Clinical Trials Register

Summary
EudraCT Number:	2011-001752-10
Sponsor's Protocol Code Number:	TAK-875_302
National Competent Authority:	Italy - Italian Medicines Agency
Clinical Trial Type:	EEA CTA
Trial Status:	Prematurely Ended
Date on which this record was first entered in the EudraCT database:	2012-09-21
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

2011-001752-10

A.3

Full title of the trial

A Multicenter, Randomized, Double-Blind, Placebo- and Active-Controlled, Phase 3 Study to Evaluate the Efficacy and Safety of TAK-875 25 mg and 50 mg Compared to Placebo and Sitagliptin 100 mg When Used in Combination with Metformin in Subjects with Type 2 Diabetes

Studio di fase 3, multicentrico, randomizzato, in doppio cieco, controllato con farmaco attivo e con placebo, mirato a valutare l’efficacia e la sicurezza di TAK-875 25 mg e 50 mg rispetto al placebo e a sitagliptin 100 mg, quando usato in combinazione con metformina in soggetti affetti da diabete di tipo 2

A.3.1

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

Efficacy and Comparing Study in Subjects with Type 2 Diabetes

Studio di efficacia e confronto in soggetti affetti da diabete di tipo 2

A.4.1

Sponsor's protocol code number

TAK-875_302

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	TAKEDA EUROPE RESEARCH & DEVELOPMENT CENTRE LTD
B.1.3.4	Country	United Kingdom
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	Takeda Global Research & Development Centre (Europe)
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	Takeda Global Research & Development Centre (Europe) Ltd.
B.5.2	Functional name of contact point	Program Manager
B.5.3	Address:
B.5.3.1	Street Address	61 Aldwych
B.5.3.2	Town/ city	London
B.5.3.3	Post code	WC2B 4AE
B.5.3.4	Country	United Kingdom
B.5.4	Telephone number	0044 020 3116 8000
B.5.5	Fax number	0044 020 3116 8199
B.5.6	E-mail	clinicaloperations@tgrd.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	NA
D.3.2	Product code	TAK-875
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.3.9.2	Current sponsor code	TAK-875
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	25
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	Comparator
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	Januvia
D.2.1.1.2	Name of the Marketing Authorisation holder	Merck Sharp & Dohme Ltd.
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.3.4	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	SITAGLIPTIN PHOSPHATE MONOHYDRATE
D.3.9.1	CAS number	654671-77-9
D.3.9.4	EV Substance Code	SUB25198
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	100
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: 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	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	NA
D.3.2	Product code	TAK-875
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.3.9.2	Current sponsor code	TAK-875
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	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	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	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	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

Type 2 diabetes mellitus (T2DM)

Diabete Mellito di tipo 2 (T2DM)

E.1.1.1

Medical condition in easily understood language

Type 2 diabetes

Diabete di tipo 2

E.1.1.2

Therapeutic area

Diseases [C] - Nutritional and Metabolic Diseases [C18]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	15.0
E.1.2	Level	LLT
E.1.2	Classification code	10063624
E.1.2	Term	Type II diabetes mellitus inadequate control
E.1.2	System Organ Class	10027433 - Metabolism and nutrition disorders

E.1.2 Medical condition or disease under investigation

E.1.2	Version	15.0
E.1.2	Level	LLT
E.1.2	Classification code	10045242
E.1.2	Term	Type II diabetes mellitus
E.1.2	System Organ Class	10027433 - Metabolism and nutrition disorders

E.1.2 Medical condition or disease under investigation

E.1.2	Version	15.0
E.1.2	Level	LLT
E.1.2	Classification code	10012613
E.1.2	Term	Diabetes mellitus non-insulin-dependent
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 the efficacy of TAK-875 plus metformin compared to placebo plus metformin and sitagliptin plus metformin on glycemic control as measured by change from baseline in HbA1c over a 24-week Treatment Period.

Valutare l’efficacia di TAK-875 più metformina rispetto al placebo più metformina e sitagliptin più metformina sul controllo glicemico, misurato in base al cambiamento dal basale in HbA1c durante un periodo di trattamento di 24 settimane.

