Clinical Trials Register

Summary
EudraCT Number:	2017-001418-27
Sponsor's Protocol Code Number:	20150168
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:	2017-07-31
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

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A. Protocol Information

A.1

Member State Concerned

Spain - AEMPS

A.2

EudraCT number

2017-001418-27

A.3

Full title of the trial

A RANDOMIZED, DOUBLE-BLIND, ACTIVE-CONTROLLED PHASE 3 STUDY EVALUATING THE EFFICACY AND SAFETY OF ABP 959 COMPARED WITH ECULIZUMAB IN ADULT SUBJECTS WITH PAROXYSMAL NOCTURNAL HEMOGLOBINURIA (PNH)

Estudio de fase III, aleatorizado, doble ciego y controlado con principio activo para evaluar la eficacia y la seguridad de ABP 959 en comparación con eculizumab en sujetos adultos con hemoglobinuria paroxística nocturna (HPN)

A.3.1

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

This trial is designed to determine what effects the investigational medicine, ABP 959, has on the human body, and what effects the body has on the
investigational medicine after you have been given it, and if this is
comparable to what is seen for the licensed medicine, eculizumab, in
patients with Paroxysmal Nocturnal Hemoglobinuria (PNH).
This study will assess if the investigational medicine is safe and effective in
treating PNH compared to the licensed medicine.

Este enayo está diseñado para determinar los efectos que el medicamento investigado, ABP 959, tiene sobre el cuerpo humano y que efectos tiene el cuerpo sobre la medicación investigada una vez administrada, y si estos son comparables con los vistos para la medicina comercializada, eculizumab, en pacientes con hemoglobinuria paroxística nocturna (HPN).
Este estudio evaluará si el medicamento investigado es seguro y efectivo en el tratamiento de la HPN comparado con la medicación comercializada.

A.3.2

Name or abbreviated title of the trial where available

Not applicable

No aplica

A.4.1

Sponsor's protocol code number

20150168

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	Amgen Inc.
B.1.3.4	Country	United States
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	Amgen Inc.
B.4.2	Country	United States
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Amgen (EUROPE) GmbH
B.5.2	Functional name of contact point	IHQ Medical Info-Clinical Trials
B.5.3	Address:
B.5.3.1	Street Address	Dammstr. 23, PO Box 1557
B.5.3.2	Town/ city	Zug
B.5.3.3	Post code	6300
B.5.3.4	Country	Switzerland
B.5.6	E-mail	Medinfointernational@amgen.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	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	ABP 959
D.3.2	Product code	ABP 959
D.3.4	Pharmaceutical form	Solution for infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	ECULIZUMAB
D.3.9.1	CAS number	219685-50-4
D.3.9.2	Current sponsor code	ABP 959
D.3.9.3	Other descriptive name	ABP 959 - biosimilar to eculizumab
D.3.9.4	EV Substance Code	SUB25187
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	900
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	No
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	Yes
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	Yes
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	Soliris
D.2.1.1.2	Name of the Marketing Authorisation holder	Alexion Pharmaceuticals Inc.
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	Soliris
D.3.4	Pharmaceutical form	Solution for infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	ECULIZUMAB
D.3.9.1	CAS number	219685-50-4
D.3.9.4	EV Substance Code	SUB25187
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	900
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	No
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	Yes
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	Yes
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

Paroxysmal Nocturnal Hemoglobinuria (PNH)

Hemoglobinuria paroxística nocturna (HPN)

E.1.1.1

Medical condition in easily understood language

Paroxysmal Nocturnal Hemoglobinuria (PNH)

Hemoglobinuria paroxística nocturna (HPN)

E.1.1.2

Therapeutic area

Diseases [C] - Blood and lymphatic diseases [C15]

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 primary objective for this study is to evaluate the efficacy of ABP 959 compared with that of eculizumab based on control of intravascular hemolysis.

