Clinical Trials Register

Summary
EudraCT Number:	2015-002356-27
Sponsor's Protocol Code Number:	XCGD_MOBI1
National Competent Authority:	Italy - Italian Medicines Agency
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2015-07-29
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

Italy - Italian Medicines Agency

A.2

EudraCT number

2015-002356-27

A.3

Full title of the trial

A multicentric, exploratory, non-randomised, non-controlled, prospective, open-label phase II, study evaluating safety and efficacy of IBU, G-CSF and Plerixafor as a stem cell mobilization regimen in patients affected by X-CGD.

Studio multicentrico, esplorativo, non randomizzato, non controllato, prospettico, in aperto, atto a valutare la sicurezza e l'efficacia di Ibuprofene (IBU), G-CSF e Plerixafor come regime di mobilizzazione di cellule staminali in pazienti affetti da XCGD.

A.3.1

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

Evaluation of safety and efficacy of the combination of Ibuprofen (IBU), G-CSF and Plerixafor as a stem cell mobilization regimen in patients affected by XCGD

Valutazione della sicurezza e dell’effetto di Ibuprofene (IBU), G-CSF e Plerixafor come regime di mobilizzazione di cellule staminali in pazienti affetti da XCGD

A.4.1

Sponsor's protocol code number

XCGD_MOBI1

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	Ospedale San Raffaele
B.1.3.4	Country	Italy
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	Fondazione Telethon
B.4.2	Country	Italy
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Ospedale San Raffaele
B.5.2	Functional name of contact point	TIGET Clinical Trial Office (TCTO)
B.5.3	Address:
B.5.3.1	Street Address	Via Olgettina, 60
B.5.3.2	Town/ city	Milano
B.5.3.3	Post code	20132
B.5.3.4	Country	Italy
B.5.4	Telephone number	00390226434875
B.5.5	Fax number	00390226436545
B.5.6	E-mail	tcto@hsr.postecert.it

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.2.5	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	Ibuprofen
D.3.4	Pharmaceutical form	Film-coated tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	IBUPROFEN
D.3.9.1	CAS number	15687-27-1
D.3.9.2	Current sponsor code	NA
D.3.9.3	Other descriptive name	NA
D.3.9.4	EV Substance Code	SUB08098MIG
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	200
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	MYELOSTIM 34 milions UI/ml, powder and solvent for solution for injection or infusion
D.2.1.1.2	Name of the Marketing Authorisation holder	ITALFARMACO S.p.A.
D.2.1.2	Country which granted the Marketing Authorisation	Italy
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	MYELOSTIM 34 milions UI/ml - powder and solvent for solution for injection/infusion
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	Subcutaneous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	LENOGRASTIM
D.3.9.1	CAS number	135968-09-1
D.3.9.4	EV Substance Code	SUB02888MIG
D.3.10	Strength
D.3.10.1	Concentration unit	U/ml unit(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	34
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: 3
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	Mozobil 20mg/mL vial (injectable solution for subcutaneous use)
D.2.1.1.2	Name of the Marketing Authorisation holder	Genzyme Europe B.V.
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	Mozobil 20mg/mL vial (injectable solution, subcutaneous use)
D.3.4	Pharmaceutical form	Solution for injection
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Subcutaneous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Plerixafor
D.3.9.1	CAS number	110078-46-1
D.3.9.3	Other descriptive name	Plerixafor
D.3.9.4	EV Substance Code	SUB28849
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	20
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.3.11.13.1	Other medicinal product type	Mozobil is a selective reversible antagonist of the CXCR4 chemokine receptor.
D.IMP: 4
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	Italy
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	Pantoprazolo 20 mg gastro-resistant tablets
D.3.4	Pharmaceutical form	Gastro-resistant tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Pantoprazole
D.3.9.1	CAS number	102625-70-7
D.3.9.3	Other descriptive name	PANTOPRAZOLE
D.3.9.4	EV Substance Code	SUB09608MIG
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	20
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

X-linked chronic granulomatous disease

Malattia granulomatosa cronica X-linked (X-CGD)

E.1.1.1

Medical condition in easily understood language

Chronic granulomatous disease

Malattia granulomatosa cronica

E.1.1.2

Therapeutic area

Diseases [C] - Immune System Diseases [C20]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	18.0
E.1.2	Level	PT
E.1.2	Classification code	10008906
E.1.2	Term	Chronic granulomatous disease
E.1.2	System Organ Class	10010331 - Congenital, familial and genetic disorders

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

1. To explore the safety of IBU, G-CSF and Plerixafor when administered as a stem cell mobilization regimen in patients affected by X-CGD.
2. To explore the effect of IBU, G-CSF and Plerixafor in mobilizing CD34+ cells thus allowing the collection of a number of HSPC deemed sufficient for ex vivo gene therapy in patients affected by X-CGD.

1. Esplorare la sicurezza di Ibuprofene, G-CSF e Plerixafor, somministrati come regime mobilizzante in pazienti affetti da X-CGD.
2. Esplorare l’effetto di Ibuprofene, G-CSF e Plerixafor nella mobilizzazione delle cellule CD34+, permettendo una raccolta di cellule ematopoietiche staminali progenitrici che possa essere ritenuta adeguata per terapia genica ex vivo in pazienti affetti da X-CGD.

