Clinical Trials Register

Summary
EudraCT Number:	2012-001309-26
Sponsor's Protocol Code Number:	CSL689_2001
National Competent Authority:	Spain - AEMPS
Clinical Trial Type:	EEA CTA
Trial Status:	Prematurely Ended
Date on which this record was first entered in the EudraCT database:	2015-04-27
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

2012-001309-26

A.3

Full title of the trial

A multicenter, open-label, multiple-dose, dose escalation study to investigate the pharmacokinetics, efficacy, and safety of rVIIa-FP (CSL689) in subjects with hemophilia (A or B) and inhibitors.

Estudio multicéntrico, abierto, de dosis múltiple, con escalada de dosis para investigar la farmacocinética, eficacia y seguridad de PF-VIIar (CSL689) en sujetos con hemofilia (A o B) e inhibidores.

A.3.1

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

Study of recombinant factor VIIa fusion protein (rVIIa-FP, CSL689) for on-demand treatment of bleeding episodes in patients with hemophilia A or B with inhibitors.

Estudio de la proteína de fusión factor VIIa recombinante (rVIIa-FP, CSL 689) para
tratamiento a demanda de los episodios hemorrágicos en pacientes con hemofilia A
o B con inhibidores.

A.4.1

Sponsor's protocol code number

CSL689_2001

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	CSL Behring GmbH
B.1.3.4	Country	Germany
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	CSL Behring GmbH
B.4.2	Country	Germany
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	CSL Behring GmbH
B.5.2	Functional name of contact point	Trial Registration Coordinator
B.5.3	Address:
B.5.3.1	Street Address	Emil-von-Behring Straße 76
B.5.3.2	Town/ city	Marburg
B.5.3.3	Post code	35041
B.5.3.4	Country	Germany
B.5.4	Telephone number	0034917088600
B.5.6	E-mail	clinicaltrials@cslbehring.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	Yes
D.2.5.1	Orphan drug designation number	EMA/OD/133/10 and EMA/OD/132/10
D.3 Description of the IMP
D.3.1	Product name	Recombinant fusion protein, linking activated coagulation factor VII with albumin
D.3.2	Product code	CSL689
D.3.4	Pharmaceutical form	Lyophilisate and solvent for 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	CSL689 (rVIIa-FP)
D.3.9.2	Current sponsor code	CSL689 (rVIIa-FP)
D.3.9.3	Other descriptive name	Recombinant fusion protein, linking activated coagulation factor VII with albumin
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	10
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	NovoSeven
D.2.1.1.2	Name of the Marketing Authorisation holder	Novo Nordisk A/S
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.3.4	Pharmaceutical form	Powder and solvent for 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	EPTACOG ALFA
D.3.9.3	Other descriptive name	EPTACOG ALFA
D.3.9.4	EV Substance Code	SUB01922MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	1
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

Hemophilia A with inhibitors, Hemophilia B with inhibitors

Hemofilia A e inhibidores, Hemofilia B e inhibidores

E.1.1.1

Medical condition in easily understood language

Hemophilia (A or B)

Hemofilia (A o B)

E.1.1.2

Therapeutic area

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

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	18.0
E.1.2	Level	LLT
E.1.2	Classification code	10053751
E.1.2	Term	Hemophilia A with anti factor VIII
E.1.2	System Organ Class	100000004850

E.1.2 Medical condition or disease under investigation

E.1.2	Version	18.0
E.1.2	Level	LLT
E.1.2	Classification code	10053752
E.1.2	Term	Hemophilia B with anti factor IX
E.1.2	System Organ Class	100000004850

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

Part 1 (PK part): To evaluate the single-dose PK of CSL689 (low dose, high dose) in subjects with hemophilia A or B and inhibitors and to compare with the single-dose PK of Eptacog alfa (low dose or high dose).
Part 2 (Dose-evaluation part): To determine the best dose ("population-based best dose") of the 2 CSL689 dose levels evaluated.
Part 3 (Repeated-dose part): To evaluate the clinical efficacy of the population-based best dose of CSL689 for on-demand therapy of bleeding events in subjects with hemophilia A or B and inhibitors.

Parte 1 (farmacocinética) evaluar la dosis única de CSL689 (dosis baja y alta) en sujetos con hemofilia A o B e inhibidores y comparar con la farmacocinética de dosis única de Eptacog alfa (dosis baja y alta).
Parte 2 (evaluación de dosis): determinar la mejor dosis (mejor dosis basada en la población) de entre las 2 dosis de CSL689 evaluadas
Parte 3 (dosis repetidas): evaluar la eficacia clínica de la mejor dosis basada en la población de CSL689 para el tratamiento a demanda de episodios hemorrágicos en pacientes con hemofilia (A o B) e inhibidores.

E.2.2

Secondary objectives of the trial

To evaluate the safety and tolerability of IV administration of CSL689.

Evaluar seguridad y tolerabilidad de CSL689 por vía intravenosa

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Male subjects with hemophilia A or B and inhibitors.
2. Age ? 12 and ? 65 years.
3. High responding inhibitor with documented historical inhibitor titer > 5 Bethesda Units/mL.

