Clinical Trials Register

Summary
EudraCT Number:	2020-000142-34
Sponsor's Protocol Code Number:	ITCC-092/IST11028
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:	2022-05-30
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

2020-000142-34

A.3

Full title of the trial

A Phase Ib study of Vyxeos® (liposomal daunorubicin and cytarabine) in combination with Clofarabine in children with relapsed/refractory AML, ITCC-092

Estudio de fase Ib de Vyxeos® (daunorrubicina y citarabina liposomal) en combinación con clofarabina para el tratamiento de la leucemia mieloide aguda recidivante o refractaria en pacientes pediátricos. Estudio ITCC-092

A.3.1

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

Vyxeos® and Clofarabine in children with a specific type of blood cancer (AML) that has returned or is persistent

Vyxeos® y clofarabina en niños con un tipo específico de cáncer de la sangre (LMA) que ha vuelto a aparecer o es persistente

A.3.2

Name or abbreviated title of the trial where available

Vyxeos® and Clofarabine in relapsed/refractory pediatric AML

Vyxeos® y clofarabina en pacientes pediátricos con LMA recidivante o refractaria

A.4.1

Sponsor's protocol code number

ITCC-092/IST11028

A.5.4

Other Identifiers

Name:

Nederlands Trialregister (NTR)

Number:

NL8134

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	Princess Máxima Center for pediatric oncology
B.1.3.4	Country	Netherlands
B.3.1 and B.3.2	Status of the sponsor	Non-Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Princess Máxima Center for pediatric oncology
B.4.2	Country	Netherlands
B.4.1	Name of organisation providing support	ErasmusMC Rotterdam (Sophia B.V.)
B.4.2	Country	Netherlands
B.4.1	Name of organisation providing support	Jazz Pharmaceuticals
B.4.2	Country	Ireland
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Princess Máxima Center for pediatric oncology
B.5.2	Functional name of contact point	Trialmanagement
B.5.3	Address:
B.5.3.1	Street Address	Heidelberglaan 25
B.5.3.2	Town/ city	Utrecht
B.5.3.3	Post code	3584 CS
B.5.3.4	Country	Netherlands
B.5.4	Telephone number	+3188 97 25206
B.5.5	Fax number	+3188 97 290 09
B.5.6	E-mail	trialmanagement@prinsesmaximacentrum.nl

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	Vyxeos liposomal
D.2.1.1.2	Name of the Marketing Authorisation holder	Jazz Pharmaceuticals Ireland Limited
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	Yes
D.2.5.1	Orphan drug designation number	EU/3/11/942
D.3 Description of the IMP
D.3.1	Product name	Vyxeos liposomal
D.3.2	Product code	CPX-351
D.3.4	Pharmaceutical form	Powder for concentrate for 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	Daunorubicin
D.3.9.1	CAS number	20830-81-3
D.3.9.3	Other descriptive name	DAUNORUBICIN
D.3.9.4	EV Substance Code	SUB06917MIG
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	2.2
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Cytarabine
D.3.9.1	CAS number	147-94-4
D.3.9.3	Other descriptive name	CYTARABINE
D.3.9.4	EV Substance Code	SUB06880MIG
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	5
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No
D.IMP: 2
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	Yes
D.2.1.1.1	Trade name	Evoltra
D.2.1.1.2	Name of the Marketing Authorisation holder	Genzyme Europe BV
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	Concentrate for 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	CLOFARABINE
D.3.9.1	CAS number	123318-82-1
D.3.9.4	EV Substance Code	SUB21902
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

Relapsed or refractory pediatric acute myeloid leukemia

Leucemia mieloide aguda en recaída/refractaria

E.1.1.1

Medical condition in easily understood language

Returning or treatment-resistant acute cancer of the myeloid line of blood cells in children

Cáncer agudo de la línea mieloide de células sanguíneas en niños que ha regresado o es resistente al tratamiento

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	21.0
E.1.2	Level	LLT
E.1.2	Classification code	10060558
E.1.2	Term	Acute myeloid leukemia recurrent
E.1.2	System Organ Class	100000004864

E.1.2 Medical condition or disease under investigation

E.1.2	Version	21.1
E.1.2	Level	LLT
E.1.2	Classification code	10081514
E.1.2	Term	Acute myeloid leukemia refractory
E.1.2	System Organ Class	100000004864

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 the recommended phase 2 dose of Vyxeos®/CPX-351 in combination with clofarabine in children with relapsed/refractory AML

Establecer la dosis recomendada para la fase 2 de Vyxeos®/CPX-351 en combinación con clofarabina en niños con LMA en recaída/refractaria

E.2.2

Secondary objectives of the trial

• To determine the safety and tolerability of this combination.
• To determine the (preliminary) efficacy in terms of the hematological remission rate in these patients as determined by morphology with flow cytometric confirmation.
• To describe the durability of response, including the number of patients that undergo stem- cell transplant after re-induction with this regimen

• Determinar la seguridad y la tolerabilidad de esta combinación.
• Determinar la eficacia (preliminar) en términos de tasa de remisión hematológica en estos pacientes según la morfología y con confirmación por citometría de flujo.
• Describir la duración de respuesta, incluido el número de pacientes que se someten a un trasplante de células madre después de la reinducción con esta pauta.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