El objetivo principal de este estudio es evaluar la eficacia de ABP 959 en comparación con la de eculizumab en base al control de la hemólisis intravascular.

E.2.2

Secondary objectives of the trial

The secondary objective is to assess the safety, pharmacokinetics (PK),
and immunogenicity of ABP 959 compared with that of eculizumab.

El objetivo secundario es evaluar la seguridad, la farmacocinética (FC) y la inmunogenia de ABP 959 en comparación con las de eculizumab.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

The study will enroll subjects with PNH who are stable on eculizumab treatment. Subjects cannot be enrolled or randomized before all inclusion criteria (including test results) are confirmed:
1. Men and women ≥ 18 years of age
2. Confirmed diagnosis of PNH by documented flow cytometry
3. Administration of eculizumab for ≥ 6 months and currently receiving 900 mg of eculizumab every 14 ± 2 days
4. Hemoglobin ≥ 9.0 g/dL for at least 6 weeks prior to randomization
5. Lactate dehydrogenase (LDH) < 1.5 × the upper limit of normal at screening
6. Platelet count ≥ 50 × 10^9/L
7. Absolute neutrophil count > 0.5 x 10^9/L (500/μL)
8. Subjects must be vaccinated against Neisseria meningitidis. Subjects must be vaccinated or revaccinated according to current national guidelines for vaccination use.
9. Subjects must sign an institutional review board/independent ethics committee-approved informed consent form before participation in any procedures.

El estudio incluirá sujetos con HPN con un tratamiento estable con eculizumab. No se podrá incluir o aleatorizar a los sujetos antes de que se hayan confirmado todos los criterios de inclusión (incluidos los resultados de las pruebas):
1. Hombres y mujeres con ≥ 18 años de edad
2. Diagnóstico confirmado de HPN mediante citometría de flujo documentada
3. Administración de eculizumab durante ≥ 6 meses y que actualmente reciban 900 mg de eculizumab cada 14 ± 2 días
4. Hemoglobina ≥ 9,0 g/dl durante al menos 6 semanas antes de la aleatorización
5. Lactato-deshidrogenasa (LDH) < 1,5 × el límite superior de la normalidad en la selección.
6. Recuento de plaquetas ≥ 50 × 10^9/l
7. Recuento absoluto de neutrófilos > 0,5 x 10^9/l (500/μl)
8. Los sujetos deben estar vacunados contra la Neisseria meningitidis. Los sujetos deben estar vacunados o revacunados de acuerdo con las directrices nacionales vigentes de uso de vacunas.
9. Los sujetos deben firmar un formulario de consentimiento informado aprobado por la junta de revisión institucional o el comité de ética independiente antes de la participación en cualquier procedimiento.

E.4

Principal exclusion criteria

If any of the following apply, the subject MUST NOT enter the study:
1. Known or suspected hereditary complement deficiency
2. Clinically significant cardiovascular disease (including myocardial infarction, unstable angina, symptomatic congestive heart failure [New York Heart Association ≥ Class III], serious uncontrolled cardiac arrhythmia), peripheral vascular disease, cerebrovascular accident, or transient ischemic attack in the previous 6 months
3. Evidence of acute thrombosis (liver Doppler ultrasound of hepatic and portal veins)
4. Known to be positive for human immunodeficiency virus
5. Woman who is pregnant or breastfeeding
6. Woman of childbearing potential who does not consent to use a highly effective method of birth control (e.g., true abstinence, sterilization, birth control pills, Depo Provera injections, or contraceptive implants) during treatment and for an additional 5 months after the last administration of protocol-specified treatment
7. Man with a partner of childbearing potential who does not consent to use a highly effective method of birth control (eg, true abstinence, vasectomy, or a condom in combination with hormonal birth control or barrier methods used by the woman) during treatment and for an additional 5 months after the last administration of protocol-specified treatment
8. Subject is currently enrolled in or has not yet completed at least 30 days since ending other investigational device or drug study(s), or subject is receiving other investigational agent(s).
9. Subject has known sensitivity to any of the products to be administered during the study, including mammalian cell-derived drug products.
10. History or evidence of clinically significant disorder, infection, condition, or disease that, in the opinion of the investigator or Amgen physician, if consulted, would pose a risk to subject safety or interfere with the study evaluation, procedures, or completion.

