Clinical Trials Register

Summary
EudraCT Number:	2013-000973-54
Sponsor's Protocol Code Number:	RD.03.SPR.29112
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:	2013-05-16
Trial results	View 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

Expand All Collapse All

A. Protocol Information

A.1

Member State Concerned

Spain - AEMPS

A.2

EudraCT number

2013-000973-54

A.3

Full title of the trial

Multi-centre, randomized, investigator-blind, intra-individual active and vehicle-controlled study, comparing Metvix® Natural Daylight Photodynamic Therapy versus Metvix® conventional Photodynamic Therapy in subjects with actinic keratosis

Estudio multicéntrico, aleatorizado, enmascarado para el investigador, con control intraindividual con fármaco activo y con
vehículo, de comparación entre el tratamiento fotodinámico Metvix® con luz solar natural y el tratamiento fotodinámico
Metvix® convencional en pacientes con queratosis actínica

A.3.1

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

Study to compare the Metvix® efficacy in eliminating the actinic (solar) keratoses when activated by the natural daylight or by a red lamp

Estudio para comparar la eficacia de Metvix en la eliminación de la queratosis actínica (solar), cuando se activa con luz natural solar o luz roja.

A.3.2

Name or abbreviated title of the trial where available

Phase 3b study of Metvix NDL-PDT versus Metvix c-PDT in subjects with actinic keratoses

A.4.1

Sponsor's protocol code number

RD.03.SPR.29112

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	Galderma R&D SNC
B.1.3.4	Country	France
B.3.1 and B.3.2	Status of the sponsor	Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Galderma R&D SNC
B.4.2	Country	France
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Galderma R&D SNC
B.5.2	Functional name of contact point	Clinical Project Manager
B.5.3	Address:
B.5.3.1	Street Address	Les Templiers, 2400 route des Colles, BP 87
B.5.3.2	Town/ city	BIOT CEDEX
B.5.3.3	Post code	06410
B.5.3.4	Country	France
B.5.4	Telephone number	0033492386706
B.5.5	Fax number	0033493957164
B.5.6	E-mail	catherine.bosc@galderma.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	Metvix® 160 mg/g crema
D.2.1.1.2	Name of the Marketing Authorisation holder	Laboratorios Galderma S.A.
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	Metvix® NDL
D.3.2	Product code	CD 06809-41 NDL
D.3.4	Pharmaceutical form	Cream
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Topical use (Noncurrent) Cutaneous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	METHYL AMINOLEVULINATE HYDROCHLORIDE
D.3.9.1	CAS number	79416-27-6
D.3.9.2	Current sponsor code	CD-06809-41
D.3.9.3	Other descriptive name	METHYL AMINOLEVULINATE HYDROCHLORIDE
D.3.9.4	EV Substance Code	SUB21579
D.3.10	Strength
D.3.10.1	Concentration unit	mg/g milligram(s)/gram
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	160
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	Metvix® 160 mg/g crema
D.2.1.1.2	Name of the Marketing Authorisation holder	Laboratorios Galderma S.A.
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	Metvix® RED light
D.3.2	Product code	CD 06809-41 c-PDT
D.3.4	Pharmaceutical form	Cream
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Topical use (Noncurrent) Cutaneous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	METHYL AMINOLEVULINATE HYDROCHLORIDE
D.3.9.1	CAS number	79416-27-6
D.3.9.2	Current sponsor code	CD-06809-41
D.3.9.3	Other descriptive name	METHYL AMINOLEVULINATE HYDROCHLORIDE
D.3.9.4	EV Substance Code	SUB21579
D.3.10	Strength
D.3.10.1	Concentration unit	mg/g milligram(s)/gram
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	160
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
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Cream
D.8.4	Route of administration of the placebo	Cutaneous use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Mild and/or moderate Actinic Keratoses

Queratosis actínica leve y/o moderada

E.1.1.1

Medical condition in easily understood language

Actinic (solar) keratosis

Queratosis actínica (solar)

E.1.1.2

Therapeutic area

Diseases [C] - Skin and Connective Tissue Diseases [C17]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	16.0
E.1.2	Level	HLT
E.1.2	Classification code	10020648
E.1.2	Term	Hyperkeratoses
E.1.2	System Organ Class	100000004858

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

Primary efficacy objective:
To show the non-inferior efficacy of Metvix® Natural Day Light Photo Dynamic Therapy (NDL-PDT) versus Metvix® conventional Photo Dynamic Therapy (c-PDT) in Subjects with mild and moderate AKs at Week 12 in terms of percent reduction in lesions count.

