Clinical Trials Register

Summary
EudraCT Number:	2022-003046-13
Sponsor's Protocol Code Number:	2021/ABM/03/00008
National Competent Authority:	Poland - Office for Medicinal Products
Clinical Trial Type:	EEA CTA
Trial Status:	Trial now transitioned
Date on which this record was first entered in the EudraCT database:	2024-09-13
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

Poland - Office for Medicinal Products

A.2

EudraCT number

2022-003046-13

A.3

Full title of the trial

Sacubitril/Valsartan in PriMAry preventIoN of the cardiotoxicity of systematic breaST canceR trEAtMent. Randomized, multicenter, double-blind, placebo-controlled study.

Sakubitryl/walsartan w prewencji pierwotnej kardiotoksyczności systemowego leczenia chorych na raka piersi. Badanie randomizowane, wieloośrodkowe, podwójnie zaślepione, kontrolowane placebo.

A.3.1

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

Sacubitril/Valsartan in prevention of heart damage during breast cancer treatment

Sakubitryl/walsartan w zapobieganiu uszkodzeniu serca w trakcie leczenia chorych na raka piersi

A.3.2

Name or abbreviated title of the trial where available

MAINSTREAM

A.4.1

Sponsor's protocol code number

2021/ABM/03/00008

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	Śląskie Centrum Chorób Serca
B.1.3.4	Country	Poland
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	Agencja Badań Medycznych
B.4.2	Country	Poland
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Dr hab. n. med. Mateusz Tajstra / Śląskie Centrum Chorób Serca w Zabrzu
B.5.2	Functional name of contact point	Koordynator Krajowy
B.5.3	Address:
B.5.3.1	Street Address	Marii Curie-Skłodowskiej 9
B.5.3.2	Town/ city	Zabrze
B.5.3.3	Post code	41-800
B.5.3.4	Country	Poland
B.5.4	Telephone number	483237 33 860
B.5.6	E-mail	mateusztajstra@wp.pl

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	Entresto 49 mg/51 mg
D.2.1.1.2	Name of the Marketing Authorisation holder	Novartis Europharm Limited Vista Building Elm Park, Merrion Road Dublin. Irlandia
D.2.1.2	Country which granted the Marketing Authorisation	Poland
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	Entresto 49mg/51mg
D.3.4	Pharmaceutical form	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	sacubitril
D.3.9.3	Other descriptive name	Sacubitril valsartan sodium hydrate
D.3.9.4	EV Substance Code	SUB183754
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	49
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	valsartan
D.3.9.3	Other descriptive name	Sacubitril valsartan sodium hydrate
D.3.9.4	EV Substance Code	SUB183754
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	51
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	Entresto 97 mg/103 mg
D.2.1.1.2	Name of the Marketing Authorisation holder	Novartis Europharm Limited Vista Building Elm Park, Merrion Road Dublin 4 Irlandia
D.2.1.2	Country which granted the Marketing Authorisation	Poland
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	Entresto 97mg/103mg
D.3.4	Pharmaceutical form	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	sacubitril
D.3.9.3	Other descriptive name	Sacubitril valsartan sodium hydrate
D.3.9.4	EV Substance Code	SUB183754
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	97
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	valsartan
D.3.9.3	Other descriptive name	Sacubitril valsartan sodium hydrate
D.3.9.4	EV Substance Code	SUB183754
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	103
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
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Coated tablet
D.8.4	Route of administration of the placebo	Oral use
D.8 Placebo: 2
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Coated 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

Heart failure – post-anthracycline cardiomyopathy

Niewydolność serca – kardiomiopatia poantracyklinowa

E.1.1.1

Medical condition in easily understood language

Damage to the heart caused by chemotherapy for breast cancer.

Uszkodzenie serca powstałe na skutek chemioterapii nowotworu piersi.

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	10019279
E.1.2	Term	Heart failure
E.1.2	System Organ Class	10007541 - Cardiac 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

Estimation of whether prophylactic use of sacubitril/valsartan will prevent cardiotoxicity associated with systemic breast cancer treatment, defined as a decrease in left ventricular ejection fraction ≥ 5% in an ultrasound scan during 24 months from randomization.

Oszacowanie czy prewencyjne zastosowanie sakubitrylu/walsartanu zapobiegnie kardiotoksyczności związanej z systemowym leczeniem raka piersi definiowanej jako spadek frakcji wyrzutowej lewej komory ≥ 5% w badaniu UKG przezklatkowym w ciągu 24 miesięcy od randomizacji.

