Clinical Trials Register

Summary
EudraCT Number:	2016-001467-36
Sponsor's Protocol Code Number:	FER-CARS-06
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:	2021-08-03
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

2016-001467-36

A.3

Full title of the trial

A Randomised, Double-blind Placebo Controlled Trial Comparing the Effect of Intravenous Ferric Carboxymaltose on Hospitalisations and Mortality in Iron Deficient Patients Admitted for Acute Heart Failure (Affirm-AHF)

Studio randomizzato, in doppio cieco, controllato con placebo, teso a confrontare l’effetto di carbossimaltosio ferrico per via endovenosa sui ricoveri e sulla mortalità in pazienti sideropenici ricoverati per insufficienza cardiaca acuta (Affirm AHF)

A.3.1

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

A study to compare the use of ferric carboxymaltose with placebo in patients with acute heart failure and iron deficiency

Studio per confrontare l'uso di carbossimaltosio ferrico verso placebo in pazienti sidorepenici affetti da insufficienza cardiaca acuta

A.3.2

Name or abbreviated title of the trial where available

Affirm-AHF

A.4.1

Sponsor's protocol code number

FER-CARS-06

A.5.2

US NCT (ClinicalTrials.gov registry) number

NCT02937454

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	VIFOR (INTERNATIONAL) INC.
B.1.3.4	Country	Switzerland
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	Vifor (International) Inc.
B.4.2	Country	Switzerland
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Vifor (International) Inc.
B.5.2	Functional name of contact point	Clinical Trial Information Desk
B.5.3	Address:
B.5.3.1	Street Address	Flughofstrasse 61
B.5.3.2	Town/ city	Glattbrugg
B.5.3.3	Post code	CH-8152
B.5.3.4	Country	Switzerland
B.5.4	Telephone number	0041588518126
B.5.5	Fax number	0041588518001
B.5.6	E-mail	clinicalresearch@viforpharma.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	Ferinject
D.2.1.1.2	Name of the Marketing Authorisation holder	Vifor France SA
D.2.1.2	Country which granted the Marketing Authorisation	United Kingdom
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	NA
D.3.2	Product code	[NA]
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	Intravenous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	CARBOSSIMALTOSIO FERRICO
D.3.9.1	CAS number	9007-72-1
D.3.9.2	Current sponsor code	n/a
D.3.9.4	EV Substance Code	SUB66620
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	50
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	No

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	Solution for injection
D.8.4	Route of administration of the placebo	Intravenous use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Acute heart failure with iron deficiency

Insufficienza cardiaca acuta con sideropenia

E.1.1.1

Medical condition in easily understood language

Acute heart failure with iron deficiency

Insufficienza cardiaca acuta con sideropenia

E.1.1.2

Therapeutic area

Diseases [C] - Cardiovascular Diseases [C14]

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	10000803
E.1.2	Term	Acute heart failure
E.1.2	System Organ Class	10007541 - Cardiac disorders

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.0
E.1.2	Level	SOC
E.1.2	Classification code	10007541
E.1.2	Term	Cardiac disorders
E.1.2	System Organ Class	10007541 - Cardiac disorders

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	10022970
E.1.2	Term	Iron deficiency
E.1.2	System Organ Class	10027433 - Metabolism and nutrition 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

To evaluate, relative to placebo, the effect of intravenous (IV) FCM on repeated heart failure (HF) hospitalizations and cardiovascular (CV) death.

Valutare l’effetto di FCM per via endovenosa (e.v.) rispetto al placebo su ricoveri ripetuti per insufficienza cardiaca (IC) e morte cardiovascolare (CV).

E.2.2

Secondary objectives of the trial

To evaluate, relative to placebo, the effect of IV FCM on: HF hospitalizations, CV hospitalizations, CV mortality and all cause mortality
Quality of life and New York Heart Association Classification (NYHA)
Tolerability and safety.

Valutare l’effetto di FCM e.v. rispetto al placebo su:
ricoveri per IC, ricoveri per malattie CV, mortalità per malattie CV e mortalità per ogni causa.
Qualità della vita e classificazione della New York Heart Association (NYHA).
Tollerabilità e sicurezza.

