Clinical Trials Register

Summary
EudraCT Number:	2017-005017-31
Sponsor's Protocol Code Number:	DERN
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:	2021-05-24
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

2017-005017-31

A.3

Full title of the trial

DENOSUMAB IN EBV RELATED NASOPHARYNGEAL CARCINOMA (NPC) AS A MODEL FOR RANK-MEDIATED IMMUNOLOGIC MODULATION OF VIRUS-RELATED TUMOURS – DERN STUDY

DENOSUMAB NEL CARCINOMA NASOFARINGEO (NPC) ASSOCIATO AL VIRUS EBSTAIN BARR (EBV) COME MODELLO DI MODULAZIONE IMMUNOLOGICA RANK-MEDIATA IN TUMORI VIRUS RELATI. STUDIO DERN

A.3.1

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

DENOSUMAB IN EBV RELATED NASOPHARYNGEAL CARCINOMA (NPC) AS A MODEL FOR RANK-MEDIATED IMMUNOLOGIC MODULATION OF VIRUS-RELATED TUMOURS – DERN STUDY

DENOSUMAB NEL CARCINOMA NASOFARINGEO (NPC) ASSOCIATO AL VIRUS EBSTAIN BARR (EBV) COME MODELLO DI MODULAZIONE IMMUNOLOGICA RANK-MEDIATA IN TUMORI VIRUS RELATI. STUDIO DERN

A.3.2

Name or abbreviated title of the trial where available

DERN

A.4.1

Sponsor's protocol code number

DERN

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	G.O.N.O. - GRUPPO ONCOLOGICO DEL NORD OVEST
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	Amgen Limited
B.4.2	Country	United Kingdom
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Fondazione G.O.N.O.
B.5.2	Functional name of contact point	Lital Hollander
B.5.3	Address:
B.5.3.1	Street Address	VIA GOFFREDO MAMELI 3/1
B.5.3.2	Town/ city	Genova
B.5.3.3	Post code	16122
B.5.3.4	Country	Italy
B.5.4	Telephone number	0239014640
B.5.5	Fax number	0233200231
B.5.6	E-mail	lital.hollander@gmail.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.2.1.1.1	Trade name	XGEVA
D.2.1.1.2	Name of the Marketing Authorisation holder	Amgen Europe
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	Denosumab
D.3.2	Product code	[IMP1]
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	00320700
D.3.9.1	CAS number	615258-40-7
D.3.9.2	Current sponsor code	IMP1
D.3.10	Strength
D.3.10.1	Concentration unit	mg/l milligram(s)/litre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	70
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	Information not present in EudraCT
D.3.11.3.2	Gene therapy medical product	Information not present in EudraCT
D.3.11.3.3	Tissue Engineered Product	Information not present in EudraCT
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	Information not present in EudraCT
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	Information not present in EudraCT
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	Yes
D.3.11.13.1	Other medicinal product type	Anticorpo monoclonale

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

advanced or metastatic Nose Pharynx Cancer

carcinoma Naso-faringe avanzato o metastatico

E.1.1.1

Medical condition in easily understood language

advanced or metastatic Nose Pharynx Cancer

carcinoma Naso-faringe avanzato o metastatico

E.1.1.2

Therapeutic area

Diseases [C] - Cancer [C04]

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	10028793
E.1.2	Term	Nasopharyngeal carcinoma
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 evaluate the impact of denosumab on a recognized viral surrogate marker of tumour response in nasopharyngeal cancer.

Valutare l'impatto di Denosumab su di un marcatore virale surrogato in caso di cancro al Nasofaringe (NPC) associato al virus Epstain-Barr Virus.

E.2.2

Secondary objectives of the trial

To evaluate the clinical activity of denosumab and chemotherapy vs chemotherapy alone in terms of the improvement in PFS of denosumab-treated patients.
To assess the safety of denosumab when added to chemotherapy in first line treatment of recurrent/metastatic NPC
To evaluate the immunologic effects of denosumab therapy in a population of patients at first line chemotherapy for recurrent/metastatic nasopharyngeal cancer