E.2.2

Secondary objectives of the trial

Estimation of whether NT-proBNP and troponin markers can be used as indicators of the prevention of cardiotoxicity associated with systemic treatment of sacubitril/valsartan breast cancer.
Estimation of genetic correlation with prevention of cardiotoxicity associated with systemic treatment of breast cancer with sacubitril/valsartan.
Estimation of the reversibility of cardiotoxicity associated with systemic breast cancer treatment defined as a decrease in left ventricular ejection fraction.
Comparison of the detection sensitivity of cardiotoxicity associated with systemic treatment of breast cancer defined as a decrease in LVEF ≥ 5% in ultrasound examination with other imaging tests – ultrasound of the heart (UKG-echocardiography)
Estimation of the role of novel markers of cardiotoxicity (myeloperoxidase (MPO), galectin 3, GDF-15 protein and circulating receptor for IL-33 (sST2), but other considered biomarkers (PIGF, suPAR) and potential genomic markers (microRNAs)

Oszacowanie czy markery NT-proBNP i troponina mogą być używane jako wskaźniki prewencji kardiotoksyczności związanej z systemowym leczeniem raka piersi z zastosowaniem sakubitrylu/walsartanu .
Oszacowanie korelacji genetycznej z prewencją kardiotoksyczności związanej z systemowym leczeniem raka piersi z zastosowaniem sakubitrylu/walsartanu .
Oszacowanie odwracalności kardiotoksyczności związanej z systemowym leczeniem raka piersi definiowanej jako spadek frakcji wyrzutowej lewej komory.
Porównanie czułości detekcji kardiotoksyczności związanej z systemowym leczeniem raka piersi definiowanej jako spadek frakcji wyrzutowej lewej komory ≥ 5% w badaniu UKG z innymi badaniami obrazowymi – ultrasonografia serca (UKG)
Oszacowanie roli nowych markerów kardiotoksyczności (mieloperoksydazy (MPO), galektyny 3, białka GDF-15 i krążącego receptora dla IL-33 (sST2), ale inne rozważane biomarkery (PIGF, suPAR) i potencjalne markery genomiczne (mikroRNA)

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Written informed consent
2. Female gender, aged 18 years and over
3. Patients with histologically confirmed breast cancer and complete assessment of tumor phenotype (ER, PR, HER2, Ki67)
4. Ability to take oral medication and willingness to adhere to the planned regimen
5. Tumor grade IA-IIIC or oligometastatic grade IV
6. Radical treatment plan including surgery or post-radical surgical treatment
7. Plan of use of systemic treatment (preoperative, postoperative or combined) with anthracyclines and/or anti-HER2 drugs
8. ECOG 0-2 general status
9. LVEF ≥ 50% as assessed by echocardiography
10. Sinus rhythm

1. Wyrażenie pisemnej i opatrzonej datą świadomej zgody na udział w badaniu
2. Kobieta, w wieku 18 lat i więcej
3. Pacjentki z potwierdzonym histologicznie rakiem piersi i pełną oceną fenotypu nowotworu (ER, PR, HER2, Ki67)
4. Zdolność do przyjmowania leków doustnych i gotowość do przestrzegania schematu leczenia
5. Stopień zaawansowania nowotworu IA-IIIC lub stopień́ IV przy rozpoznaniu choroby skąpoprzerzutowej/oligometastatycznej
6. Plan leczenia radykalnego zakładający leczenie operacyjne lub stan po radykalnym leczeniu operacyjnym
7. Plan wykorzystania leczenia systemowego (leczenie przedoperacyjne, pooperacyjne lub łącznie) z wykorzystaniem antracyklin i/lub leków anty-HER2
8. Stan ogólny w skali ECOG 0-2
9. LVEF ≥ 50% w ocenie w badaniu UKG
10. Rytm zatokowy

E.4

Principal exclusion criteria

1. Lack of Written informed consent
2. Prior anthracycline-based chemotherapy and/or left-sided radiotherapy (prior to diagnosis of the cancer being the present cause of therapy)
3. Clinically relevant HF (NYHA II-IV)
4. MI within the last < 3 months
5. Symptomatic hypotension or SBP < 90 mmHg
6. Significant valvular disease, symptomatic coronary artery disease (CCS>2), significant AV block, symptomatic sinus node dysfunction
7. Expected survival <12 months
8. GFR<30 ml/min/1.73 m2 (screening visit)
9. K+>5.5mmol/L (screening visit)
10. Contraindications to ACE-I/ARB or LCZ696 if not listed among criteria
11. Active untreated liver disease
12. Pregnancy
13. Conditions/circumstances that may lead to non-compliance with medical staff recommendations (e.g. active drug/alcohol dependence, poorly controlled mental illness)