Primary safety objective:
To compare the Subject?s self-assessment of pain of Metvix® NDL-PDT with that of Metvix® c-PDT.

Los objetivos del presente estudio son confirmar que el procedimiento de Metvix® TFD-LSN
tiene una eficacia similar y es menos doloroso que el procedimiento de Metvix® TFD-c para
tratar pacientes con QA leves y moderadas, en la semana 12 (después de una sola sesión de
tratamiento).
.. Objetivo principal de eficacia:
• Demostrar que la eficacia de Metvix® TFD-LSN no es inferior a Metvix® TFD-c en
pacientes con QA leves y moderadas, en la semana 12.
.. Objetivo principal de seguridad:
• Comparar la valoración del dolor efectuada por los propios pacientes que recibieron
Metvix® TFD-LSN con la de los que recibieron Metvix® TFD-c.

E.2.2

Secondary objectives of the trial

Not Applicable

No procede

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

- Male or female, who is at least 18 years of age or older,
- Clinical diagnosis of mild (Grade 1) and/or moderate (Grade 2) AKs on the face or the scalp on treated areas (TAs) according to Olsen et al scale (1991). (e.g.: thin and/or non-hyperkeratotic AKs),
- Subject with two symmetrical TAs (either two half scalps or two half faces excluding ears, chin, bridge of the nose, eyelids and lips inside the vermillion border): no more than a twofold difference in terms of total number of lesions between the two TAs
- TA comparable in terms of size: 6 by 16 cm at a maximum
- A minimum of 5 AKs (either mild, moderate or both) per TA
- No more than two lesions difference in number of moderate AKs between the two TAs.
- Female of non-childbearing potential, OR female of childbearing potential with a negative urine pregnancy test (UPT).
- If female of childbearing potential, they should:
- have been strictly abstinent 1 month prior to Baseline and agrees to remain abstinent for the duration of the clinical trial,
- and/or agree to use a highly effective and approved contraceptive method(s) during the duration of the clinical trial (bilateral tubal ligation OR combined oral contraceptives (oestrogens and progesterone) or implanted or injectable contraceptives with a stable dose for at least 1 month prior to Baseline OR vasectomized partner for at least 3 months prior to Baseline OR hormonal intra uterine device (IUD) inserted at least 1 month prior to Baseline.

-Hombre o mujer de 18 o mayor.
-Diagnóstico clínico de QA leves (grado 1) y moderadas (grado 2) en la cara o el cuero
cabelludo en las superficies tratadas (ST) según la escala de Olsen et al. (1991) (p. ej.: QA delgada y no hiperqueratósica)
-Paciente con dos superficies tratadas simétricas (ya sea dos medios cueros cabelludos o dos
medios rostros, excluidos las orejas, el mentón, el caballete de la nariz, los párpados y los
labios dentro del borde bermellón): la diferencia entre el número total de lesiones en cada
una de las dos superficies tratadas debe ser inferior al doble.
-Superficie tratada comparable en cuanto a tamaño: 6 x 16 cm como máximo
-Cinco QA como mínimo (ya sean leves, moderadas o ambas) por superficie tratada.
-La diferencia del número de QA moderadas entre las dos ST debe ser inferior a dos
lesiones.
-Mujeres que no estén en edad fértil O mujeres en edad fértil con un resultado negativo en la prueba de embarazo en orina.
-Si se trata de una mujer en edad fértil, debe:
-abstenerse rigurosamente de mantener relaciones sexuales desde 1 mes antes de iniciarse el ensayo clínico
-y estar de acuerdo en seguir observando dicha abstinencia
hasta el final del mismo
- y/o estar de acuerdo en utilizar, hasta el final del ensayo clínico, métodos anticonceptivos aprobados de gran eficacia (ligadura bilateral de trompas O anticonceptivos orales combinados (estrógenos y progesterona) o anticonceptivos implantados o inyectables con una dosis estable durante por lo menos 1 mes antes
del inicio del ensayo, O que su pareja se haya vasectomizado como mínimo 3 meses antes del inicio del ensayo O tener un dispositivo intra-uterino (DIU) hormonal colocado por lo menos un mes antes del inicio del ensayo