E.2.3

Trial contains a sub-study

Yes

E.2.3.1

Full title, date and version of each sub-study and their related objectives

Other types of substudies
Specify title, date and version of each substudy with relative objectives: Biomarker Blood Samples
It is planned to perform biomarker analyses in blood samples from
approximately 60% of randomised subjects. The decision concerning
which biomarkers will be analysed will be made by in collaboration with
the Study Steering Committee, together with the Sponsor. If the
biomarker samples will not be analysed, they will be destroyed. Details
concerning the blood samples storage will be provided in an instruction
manual. If conducted, the statistical analysis for the biomarker blood
samples will be detailed in a separate biomarker SAP and results of
these exploratory analyses will be not part of the clinical study report of
the main study .

Altre tipologie di sottostudi
specificare il titolo, la data e la versione di ogni sottostudio con i relativi obiettivi: Biomarker Blood Samples
It is planned to perform biomarker analyses in blood samples from
approximately 60% of randomised subjects. The decision concerning
which biomarkers will be analysed will be made by in collaboration with
the Study Steering Committee, together with the Sponsor. If the
biomarker samples will not be analysed, they will be destroyed. Details
concerning the blood samples storage will be provided in an instruction
manual. If conducted, the statistical analysis for the biomarker blood
samples will be detailed in a separate biomarker SAP and results of
these exploratory analyses will be not part of the clinical study report of
the main study .

E.3

Principal inclusion criteria

1 Currently hospitalised for an episode of acute heart failure (AHF) where AHF was the primary reason for hospitalisation. All of the following (i.e., items a to d) must apply:
a. Upon admission for the AHF episode, persistent dyspnoea at rest in a recumbent sitting position (30-45°) or with minimal exertion
b. Upon or during the AHF admission, at least two (2) of the following clinical findings were present:
i. Congestion on chest x-ray
ii. Rales on chest auscultation
iii. Oedema =1+ on a 0-3+ scale, indicating indentation of skin with mild digital pressure that requires 10 or more seconds to resolve in any
dependent area including extremities or sacral region
iv. Elevated jugular venous pressure (=8 cm H2O)
c Natriuretic peptide levels, measured =24 hours of the AHF admission must have been:
i. Brain natriuretic peptide (BNP) =400 pg/mL or N-terminal-pro-brain natriuretic peptide (NT-proBNP) =1,600 pg/mL or
ii. BNP =600 pg/mL or NT-proBNP =2,400 pg/mL for subjects presenting with atrial fibrillation when the blood sample was taken
d AHF episode treated with minimally 40 mg of IV furosemide (or equivalent IV loop diuretic defined as 20 mg of torsemide or 1 mg of bumetanide)
2. Subject is iron deficient defined as serum ferritin <100 ng/mL or 100 ng/mL = serum ferritin =299 ng/mL if TSAT <20%.
3. Left ventricular ejection fraction <50% (assessed and documented within 12 months prior to randomisation).
4. Male or female aged =18 years old.
5. Subject (or legally acceptable representative)* has provided the appropriate written informed consent. Subject must provide written informed consent before any study-specific procedures are performed.
*Following section in Italics are applicable for the Netherlands only (NL only): The option that legally accepted representatives of subjects can sign the written informed consent is not valid for sites in the Netherlands.