Valutare l'attività clinica di Denosumab e chemioterapia messo a confronto con la sola chemioterapia in termini di miglioramento della PFS dei pazienti trattati con Denosumab.
Valutare i margini di sicurezze di Denosumab quando viene associato al trattamento chemioterapico in pazienti di prima linea trattati per tumore Nasofaringeo metastatico e/o ricorrente
Valutare gli effetti immunologici della terapia con Denosumab in una popolazione di pazienti trattati con chemioterapia di prima linea per il trattamento di carcinoma nasofaringeo recidivante e/o metastatico

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. EBV related nasopharyngeal cancer
2. Detectable and quantifiable plasmatic EBV DNA
3. Recurrent and/or metastatic disease not suitable for curative treatment
4. PS < 2
5. Suitable for polychemotherapy
6. Age = 18 years
7. Informed consent signed
8. Subject has adequate organ functions, evidenced by the following:
a. AST (SGOT), ALT (SGPT) = 2.5 x upper limit of normal range (ULN), or = 5 x ULN range if liver metastasis present
b. Total bilirubin = 1.5 x ULN
c. creatinine clearance 24/h > 50 mL/min
d. Total serum calcium > 8.8 mg/dL
e. Absolute neutrophil count = 1.5 x 10*9 cells/L
f. Platelets = 100 x 10*9 cells/L
g. Haemoglobin = 9 g/dL
9. If of childbearing potential, willingness to use effective contraceptive method (Pearl Index < 1; e.g. oral contraceptive (pill), hormone spiral, hormone implant, transdermal patch, a combination of two barrier methods (condom and diaphragm), sterilisation, sexual abstinence) for the study duration and 5 months post-dosing.
10. Subject understands and voluntarily signs an ICF prior to any study-related assessments/procedures are conducted.
11. Subject is able to adhere to the study visit schedule and other protocol requirements.

1. Carcinoma nasofaringea correlata con EBV
2. EBV DNA a livello plasmatico rilevabile e quantificabile
3. Malattia ricorrente e / o metastatico non adatto al trattamento curativo
4. PS ECOG<2
5. Paziente a cui è possibile somministrare un trattamento di polichemioterapia
6. Età = 18 anni
7. Il soggetto comprende e sottoscrive in maniera volontaria il consenso Informato
8. Adequata funzionalità d’organo, evidenziata dai risultati dei test:
a. Aspartato aminotransferasi (AST)/alanina aminotransferasi (ALT)>2,5 x ULN, se metastasi epatiche >5 x ULN;
b. Bilirubina totale >1,5 x ULN;
c. clearance della creatinina 24/h > 50 mL/min;
d. Calcemia nel siero > 8,8 mg/dL;
e. Conta assoluta dei neutrofili =1,5 x 10*9 cells/L;
f. Piastrine = 100 x 10* cells/L;
g. Emoglobina = 9 g/dL.

9. Se paziente in età potenzialmente fertile, disponibilità ad usare un metodo contraccettivo efficace (Pearl Index <1, es. Contraccettivo orale (pillola), spirale ormonale, impianto ormonale, cerotto transdermico, una combinazione di due metodi barriera (preservativo e diaframma), sterilizzazione, sessuale astinenza) per la durata dello studio e 5 mesi dopo la somministrazione.

10. Il soggetto è in grado di aderire al programma delle visite di studio e agli altri requisiti del protocollo.

E.4

Principal exclusion criteria

1. Having received 1 or more chemotherapy line for recurrent/metastatic disease
2. Any residual CTCAE grade = 2 toxicity
3. Subject has any other malignancy within 3 years prior to randomization, with the exception of adequately treated in situ carcinoma of the cervix, uteri, or non-melanoma skin cancer (all treatment of which should have been completed 6 months prior to enrolment), in situ squamous cell carcinoma of the breast, or incidental prostate cancer T1a, Gleason < 7, PSA <10 ng/ml.
4. Subject has had radiotherapy = 4 weeks or limited field radiation for palliation = 2 weeks prior to starting IP, and/or from whom = 30% of the bone marrow was irradiated.
5. Having participated in another clinical trial or having received any investigational agent in the preceding 30 days before study entry.
6. Chronic systemic immunosuppressive therapy that cannot be interrupted during treatment study.
7. Subject has significant active cardiac disease within the previous 6 months including unstable angina or angina requiring surgical or medical intervention, significant cardiac arrhythmia, or New York Heart Association (NYHA) class 3 or 4 congestive heart failure.
8. Subject has a known or suspected hypersensitivity to study drugs.
9. Subject is pregnant or breast feeding.
10. Subject is receiving prohibited medication as per section 7.4.2 and suspension of such treatment is considered unsafe.
11. Subject has history of prior or current osteonecrosis of the jaw (ONJ).
12. Subject has history of prior irradiation to the mandible, specified as:
Dose constraints to the mandible: Dmax = 70 Gy, V50 = 62 Gy and V60 = 20 Gy
Mandible should be contoured as whole organ, with alveolar bone, excluding teeth.
13. Subject has any other concurrent severe and/or uncontrolled medical condition that would, in the Investigator’s judgment, contraindicate subject participation in the clinical study.

