Clinical Trials Register

Summary
EudraCT Number:	2015-003326-13
Sponsor's Protocol Code Number:	BTI-011-EC/15/QUER
National Competent Authority:	Spain - AEMPS
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2015-11-20
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

2015-003326-13

A.3

Full title of the trial

Randomized, parallel groups, multicenter and blind to evaluators clinical trial, to evaluate the efficacy and safety of PRGF-Endoret eye drops, in patients with stage 2 and 3 neurotrophic keratitis.

Ensayo clínico aleatorizado, de grupos paralelos, multicéntrico y ciego para evaluadores, para evaluar la eficacia y la seguridad del colirio de PRGF-Endoret, en pacientes con Queratitis Neurotrófica en estadios 2 y 3.

A.3.1

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

Clinical study to assess the eficaccy and safety of PRGF-Endoret eye drops in patients with neurotrophic keratitis, syages 2 and 3.

Estudio clínico para valorar la eficacia y la seguridad del colirio de PRGF-Endoret en el tratamiento de pacientes con Queratitis Neurotrófica en estadios 2 y 3.

A.3.2

Name or abbreviated title of the trial where available

PRGF-Endoret eye drops in Keratitis Neurotrófica

Colirio PRGF-Endoret en Queratitis Neurotrófica

A.4.1

Sponsor's protocol code number

BTI-011-EC/15/QUER

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	BTI Biotechnology Institute I mas D
B.1.3.4	Country	Spain
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	BTI Biotechnology Institute I mas D
B.4.2	Country	Spain
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	BTI Biotechnology Institute I mas D
B.5.2	Functional name of contact point	Clinical Affairs Coordinator
B.5.3	Address:
B.5.3.1	Street Address	C/ Jacinto Quincoces 39
B.5.3.2	Town/ city	Vitoria
B.5.3.3	Post code	01007
B.5.3.4	Country	Spain
B.5.4	Telephone number	34945160653
B.5.5	Fax number	34945160657
B.5.6	E-mail	leire.begona@bti-implant.es

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	No
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	PRP Obtenido por PRGF-Endoret
D.3.4	Pharmaceutical form	Eye drops
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Ocular use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Platelet Rich Plasma
D.3.9.3	Other descriptive name	AUTOLOGOUS PLASMA
D.3.9.4	EV Substance Code	SUB117286
D.3.10	Strength
D.3.10.1	Concentration unit	ml millilitre(s)
D.3.10.2	Concentration type	range
D.3.10.3	Concentration number	1 to 3
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	Yes
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	Hidrathea
D.2.1.2	Country which granted the Marketing Authorisation	Spain
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	Hidrathea
D.3.4	Pharmaceutical form	Eye drops, solution
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Ocular use
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

Neurotrophic Keratitis (NK)

Queratitis Neurotrófica (QN)

E.1.1.1

Medical condition in easily understood language

Neurotrophic Keratitis (NK)

Queratitis Neurotrófica (QN)

E.1.1.2

Therapeutic area

Diseases [C] - Eye Diseases [C11]

MedDRA Classification

E.1.3

Condition being studied is a rare disease

Yes

E.2 Objective of the trial

E.2.1

Main objective of the trial

The main objective of this study is to demonstrate the superiority of the PRGF-Endoret eye drops (Plasma Rich in Growth Factors) administered four times a day, and for 1 month of treatment, in patients with stages 2 and 3 of neurotrophic keratitis, compared to treatment with moustirizing artificial tear drops.

El objetivo principal de este estudio es demostrar la superioridad del colirio PRGF-Endoret (Plasma Rich in Growth Factors) administrado cuatro veces al día, y durante 1 mes de tratamiento, en pacientes con Queratitis Neurotrófica estadíos 2 y 3, frente al tratamiento con colirio de lagrima artificial humectante.

E.2.2

Secondary objectives of the trial

The secondary objective of the study is to determine the tolerance and safety of PRGF-Endoret topical eye drops in patients with stages 2 and 3 neurotrophic keratitis.