1. Pacientes varones con hemofilia A o B e inhibidores.
2. Edad ? 12 y ? 65 años.
3. Inhibidores de alta respuesta, con un título histórico de
inhibidores documentado >5 unidades Bethesda (UB)/ml.

E.4

Principal exclusion criteria

1. Congenital or acquired coagulation disorders other than hemophilia A or B.
2. Ongoing immune tolerance induction therapy or planned during study.
3. Known or suspected hypersensitivity to activated recombinant human FVII or to any excipient of CSL689.
4. Body mass index > 30 kg/m².
5. Major surgery within 28 days before screening or scheduled major and / or orthopedic surgery during the study.
6. Advanced atherosclerotic disease (ie, known history of ischemic heart disease, or ischemic stroke).
7. Any clinical signs or known history of thromboembolic events, including known deep vein thrombosis.
8. Human immunodeficiency virus (HIV)-positive subjects who have low cluster of differentiation 4 (CD4)+ lymphocyte count (200/?L or less) at screening.
9. Use of the following within the screening period and planned during study: a) plasma or coagulation factor concentrates other than rescue therapy or therapy during the PK Module, b) other platelet inhibitors, c) desmopressin, and d) fibrinolysis inhibitors (except if used as local treatment (eg, for oral bleeds).

1. Trastornos de la coagulación, congénitos o adquiridos, distintos de la hemofilia A o B.
2. Tratamiento de inducción de inmunotolerancia en curso o previsto durante el período del estudio hasta la última visita de seguimiento.
3. Hipersensibilidad conocida o sospechada a cualquierexcipiente de CSL689.
4. Alergia conocida o clínicamente sospechada al factor FVII activado recombinante humano.
5. Pseudotumores activos conocidos.
6. Índice de masa corporal > 30 kg/m².
7. Cifra de plaquetas < 50 000 plaquetas /?l.
8. Cirugía mayor en los 28 días anteriores a la selección (son aceptables cateterismos, stents, procedimientos dentales y de inserción de puertos).
9. Cirugía mayor y/u ortopédica programada

E.5 End points

E.5.1

Primary end point(s)

PK of plasma factor VIIa activity (in Part 1 only): Area under the curve (AUC0-t); Incremental recovery; Elimination half-life; Total clearance.

Efficacy: Treatment success with first CSL689 injection (in Part 2 only); Treatment success with first CSL689 injection at the population best dose (in Part 3 only); Treatment success with first or second CSL689 injection at the population best dose (in Part 3 only).

La farmacocinética de la actividad plasmática del FVIIa (sólo en parte 1): Área bajo la curva (ABC0t), Recuperación incremental, t1/2, Cl total.
Eficacia: Porcentaje de episodios hemorrágicos tratados con éxito con una inyección de CSL689 a cada dosis (sólo en parte 2), Porcentaje de episodios hemorrágicos tratados con éxito con una inyección de CSL689 a la mejor dosis basada en la población (sólo en la parte 3), Porcentaje de episodios hemorrágicos tratados con éxito con una o dos inyecciones de CSL689 a la mejor dosis basada en la población (sólo en la parte 3)

E.5.1.1

Timepoint(s) of evaluation of this end point

PK: Before injection and/or at up to 6 time points until 24 hours after injection for Eptacog alfa; before injection and/or at up to 7 time points until 48 hours after injection for CSL689. Elimination half-life: Up to 24 hours after injection for Eptacog alfa; up to 48 hours after injection for CSL689.

Efficacy: Up to 16 hours after first CSL689 injection for each bleeding event

Farmacocinética: antes de la inyección y/o hasta en el 6 ocasiones hasta 24h después de la inyección de Eptacog alfa; antes de la inyección y/o hasta en el 7 ocasiones hasta 24h después de la inyección de CSL689. Semivida de eliminación: hasta 24h después de la inyección de Eptacog alfa, hasta 48h después de la inyección de CSL689.

Eficacia: hasta 16h después de la primera inyección por cada episodio hemorrágico.

E.5.2

Secondary end point(s)

"Efficacy: Treatment success with first or second CSL689 injection ( in Part 2 only); Number of bleeding events requiring > 1 CSL689 injection (for Part 2 and for Part 3); Number of CSL689 injections per bleeding event (for Part 2 and for Part 3); Total dose of CSL689 per bleeding event (for Part 2 and for Part 3); Treatment success with first CSL689 injection at the population best dose in subjects participating in Parts 2 and 3; Percentage of first bleeding events successfully treated with first CSL689 injection at population best dose in Part 3; Treatment success at population best dose; Treatment success with CSL689 at the dose level that is not the population best dose; Percentage of bleeding events with only ?definite? or ?abrupt? subject-reported pain relief at the population best dose; Percentage of bleeding events with ?good? or ?excellent? investigator-reported assessment of treatment response at the population best dose of CSL689; Proportion of recurrences; Proportion of bleeding events with ultrarapid progression; Proportion of bleeding events requiring post-hemostatic maintenance dosing.

Safety: Number and percentage of subjects with treatment-emergent adverse events (TEAEs); Number and percentage of subjects with an antibody response.

