivo que produzcan la mayor coincidencia con la interpretación visual por parte de un médico nuclear o radiólogo con formación.
10. Valores límite de Centiloid, SUVR o BPND para un estado de amiloide negativo/positivo/zona gris que produzcan la máxima precisión para predecir el deterioro cognitivo (o atrofia cerebral medida mediante RM).

E.5.2.1

Timepoint(s) of evaluation of this end point

Cross-sectionally at baseline visit of all subjects;
Longitudinally at the end of the trial.

Corte transversal en la visita basal de todos los sujetos;
Longitudinalmente al final del ensayo.

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

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

E.8.1.1

Randomised

E.8.1.2

Open

Yes

E.8.1.3

Single blind

E.8.1.4

Double blind

E.8.1.5

Parallel group

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

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

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

Belgium

France

Germany

Italy

Netherlands

Spain

Sweden

Switzerland

United Kingdom

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:

800

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

1200

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

Yes

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

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

Yes

F.3.3.6.1

Details of subjects incapable of giving consent

Patients with dementia due to Alzheimer's Disease

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

1800

F.4.2.2

In the whole clinical trial

2000

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
G.4 Investigator Network to be involved in the Trial: 1
G.4.1	Name of Organisation	Stichting VUmc
G.4.3.4	Network Country	Netherlands
G.4 Investigator Network to be involved in the Trial: 2
G.4.1	Name of Organisation	University of Edinburgh
G.4.3.4	Network Country	United Kingdom
G.4 Investigator Network to be involved in the Trial: 3
G.4.1	Name of Organisation	Barcelonabeta Brain Research Center
G.4.3.4	Network Country	Spain
G.4 Investigator Network to be involved in the Trial: 4
G.4.1	Name of Organisation	Karolinska Institutet
G.4.3.4	Network Country	Sweden
G.4 Investigator Network to be involved in the Trial: 5
G.4.1	Name of Organisation	Centre Hospitalier Universitaire de Toulouse
G.4.3.4	Network Country	France
G.4 Investigator Network to be involved in the Trial: 6
G.4.1	Name of Organisation	University Hospital of Cologne
G.4.3.4	Network Country	Germany
G.4 Investigator Network to be involved in the Trial: 7
G.4.1	Name of Organisation	Université de Genève
G.4.3.4	Network Country	Switzerland

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2019-01-22

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2019-01-18

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2022-06-27

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