Clinical Trials Register

Summary
EudraCT Number:	2017-000431-14
Sponsor's Protocol Code Number:	M16-098
National Competent Authority:	Italy - Italian Medicines Agency
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2021-06-08
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

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A. Protocol Information

A.1

Member State Concerned

Italy - Italian Medicines Agency

A.2

EudraCT number

2017-000431-14

A.3

Full title of the trial

A Multicenter, Randomized, Double-Blind, Placebo Controlled Study Evaluating the Safety and Efficacy of Upadacitinib in Subjects with Active Ankylosing Spondylitis

Sperimentazione Multicentrica, Randomizzata, in Doppio Cieco, Controllata verso Placebo per Valutare la Sicurezza e l¿Efficacia di Upadacitinib in Soggetti con Spondilite Anchilosante in Fase Attiva

A.3.1

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

A Multicenter, Randomized, Double-Blind, Placebo-Controlled Study Evaluating the Safety and Efficacy of Upadacitinib in Subjects with Active Ankylosing Spondylitis

Sperimentazione Multicentrica, Randomizzata, in Doppio Cieco, Controllata verso Placebo per Valutare la Sicurezza e l¿Efficacia di Upadacitinib in Soggetti con Spondilite Anchilosante in Fase Attiva

A.3.2

Name or abbreviated title of the trial where available

A.4.1

Sponsor's protocol code number

M16-098

A.5.4

Other Identifiers

Name:

Number:

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	ABBVIE DEUTSCHLAND GMBH & CO. KG
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	AbbVie 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	AbbVie Ltd
B.5.2	Functional name of contact point	EU Clinical Trials Helpdesk
B.5.3	Address:
B.5.3.1	Street Address	AbbVie House, Vanwall Business Park, Vanwall Road
B.5.3.2	Town/ city	Maidenhead, Berkshire
B.5.3.3	Post code	SL6 4UB
B.5.3.4	Country	United Kingdom
B.5.4	Telephone number	441628561090
B.5.5	Fax number	441628461153
B.5.6	E-mail	eu-clinical-trials@abbvie.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	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	Upadacitinib
D.3.2	Product code	ABT-494
D.3.4	Pharmaceutical form	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	Upadacitinib
D.3.9.1	CAS number	1310726-60-3
D.3.9.2	Current sponsor code	na
D.3.9.4	EV Substance Code	SUB125895
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	15
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	Yes
D.3.11.13.1	Other medicinal product type	Janus Kinase (Jak) 1 inhibitor

D.8 Information on Placebo
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Tablet
D.8.4	Route of administration of the placebo	Oral use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Active Ankylosing Spondylitis

Spondilite Anchilosante in Fase Attiva

E.1.1.1

Medical condition in easily understood language

Ankylosing Spondylitis

Spondilite Anchilosante in Fase Attiva

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	20.0
E.1.2	Level	PT
E.1.2	Classification code	10002556
E.1.2	Term	Ankylosing spondylitis
E.1.2	System Organ Class	10028395 - Musculoskeletal and connective tissue disorders

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

Period 1:
1. To evaluate the efficacy of upadacitinib compared with placebo on reduction of signs and symptoms as measured by proportion of subjects who achieve an Assessment of SpondyloArthritis international Society (ASAS) 40 response at Week 14 in subjects with active ankylosing spondylitis (AS) who have had an inadequate response to at least two nonsteroidal anti-inflammatory drugs (NSAIDs) or intolerance to or a contraindication for NSAIDs, and who are biologic disease-modifying antirheumatic drug (bDMARD)-na¿ve.
2. To assess the safety and tolerability of upadacitinib in subjects with active AS who have had an inadequate response to at least two NSAIDs or intolerance to or a contraindication for NSAIDs, and who are bDMARD-na¿ve.
Period 2:
To evaluate the safety, tolerability, and efficacy of upadacitinib through up to 2 years of treatment in subjects who have completed Period 1.

