Clinical Trials Register

Summary
EudraCT Number:	2017-001271-23
Sponsor's Protocol Code Number:	C0371004
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:	2018-11-16
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

2017-001271-23

A.3

Full title of the trial

An Open-Label, Non-Investigational Product, Multi-Center, Lead-In Study To Evaluate At Least 6 Months Of Prospective Efficacy And Selected Safety Data Of Factor IX (FIX) Prophylaxis Replacement Therapy In The Usual Care Setting Of Moderately Severe To Severe Adult Hemophilia B Subjects (FIX:C≤2%) Who Are Negative For Neutralizing Antibodies (Nab) To Adeno-Associated Virus Vector (Aav)-Spark100.

Estudio Abierto De Un Producto No Experimental, Multicéntrico Y De Preinclusión Para Evaluar Como Mínimo 6 Meses De Eficacia Prospectiva Y Datos De Seguridad Seleccionados De La Terapia Profiláctica Sustitutiva Con Factor IX (FIX) En Las Condiciones Asistenciales Habituales De Sujetos Adultos Con Hemofilia B (Fix:C</= 2%) De Moderadamente Grave A Grave Con Resultado Negativo De Anticuerpos Neutralizantes (ACN) Contra El Vector Viral Adenoasociado (Aav)-Spark100

A.3.1

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

Efficacy And Selected Safety Data Of Factor IX (FIX) Preventive Replacement Treatment In The Usual Care Setting Of Moderately Severe To Severe Adult Hemophilia B Subjects.

Eficacia y datos de seguridad seleccionados de la terapia preventiva sustitutiva con Factor IX (FIX) en las condiciones asistenciales habituales de sujetos adultos con Hemofilia B de moderadamente grave a grave.

A.4.1

Sponsor's protocol code number

C0371004

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	Pfizer 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	Pfizer 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	Pfizer Inc.
B.5.2	Functional name of contact point	Clinical Trials.gov Call Center
B.5.3	Address:
B.5.3.1	Street Address	235 East 42nd Street
B.5.3.2	Town/ city	New York
B.5.3.3	Post code	NY 10017
B.5.3.4	Country	United States
B.5.4	Telephone number	+18007181021
B.5.6	E-mail	ClinicalTrials.gov_Inquiries@pfizer.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.2.1.2	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	Factor IX
D.3.2	Product code	Not Applicable
D.3.4	Pharmaceutical form	Powder and solvent for solution for injection/infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use
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	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	Yes
D.3.11.13.1	Other medicinal product type	Extended half-life FIX medicinal product

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

Moderately Severe To Severe Adult Hemophilia B Subjects (FIX:C </= 2%) Who Are Negative For Neutralizing Antibodies (NAb) To Adeno-Associated Virus Vector (AAV)-Spark100.

Sujetos Adultos Con Hemofilia B (Fix:C </= 2%) De Moderadamente Grave A Grave Con Resultado Negativo De Anticuerpos Neutralizantes (ACN) Contra El Vector Viral Adenoasociado (AAV)-Spark100

E.1.1.1

Medical condition in easily understood language

Moderately severe to severe Hemophilia B

Hemofilia B de moderamente grave a grave

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	20.0
E.1.2	Level	LLT
E.1.2	Classification code	10060614
E.1.2	Term	Hemophilia B (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

To establish a minimum of 6 months of prospective efficacy data of FIX prophylaxis replacement therapy in the usual care setting of hemophilia B subjects, who are negative for NAb to AAV-Spark100.

Establecer como mínimo 6 meses de datos de eficacia prospectiva del tratamiento profiláctico sustitutivo con FIX en el entorno habitual de atención de sujetos con hemofilia B con resultado negativo de AcN contra AAV-Spark100

E.2.2

Secondary objectives of the trial

Evaluate safety (serious adverse events and medically important events of FIX inhibitor, thrombotic and FIX hypersensitivity reactions) of FIX replacement therapy in hemophilia B subjects.