1. Ricevuto 1 o più linee di chemioterapia per malattia ricorrente / metastatica
2. Residuo di tossicità di grado = 2 secondo CTCAE v. 5.0
3. Il soggetto ha altre neoplasie nei l’ultimi 3 anni prima della randomizzazione, ad eccezione del carcinoma in situ della cervice uterina trattata o tumore cutaneo non melanoma (il cui trattamento avrebbe dovuto essere completato 6 mesi prima dell'arruolamento), carcinoma a cellule squamose della mammella in situ o carcinoma prostatico incidentale T1a, Gleason <7, PSA <10 ng / ml.
4. Il soggetto è stato sottoposto a radioterapia = 4 settimane o radiazione di campo limitata come terapia paliativo = 2 settimane prima di iniziare la terapia in studio, e / o i soggetti con = 30% del midollo osseo irradiato.
5. Aver partecipato a un'altra sperimentazione clinica o aver ricevuto agenti del principio attivo del farmaco in studio nei precedenti 30 giorni prima dell'inizio dello studio.
6. Terapia cronica sistemica con immunosoppressivi che non può essere interrotta durante il trattamento dello studio.
7. Il soggetto ha una malattia cardiaca attiva nei 6 mesi precedenti lo studio, inclusa angina o angina instabili che richiedono intervento chirurgico o medico, aritmia cardiaca significativa o insufficienza cardiaca congestizia di classe 3 o 4 della New York Heart Association (NYHA)
8. Pazienti con storia o sospetto di ipersensività nei confronti
del farmaco sperimentale o dei suoi eccipienti
9. Gravidanza o allattamento
10. Il soggetto riceve medicinali non consentiti (sezione 7.4.2) e la sospensione di questi trattamento non è considerata sicura.
11. Il soggetto ha una storia pregressa o attuale di osteonecrosi della mascella (ONJ).
12. Il soggetto ha una storia di irradiazione precedente alla mandibola, specificata come: limite di dose alla mandibola: Dmax = 70 Gy, V50 = 62 Gy e V60 = 20 GyLa mandibola deve essere sagomato come organo intero, con osso alveolare, esclusi i denti.
13. Il soggetto ha altre condizioni mediche concomitanti gravi e / o incontrollate che, a giudizio dello Sperimentatore, potrebbe essere controindicato la partecipazione dei soggetti allo studio clinico

E.5 End points

E.5.1

Primary end point(s)

Meaningful plasmatic EBV DNA reduction. Meaningful reduction will be defined as the change in circulating EBV DNA levels from baseline (prior to the first denosumab administration on day -15 with respect to first chemotherapy administration) to the third denosumab dose (denosumab day 16, equivalent to chemotherapy treatment day 1).

Valutare la riduzione di concentrazione dell’EBV DNA plasmatico. La riduzione significativa viene definita come cambiamento nei livelli di EBV DNA circolante tra il baseline (precedente alla prima somministrazione di Denosumab corrispondente al giorno -15 rispetto all’ avvio della chemioterapia) e la terza somministrazione di Denosumab (Denosumab giorno 16, corrispondente al giorno di avvio della chemioterapia).

E.5.1.1

Timepoint(s) of evaluation of this end point

At the third denosumab dose (denosumab day 16, equivalent to chemotherapy treatment day 1).

Alla terza somministrazione di Denosumab (Denosumab giorno 16, corrispondente al giorno di avvio della chemioterapia).