Periodo 1: 1.Valutare l¿efficacia di upadacitinib rispetto a placebo sulla riduzione dei segni e sintomi, determinata in base alla % di soggetti che ottengono la risposta ASAS 40 (Assessment of SpondyloArthritis international Society) alla Settimana 14, in soggetti affetti da spondilite anchilosante (AS) in fase attiva, che hanno avuto una risposta inadeguata ad almeno due farmaci antinfiammatori non steroidei (FANS) oppure intolleranza o controindicazione ai FANS, e che sono na¿ve rispetto al trattamento con farmaci antireumatici modificanti la malattia biologici (bDMARD).
2.Valutare la sicurezza e la tollerabilit¿ di upadacitinib in soggetti con AS in fase attiva che hanno avuto una risposta inadeguata ad almeno due FANS oppure intolleranza o controindicazione ai FANS e che sono na¿ve rispetto al trattamento con bDMARD.
Periodo 2:Valutare la sicurezza, tollerabilit¿ ed efficacia di upadacitinib somministrato per un massimo di 2 anni nei soggetti che hanno completato il Periodo 1

E.2.2

Secondary objectives of the trial

xxx

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Male or female = 18 years of age.
2. Subject with a clinical diagnosis of AS and meeting the modified New York Criteria for AS.
3. Subject must have baseline disease activity as defined by having a Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) score = 4 and a Patient's Assessment of Total Back Pain score = 4 based on a 0 – 10 Numeric Rating Scale (NRS) at the Screening and Baseline Visits.
4. Subject has had an inadequate response to at least two NSAIDs over an at least 4-week period in total at maximum recommended or tolerated doses, or subject has an intolerance to or contraindication for NSAIDs as defined by the Investigator.
5. If entering the study on concomitant MTX, leflunomide, SSZ and/or hydroxychloroquine, subject must be on a stable dose of MTX (= 25 mg/week) and/or SSZ (= 3 g/day) and/or hydroxychloroquine (= 400 mg/day) or leflunomide (= 20 mg/day) for at least 28 days prior to the Baseline Visit. A combination of up to two background csDMARDs is allowed EXCEPT the combination of MTX and leflunomide.
6. If entering the study on concomitant oral corticosteroids, subject must be on a stable dose of prednisone (= 10 mg/day), or oral corticosteroid equivalents, for at least 14 days prior to the Baseline Visit. Subject must be on stable dose(s) for at least 14 days prior to the Baseline Visit.

1. Soggetti di ambo i sessi e di età = 18 anni.
2. Soggetto con diagnosi clinica di AS che soddisfa i criteri modificati di New York per AS.
3. Soggetto con malattia attiva al baseline definita in base a un punteggio BASDAI (Bath Ankylosing Spondylitis Disease Activity Index) = 4 ed un punteggio della valutazione complessiva del paziente relativa al mal di schiena (Patient's Assessment of Total Back Pain) = 4 in base a una scala di valutazione numerica (Numeric Rating Scale, NRS) compresa fra 0 e 10,alle Visite di Screening e di Baseline.
4. Soggetto che ha avuto una risposta inadeguata ad almeno due FANS nell’arco di un periodo totale di almeno 4 settimane, somministrati alla dose massima raccomandata o alla dose massima tollerata, oppure soggetto che abbia dimostrato intolleranza o presenti controindicazione ai FANS secondo quanto determinato dallo sperimentatore.
5. Se al momento di entrare nella sperimentazione il soggetto è in trattamento concomitante con MTX, leflunomide, SSZ e/o idrossiclorochina, è necessario che il soggetto sia in trattamento a dose stabile con MTX (= 25 mg/settimana) e/o SSZ (= 3 g/die) e/o idrossiclorochina (= 400 mg/die) o leflunomide (= 20 mg/die) da almeno 28 giorni prima della Visita di Baseline. È permessa la combinazione di un massimo di due csDMARD di background, AD ECCEZIONE della combinazione MTX e leflunomide.
6. Se al momento di entrare nella sperimentazione il soggetto è in trattamento concomitante con corticosteroidi orali, è necessario che il soggetto sia in trattamento a dose stabile con prednisone (= 10 mg/die), oppure con corticosteroidi orali equivalenti, da almeno 14 giorni prima della Visita di Baseline.