E.2.2

Secondary objectives of the trial

To evaluate the effect of TAK-875 plus metformin compared to placebo plus metformin and sitagliptin plus metformin on other measures of glycemic control, including clinically meaningful levels of response in HbA1c and fasting plasma glucose (FPG) over a 24-week Treatment Period.

Valutare l’effetto di TAK-875 più metformina rispetto al placebo più metformina e sitagliptin più metformina su altre misure di controllo glicemico, inclusi i livelli clinicamente significativi di risposta in HbA1c e glicemia plasmatica a digiuno (fasting plasma glucose, FPG) durante un periodo di trattamento di 24 settimane.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

Subject eligibility is determined according to the following criteria: 1. The subject is male or female and 18 years of age or older with a historical diagnosis of T2DM. 2. The subject meets one of the following criteria: – The subject has an HbA1c level ≥7.5 and <10.5%, and has been on a stable daily dose of ≥1500 mg (or documented maximum tolerated dose [MTD]) of metformin for at least 2 months prior to Screening. This subject will immediately enter the Placebo Run-in Period according to Study Schedule A, or; – The subject has an HbA1c level ≥7.5 and <10.5%, and has been on a stable daily dose of <1500 mg of metformin without documented MTD for at least 2 months prior to Screening. After completing the Screening Visit, this subject will have their metformin dose immediately increased to ≥1500 mg (or MTD) for an 8-week Titration Period according to Study Schedule B. Following this 8-week period, the subject must qualify for entry into the Placebo Run-in Period by completing the Week -3 procedures including having an HbA1c level ≥7.5 and <10.5%. 3. The subject has had no treatment with antidiabetic agents other than metformin within 2 months prior to Screening (Exception: if a subject has received other antidiabetic therapy for ≤7 days within the 2 months prior to Screening). 4. The subject has a body mass index (BMI) ≤45 kg/m² at Screening. 5. Subjects regularly using other, non-excluded medications, must be on a stable dose for at least 4 weeks prior to Screening. However, PRN (as needed) use of prescription or over-the counter medications is allowed at the discretion of the investigator. 6. The subject is able and willing to monitor glucose with a home glucose monitor and consistently record his or her own blood glucose concentrations and complete subject diaries.

•Soggetti di sesso maschile o femminile, di almeno 18 anni di età, con un’anamnesi di T2DM. •Il soggetto soddisfa uno dei seguenti criteri:–il soggetto presenta un livello HbA1c ≥ 7,5% e < 10,5% e ha ricevuto una dose stabile di ≥ 1500 mg (o dose tollerata massima documentata [maximum tolerated dose, MTD]) di metformina per almeno 2 mesi prima dello screening. Tale soggetto entrerà immediatamente nel periodo run-in con placebo in base al Programma A dello studio, oppure;–il soggetto presenta un livello HbA1c ≥ 7,5% e < 10,5% e ha ricevuto una dose stabile di < 1500 mg di metformina, senza MTD documentata, per almeno 2 mesi prima dello screening. Dopo il completamento della visita di screening, la dose di metformina del soggetto sarà aumentata fino a ≥ 1500 mg (o MTD) per un periodo di titolazione di 8 settimane, in base al Programma B dello studio. Dopo questo periodo di 8 settimane, l’idoneità del soggetto alla partecipazione dovrà essere stabilita nel periodo run-in con placebo completando le procedure della Settimana-3, incluso il riscontro di un livello HbA1c ≥ 7,5% e < 10,5%. •Il soggetto non è stato sottoposto a trattamento con agenti antidiabetici diversi da metformina nel corso dei 2 mesi antecedenti allo screening (eccezione: un soggetto che abbia ricevuto altra terapia antidiabetica per ≤ 7 giorni entro i 2 mesi precedenti allo screening). •Il soggetto presenta un indice di massa corporea (Body Mass Index, BMI) al momento dello screening di ≤ 45 kg/m².• I soggetti che assumono regolarmente altri farmaci non esclusi, devono aver ricevuto una dose stabile per almeno 4 settimane prima dello screening. Comunque, all’occorrenza, l’utilizzo di farmaci su prescrizione o da banco è consentito a discrezione dello sperimentatore.•Il soggetto è in grado e disposto a controllare a casa il glucosio tramite il monitor di glucosio e, di conseguenza, a registrare le proprie concentrazioni di glucosio nel sangue e a completare i diari del soggetto.