1. Brak wyrażenia zgody na udział w badaniu
2. Wcześniejsza chemioterapia oparta o antracykliny i/lub radioterapia w obrębie klatki piersiowej (przed rozpoznaniem choroby nowotworowej będącej podstawą obecnego leczenia ww lekami)
3. Jawna klinicznie niewydolność́ serca (NYHA II-IV)
4. Zawał serca w okresie < 3 miesięcy przed wizytą screeningową
5. Objawowa hipotensja i/lub ciśnienie systemowe (podczas wizyty kwalifikacyjnej) z SBP < 90 mmHg
6. Istotna wada zastawkowa, objawowa choroba wieńcowa (CCS>2), istotne zaburzenia przewodnictwa AV, objawowa dysfunkcja węzła zatokowego
7. Spodziewany okres przeżycia < 12 miesięcy
8. GFR<30 ml/min/1.73 m2 (wizyta kwalifikacyjna)
9. K+>5.5mmol/L (wizyta kwalifikacyjna)
10. Inne niewymienione przeciwskazania do ACE-I/ARB lub sakubitrylu/walsartanu
11. Aktywna nieleczona choroba wątroby
12. Ciąża –test ciążowy (na podstawie stężenia ß-hCG z surowicy) zostanie wykonany u wszystkich kobiet przed okresem menopauzy przed rozpoczęciem leczenia.
13. Warunki/okoliczności mogące prowadzić do niestosowania się wykonywania zaleceń́ personelu medyczego (np. aktywne uzależnienie od leków/alkoholu, źle kontrolowana choroba psychiczna, brak miejsca zamieszkania)

E.5 End points

E.5.1

Primary end point(s)

Decrease in left ventricular ejection fraction ≥ 5% assessed on magnetic resonance imaging (MRI) in 24 months from randomisation

Spadek frakcji wyrzutowej lewej komory ≥ 5% ocenianej w UKG przezklatkowym w ciągu 24 miesięcy od randomizacji

E.5.1.1

Timepoint(s) of evaluation of this end point

24 months

w ciągu 24 miesięcznej obserwacji

E.5.2

Secondary end point(s)

1. Death from any cause or hospitalization for heart failure
2. Death from any cause
3. Death from cardiovascular causes
4. Hospitalization for other cardiovascular causes
5. cardiotoxicity
6. Decrease in left ventricular ejection fraction ≥ 5% (MRI) during 24 months from randomization
7. Decrease in left ventricular ejection fraction ≥ 5% during 24 months from randomization
8. Occurrence of diastolic dysfunction (UKG) within 24 months of randomization Diastolic dysfunction assessed on echocardiography
9. Development of pathological pericardial fluid volume or increase in pericardial fluid volume from baseline
10. Occurrence of cardiac tamponade
11. Occurrence of pericarditis
12. Occurrence of myocarditis
13. Development of ventricular arrhythmias
14. Development of supraventricular arrhythmias
15. Presence of conduction disturbances
16. Changes in corrected QT interval
17. Changes in BNP, NT pro-BNP, troponin T or troponin I levels

1. złożony punkt końcowy obejmujący zgon z jakiejkolwiek przyczyny lub hospitalizacja z powodu niewydolności serca
2. zgon z jakiekolwiek przyczyny
3. zgon z przyczyn sercowo-naczyniowych
4. hospitalizacja z innych przyczyn sercowo-naczyniowych
5. kardiotoksyczność (CTRCD – Cancer therapy-related cardiac dysfunction) skutkująca koniecznością wdrożenia leczenia zgodnie z wytycznymi Europejskiego Towarzystwa Kardiologicznego dotyczącymi kardioonkologii [38] spadek frakcji wyrzutowej lewej komory ≥ 5% (MRI) w ciągu 24 miesięcy od randomizacji
6. spadek frakcji wyrzutowej lewej komory ≥ 5% (MRI) w ciągu 24 miesięcy od randomizacji
7. spadek frakcji wyrzutowej lewej komory ≥ 5% w ciągu 24 miesięcy od randomizacji
8. częstość́ dysfunkcji rozkurczowej (UKG) w ciągu 24 miesięcy od randomizacji
9. pojawienie się niefizjologicznej objętości płynu w worku osierdziowym
10. tamponada serca
11. zapalenie osierdzia
12. zapalenie mięśnia sercowego
13. komorowe zaburzenia rytmu
14. nadkomorowe zaburzenia rytmu, a zwłaszcza migotanie przedsionków
15. zaburzenia przewodnictwa
16. zmiany skorygowanego odstępu QT
17. Zmiany stężęnia BNP lub NT pro-BNP oraz troponiny T lub I zgodnie z punktami odcięcia opisanymi w wytycznych ESC

E.5.2.1

Timepoint(s) of evaluation of this end point

24 months

W czasie 24 miesięcznej obserwacji

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

Yes

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)

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

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

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

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:

400

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

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

480

F.4.2

For a multinational trial

F.4.2.2

In the whole clinical trial

480

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

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	Scientia Research Institute Sp. z o.o.
G.4.3.4	Network Country	Poland

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

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2023-11-27

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2022-11-24

P. End of Trial
P.	End of Trial Status	Trial now transitioned

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