El objetivo secundario del estudio es determinar la tolerancia y la seguridad del colirio PRGF-Endoret tópico en pacientes con Queratitis Neurotrófica estadíos 2 y 3.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Patients aged 18 or over.
2. Patients with neurotrophic keratitis at stages 2 (persistent epithelial defect, PED) or 3 (corneal ulcer) affecting only one eye. Patients with the contralateral eye affected with NK at stage 1 could be included.
3. Persistent epithelial defect or corneal ulcer of at least 2 weeks duration resistant to one or more traditional non-surgical treatments for neurotrophic keratitis (as artificial tears, gels or ointments without preservatives; eye drops discontinuation and medicines for topical use with preservatives which may reduce corneal sensibility; therapeutic contact lenses).
4. Corneal sensitivity reduction test (using ?4 Cochet-Bonnet esthesiometer) in the area of the persistent epithelial defect or corneal ulcer and out of the defect area in at least one corneal quadrant.
5. No objective clinical evidence of improvement in the persistent epithelial defect or corneal ulcer in the two weeks prior to enrollment in the study.
6. Patients who have previously read and signed the informed consent.
7. Patients able and willing to comply with the study procedures.

1. Pacientes con edad igual o superior a los 18 años.
2. Pacientes con queratitis neurotrófica en estadios 2 (defecto epitelial persistente, DEP) o 3 (úlcera corneal) que afecte a un único ojo. Podrán incluirse pacientes con el ojo contralateral afectado con QN en estadio 1.
3. Defecto epitelial persistente o úlcera corneal de al menos 2 semanas de duración resistente a uno o más tratamientos no quirúrgicos tradicionales para la queratitis neurotrófica (como lágrimas artificiales, geles o pomadas sin conservantes; interrupción de los colirios y medicamentos para uso tópico con conservantes que pueden reducir la sensibilidad corneal; lentes de contacto terapéuticas).
4. Pruebas de reducción de la sensibilidad corneal (?4 usando el estesiómetro de Cochet-Bonnet) en la zona del defecto epitelial persistente o de la úlcera corneal y fuera de la zona del defecto en al menos un cuadrante corneal.
5. Sin pruebas clínicas objetivas de mejora en el defecto epitelial persistente o la úlcera corneal en las 2 semanas antes de la inscripción en el estudio.
6. Pacientes que hayan leído y formado previamente el consentimiento informado.
7. Pacientes capaces y estar dispuestos a cumplir con los procedimientos del estudio.

E.4

Principal exclusion criteria

1. Patients with neurotrophic keratitis stages 2 or 3 that affects both eyes.
2. With active ocular infection (bacterial, viral, fungal or protozoal) or active ocular inflammation not related to the neurotrophic keratitis in the affected eye.
3. Any other eye disease that requires of topical ocular treatment in the affected eye during the course of the treatment period of the study.
4. Patients with severe vision loss in the affected eye with no chance of visual improvement (> 50% Wecker scale), in the investigator's opinion, as a result of study treatment.
5. Patients with severe blepharitis and/or severe Meibomian glands disease in the affected eye.
6. History of eye surgery (including surgical or refractive laser procedures) in the affected eye in the three months prior to enter the study (except when it is considered that the eye surgery is the cause of the neurotrophic keratitis stage 2 or 3), or patients who plan to undergo surgery.
7. Having received previously surgical procedures for the treatment of neurotrophic keratitis in the affected eye (eg complete tarsorrhaphy, conjunctival flap, etc.) with the exception of a transplant of the amniotic membrane (includable only two weeks after the disappearance of the membrane in the area of persistent epithelial defect or corneal ulcer, or at least six weeks after the date of the amniotic membrane transplant procedure). Patients previously treated with Botox injections (botulinum toxin) only if the last injection was administered at least 90 days prior to enrollment in the study.
8. Use of therapeutic contact lenses or for refractive correction during the periods of the study treatment in the affected eye.
9. Patients with punctual occlusion or insertion of punctual plugs previous to the study or with an anticipated need for punctual occlusion during the study time.
10. Evidence of corneal ulcer affecting the corneal stroma posterior third, fusion or cornea perforation in the affected eye.
11. Presence or history of any disorder or ocular or systemic disease that could limit the treatment effectiveness or its evaluation, which could interfere with the interpretation of the results or that the investigator could determine incompatible with the schedule of the study visits or with its realization (eg, corneal disorders or progressive or degenerative retinal, uveitis, optic neuritis, poorly controlled diabetes, autoimmune disease, systemic infection, neoplastic diseases).
12. Any need of change (at that time or planned) in the dose of systemic drugs known to disrupt the functioning of the trigeminal nerve (eg, neuroleptics, antipsychotics, and antihistamines). These treatments will be allowed during the study if they were started before the 30 days prior to enrollment in the study, provided that they remain stable during the course of the study treatment periods.
13. Known hypersensitivity to any of the procedural compounds (eg. fluoresceine).
14. Presence of blood disorders related to platelet or clotting disorders, or who for whatever reason are receiving anticoagulants or antiplatelet agents.
15. Patients with a positive result in serological tests for syphilis, Hepatitis B, Hepatitis C or HIV I / II.
16. Patient in current treatment for their pathology already well managed.
17. Use of any investigational drug within 4 weeks prior to the screening visit.
18. Pregnant women or intended to be pregnant.
19. Participating in another clinical study while in this study.