E.4

Principal exclusion criteria

1. The subject donated or received any blood products within 12 weeks prior to Screening or is planning to donate blood during the study. 2. Hemoglobin ≤12 g/dL (≤120 g/L) for males and ≤10 g/dL (≤100 g/L) for females at Screening Visit. 3. The subject has systolic blood pressure ≥160 mm Hg or diastolic pressure ≥95 mm Hg at Screening Visit. (If the subject meets this exclusion criterion, the assessment may be repeated once at least 30 minutes after the initial measurement.) 4. The subject has a history of laser treatment for proliferative diabetic retinopathy within 6 months prior to Screening. 5. The subject has had treatment for gastric banding or gastric bypass surgery within one year prior to Screening. 6. The subject had coronary angioplasty, coronary stent placement, coronary bypass surgery, myocardial infarction, unstable angina pectoris, clinically significant abnormal ECG, cerebrovascular accident or transient ischemic attack within 3 months prior to or at Screening. 7. The subject has a history of pancreatitis.

•Il soggetto ha donato o ricevuto prodotti emoderivati entro le 12 settimane antecedenti allo screening o intende donare sangue nel corso dello studio.•Emoglobina di ≤ 12 g/dl (≤ 120 g/l) per gli uomini e di ≤ 10 g/dl (≤ 100 g/l) per le donne al momento della visita di screening.•Il soggetto presenta una pressione sanguigna sistolica di ≥ 160 mm Hg o una pressione diastolica di ≥ 95 mm Hg al momento della visita di screening. (Se il soggetto soddisfa questo criterio di esclusione, la valutazione può essere ripetuta una volta almeno 30 minuti dopo la misurazione iniziale.) •Il soggetto è stato sottoposto in passato a trattamento laser per retinopatia diabetica proliferativa 6 mesi prima dello screening.•Il soggetto è stato sottoposto a trattamento per bendaggio gastrico o a intervento chirurgico di bypass gastrico entro un anno dallo screening. •Il soggetto è stato sottoposto o ha sofferto di angioplastica coronarica, impianto di stent coronarico, intervento chirurgico di bypass coronarico, infarto miocardico, angina pectoris instabile,elettrocardiogramma anomalo significativo, incidente cerebrovascolare o attacco ischemico transitorio nei 3 mesi precedenti lo screening o allo momento dello stesso. •Il soggetto presenta un’anamnesi di pancreatite.

E.5 End points

E.5.1

Primary end point(s)

Change from baseline in HbA1c at Week 24.

•Variazione rispetto al basale in HbA1c alla Settimana 24.

E.5.1.1

Timepoint(s) of evaluation of this end point

Week 24 of treatment.

Settimana 24 di trattamento.

E.5.2

Secondary end point(s)

Secondary Endpoints: - Incidence of HbA1c <7% at Week 24. - Change from baseline in FPG at Week 24.

Gli endpoint secondari per questo studio sono: •Incidenza di HbA1c < 7% alla Settimana 24. •Variazione rispetto al basale in FPG alla Settimana 24.

E.5.2.1

Timepoint(s) of evaluation of this end point

Week 24 of treatment

Settimana 24 di trattamento.

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

Yes

E.6.7

Pharmacodynamic

Yes

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

Yes

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)

Yes

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

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

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

Croatia

Korea, Democratic People's Republic of

Malaysia

Thailand

United States

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

Number of subjects for this age range:

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:

432

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

646

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

125

F.4.2

For a multinational trial

F.4.2.1

In the EEA

528

F.4.2.2

In the whole clinical trial

1078

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)

The subject should be returned to the care of a physician and standard therapies as required.

Il soggetto deve essere restituito alle cure di un medico e alle terapie standard come richiesto.

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

2013-04-03

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2012-09-03

P. End of Trial
P.	End of Trial Status	Prematurely Ended
P.	Date of the global end of the trial	2013-12-27

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