Clinical Trials Register

Summary
EudraCT Number:	2012-001730-33
Sponsor's Protocol Code Number:	AV-951-12-205
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:	2012-10-11
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

2012-001730-33

A.3

Full title of the trial

A PHASE 2 RANDOMIZED, DOUBLE-BLIND, CROSSOVER, CONTROLLED, MULTI-CENTER, SUBJECT PREFERENCE STUDY OF TIVOZANIB HYDROCHLORIDE VERSUS SUNITINIB IN THE TREATMENT OF SUBJECTS WITH METASTATIC RENAL CELL CARCINOMA

Studio di fase 2, randomizzato, in doppio cieco, in crossover, controllato, multicentrico per confrontare la preferenza dei soggetti tra tivozanib cloridrato e sunitinib nel trattamento del carcinoma a cellule renali metastatico

A.3.1

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

A.4.1

Sponsor's protocol code number

AV-951-12-205

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	AVEO PHARMACEUTICALS, INC.
B.1.3.4	Country	United States
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	Aveo Pharmaceuticals 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	Aveo Pharmaceuticals Inc
B.5.2	Functional name of contact point	Kristina Johnson
B.5.3	Address:
B.5.3.1	Street Address	75 Sidney Street
B.5.3.2	Town/ city	Cambridge
B.5.3.3	Post code	MA 02139
B.5.3.4	Country	United States
B.5.4	Telephone number	001-617--299-5727
B.5.5	Fax number	001-617-995-4827
B.5.6	E-mail	kjohnson@aveooncology.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	Yes
D.2.5.1	Orphan drug designation number	EU/3/10/747
D.3 Description of the IMP
D.3.1	Product name	tivozanib hydrochloride
D.3.2	Product code	AV-951
D.3.4	Pharmaceutical form	Capsule, hard
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	tivozanib hydrochloride
D.3.9.1	CAS number	682745-41-1
D.3.9.2	Current sponsor code	AV-951
D.3.9.3	Other descriptive name	KRN951
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	range
D.3.10.3	Concentration number	1 to 1.5
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	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	sutinib
D.3.2	Product code	L01XE04
D.3.4	Pharmaceutical form	Capsule, hard
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	SUNITINIB
D.3.9.1	CAS number	557795-19-4
D.3.9.3	Other descriptive name	sutent
D.3.9.4	EV Substance Code	SUB22321
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	Capsule, hard
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

metastatic renal cell carcinoma

carcinoma a cellule renali metastatico

E.1.1.1

Medical condition in easily understood language

metastatic renal cell carcinoma

carcinoma a cellule renali 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	15.0
E.1.2	Level	LLT
E.1.2	Classification code	10038400
E.1.2	Term	Renal carcinoma stage IV
E.1.2	System Organ Class	100000004864

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	10038399
E.1.2	Term	Renal carcinoma stage III
E.1.2	System Organ Class	100000004864

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	10050076
E.1.2	Term	Metastatic renal 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 compare subject treatment preference of tivozanib versus sunitinib

• Confrontare la preferenza soggettiva di trattamento tra tivozanib cloridrato e sunitinib.

E.2.2

Secondary objectives of the trial

To compare overall safety and tolerability in subjects treated with tivozanib and sunitinib. To assess the frequency of dose modifications in subjects treated with tivozanib and sunitinib. To evaluate the Quality of Life (QoL) (including kidney-specific symptoms and fatigue) in subjects treated with tivozanib and sunitinib

• Confrontare la sicurezza e la tollerabilità complessive nei soggetti trattati con tivozanib cloridrato e sunitinib.
• Valutare la frequenza delle modifiche della dose in soggetti trattati con tivozanib cloridrato e sunitinib.
• Valutare la qualità della vita (Quality of Life, QoL) (compresi i sintomi specifici per i reni e l’affaticamento) in soggetti trattati con tivozanib cloridrato e sunitinib.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. ≥ 18 year old males or females 2. Subjects with unresectable mRCC 3. Histologically or cytologically confirmed RCC of any histology 4. Subjects with or without prior nephrectomy 5. Evaluable disease per RECIST Version 1.1 (see Appendix A). 6. ECOG performance status of 0 or 1 (see Appendix B) 7. A female is eligible to participate if she is of non-childbearing potential or has documentation of a negative pregnancy test prior to the start of the study treatment. Sexually active pre-menopausal female subjects (and male subjects whose sexual partners are of childbearing potential) must agree to use adequate, highly effective contraceptive measures, while on study and for 45 days after the last dose of last study drug. Effective birth control includes (a) intrauterine device (IUD) plus one barrier method; (b) oral, implantable or injectable contraceptives plus one barrier method; or (c) 2 barrier methods. Effective barrier methods are male or female condoms, diaphragms, and spermicides (creams or gels that contain a chemical to kill sperm). 8. Ability to give written informed consent and comply with protocol requirements, including drug treatments and follow-up procedures