1. Pacientes con queratitis neurotrófica en estadios 2 o 3 que afecte a ambos ojos.
2. Con infección ocular activa (bacteriana, vírica, fúngica o protozoica) o inflamación ocular activa no relacionada con la queratitis neurotrófica en el ojo afectado.
3. Cualquier otra enfermedad ocular que requiera tratamiento ocular tópico en el ojo afectado durante el curso del período de tratamiento del estudio.
4. Pacientes con pérdida de visión grave en el ojo afectado sin posibilidad de mejora visual (>50 % en escala de Wecker), en la opinión del investigador, como resultado del tratamiento del estudio.
5. Pacientes con blefaritis grave y/o enfermedad de las glándulas de Meibomio grave en el ojo afectado.
6. Antecedentes de operación quirúrgica ocular (incluyendo procedimientos quirúrgicos con láser o refractivos) en el ojo afectado en los tres meses anteriores a la incorporación al estudio. (Excepto si se considera que la operación quirúrgica ocular es la causa de la queratitis neurotrófica en estadios 2 o 3), ó pacientes que tengan previsto ser intervenidos.
7. A ver recibido procedimientos quirúrgicos anteriores para el tratamiento de la queratitis neurotrófica (por ejemplo, tarsorrafia completa, colgajo conjuntival, etc.) en el ojo afectado a excepción del trasplante de la membrana amniótica (solo incluibles dos semanas después de la desaparición de la membrana en la zona del defecto epitelial persistente o de la úlcera corneal, o al menos seis semanas después de la fecha del procedimiento de trasplante de la membrana amniótica). Los pacientes tratados con anterioridad con inyecciones de bótox (toxina botulínica) solo si la última inyección se administró al menos 90 días antes de la inscripción en el estudio.
8. Uso de lentes de contacto terapéuticas o de lentes de contacto para corrección refractiva durante los períodos de tratamiento del estudio en el ojo afectado.
9. Pacientes con oclusión puntual o inserción de tapones puntuales antes del estudio o con necesidad prevista de oclusión puntual durante el período de tratamiento del estudio.
10. Evidencia de úlcera corneal que afecta al tercio posterior del estroma corneal, fusión o perforación de la córnea en el ojo afectado.
11. Presencia o antecedentes de algún trastorno o enfermedad ocular o sistémica que pudiera limitar la eficacia del tratamiento del estudio o su evaluación, que pudiera interferir con la interpretación de los resultados del estudio o que el investigador podría determinar incompatible con el calendario de visitas del estudio o con su realización (por ejemplo, trastornos corneales o retinianos progresivos o degenerativos, uveítis, neuritis óptica, diabetes mal controlada, enfermedad autoinmunitaria, infección sistémica, enfermedades neoplásicas).
12. Toda necesidad de cambio (en ese momento o previsto) en la dosis de medicamentos sistémicos que se sabe trastornan el funcionamiento del nervio trigémino (por ejemplo, neurolépticos, antipsicóticos y antihistamínicos). Se permitirán estos tratamientos durante el estudio si se iniciaron antes de los 30 días anteriores a la inscripción en el estudio, siempre que se mantengan estables durante el curso de los períodos de tratamiento del estudio.
13. Hipersensibilidad conocida a alguno de los compuestos procedimentales (por ejemplo, fluoresceína).
14. Presencia de trastornos sanguíneos relacionados con alteraciones plaquetarias o de coagulación, o que por cualquier motivo estén recibiendo fármacos anticoagulantes o antiagregantes plaquetarios.
15. Pacientes con resultado positivo en alguna de las pruebas serológicas de Sífilis, Hepatitis B, Hepatitis C o VIH I/II.
16. Paciente en tratamiento actual para su patología que estén bien controlados.
17. Uso de algún fármaco en fase de investigación en las 4 semanas anteriores a la visita de selección.
18. Mujeres embarazadas o con intención de quedarse embarazadas
19. Participación en otro estudio clínico a la vez que en este estudio.