E.4

Principal exclusion criteria

- Subject with clinical diagnosis of at least one severe (Grade 3) AK on TAs according to Olsen et al (1991) scale (e.g. hyperkeratotic AKs),
- Subject with pigmented AK on the TAs,
- Immuno-compromised Subject for idiopathic, disease specific or therapeutic reasons;
- Subject with porphyria,
- Subject with clinical diagnosis of other skin disease (including non-melanoma skin cancer) on the TAs which, in the opinion of the investigator, might interfere with the interpretation of the clinical results,
- Subject with systemic diseases that, in the opinion of the investigator might interfere with the interpretation of the clinical results,
- History of hypersensitivity to nut products (e.g. peanut and almond oil) or soya,
- Subject with a known past history of skin cancer in the TAs
- Past history of skin melanoma
-The Subject has received, applied or taken the following treatments or Procedures within the specified time frame prior to the Baseline visit:
Topical treatment(s) on TAs:
5-Fluorouracil, diclofenac, imiquimod, retinoids, ingenol mebutat (Pep-005) : Duration 12 weeks
Surgical: elliptical excision, excision and reconstructive surgery, Mohs? micrographic surgery, chemical peels/chemosurgery, cryosurgery, dermabrasion: Duration 12 weeks
PDT: Duration 12 weeks
Laser: Duration 12 weeks
Electrocoagulation: Duration 12 weeks
Radiotherapy and UV radiation therapy: Duration 12 weeks
Investigative therapies for Actinic Keratoses: Duration 12 weeks
Alpha-hydroxy acid, salicylic acid ointment, urea: Duration 2 weeks
Systemic treatment(s)
Systemic retinoids: Duration 12 weeks
Immunosuppressive drugs (such as glucocorticoids, cytostatic, antibodies, drugs acting on immunophilins, interferon, opioids , TNF binding proteins, Mycophenolate, small biologics agents):Duration 12 weeks

-Paciente con diagnóstico clínico de al menos una QA intensa (grado 3) en las superficies
tratadas según escala de Olsen et al. (p. ej. QA hiperqueratósicas).
-Paciente con QA pigmentadas en las superficies tratadas.
-Paciente inmunodeficiente por razones idiopáticas, específicas de la enfermedad o
terapéuticas,
-Paciente con porfiria,
-Paciente con diagnóstico clínico de otra enfermedad cutánea en las superficies tratadas (incluido cáncer de piel distinto al melanoma), que a criterio del investigador, pudiera interferir con la interpretación de los resultados clínicos,
-Paciente con enfermedades sistémicas que, según la opinión del investigador, pudiera interferir con la interpretación de los resultados clínicos.
-Antecedentes de hipersensibilidad a los productos derivados de los frutos secos (p. ej. aceite de cacahuete y almendra) o la soja.
- Paciente con antecedentes de cáncer de piel en as superficies tratadas.
- Antecedentes de melanoma de piel.
- El paciente ha recibido, se ha aplicado, ha tomado o se ha sometido a los siguientes
tratamientos, procedimientos o intervenciones dentro del periodo indicado previo a la visita
inicial:
Tratamientos tópicos en las superficies tratadas: Duración
5-Fluorouracilo, diclofenaco, imiquimod, retinoides, mebutato de ingenol (Pep-005) 12 semanas
Quirúrgicos: escisión elíptica, escisión y cirugía reconstructiva, cirugía micrográfica de Mohs,
exfoliación química/quimiocirugía, criocirugía o dermoabrasión
12 semanas
TFD 12 semanas
Láser 12 semanas
Electrocoagulación 12 semanas
Radioterapia y radioterapia UV 12 semanas
Tratamientos en fase de investigación para la queratosis actínica 12 semanas
Ácido alfa-hidróxido, pomada de ácido salicílico o urea 2 semanas
Tratamientos sistémicos:
Retinoides sistémicos 12 semanas
Inmunodepresores (como glucocorticoides, citostáticos, anticuerpos, fármacos que actúan sobre
las inmunofilinas, interferones, opioides, proteínas de unión al TNF, micofenolatos o agentes
biológicos pequeños)
12 semanas