1. Maschi o femmine di ≥ 18 anni di età
2. Soggetti con RCC metastatico non resecabile chirurgicamente
3. RCC confermato istologicamente o citologicamente di qualsiasi istologia
4. Soggetti con o senza nefrectomia precedente devono essere stati sottoposti a precedente nefrectomia (completa o parziale) per l’escissione del tumore primario
5. Malattia valutabile in base a RECIST Versione 1.1
6. Stato prestazionale ECOG di 0 o 1
7. Un soggetto di sesso femminile è idoneo a partecipare se non è fertile o se è in possesso di documentazione di test di gravidanza negativo prima dell’inizio del trattamento dello studio. Soggetti di sesso femminile sessualmente attivi prima della menopausa (e soggetti di sesso maschile le cui partner sono fertili) devono acconsentire ad adottare misure contraccettive adeguate e altamente efficaci durante lo studio e per 45 giorni dopo l’ultima dose dell’ultimo farmaco dello studio. Il controllo efficace delle nascite comprende: (a) dispositivo intrauterino (IUD) più un metodo di barriera; (b) contraccettivo orale, impiantabile o iniettabile più un metodo di barriera; o (c) 2 metodi di barriera. Per metodi di barriera efficaci si intendono preservativi maschili o femminili, diaframmi e spermicidi (creme o gel contenenti una sostanza chimica che uccide gli spermatozoi).
8. Capacità di fornire il consenso informato scritto e attenersi ai requisiti previsti dal protocollo, inclusi i trattamenti farmacologici e le procedure di follow-up.

E.4

Principal exclusion criteria

1. Any prior systemic therapy for treatment of mRCC 2.Central nervous system metastases. 3.Any of the following hematologic and coagulation abnormalities: Hemoglobin < 9.0 g/dL; oAbsolut e neutrophil count (ANC) < 1500 per mm3; Platelet count < 100,000 per mm3. 4.Any of the following serum chemistry and urinalysis abnormalities: oTotal bilirubin > 1.5 × ULN (or > 2.5 x ULN for subjects with asymptomatic Gilbert’s syndrome) oAspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 2.5 × ULN (or > 5 × ULN for subjects with liver metastasis); oAlkaline phosphatase > 2.5 × ULN (or > 5 × ULN for subjects with liver or bone metastasis); oCreatinine > 2.0 × ULN; oProteinuria > 3+ by urinalysis or urine dipstick. 5.Significant cardiovascular disease, 6.Non-healing wound, bone fracture, or skin ulcer. 7.Active peptic ulcer disease, inflammatory bowel disease, ulcerative colitis, or other gastrointestinal condition with increased risk of perforation; history of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within 4 weeks prior to administration of first dose of study drug. 8.Serious/active infection or infection requiring parenteral antibiotics. 9.Corrected QT interval (QTc) of >480 msec using Bazett’s formula. 10.Radiotherapy or minor surgical procedure within 2 weeks, or major surgical procedure within 4 weeks prior to administration of first dose of study drug; inadequate recovery from prior surgical procedure. 11.Significant thromboembolic or vascular disorders within 6 months prior to administration of first dose of study drug. 12 Significant bleeding disorders within 6 months prior to administration of first dose of study drug 13.Currently active second primary malignancy, including hematologic malignancies (leukemia, lymphoma, multiple myeloma, etc.), other than non-melanoma skin cancers, non-metastatic prostate cancer, in situ cervical cancer, and ductal or lobular carcinoma in situ of the breast. Subjects are considered to have a currently active malignancy if they have completed anti-cancer therapy and have not been disease free for > 2 years. 14.Pregnant or lactating females. 15.History of genetic or acquired immune suppression disease such as human immunodeficiency virus (HIV); subjects on immune suppressive therapy for organ transplant. 16.Life-threatening illness or organ system dysfunction compromising safety evaluation. 17.Requirement for hemodialysis or peritoneal dialysis. 18.Inability to swallow capsules, malabsorption syndrome or gastrointestinal disease that severely affects the absorption of study drugs, major resection of the stomach or small bowel, or gastric bypass procedure. 19.Known hypersensitivity to drugs chemically related to tivozanib hydrochloride or sunitinib or their excipients. 20.Psychiatric disorder or altered mental status precluding informed consent or protocol related testing