E.4

Principal exclusion criteria

1. Prior exposure to any Janus kinase (JAK) inhibitor (including but not limited to tofacitinib, baricitinib, and filgotinib).
2. Prior exposure to any biologic therapy with a potential therapeutic impact on spondyloarthritis (SpA).
3. Intra-articular joint injections, spinal/paraspinal injection(s), or parenteral administration of corticosteroids within 28 days prior to the Baseline Visit. Inhaled or topical corticosteroids are allowed.
4. Subject on any other DMARDs (other than those allowed), thalidomide, or apremilast within 28 days or five half-lives (whichever is longer) of the drug prior to the Baseline Visit.
5. Subject on opioid analgesics (except for combination acetaminophen/codeine or acetaminophen/hydrocodone which are allowed) or use of inhaled marijuana within 14 days prior to the Baseline Visit.
6. Subject has a history of inflammatory arthritis of different etiology other than axial SpA (including but not limited to rheumatoid arthritis [RA], psoriatic arthritis [PsA], mixed connective tissue disease, systemic lupus erythematosus, reactive arthritis, scleroderma, polymyositis, dermatomyositis, fibromyalgia), or any arthritis with onset prior to 17 years of age.
7. Laboratory values meeting the following criteria within the Screening period prior to the first dose of study drug: serum aspartate transaminase (AST) > 2 × ULN; serum alanine transaminase (ALT) > 2 × ULN; estimated glomerular filtration rate (GFR) by simplified 4-variable Modification of Diet in Renal Disease (MDRD) formula < 40 mL/min/1.73m2; hemoglobin < 10 g/dL, total white blood cell (WBC) count < 2,500/µL; absolute neutrophil (ANC) count < 1,500/µL; absolute lymphocyte count < 800/µL; and platelet count < 100,000/µL.

1. Esposizione pregressa a qualsiasi inibitore della proteine Janus chinasi (JAK) (compresi, a titolo esemplificativo ma non esaustivo, tofacitinib, baricitinib e filgotinib).
2. Esposizione pregressa a qualsiasi terapia biologica con un potenziale impatto terapeutico sulla spondiloartrite (SpA).
3. Iniezioni intra-articolari, iniezione/i spinali/paravertebrali, oppure somministrazione parenterale di corticosteroidi nei 28 giorni precedenti la Visita di Baseline. È permessa la somministrazione di corticosteroidi per inalazione o per via topica.
4. Soggetti in trattamento con altri DMARD (diversi da quelli permessi), talidomide, o apremilast nei 28 giorni, oppure un periodo corrispondente a 5 emivite del medicinale (quale dei due periodi sia più lungo), prima della Visita di Baseline.
5. Soggetti in trattamento con analgesici oppiacei (ad eccezione delle combinazioni acetaminofene/codeina oppure acetaminofene/idrocodone che sono permesse) oppure uso di cannabis per via inalatoria nei 14 giorni precedenti la Visita di Baseline.
6. Soggetto con storia di artrite infiammatoria di eziologia diversa dalla SpA assiale (compresi, a titolo esemplificativo ma non esaustivo, artrite reumatoide [AR], artrite psoriasica [APs], malattie miste del tessuto connettivo, lupus eritematoso sistemico, artrite reattiva, sclerodermia, polimiosite, dermatomiosite, fibromialgia) oppure qualsiasi altra forma di artrite con esordio prima dei 17 anni di età.
7. Parametri di laboratorio che soddisfano i seguenti criteri durante il periodo di screening prima della somministrazione della prima dose di medicinale sperimentale: valore sierico di aspartato aminotransferasi (AST) > 2 × ULN; valore sierico di alanina aminotransferasi (ALT) > 2 × ULN; tasso di filtrazione glomerulare stimata (GFR), calcolata in base alla formula MDRD (Modification of Diet in Renal Disease) semplificata a 4 variabili < 40 mL/min/1,73m2; emoglobina < 10 g/dL, livello di globuli bianchi totali (WBC) < 2.500/µL; conta assoluta dei neutrofili (ANC) < 1.500/µL; conta assoluta dei linfociti < 800/µL e livelli di piastrine < 100.000/µL.