1. Soggetto attualmente ricoverato per un episodio di insufficienza cardiaca acuta (ICA), laddove l’ICA sia stata il motivo principale del ricovero. Tutti i seguenti criteri (ossia punti da a. a d.) devono essere soddisfatti:
a. Al momento del ricovero per l’episodio di ICA, dispnea persistente a riposo in posizione seduta reclinata (30 45°) o con minimo sforzo
b. Al momento del ricovero per ICA o durante l’ospedalizzazione, presenza di almeno due (2) delle seguenti situazioni cliniche
i. congestione all’esame radiografico del torace
ii. rantoli all’auscultazione del torace
iii. edema =1+ su una scala da 0 a 3+, che indica un’indentazione della cute provocata da una lieve pressione delle dita, la cui risoluzione necessita di 10 o più secondi, in qualsiasi zona interessata, compresi gli arti o la regione sacrale
iv. pressione venosa giugulare elevata (=8 cm H2O)
c. I livelli di peptide natriuretico, misurati =24 ore dopo il ricovero per ICA devono essere stati:
i. peptide natriuretico cerebrale (BNP) =400 pg/mL o porzione N terminale del propeptide natriuretico cerebrale (NT proBNP) =1.600 pg/mL o
ii. BNP =600 pg/mL o NT proBNP =2.400 pg/mL nei soggetti che presentano fibrillazione atriale al momento del prelievo del campione ematico
d. Episodio di ICA trattato con un minimo di 40 mg di furosemide e.v. (o equivalente diuretico dell’ansa e.v., definito come 20 mg di torsemide o 1 mg di bumetanide)
2. Il soggetto è sideropenico, definito come presentante un valore di ferritina sierica <100 ng/mL, oppure un valore di ferritina sierica compreso tra 100 ng/mL e 299 ng/mL se associata a TSAT <20%.
3. Frazione di eiezione ventricolare sinistra <50% (valutata e documentata nei 12 mesi precedenti alla randomizzazione).
4. Soggetti di entrambi i sessi di età =18 anni.
5. Il soggetto (o il rappresentante legalmente riconosciuto)* ha fornito il consenso informato scritto appropriato. Il soggetto deve rilasciare il consenso informato scritto prima dell’esecuzione di qualsiasi indagine specifica per lo studio.
*La sezione successiva in corsivo è applicabile solo per i Paesi Bassi (NL solamente): l'opzione che i rappresentanti legalmente riconosciuti possano firmare il consenso informato scritto non è valido per i centri nei Paesi Bassi.

E.4

Principal exclusion criteria

1. Dyspnoea due to non-cardiac causes such as acute or chronic respiratory disorders or infections (i.e., severe chronic obstructive pulmonary disease, acute bronchitis, pneumonia, primary pulmonary
hypertension).
2. Temperature >38°C (oral or equivalent), active infective endocarditis, sepsis, systemic inflammatory response syndrome, or any other active
infection requiring anti-microbial treatment at any time during an Index hospitalisation.
3. Clinical evidence of acute coronary syndrome, transient ischemic attack or stroke, within the last 30 days prior randomisation.
4. Coronary-artery bypass graft, cardiac resynchronisation therapy device implantation, percutaneous intervention (e.g., cardiac,
cerebrovascular, aortic; diagnostic catheters are allowed) or major surgery that led to significant blood loss, including thoracic and cardiac surgery, within the last 3 months prior to randomisation.
5. Subject has a body weight <35 kg at randomisation.
6. Subject at an immediate need of transfusion or with a Hb <8 g/dL* or with a Hb >15 g/dL.
7. Subject with a known anaemia not attributed to ID (e.g., other microcytic anaemia) or with an evidence of iron overload (e.g., haemochromatosis) or disturbances in the utilisation of iron.
8. Subject has known hypersensitivity to any of the study products to be administered or known serious hypersensitivity to other parenteral iron products.
9. Renal dialysis (previous, current or planned within the next 6 months).
10. Chronic liver disease (including active hepatitis) and/or alanine transaminase or aspartate transaminase above 3 times the upper limit of
the normal range.
11. Subjects with known hepatitis B surface antigen positivity and/or hepatitis C virus ribonucleic acid positivity.
12. Subject is pregnant (e.g., positive human chorionic gonadotropin test) or breast feeding.
*Following section in Italics are applicable for the Netherlands only (NL only): The lower threshold of Hb values is set to 10 g/dL.