• Age ≥1 year and ≤21 years
• Any ≥ 2nd relapse of AML
• Refractory AML (defined as ≥ 20% blasts in the bone marrow after standard (re-)induction therapy)
• Early 1st relapse (defined as relapse within one year from initial diagnosis) of AML
• Any relapse of AML after prior allogenic HSCT
• Any relapse of AML with high risk cytogenetic characteristics (as defined in Appendix V)
• Complete initial work-up within 7 days prior to study entry, including bone-marrow aspiration, lumbar puncture (without intrathecal therapy)
• Lansky play score ≥ 60 for patients <16 years of age; or Karnofsky performance status ≥ 60 for patients ≥ 16 years of age (see Appendix I for Performance scales).
• Life expectancy > 6 weeks
• The patient must have a calculated GFR ≥ 70mL/min/1.73 m2.
• Liver function: total serum bilirubin ≤ 3 mg/dl or 50 µmol/L and aspartate transaminase (AST) and alanine transaminase (ALT) ≤200 U/L
• Adequate cardiac function (defined as shortening fraction ≥28% or ejection fraction ≥50%)
• For female patients with childbearing potential, a negative test for pregnancy is to be performed before entry on study.
• Male and female patients must use a highly effective contraceptive method during the study and for a minimum of 6 months after study treatment.
• Female patients may not breastfeed during the study and for a minimum of 3 months after study treatment.
• Absence of any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule is required; those conditions should be discussed with the patient before registration in the trial.
• Before patient registration, written informed consent must be given according to ICH/GCP, and national/local regulations.

Concomitant treatments:
• Concomitant administration of any other experimental drug under investigation, or concurrent treatment with any other anti-cancer therapy other than specified in the protocol is not allowed.
• GCSF will not be used for priming and no routine GCSF support is allowed during the 1st course, except for life-threatening infections.

Additional criteria:
• At least 6 patients must be enrolled with an M3 or a WBC count >10x109/L with blasts

• Edad ≥1 año y ≤21 años.
• ≥ 2 recaídas de LMA.
• LMA refractaria (definida como ≥20 % de blastos en la médula ósea después de la terapia de [re]inducción estándar).
• 1.ª recaída temprana (definida como recaída en el plazo de un año desde el diagnóstico inicial) de la LMA.
• Cualquier recaída de la LMA después de un TCMH alogénico previo.
• Cualquier recaída de la LMA con características citogenéticas de riesgo elevado (se definen en el Anexo V).
• Estudio inicial completo durante los 7 días anteriores a la entrada en el estudio, incluyendo aspirado de médula ósea y punción lumbar (sin terapia intratecal).
• Puntuación de Lansky relacionada con el juego ≥60 en pacientes <16 años de edad; o estado funcional de Karnofsky ≥60 en pacientes ≥16 años de edad (véase el Anexo I sobre escalas de estado funcional).
• Esperanza de vida >6 semanas.
• El paciente debe tener una TFG calculada ≥70 ml/min/1,73 m2.
• Función hepática: bilirrubina sérica total ≤3 mg/dl o 50 μmol/l y aspartato transaminasa (AST) y alanino transaminasa (ALT) ≤200 U/l.
• Función cardíaca adecuada (definida como una fracción de acortamiento ≥28 % o una fracción de eyección ≥50 %).
• Las pacientes con posibilidad de quedarse embarazadas deberán presentar un resultado negativo en una prueba de embarazo antes de entrar en el estudio.
• Los pacientes de ambos sexos deberán utilizar un método anticonceptivo altamente eficaz durante el estudio y durante un mínimo de 6 meses después del tratamiento del estudio.
• Las pacientes no podrán amamantar durante el estudio ni durante un mínimo de 3 meses después del tratamiento del estudio.
• No debe existir ningún problema psicológico, familiar, sociológico o geográfico que pueda dificultar el cumplimiento del protocolo del estudio y del calendario de seguimiento; dichos problemas deberán comentarse con el paciente antes de entrar en el ensayo.
• Antes de que el paciente entre en el estudio, deberá otorgar un consentimiento informado por escrito de acuerdo con la BPC de la ICH y la normativa nacional/local.

Tratamientos concomitantes:
• No se permite la administración concomitante de ningún otro fármaco experimental en investigación ni el tratamiento concurrente con ningún otro tratamiento contra el cáncer, salvo los especificados en el protocolo.
• No se utilizará FEC-G para la dosis de carga y no está permitido el uso rutinario de FEC-G como apoyo durante el primer ciclo, excepto en el caso de que se trate de infecciones potencialmente mortales.

Criterios adicionales:
• Se deberán reclutar al menos 6 pacientes con un subtipo M3 de LMA o con un recuento de leucocitos >10 × 109/l con blastos.