Evaluar la seguridad (acontecimientos adversos graves y acontecimientos de importancia médica de inhibidor del FIX, trombóticos y reacciones de hipersensibilidad al FIX) del tratamiento sustitutivo con FIX en sujetos con hemofilia B

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1.Males 18 and <65 years of age with moderate severe to severe hemophilia B and documented FIX activity (</= 2%) within the last 12 months prior to baseline visit.
2.Previous experience with FIX therapy (>/= 50 documented exposure days to a FIX protein product such as recombinant, plasma-derived or extended half-life FIX product).
3.Subjects as per usual care setting on FIX prophylaxis replacement therapy (recombinant, plasma-derived or extended half-life FIX product) must have the intention to remain on FIX prophylaxis replacement therapy for the duration of the study.
4.No known hypersensitivity to FIX replacement product.
5.No history of FIX inhibitor (clinical or laboratory-based assessment) defined as a titer 0.6 BU/mL, regardless of the laboratory normal range, or any measured Bethesda inhibitor titer greater than the upper limit of normal for the laboratory performing the assay. Clinically, no signs or symptoms of decreased response to FIX administration.
Subjects will not be required to undergo diagnostic evaluation of inhibitor status to participate in the study.

1. Hombres de 18 a <65 años con hemofilia B de moderada a grave y actividad de FIX documentada (</=2 %) en los 12 meses previos a la visita inicial.
2. Experiencia previa con tratamiento con FIX (>/= 50 días de exposición documentada a un producto proteico de FIX, como el producto de FIX recombinante derivado del plasma o de semivida prolongada).
3. Los sujetos en tratamiento profiláctico sustitutivo con FIX (producto de FIX recombinante derivado del plasma o de semivida prolongada) según la práctica habitual deben tener la intención de mantener el tratamiento profiláctico sustitutivo con FIX durante todo el estudio.
4. Sin hipersensibilidad conocida a un producto sustitutivo de FIX.
5. Sin antecedentes de inhibidor de FIX (evaluación clínica o de laboratorio), que se define como un valor de 0,6 UB/ml, independientemente del intervalo de laboratorio normal, o cualquier valor de inhibidores de Bethesda superior al límite superior de la normalidad para el laboratorio que realiza el análisis. Clínicamente, sin signos ni síntomas de reducción de la respuesta a la administración de FIX.
Los sujetos no tendrán que someterse a la evaluación de diagnóstico del estado del inhibidor para participar en el estudio.

E.4

Principal exclusion criteria

1.Anti-AAV-Spark100 neutralizing antibodies titer (above the lowest detectable titer) performed by a central laboratory during screening.
2. Lack of patient compliance with documentation of bleeds and/or FIX prophylaxis replacement therapy administration.
3. If there is no documentation regarding hepatitis status, as defined below, within the last 12 months prior to screening for hepatitis B and 6 months prior to screening for hepatitis C, then subjects will be required to have the following hepatitis testing performed at screening:
a. Hepatitis B screening (acute and chronic):
HBsAg (also referred to as Hepatitis B surface antigen), HBV-DNA viral assay (also referred to as a nucleic acid test for Hepatitis B virus DNA), and Anti-HBc (also referred to as Total Hepatitis B core antibody).
-A subject is not eligible if either HbsAg is positive or HBV-DNA is positive/detectable.
-Anti-HBc must be obtained in all subjects for determination of whether the subject had prior hepatitis B. If the anti-HBc is positive and both HBsAg and HBV DNA are negative this would be consistent with a prior infection and the subject would be eligible for the study. Anti-HBc must be obtained in all subjects to discriminate between those with no prior hepatitis B and those with prior infection in the event of reactivation. FDA has noted reactivation of hepatitis B virus exists.
-One documented negative HBV-DNA viral load is sufficient to assess eligibility. A subject who is currently undergoing anti-viral therapy for hepatitis B is not eligible.
b. Hepatitis C (acute or chronic):
-A subject who is currently undergoing anti-viral therapy for chronic hepatitis C is not eligible.
-Subjects treated with anti-viral therapy for chronic hepatitis C, must have completed anti-viral therapy at least 6 months prior to screening and have a negative HCV-RNA at least 6 months prior to screening.
-All subjects (who are not currently undergoing anti-viral therapy for chronic hepatitis C) must have a single HCV-RNA load assay (also referred to as a nucleic acid test [NAT] for HCV RNA) obtained during the 6 months preceding screening. This includes subjects with prior known chronic hepatitis C who have completed treatment with anti-viral therapy.
-A subject is not eligible if his HCV-RNA load assay result is positive/detectable.
4. Currently on antiviral therapy for hepatitis B or C.
5. A subject is not eligible if any of the following pre-existing diagnoses, which are indicative of significant underlying liver disease, are present in the medical record:
- Portal hypertension; or
- Splenomegaly; or
- Hepatic encephalopathy.
All subjects who do not have the listed pre-existing diagnoses above must have the following assessments performed within the last 12 months prior to screening and if not will need to be tested for liver fibrosis status at screening:
-Measurement of serum albumin. A subject is not eligible if the serum albumin level is below the testing laboratory’s lower limit of normal; and
-At least one of the following diagnostic tests for liver fibrosis indicating ≥ stage 3. The following results are indicative of fibrosis ≥ stage 3 and exclude the subject from participation:
-FibroScan, with a score >8.3 kPa units;
-FibroTest/FibroSURE with a result >0.48; or
-AST-to-Platelet Ratio Index (APRI) >1.
6. Documented serological evidence of human immunodeficiency virus HIV-1 or HIV-2 with Cluster of Differentiation 4 positive (CD4+) cell count ≤200 mm3 within the last 12 months prior to screening. Subjects who are HIV positive and stable, have an adequate CD4 count (>200/mm3 ) and undetectable viral load (<50 gc/mL) documented within the preceding 12 months, and are on an antiretroviral drug regimen are eligible to enroll. Subjects who have not been tested within the prior 12 months of screening will need to be tested for HIV status at screening
7. Any patient who previously received SPK-9001 or any AAV gene based therapy.
8. Any patient with a planned surgical procedure requiring FIX surgical prophylactic factor treatment in the next 24 months.