E.5 End points

E.5.1

Primary end point(s)

Proportion of participants with Assessment of SpondyloArthritis international Society (ASAS) 40 response (It is defined as a >= 40% improvement and an absolute improvement of >= 2 units (on a scale of 0 to 10) from Baseline in at least three of the following four domains, with no worsening at all in the
remaining domain:
a. Patient's Global Assessment
b. Pain
c. Function
d. Inflammation)

Percentuale di soggetti con risposta ASAS 40, definita in base a un miglioramento = 40% ed a un miglioramento assoluto di = 2 unità (su una scala compresa fra 0 e 10) rispetto al Baseline in almeno tre fra i seguenti quattro domini:
- valutazione globale dell’attività della malattia da parte del paziente;
- dolore;
- funzione;
- infiammazione;

E.5.1.1

Timepoint(s) of evaluation of this end point

Week 14

alla setimana 14

E.5.2

Secondary end point(s)

Key multiplicity adjusted secondary efficacy endpoints are:
1. Change from Baseline in Ankylosing Spondylitis Disease Activity Score (ASDAS);
2. Change from Baseline in magnetic resonance imaging (MRI) Spondyloarthritis Research Consortium of Canada (SPARCC) score (Spine);
3. Proportion of subjects with BASDAI 50 response;
4. Change from Baseline in Ankylosing Spondylitis Quality of Life (AS QoL);
5. Proportion of subjects with ASAS partial remission (PR);
6. Change from Baseline in Bath Ankylosing Spondylitis Functional Index (BASFI);
7. Change from Baseline in Linear Bath Ankylosing Spondylitis Metrology Index (BASMIlin);
8. Change from Baseline in Maastricht Ankylosing Spondylitis Enthesitis Score (MASES);
9. Change from Baseline in Work Productivity and Activity Impairment (WPAI);
10. Change from Baseline in ASAS Health Index (HI);
11. ASAS 20;
12. Change from Baseline in MRI Spondyloarthritis Research Consortium of Canada (SPARCC) score Sacroiliac (SI) joints.

Endpoint secondari di efficacia corretti per molteplicit¿ sono:
1. Variazione rispetto al Baseline del punteggio ASDAS (Ankylosing Spondylitis Disease Activity Score);
2. Variazione rispetto al Baseline dei riscontri al punteggio SPARCC (Spondyloarthritis Research Consortium of Canada) alla risonanza magnetica (MRI) (Rachide);
3. Percentuale di soggetti con risposta BASDAI 50;
4. Variazione rispetto al Baseline del punteggio AS QoL (Ankylosing Spondylitis Quality of Life);
5. Percentuale di soggetti con remissione parziale (PR) in base al criterio ASAS;
6. Variazione rispetto al Baseline del punteggio BASFI (Bath Ankylosing Spondylitis Functional Index);
7. Variazione rispetto al Baseline del punteggio BASMIlin (Linear Bath Ankylosing Spondylitis Metrology Index);
8. Variazione rispetto al Baseline del punteggio MASES (Maastricht Ankylosing Spondylitis Enthesitis Score);
9. Variazione rispetto al Baseline del punteggio WPAI (Work Productivity and Activity Impairment);
10. Variazione rispetto al Baseline del punteggio ASAS Health Index (HI).
11. Percentuale di soggetti con risposta ASAS 20
12. Variazione rispetto al Baseline del punteggio SPARCC in base a RM (articolazioni sacro-iliache).

E.5.2.1

Timepoint(s) of evaluation of this end point

Week 14

alla settimana 14

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

Yes

E.6.11

Pharmacogenomic

Yes

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

Yes

E.8.1.2

Open

E.8.1.3

Single blind

E.8.1.4

Double blind

Yes

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

Yes

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

Information not present in EudraCT

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

Japan

Korea, Democratic People's Republic of

New Zealand

United States

Switzerland

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

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:

161

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

100

F.4.2.2

In the whole clinical trial

170

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 who complete the last visit will have a follow-up visit approximately 30 days after the last dose of oral study drug to obtain information on any new or ongoing AEs and to collect vital signs and clinical laboratory tests.

I soggetti che completano l'ultima visita avranno una visita di follow-up circa 30 giorni dopo l'ultima dose di farmaco per via orale per ottenere informazioni su eventuali AE nuovi o in corso e per raccogliere segni vitali e test clinici di laboratorio.

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

2017-09-14

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2017-09-19

P. End of Trial
P.	End of Trial Status	Completed

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