E.5 End points

E.5.1

Primary end point(s)

Primary efficacy endpoint(s)
The primary efficacy endpoint is the lesion complete response rate, defined as the percentage of pre-existing and treated lesions at baseline that were assessed as clear at Week 12.

El principal criterio de valoración de la eficacia es la tasa de respuesta completa de la lesión, definida como el porcentaje de las lesiones preexistentes y tratadas al iniciarse el estudio que se valoraron como remitidas en la semana 12.

E.5.1.1

Timepoint(s) of evaluation of this end point

At week 12

En la semana 12

E.5.2

Secondary end point(s)

Secondary efficacy endpoint(s)
- Lesion complete response rate for mild lesions only.
- Subject-side complete response rate defined as the percentage of subjects with all treated lesions clear in the corresponding TA, at Week 12.
- change in lesion severity
- number of new lesion

Primary Safety endpoint
- subject's self assessment of pain at baseline post-PDT procedures

Secondary Safety endpoint
- Incidence and severity of Adverse Events
- skin aspect of lesion in complete response

Other endpoint: weather and light asessment

Variables secundarias de eficacia:
- Tasa de respuesta completa de las lesiones solamente para lesiones leves.
- Tasa de respuesta lateral completa de los pacientes, definida como el
porcentaje de pacientes en los que han remitido todas las lesiones de la
superficie tratada correspondiente en la semana 12.
- Cambio en la gravedad de las lesiones.
- número de nuevas lesiones.

Variable principal de seguridad
-auto evaluación de los sujetos, acerca del dolor en la visita basal después del tratamiento TFD.

Variables secundarias de seguridad
- Incidencia y severidad de los acontecimientos adversos
- aspecto de la piel de la lesión con respuesta completa

Otras variables: climatología y luz

E.5.2.1

Timepoint(s) of evaluation of this end point

Secondary efficacy endpoint(s): at week 12

Safety primary endpoint: at Baseline post PDT-procedure

Secondary safety endpoint:
- adverse event: all along the study
- skin aspect at week 12

Variables secundarias de eficacia: en la semana 12

Variables primarias de seguridad: al inicio, después del procedimiento de TFD

Variables secundarias de seguridad:
- acontecimientos adversos: a lo largo del estudio

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)

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

E.8.1.3

Single blind

Yes

E.8.1.4

Double blind

E.8.1.5

Parallel group

E.8.1.6

Cross over

E.8.1.7

Other

Yes

E.8.1.7.1

Other trial design description

Intraindividual comparison

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

Yes

E.8.2.2

Placebo

Yes

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

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 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:

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

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)

At the end of the study, after all procedures are completed, the investigator is free to treat any residual actinic keratoses with the treatment of his choice.

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

2013-06-24

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2013-06-20

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2014-01-06

Select Country:	Select Age Range:
Select Trial Status:	Select Trial Phase:
Select Gender:
Select Date Range: to
Select Rare Disease:
IMP with orphan designation in the indication
Orphan Designation Number:
Results Status:
Clear advanced search filters

Austria
Belgium
Bulgaria
Croatia
Cyprus
Czechia
Denmark
Estonia
Finland
France
Germany
Greece
Hungary
Iceland
Ireland
Italy
Latvia
Liechtenstein
Lithuania
Luxembourg
Malta
Netherlands
Norway
Poland
Portugal
Romania
Slovakia
Slovenia
Spain
Sweden
United Kingdom
Outside EU/EEA

Clinical trials