1. Valor de anticuerpos neutralizantes anti-AAV-Spark100 (por encima del valor detectable más bajo) determinado por un laboratorio central durante la selección.
2. Falta de cumplimiento del paciente de la documentación de las hemorragias y/o la administración de tratamiento profiláctico sustitutivo con FIX.
3. Si no hay documentación sobre el estado de la hepatitis, tal como se define a continuación, en los 12 meses anteriores a la selección para la hepatitis B y los 6 meses anteriores a la selección para la hepatitis C, se pedirá a los pacientes que se sometan a las siguientes pruebas de hepatitis en la selección:
a. Selección para hepatitis B (aguda y crónica):
HBsAg (también conocido como antígeno de superficie de la hepatitis B), análisis vírico del ADN del VHB (también conocido como prueba de ácidos nucleicos para el ADN del virus de la hepatitis B) y anti-HBc (también conocido como anticuerpo central de la hepatitis B total).
- Un sujeto no es apto si HBsAg es positivo o el ADN del VHB es positivo o detectable.
- Debe obtenerse el valor de anti-HBc en todos los sujetos para determinar si el sujeto tuvo hepatitis B previa. Si el anti-HBc es positivo y tanto HBsAg como el ADN del VHB son negativos, esto sería compatible con una infección previa y el sujeto sería apto para el estudio. El anti-HBc se debe obtener en todos los sujetos para discriminar entre sujetos sin hepatitis B previa y sujetos con infección previa en caso de reactivación. La Administración de Medicamentos y Alimentos de Estados Unidos (Food and Drug Administration, FDA) ha observado que existe una reactivación del virus de la hepatitis B.
-Una carga vírica de ADN del VHB negativa documentada es suficiente para evaluar la idoneidad. Un sujeto que está actualmente en tratamiento antivírico para la hepatitis B no es apto.
b. Hepatitis C (aguda o crónica):
- Un sujeto que está actualmente en tratamiento antivírico para la hepatitis C crónica no es apto.
- Los sujetos tratados con terapia antivírica para la hepatitis C crónica deben haber completado el tratamiento antivírico al menos 6 meses antes de la selección y tener un resultado negativo para el ARN del VHC al menos 6 meses antes de la selección.
- Todos los sujetos (que no estén actualmente en tratamiento antivírico para la hepatitis C crónica) deben tener un único análisis de carga de ARN del VHC (también conocido como prueba de ácidos nucleicos para ARN del VHC) realizado durante los 6 meses anteriores a la selección. Esto incluye a los sujetos con hepatitis C crónica conocida previa que hayan recibido tratamiento antivírico.
- Un sujeto no es apto si el resultado de un análisis de carga de ARN del VHC es positivo/detectable.
4. Actualmente en tratamiento antivírico para la hepatitis B o C.
5. Un sujeto no es apto si hay alguno de los siguientes diagnósticos preexistentes, que son un indicador de enfermedad hepática subyacente significativa, presente en la historia clínica:
- Hipertensión portal
- Esplenomegalia
- Encefalopatía hepática
Todos los sujetos que no presenten estos diagnósticos preexistentes deben haberse sometido a las siguientes evaluaciones en los 12 meses anteriores a la selección y, de lo contrario, deben someterse a un análisis para determinar el estado de fibrosis hepática en la selección:
- Medición de la albúmina sérica. Un paciente no es apto si el nivel de albúmina sérica está por debajo del límite inferior de la normalidad del laboratorio que realiza el análisis.
- Además, al menos una de las siguientes pruebas de diagnóstico para la fibrosis hepática indica estadio >/= 3. Los siguientes resultados son indicativos de fibrosis en estadio >/= 3 y excluyen al paciente de la participación:
- FibroScan, con una puntuación >8,3 kPa
- FibroTest/FibroSURE con un resultado >0,48
- Índice de la relación AST–plaquetas >1
6. Signos serológicos documentados del virus de inmunodeficiencia humana (VIH-1 o VIH-2) con recuento de células del grupo de diferenciación 4 positivo (CD4+) </= 200 mm3 en los 12 meses anteriores a la selección. Los sujetos con resultado positivo en VIH y estables que tengan un recuento suficiente de linfocitos CD4 (>200/mm3) y carga vírica indetectable (<50 gc/ml) documentada en los últimos 12 meses y que reciban una pauta de fármacos antirretrovíricos son aptos para inscribirse. Los sujetos que no se hayan realizado un análisis en los 12 meses anteriores a la selección deberán someterse a un análisis para determinar el estado del VIH en la selección.
7. Cualquier paciente que recibiera previamente SPK-9001 o cualquier tratamiento basado en el gen VAA.
8. Cualquier paciente con una intervención quirúrgica programada que requiera tratamiento profiláctico quirúrgico con FIX en los próximos 24 meses