Si se da alguna de las siguientes situaciones, el sujeto NO DEBE participar en el estudio:
1. Deficiencia del complemento hereditaria conocida o sospechada
2. Enfermedad cardiovascular clínicamente significativa (lo que incluye infarto de miocardio, angina inestable, insuficiencia cardíaca congestiva sintomática [Asociación del Corazón de Nueva York ≥ Clase III], arritmia cardíaca grave no controlada), enfermedad vascular periférica, accidente cerebrovascular o accidente isquémico transitorio en los 6 meses anteriores
3. Evidencias de trombosis aguda (ecografía Doppler hepática de venas hepáticas y portales)
4. Infección por el virus de la inmunodeficiencia humana positiva
5. Mujer embarazada o amamantando
6. Mujer con capacidad de concebir que no acepte utilizar un método de regulación de la natalidad de alta eficacia (p. ej., abstinencia verdadera, esterilización, píldoras para la regulación de la natalidad, inyecciones de Depo-Provera o implantes anticonceptivos) durante el tratamiento y durante 5 meses adicionales después de la última administración del tratamiento especificado en el protocolo
7. Hombre con una pareja con capacidad de concebir que no acepte utilizar un método de regulación de la natalidad de alta eficacia (p. ej., abstinencia verdadera, vasectomía o un preservativo en combinación con métodos de regulación de la natalidad hormonales o de barrera utilizados por la mujer) durante el tratamiento y durante 5 meses adicionales después de la última administración del tratamiento especificado en el protocolo
8. El sujeto está incluido actualmente en otro estudio de un dispositivo o fármaco en fase de investigación o todavía no han transcurrido al menos 30 días desde la finalización del mismo, o el sujeto está recibiendo otros agentes en fase de investigación
9. Sujeto que tenga sensibilidad conocida a cualquiera de los productos que se administrarán durante el estudio, incluidos productos farmacológicos derivados de células mamarias
10. Antecedentes o evidencia de trastorno, infección, afección o enfermedad clínicamente significativos que, en opinión del investigador o médico de Amgen, si es consultado, pondría en riesgo la seguridad del sujeto o interferiría con la evaluación, procedimientos o finalización del estudio

E.5 End points

E.5.1

Primary end point(s)

Primary Endpoint for Parallel Comparison:
• Hemolysis, as measured by LDH at week 27
Primary Endpoint for Crossover Comparison:
• Hemolysis, as measured by the time-adjusted AUEC of LDH from week 39 to 53 and from week 65 to 79

Criterio de valoración principal para la comparación con grupos paralelos:
• Hemólisis, medida mediante la LDH en la semana 27
Criterio de valoración principal para la comparación con grupos cruzados:
• Hemólisis, medida mediante el AUEC ajustada por el tiempo de LDH desde la semana 39 a la 53 y desde la semana 65 a la 79

E.5.1.1

Timepoint(s) of evaluation of this end point

The primary analysis of the primary endpoint of week 27 LDH for the parallel comparison will be conducted on the Full Analysis Set (FAS), consisting of all randomized subjects, with treatment as randomized in Period 1 regardless of treatment actually received.
The primary analysis of the primary endpoint of time-adjusted AUEC of LDH for the crossover comparison will be conducted on the Modified Full Analysis Set (mFAS), consisting of all randomized subjects who have an LDH-time profile evaluable for the time-adjusted AUEC within weeks 39 to 53 and/or within weeks 65 to 79, according to treatment per the randomized sequence regardless of treatment actually received.