1. Dispnea attribuibile a cause non cardiache, come patologie o infezioni respiratorie acute o croniche (ossia, severa broncopneumopatia cronica ostruttiva, bronchite acuta, polmonite, ipertensione polmonare primaria).
2. Temperatura >38°C (orale o equivalente), endocardite infettiva attiva, sepsi, sindrome da risposta infiammatoria sistemica o qualsiasi altra infezione in atto necessitante di terapia antimicrobica in qualsiasi momento durante il ricovero di riferimento.
3. Evidenza clinica di sindrome coronarica acuta, attacco ischemico transitorio o ictus nei 30 giorni precedenti alla randomizzazione.
4. Bypass aortocoronarico, impianto di dispositivo per la terapia di resincronizzazione cardiaca, intervento percutaneo (ad. es., cardiaco, cerebrovascolare, aortico; sono ammessi i cateteri diagnostici) o intervento di chirurgia maggiore che ha comportato un’importante perdita ematica, compresi gli interventi di chirurgia toracica e cardiaca, nei 3 mesi precedenti alla randomizzazione.
5. Soggetto con peso corporeo <35 kg alla randomizzazione.
6. Soggetto con immediata necessità di trasfusione o con valori di Hb <8 g/dL* o >15 g/dL.
7. Soggetto con nota anemia non attribuibile alla sideropenia (ad es., altra anemia microcitica) o con evidenza di sovraccarico di ferro (ad es., emocromatosi) o disturbi dell’utilizzo del ferro.
8. Soggetto con nota ipersensibilità a uno qualsiasi dei prodotti in sperimentazione da somministrare o grave ipersensibilità nota ad altri prodotti per via parenterale a base di ferro.
9. Dialisi renale (pregressa, attuale o pianificata nei prossimi 6 mesi).
10. Epatopatia cronica (compresa epatite in atto) e/o alanina aminotransferasi o aspartato aminotransferasi superiore a 3 volte il limite superiore della norma.
11. Soggetti con nota positività verso l’antigene di superficie dell’epatite B e/o positivi verso l’acido ribonucleico del virus dell’epatite C.
12. Il soggetto è in gravidanza (ad es., test positivo della gonadotropina corionica umana) o sta allattando al seno.
*La sezione successiva in corsivo è applicabile solo per i Paesi Bassi (NL solamente): La soglia inferiore dei valori Hb è definata da 10 g / dL.

E.5 End points

E.5.1

Primary end point(s)

The composite of recurrent HF hospitalizations and CV death up to 52 weeks after randomization.

Il numero composito di ricoveri ricorrenti per IC e di morte CV fino a 52 settimane dopo la randomizzazione.

E.5.1.1

Timepoint(s) of evaluation of this end point

Up to 52 weeks after randomization.

Fino a 52 settimane dopo la randomizzazione

E.5.2

Secondary end point(s)

Safety Endpoints :
• Summary of adverse events (AEs): by system organ class and preferred term (Medical Dictionary for Regulatory Activities (MedDRA) coded term), by severity and relation to study product.
• Summary of serious adverse events (SAEs) by study treatment group presented by system organ class and preferred terms (MedDRA coded term).
• Summary of clinical laboratory panels and cardiac biomarkers (absolute and change from baseline).

Endpoint di sicurezza
• Riepilogo degli eventi avversi (AE): classificati per sistemi e organi e termine preferito [termine codificato secondo il Medical Dictionary for Regulatory Activities (MedDRA)], in base alla severità e alla relaziona causale con il prodotto in studio.
• Riepilogo degli eventi avversi seri (SAE) suddivisi per gruppo di trattamento e presentati secondo la classificazione per sistemi e organi e termini preferiti (termine codificato secondo MedDRA).
• Riepilogo delle analisi cliniche di laboratorio e dei biomarker cardiaci (valore assoluto e variazione dal basale).

E.5.2.1

Timepoint(s) of evaluation of this end point

Up to 52 weeks after randomization

Fino a 52 settimane dopo la randomizzazione

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)

E.7.3

Therapeutic confirmatory (Phase III)

E.7.4

Therapeutic use (Phase IV)

Yes

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

Brazil

Georgia

Israel

Lebanon

Singapore

Ukraine

Croatia

Italy

Netherlands

Poland

Romania

Spain

Sweden

United Kingdom

Argentina

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:

500

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

600

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

250

F.4.2

For a multinational trial

F.4.2.1

In the EEA

450

F.4.2.2

In the whole clinical trial

650

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)

Should patients require additional iron post repletion and completion of the study, either Ferinject or alternative iron replacement therapies are available for use by treating physicians.

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

2016-12-09

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2017-02-08

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

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IMP with orphan designation in the indication
Orphan Designation Number:
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