1-Qualsiasi terapia sistemica precedente per il trattamento dell’RCC metastatico.
2-Metastasi al sistema nervoso centrale
3-Qualunque delle seguenti anomalie ematologiche e della coagulazione: Emoglobina < 9,0 g/dl; Conta assoluta dei neutrofili (ANC) < 1500/mm3; Conta piastrinica < 100.000/mm3.
4 Qualsiasi delle seguenti anomalie della chimica del siero e analisi delle urine:
Aspartato aminotransferasi (AST) o alanina aminotransferasi (ALT) > 2,5 × ULN (o > 5 × ULN in soggetti con metastasi epatica); Fosfatasi alcalina > 2,5 × ULN (o > 5 × ULN per soggetti con metastasi epatica od ossea); Creatinina > 2,0 × ULN; Proteinuria > 3+ in base agli esami delle urine o stick urinario.
5- Malattia cardiovascolare significativa
6-Ferita che non si rimargina, frattura ossea o ulcera cutanea.
7-Malattia ulcerosa peptica attiva, malattia infiammatoria intestinale, colite ulcerosa o altra patologia gastrointestinale con aumento del rischio di perforazione; anamnesi di fistola addominale, perforazione gastrointestinale o ascesso intraddominale nelle 4 settimane precedenti la somministrazione della prima dose di farmaco dello studio.
8-Infezione grave/attiva o infezione che necessita di antibiotici parenterali.
9-Intervallo QT corretto (QTc) > 480 msec con la formula di Bazett.
10-Radioterapia o intervento chirurgico di lieve entità entro 2 settimane o intervento chirurgico di rilievo nelle 4 settimane prima della somministrazione della prima dose di farmaco dello studio; ripresa inadeguata dall’intervento chirurgico precedente.
11-Disturbi tromboembolici o vascolari significativi nei 6 mesi precedenti la somministrazione della prima dose di farmaco dello studio,
12-Disturbi della coagulazione del sangue significativi nei 6 mesi precedenti la somministrazione della prima dose di farmaco dello studio
13-Secondi tumori primari attualmente attivi, incluse malignità ematologiche (leucemia, linfoma, mieloma multiplo, ecc.), diversi dal carcinoma della pelle non-melanoma, carcinoma prostatico non metastatico, carcinoma cervicale in situ e carcinoma mammario duttale o lobulare. I soggetti sono considerati come aventi un tumore attualmente attivo se hanno completato la terapia anticancro e non sono liberi da malattia da > 2 anni.
14-Donne incinte o in allattamento.
15-Anamnesi di malattia immunodepressiva genetica o acquisita, quale il virus dell’immunodeficienza umana (HIV); soggetti in terapia immunosoppressiva per il trapianto d’organi.
16-Patologia potenzialmente letale o disfunzione organica che compromette le valutazioni di sicurezza.
17-Necessità di emodialisi o dialisi peritoneale.
18-Incapacità di ingoiare capsule, sindrome da malassorbimento o malattia gastrointestinale che compromette fortemente l’assorbimento dei farmaci dello studio, resezione importante dello stomaco o dell’intestino tenue o intervento di bypass gastrico.
19-Ipersensibilità nota ai farmaci chimicamente correlati a tivozanib cloridrato o sunitinib o ai loro eccipienti.
20-Disturbo psichiatrico o stato mentale alterato che preclude il consenso informato o gli esami correlati al protocollo.

E.5 End points

E.5.1

Primary end point(s)

Proportion of subjects who prefer tivozinab Hydrocloride or sutinib

porzione di pazienti che preferisce tivozinab cloriodrato o sutinib

E.5.1.1

Timepoint(s) of evaluation of this end point

up to 25 weeks

a 25 settimane

E.5.2

Secondary end point(s)

safety and tolerability during the course of the study

sicurezza e tllerabilità durante la sperimentazione

E.5.2.1

Timepoint(s) of evaluation of this end point

up to 25 weeks

a 25 settimane

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

Yes

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

Yes

E.6.13.1

Other scope of the trial description

questionari sulla qualità della vita

preferenza dei soggetti per tivozanib verso sunitinib

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

E.8.1.3

Single blind

E.8.1.4

Double blind

Yes

E.8.1.5

Parallel group

E.8.1.6

Cross over

Yes

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

Yes

E.8.2.3

Other

Yes

E.8.2.3.1

Comparator description

sunitinib

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

United States

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

last Visit last Subject

Ultima visita ultimo soggetto

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:

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

112

F.4.2.2

In the whole clinical trial

160

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 continuing on tivozanib will have the oportunity to participate in a Rollover Protocol to Allow Continued Access to Tivozanib (AV 951) for Subjects Enrolled in Other Tivozanib Protocols subjects continuing on sutent will receive drug off study

I soggetti che prediligeranno tivozanib avranno la possibilità di partecipare ad uno studio di roll-over che consentirà loro di continuare il trattamento con tivozanib; i soggetti che prediligeranno sutent riceveranno il farmaco come da normale pratica clinica, al di fuori da ogni studio clinico

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

2013-02-13

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2012-10-01

P. End of Trial
P.	End of Trial Status	Prematurely Ended
P.	Date of the global end of the trial	2013-07-19

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