E.5 End points

E.5.1

Primary end point(s)

Reduction at 4 weeks of 50% or more of the area of corneal ulcer/keratitis respect to its initial area determined by corneal staining with fluoresceine.

Reducción, a las 4 semanas, del 50% o más del área de la úlcera corneal/queratitis, respecto a su área inicial determinada mediante tinción corneal con fluoresceína.

E.5.1.1

Timepoint(s) of evaluation of this end point

basal, 2 and 4 weeks

basal, 2 y 4 semanas

E.5.2

Secondary end point(s)

- Reduction at 2 weeks, of the 50% or more of the area of corneal ulcer/keratitis
- Complete healing of the cornea after 4 weeks (100% reduction of corneal ulcer/keratitis).
- Partial response (reduction of 75% or more of the area of corneal/keratitis ulcer) at 4 weeks.
- Complete corneal healing at two weeks.
- Partial response (reduction of 75% or more of the surface of the corneal ulcer/keratitis) at 2 weeks.
- Evaluation of the depth of the corneal/keratitis ulcer at 2 and 4 weeks.
- Better visual acuity corrected in four weeks (VA LogMAR). The best corrected VA will be measured with the best correction of the patient and will be recorded in LogMAR.
- Evaluation of the overall symptoms of the disease (including eye pain) using the VAS score at 2 and 4 weeks..
- Osmolarity at 2 and 4 weeks.

- Reducción a las 2 semanas, del 50% o más del área de la úlcera corneal/queratitis
- Cicatrización completa de la córnea a las 4 semanas (Reducción al 100% de la úlcera corneal/queratitis).
- Respuesta parcial, (reducción de 75% o más del área de la úlcera corneal/queratitis) a las 4 semanas
- Cicatrización corneal completa a las 2 semanas.
- Respuesta parcial (reducción de 75% o más de la superficie de la úlcera corneal/queratitis) a las 2 semanas.
- Evaluación de la profundidad de la úlcera corneal/queratitis a las 2 semanas y a las 4 semanas.
- Mejor agudeza visual corregida en 4 semanas (AV LogMAR).
La AV mejor corregida se medirá con la mejor corrección del paciente y se registrará en LogMAR.
- - Evaluación de los síntomas globales de la patología (incluyendo el dolor ocular), utilizando la Escala EVA a las 2 y 4 semanas..

- Osmolaridad a las 2 y 4 semanas.

E.5.2.1

Timepoint(s) of evaluation of this end point

Basal, 2 and 4 weeks

Basal, 2 y 4 semanas

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)

E.7.4

Therapeutic use (Phase IV)

Yes

E.8 Design of the trial

E.8.1

Controlled

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

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

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

Ultima visita del ultimo paciente

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

F.1.1.5

Children (2-11years)

F.1.1.6

Adolescents (12-17 years)

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

F.1.3

Elderly (>=65 years)

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.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

2016-01-05

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2015-11-05

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

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