E.5 End points

E.5.1

Primary end point(s)

Efficacy Endpoints:
1)Annualized bleeding rate (ABR).

Safety Endpoints:
1)Incidence of serious adverse events.
2)Events of Special Interest:
-FIX inhibitor;
-Thrombotic events;
-FIX hypersensitivity events.

Criterios de valoración de la eficacia:
1) Tasa anual de hemorragias (TAH).

Criterios de valoración de seguridad:
1) Incidencia de acontecimientos adversos graves.
2) Acontecimientos de interés especial:
- Inhibidor del FIX;
- Acontecimientos trombóticos;
-Acontecimientos de hipersensibilidad al FIX;

E.5.1.1

Timepoint(s) of evaluation of this end point

Efficacy analysis population is defined as subjects identified as NAb negative during screening and have completed a minimum of 6 months data collection.

Safety Endpoints: From Screening visit: Day - 42 to Day -1 till End of Study / Early Termination Visit: Minimum 180 days from Day 1

La población de análisis de eficacia se define como aquellos sujetos identificados como con resultado negativo en el AcN durante la selección y que hayan completado como mínimo 6 meses de obtención de datos.

Criterios de valoración de seguridad: Desde la visita de selección: Día - 42 al Día -1 hasta el Fin de Estudio / Visita Finalización Anticipada: Mínimo 180 días desde el Día 1

E.5.2

Secondary end point(s)

Efficacy Endpoints:
1)Annualized number of infusions (AIR)

Criterios de valoración de la eficacia:
1) Tasa anual de hemorragias (TAH).

E.5.2.1

Timepoint(s) of evaluation of this end point

Efficacy analysis population is defined as subjects identified as NAb negative during screening and have completed a minimum of 6 months data collection.

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

Yes

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

E.8.1.1

Randomised

E.8.1.2

Open

E.8.1.3

Single blind

E.8.1.4

Double blind

E.8.1.5

Parallel group

E.8.1.6

Cross over

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

E.8.2.3

Other

E.8.3

The trial involves single site in the Member State concerned

E.8.4

The trial involves multiple sites in the Member State concerned

Yes

E.8.4.1

Number of sites anticipated in Member State concerned

E.8.5

The trial involves multiple Member States

Yes

E.8.5.1

Number of sites anticipated in the EEA

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

Yes

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.6.3

If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned

Australia

Brazil

Canada

European Union

Israel

Japan

Korea, Democratic People's Republic of

Saudi Arabia

Taiwan

Turkey

United States

E.8.7

Trial has a data monitoring committee

E.8.8

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

LVLS

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

E.8.9.2

In all countries concerned by the trial years

E.8.9.2

In all countries concerned by the trial months

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.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

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.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)

Patients will continue to receive normal standard of care as directed by their treating physician.

Los pacientes continuarán recibiendo la atención habitual normal según indique el médico que los trata.

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

2019-01-28

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2019-01-21

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

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