El análisis principal del criterio de valoración principal de la LDH de la semana 27 para los grupos paralelos se realizará en el conjunto de análisis completo (Full Analysis Set, FAS), que consta de todos los sujetos aleatorizados, con tratamiento como aleatorizado en el período 1, independientemente del tratamiento real recibido.
El análisis principal del criterio de valoración principal del AUEC ajustada por tiempo de LDH para la comparación cruzada se realizará en el conjunto de análisis completo modificado, que consta de todos los sujetos aleatorizados con un perfil de tiempo de LDH evaluable para el AUEC ajustada por tiempo de las semanas 39 a la 53 y/o 65 a la 79, de acuerdo al tratamiento conforme a la secuencia aleatorizada, independientemente del tratamiento real recibido.

E.5.2

Secondary end point(s)

• Total complement (CH50), total hemoglobin, serum-free hemoglobin, haptoglobin, bilirubin, degree of hemoglobinuria, and type III erythrocytes at week 27, week 39, week 53, and post-crossover week 65 and week 79
• LDH-time profile
• Red blood cell transfusion
• Pharmacokinetic area under the curve (AUC) of ABP 959 and eculizumab from week 13 to 15, and trough PK

• Complemento total (CH50), hemoglobina total, hemoglobina libre en suero, haptoglobina, bilirrubina, grado de hemoglobinuria y eritrocitos tipo III en la semana 27, la semana 39, la semana 53, y las semanas 65 y 79 posteriores al cruce
• Perfil de tiempo de LDH
• Transfusión de glóbulos rojos
• Área bajo la curva (ABC) farmacocinética de ABP 959 y eculizumab desde la semana 13 a la 15 y FC mínima

E.5.2.1

Timepoint(s) of evaluation of this end point

The analysis of secondary endpoints (except for PK) will be conducted on the FAS. Total complement, total hemoglobin, serum-free hemoglobin, haptoglobin, bilirubin, degree of hemoglobinuria, and type III erythrocytes (%) at weeks 27, 39, 53, 65, and 79 will be summarized descriptively. For the endpoint of red blood cell transfusions, summary statistics for the number of packed red cells transfused per month after week 13 will be presented. A descriptive summary of LDH at each time point through the end of the study will be presented. Individual and mean LDH-time profile during the study will also be presented graphically.

El análisis de los criterios de valoración secundarios (excepto para FC) se realizará en el FAS. El complemento total, la hemoglobina total, la hemoglobina libre en suero, la haptoglobina, la bilirrubina, el grado de hemoglobinuria y los eritrocitos tipo III (%) en la semana 27, 39, 53, 65 y 79 se resumirán descriptivamente. Para el criterio de valoración de las transfusiones de glóbulos rojos, se presentarán los datos estadísticos resumidos del número de glóbulos rojos concentrados transfundidos al mes después de la semana 13. Se presentará un resumen descriptivo de la LDH en cada punto temporal hasta el final del estudio. También se presentará gráficamente el perfil individual y de tiempo de LDH medio durante el 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

Yes

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

Yes

E.6.7

Pharmacodynamic

Yes

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

Yes

E.6.13.1

Other scope of the trial description

Anti-drug Antibody testing

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

E.8.1.4

Double blind

Yes

E.8.1.5

Parallel group

Yes

E.8.1.6

Cross over

Yes

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

Yes

E.8.2.2

Placebo

E.8.2.3

Other

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

E.8.4

The trial involves multiple sites in the Member State concerned

Yes

E.8.4.1

Number of sites anticipated in Member State concerned

E.8.5

The trial involves multiple Member States

Yes

E.8.5.1

Number of sites anticipated in the EEA

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

France

Germany

Italy

Japan

Korea, Republic of

Netherlands

Russian Federation

Spain

United Kingdom

E.8.7

Trial has a data monitoring committee

Yes

E.8.8

Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial

LVLS

Última visita del último 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

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:

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

F.4.2.2

In the whole clinical trial

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

2017-08-28

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2017-08-21

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2022-07-12

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