PK: AUC(0-inf); Maximum observed plasma FVIIa activity; Time of occurrence of maximum observed plasma FVIIa activity; Volume of distribution at steady state; Mean residence time."

Eficacia: Porcentaje de episodios hemorrágicos tratados con éxito con una o dos inyecciones de CSL689 a cada dosis (sólo en parte 2); Número de episodios hemorrágicos y proporción de ellos que requirieron >1 inyección de CSL689 (en partes 2 y 3); Número de inyecciones de CSL689 por episodio hemorrágico (en partes 2 y 3); Dosis total de CSL689 necesaria por episodio hemorrágico (en partes 2 y 3), Porcentaje de episodios hemorrágicos tratados con éxito con una inyección de CSL689 a la mejor dosis basada en la población; Porcentaje de episodios hemorrágicos tratados con éxito con una inyección de CSL689 a la mejor dosis basada en lapoblación en la parte 3; Porcentaje de episodios hemorrágicos tratados con éxito con una o dos inyecciones de CSL689 a la mejor dosis basada en la población en los grupos A, B y C. Porcentaje de episodios hemorrágicos tratados con éxito con una, dos o tres inyecciones de CSL689 a la mejor dosis
basada en la población en los grupos A, B y C. Porcentaje de episodios hemorrágicos tratados con éxito con una inyección de CSL689 a la dosis que no es la mejor dosis
basada en la población en los grupos A y B. Porcentaje de episodios hemorrágicos tratados con éxito con una o dos inyecciones de CSL689 a la dosis que no es la
mejor dosis basada en la población en los grupos A y B. Porcentaje de episodios hemorrágicos tratados con éxito con una, dos o tres inyecciones de CSL689 a la dosis que no es la mejor dosis basada en la población en los grupos A y B. Porcentaje de episodios hemorrágicos con valoración de alivio del dolor por parte del paciente únicamente de «claro» o «súbito» a la mejor dosis basada en la población de CSL689 en los grupos A, B y C. Porcentaje de episodios hemorrágicos con valoración de respuesta al tratamiento por parte del investigador de «buena» o «excelente» a la mejor dosis basada en la población de CSL689 en los grupos A, B y C. Número de episodios hemorrágicos y proporción de ellos que requirieron >1 inyección de CSL689 en los grupos A, B y C. Porcentaje de episodios hemorrágicos tratados con éxito con una inyección de CSL689 a la mejor dosis basada en la población en los grupos A, B y C, utilizando un intervalo de confianza (IC) del 95 % con corrección del sesgo y aceleración bootstrap. Proporción de recaídas (definidas como una hemorragia en la misma articulación o localización anatómica en el plazo de 24 horas después de una respuesta inicial «buena» o «excelente»). Proporción de episodios hemorrágicos con progresión ultrarrápida. Proporción de episodios hemorrágicos que requirieron administraciones de mantenimiento.
Seguridad: Número y porcentaje de pacientes con acontecimientos adversos surgidos durante el tratamiento (AAST). Número y porcentaje de pacientes con anticuerpos frente a CSL689.

Farmacocinética: actividad plasmática máxima observada del factor FVIIa (Cmáx), tiempo correspondiente a la Cmáx, volumen de distribución en estado de equilibrio, y tiempo medio de permanencia

E.5.2.1

Timepoint(s) of evaluation of this end point

Efficacy: Up to 24 hours after the relevant CSL689 injection for the relevant bleeding event for the first eight endpoints; Up to 9 months for the last five endpoints.

Safety: Up to 16 months.

PK: Before injection and at up to 6 time points until 24 hours after injection for Eptacog alfa; before injection and at up to 7 time points until 48 hours after injection for CSL689.

Eficacia: hasta 24h después de la inyección relevante de CSL689 para el episodio hemorrágico relevante en los primeros 8 criterios; hasta 9 meses por los últimos 5 criterios.
Seguridad; hasta 16 meses
Farmacocinética: antes de la inyección y/o hasta en el 6 ocasiones hasta 24h después de la inyección de Eptacog alfa; antes de la inyección y/o hasta en el 7 ocasiones hasta 24h después de la inyección de CSL689

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

E.6.8

Bioequivalence

E.6.9

Dose response

Yes

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)

Yes

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

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

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

Australia

Canada

European Union

Georgia

Japan

Korea, Republic of

Malaysia

Russian Federation

Serbia

South Africa

Thailand

Turkey

Ukraine

United States

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

E.8.9.2

In all countries concerned by the trial days

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1.1

In Utero

F.1.1.2

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

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

F.1.1.5

Children (2-11years)

F.1.1.6

Adolescents (12-17 years)

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

F.1.3

Elderly (>=65 years)

F.1.3.1

Number of subjects for this age range:

F.2 Gender

F.2.1

Female

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

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

This clinical trial will be conducted in adults, but also in adolescents.

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)

Subjects completing study CSL689_2001 will be invited to participate in a prophylaxis study.

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

2015-06-02

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2015-05-21

P. End of Trial
P.	End of Trial Status	Prematurely Ended
P.	Date of the global end of the trial	2018-04-05

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