E.2.2

Secondary objectives of the trial

1. To explore the effect of Ibuprofen in mobilizing CD34+ cells in the PB.
2. To explore the in vitro efficacy of a lentiviral vector encoding for a corrective cDNA of the human gp91phox gene in transducing CD34+ cells obtained by the XCGD-MOBI protocol and correcting the func-tional defects in the differentiated myeloid progeny.
3. To functionally characterize the properties of IBU, G-CSF and Plerixafor mobilized CD34+ cells from X-CGD patients

1. Esplorare l’effetto della mobilizzazione delle cellule CD34+ in sangue periferico con Ibuprofene.
2. Esplorare l'efficacia in vitro di trasduzione tramite un vettore lentivirale contente il gene della gp91phox umana nelle cellule CD34+ ottenute da questo regime di mobilizzazione e correggere i difetti funzionali nella progenie mieloide differenziata.
3. Caratterizzare funzionalmente le proprietà delle cellule CD34+ mobilizzate con IBU, G-CSF e Plerixafor da pazienti X-CGD.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

•Genetic diagnosis of X-CGD
•18-45 years of age
•Karnofsky Index > 80 %
•Adequate cardiac, renal, hepatic and pulmonary function.
•Negative thrombophilic screen and negative history for previous thrombotic events
•Written informed consent.

•Diagnosi genetica di X-CGD
•18-45 anni di età
•Indice di Karnofsky> 80%
•Adeguata funzionalità cardiaca, renale, epatica e polmonare.
•Screening trombofilico negativo e anamnesi negativa per precedenti eventi trombotici
•Firma del consenso informato

E.4

Principal exclusion criteria

•Previous Bone Marrow Transplantation or previous Gene Therapy.
•Use of other investigational agents within 4 weeks prior to study en-rolment (within 6 weeks if use of long-acting agents).
•Ongoing IFN-γ treatment (within 4 weeks).
•Symptomatic inflammatory bowel disease.
•Symptomatic viral, bacterial, or fungal infection within 6 weeks of eli-gibility evaluation or active infection (including fever of unknown origin)
•Neoplasia (except local skin cancer) or history of “familial” cancer.
•Myelodysplasia or other serious hematological disorder
•History of uncontrolled seizures and deep venous thrombosis
•Other systemic disease judged as incompatible with the procedure
•Positivity for HIV and/or HCV RNA and/or HbsAg and/or HBV DNA
•Active alcohol or substance abuse within 6 months of the study.
•Contraindications to IBU, G-CSF, Plerixafor or Pantoprazole administration

•L'uso di altri farmaci sperimentali nelle 4 settimane prima dell'arruolamento nello studio (entro 6 settimane se sono stati utilizzati farmaci a lunga durata d'azione).
•Precedente trapianto di midollo osseo o terapia genica.
•Malattia infiammatoria intestinale sintomatica.
•Trattamento con IFN-γ in corso (entro 4 settimane).
•Infezione virale, batterica o fungina sintomatica entro 6 settimane dalla valutazione di ammissibilità o infezione attiva (compresa la febbre di origine sconosciuta).
•Neoplasia (eccetto tumori cutanei localizzati) o storia di cancro "familiare".
•Mielodisplasia o altri gravi disturbi ematologici
•Storia di convulsioni non controllate e trombosi venosa profonda
•Altre malattie sistemiche giudicate incompatibili con la procedura
•Positività per l'HIV e / o HCV RNA e / o HBsAg e / o HBV DNA
•Controindicazioni alla somministrazione di Ibuprofene, G-CSF, Plerixafor o Pantoprazolo.

E.5 End points

E.5.1

Primary end point(s)

1) Safety
Incidence and severity of adverse events following IBU, G-CSF and Plerixafor administration (any grade) occurring between day 0 and 30 days after the last LP.
2) Efficacy - Harvest of >= 8X10^6 CD34+/Kg in one or more collections

1) Sicurezza - incidenza e gravità degli eventi avversi conseguenti alla somministrazione di Ibuprofene, G-CSF e Plerixafor (qualsiasi grado) che si verificano
2) Efficacia - Raccolta di ≥ 8 x10 ^ 6 cellule CD34 + / kg in una o più raccolte.

E.5.1.1

Timepoint(s) of evaluation of this end point

1) From Day 0 to 30 days after the last LP
2) from the first to the last LP

1) tra il giorno 0 e 30 giorni dopo l'ultima leucoaferesi (LP).
2) dalla prima all’ultima Leucaferesi.

E.5.2

Secondary end point(s)

1.Increase in PB CD34+ cell count after administration of Ibuprofen.
2.Efficient transduction of mobilized HSPC and oxidase activity restoration in their myeloid progeny following gene transfer with a lentiviral vector encoding for human gp91phox.
3.Maintenance of repopulating activity of transduced HSPC in immunodeficient mice

1) Aumento delle cellule CD34+ dosate nel sangue periferico dopo somministrazione di Ibuprofene.
2) Efficienza di trasduzione e ripristino dell’attività ossidasica nella progenie mielodie dopo trasduzione con vettore lentivirale codificante per la proteina gp91 phox umana.
3) Mantenimento dell’attività di ripopolamento delle cellule CD34+ mobilizzate trasdotte in topi immunodeficienti.

E.5.2.1

Timepoint(s) of evaluation of this end point

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

Yes

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

Yes

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

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

End of laboratory experiments

Fine degli esperimenti di laboratorio

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1.1

In Utero

F.1.1.2

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

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

F.1.1.5

Children (2-11years)

F.1.1.6

Adolescents (12-17 years)

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

F.1.3

Elderly (>=65 years)

F.2 Gender

F.2.1

Female

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)

At the end of the therapeutic phase a follow-up is forseen for 30 days after the last leukapheresis.
No other follow-up is planned. Patients will be followed in their reference center for their disease.

Al termine della fase terapeutica è previsto un follow-up ad una settimana e a 30 giorni dall’ultima leucoaferesi.
Trascorsi questi 30 giorni non sono necessari altri follow-up futuri. I pazienti proseguiranno il follow-up previsto dalla patologia di base nel centro di riferimento.

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

2015-10-16

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2015-10-08

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

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