E.5.2

Secondary end point(s)

Absolute change in blood and salivary miRNA NPC profiles, (chosen among selected miRNAs having previously shown correlation with immune activity and with NPC), measured at each planned time point (at 16 days, 2 and 6 months after Denosumab treatment start).; Absolute change of serum levels of RANKL and its inhibitor osteoprotegerin (OPG), measured at each planned time point (at 16 days, 2 and 6 months after treatment start).; Absolute change in EBV DNA levels at each other planned time point (at 2 months after denosumab treatment start, prior to administration of 3rd denosumab treatment, and at 6 months, prior to administration of 7th denosumab treatment).; PFS; Safety; Absolute change in cellular immunity to EBV. Cellular immunity will be defined blood lymphocytes activity against LMP and EBNA antigens. Absolute change will be defined as the difference in such activity from baseline (i.e. prior to first denosumab administration, chemotherapy day -15 and denosumab day 1) and the subsequent planned time point (16 days, 2 and 6 months after denosumab treatment start).

Valutazione del cambiamento della concentrazione dei miRNA presenti nella saliva e nel sangue, correlati con il profilo immunologico di NPC a determinati time point (a 16 giorni, 2 mesi e 6 mesi dall’ inizio del trattamento con Denosumab); Cambiamento assoluto della concentrazione sierica dei RANKL e del suo inibitore: osteoprotegerina (OPG), misurati a 16 giorni, 2 e 6 mesi dopo l'inizio del trattamento con Denosumab; Variazione della concentrazione del livello dell’EBV DNA a differenti time point individuati a 2 mesi dall’ inizio del trattamento con Denosumab (prima della somministrazione della terza infusione) e a 6 mesi (prima della settima infusione di Denosumab).; PFS; Safety; Valutazione del cambiamento della concentrazione della risposta immunitaria contro EBV. L’ immunità cellulare sarà valutata in funzione dell’attività linfocitaria verso gli antigeni LMP e EBNA. Il cambiamento sarà definito come la differenza di questa attività registrata tra il baseline (prima dell’avvio del trattamento con Denosumab, equivalente al giorno -15 rispetto all’ avvio della chemioterapia) ed alcuni time point definiti a 16 giorni dal baseline, a 2 e a 6 mesi dall’ avvio del trattamento con Denosumab.

E.5.2.1

Timepoint(s) of evaluation of this end point

at 16 days, 2 and 6 months after Denosumab treatment start.; at 16 days, 2 and 6 months after treatment start; at 2 months after denosumab treatment start, prior to administration of 3rd denosumab treatment, and at 6 months, prior to administration of 7th denosumab treatment; PFS will be evaluated every 6 weeks until the end of chemotherapy treatment and every 9 weeks during the following 12 months in responsive patients.; During the treatment phase.; Absolute change will be defined as the difference in such activity from baseline (i.e. prior to first denosumab administration, chemotherapy day -15 and denosumab day 1) and the subsequent planned time point (16 days, 2 and 6 months after denosumab treatment start).

a 16 giorni, 2 mesi e 6 mesi dall’ inizio del trattamento con Denosumab); a 16 giorni, 2 e 6 mesi dopo l'inizio del trattamento con Denosumab; a 2 mesi dall’ inizio del trattamento con Denosumab (prima della somministrazione della terza infusione) e a 6 mesi (prima della settima infusione di Denosumab); La PFS verrà valutata ogni 6 settimane fino al completamento della chemioterapia e ogni 9 settimane nei 12 mesi successivi in caso di risposta.; Per tutta la durata del trattamento.; Il cambiamento sarà definito come la differenza di questa attività registrata tra il baseline (prima dell’avvio del trattamento con Denosumab, equivalente al giorno -15 rispetto all’ avvio della chemioterapia) ed alcuni time point definiti a 16 giorni dal baseline, a 2 e a 6 mesi dall’ avvio del trattamento con

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

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

Yes

E.8.1.1

Randomised

Yes

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)

E.8.2.2

Placebo

E.8.2.3

Other

Yes

E.8.2.3.1

Comparator description

farmaci utilizzati in standard of care

standard of care

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

Information not present in EudraCT

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)

Yes

F.1.3.1

Number of subjects for this age range:

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

Yes

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

Yes

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

F.3.3.6

Subjects incapable of giving consent personally

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

F.4.2

For a multinational trial

F.4.2.1

In the EEA

F.4.2.2

In the whole clinical trial

F.5

Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)

le patient after at the end of the study will be treated following standard of care

i pazienti ala termine della partecipazione allo studio verranno trattati secondo pratica clinica

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

2019-01-29

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2018-12-20

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

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IMP with orphan designation in the indication
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