E.4

Principal exclusion criteria

• Evidence of a currently uncontrolled bacterial, viral or parasitic infection
• Evidence of a fungal infection, defined as either:
- Pulmonary infiltrates suggestive of a fungal infection at HR-CT (within 3 weeks prior to enrollment)
- Positive Aspergillus serum test (galactomannan), according to local laboratory practice (within 3 weeks prior to enrollment)
• Evidence of isolated extramedullary relapse, including isolated CNS-relapse
• Evidence of CNS3 or symptomatic CNS leukemia
• Down Syndrome
• Evidence of relapsed/refractory acute promyelocytic leukemia (APL)
• Use of any anticancer therapy within 2 weeks before study entry. The patient must have recovered from all acute toxicities from any previous therapy (note: hematological toxicities do not need to be considered since the patient has overt leukemia)
• History of prior veno-occlusive disease (VOD)
• Known hypersensitivity to cytarabine, clofarabine or liposomal daunorubicin
• Known copper metabolism deficiency, such as Wilson's disease

• Indicios de una infección bacteriana, vírica o parasitaria actualmente no controlada
• Indicios de una infección por hongos, definida como:
- Infiltrados pulmonares que parezcan indicar una infección por hongos en una TCAR (durante las 3 semanas anteriores al reclutamiento).
- Prueba de Aspergillus (galactomanano) en suero positiva, según la práctica del laboratorio local (durante las 3 semanas anteriores al reclutamiento).
• Indicios de recaída extramedular aislada, incluida la recaída aislada que afecte al SNC.
• Indicios de SNC3 o leucemia sintomática en el SNC.
• Síndrome de Down.
• Indicios de leucemia promielocítica aguda (LPA) en recaída/refractaria.
• Uso de cualquier terapia contra el cáncer durante las 2 semanas anteriores a la entrada en el estudio. El paciente debe haberse recuperado de todas las toxicidades agudas debidas a cualquier tratamiento anterior (nota: no se tendrán en cuenta las toxicidades hematológicas, ya que el paciente padece leucemia manifiesta).
• Antecedentes de enfermedad venooclusiva previa (EVO).
• Hipersensibilidad conocida a citarabina, clofarabina o daunorubicina liposomal.
• Deficiencia conocida del metabolismo del cobre, como enfermedad de Wilson.

E.5 End points

E.5.1

Primary end point(s)

Dose-limiting toxicities (DLTs) during the first course of therapy.

Frecuencia de toxicidades limitantes de dosis (TLD) durante el primer ciclo de tratamiento.

E.5.1.1

Timepoint(s) of evaluation of this end point

DLT evaluation after course 1

Evaluación TLD después del primer ciclo de tratamiento

E.5.2

Secondary end point(s)

1. Safety and tolerability: frequency of AEs, frequency of clinically significant laboratory abnormalities and number of toxic deaths
2. Measures of anti-leukemic activity: ORR after 1 course and as best response and ORR after 2 courses, which includes CR, CRi, and PR, determined by morphology with flow cytometric confirmation
3. Overall patient survival (OS) and relapse-free survival
4. Number of patients undergoing HSCT after treatment

1. Seguridad y tolerabilidad: frecuencia de AA, frecuencia de anomalías de interés clínico en las
pruebas analíticas y número de muertes por toxicidad.
2. Mediciones de la actividad antileucémica: TGR después de un ciclo y como mejor respuesta y TGR
después de 2 ciclos, que incluye RC, RCi y RP, determinada por la morfología y con confirmación por
citometría de flujo.
3. Supervivencia global (SG) del paciente y supervivencia sin recaída.
4. Número de pacientes que se someten a un trasplante de células madre hematopoyéticas (TCMH) después del tratamiento.

E.5.2.1

Timepoint(s) of evaluation of this end point

• After course 1, after each subsequent course of therapy, and at 4wks, 10wks, 3months, 6 months and 9 months, 12 months, 18 months and 24 months of FUP
• end of study (EOS)

• Después del primer ciclo de tratamiento, después de cada ciclo posterior de tratamiento, y a las 4 semanas, 10 semanas, 3 meses, 6 meses, 9 meses, 12 meses, 18 meses, 24 meses y seguimiento.
• Fin del estudio (EoS)

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

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

Yes

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

Yes

E.7.1.3.1

Other trial type description

First administration of combination clofarabine with Vyxeos/CPX-351 in pediatric population

E.7.2

Therapeutic exploratory (Phase II)

E.7.3

Therapeutic confirmatory (Phase III)

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.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

E.8.4

The trial involves multiple sites in the Member State concerned

Yes

E.8.4.1

Number of sites anticipated in Member State concerned

E.8.5

The trial involves multiple Member States

Yes

E.8.5.1

Number of sites anticipated in the EEA

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.7

Trial has a data monitoring committee

E.8.8

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

LVLS

Última visita 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

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

Yes

F.1.1

Number of subjects for this age range:

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)

Yes

F.1.1.4.1

Number of subjects for this age range:

F.1.1.5

Children (2-11years)

Yes

F.1.1.5.1

Number of subjects for this age range:

F.1.1.6

Adolescents (12-17 years)

Yes

F.1.1.6.1

Number of subjects for this age range:

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

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
G.4 Investigator Network to be involved in the Trial: 1
G.4.1	Name of Organisation	ITCC
G.4.3.4	Network Country	Netherlands

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2022-09-29

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2022-09-09

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

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