Clinical Trials Register

Summary
EudraCT Number:	2016-002006-39
Sponsor's Protocol Code Number:	ESTER
National Competent Authority:	Italy - Italian Medicines Agency
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2021-06-08
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

Italy - Italian Medicines Agency

A.2

EudraCT number

2016-002006-39

A.3

Full title of the trial

Study on Efficacy and safety of an early proactive Switch To ElvitegraviR/cobicistat/emtricitabine/tenofovir alafenamide (E/C/F/TAF) in patients with a primary HIV-1 infection

A.3.1

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

Study on Efficacy and safety of switch ElvitegraviR/cobicistat/emtricitabine/tenofovir alafenamide (E/C/F/TAF) in patients with a HIV infection

Studio sull¿ Efficacia e la sicurezza di passaggio a ElvitegraviR/cobicistat/emtricitabina/tenofovir alafenamide (E/C/F/TAF) in pazienti con infettati dal virus HIV

A.3.2

Name or abbreviated title of the trial where available

ESTER

A.4.1

Sponsor's protocol code number

ESTER

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	ISTITUTO NAZIONALE PER LE MALATTIE INFETTIVE "LAZZARO SPALLANZANI"
B.1.3.4	Country	Italy
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	Gilead Sciences
B.4.2	Country	Italy
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Istituto Nazionale per le Malattie Infettive ''Lazzaro Spallanzani''
B.5.2	Functional name of contact point	Immunodeficenze virali
B.5.3	Address:
B.5.3.1	Street Address	Via Portuense 292
B.5.3.2	Town/ city	Roma
B.5.3.3	Post code	00149
B.5.3.4	Country	Italy
B.5.4	Telephone number	06 55170546
B.5.5	Fax number	06 55170477
B.5.6	E-mail	andrea.antinori@inmi.it

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	Genvoya
D.2.1.1.2	Name of the Marketing Authorisation holder	GIlead Sciences
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	Film-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	elvitegravir
D.3.9.1	CAS number	697761-98-1
D.3.9.2	Current sponsor code	-
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	150
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	cobicistat
D.3.9.1	CAS number	1004316-88-4
D.3.9.2	Current sponsor code	-
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	150
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	EMTRICITABINA
D.3.9.1	CAS number	143491-57-0
D.3.9.2	Current sponsor code	-
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	200
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Tenofovir alafenamide
D.3.9.1	CAS number	379270-37-8
D.3.9.2	Current sponsor code	-
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	10
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

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Treatment of HIV infection

Trattamento dell¿ infezione da HIV

E.1.1.1

Medical condition in easily understood language

Treatment of HIV infection

Trattamento dell¿ infezione da HIV

E.1.1.2

Therapeutic area

Diseases [C] - Virus Diseases [C02]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.1
E.1.2	Level	LLT
E.1.2	Classification code	10068341
E.1.2	Term	HIV-1 infection
E.1.2	System Organ Class	100000004862

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 efficacy of an early proactive switch to 1 single-pill E/C/F/TAF (elvitegravir 150 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir alafenamide 10 mg or E/C/F/TAF) from 4-pill treatment with either DRV (800 mg QD)+ RTV (100 mg QD) or DRV/C (800/150 mg QD) + RAL (400 mg BID) + TDF/FTC (300/200 mg QD) in patients with primary HIV-1 infection

Valutare l¿ efficacia di uno Switch proattivo precoce ad una compressa di ElvitegraviR/cobicistat/emtricitabina/tenofovir alafenamide (E/C/F/TAF) dopo una fase di induzione con un regime a 4 farmaci DRV (800 mg QD)+ RTV (100 mg QD) oppure or DRV/C (800/150 mg QD) + RAL (400 mg BID) + TDF/FTC (300/200 mg QD), in pazienti con infezione primaria da HIV-1

E.2.2

Secondary objectives of the trial

¿ To evaluate immune recovery and immune activation in peripheral blood compartment
¿ To evaluate safety
¿ To evaluate adherence levels to ARVs by patient self-report
¿ To evaluate levels of proviral HIV DNA
¿ To evaluate HIV-1 RNA and HIV-1 DNA decay rates
¿ To evaluate BMD change by DXA scan and on bone turn-over markers (BTM)
¿ To evaluate renal function (e-GFR and eGFRcys), urinary tubular damage markers (a1-microglobulin, ¿2-microglobulin, RBP) and albumin-creatinine ratio (ACR)
¿ To evaluate patient-reported quality of life
¿ To evaluate neurocognitive performance
¿ To evaluate resistance mutation development in subjects with virological failure

- Valutare il recupero immunitario e l¿ attivazione del sistema immunitario nel sangue periferico
- Valutare la sicurezza del farmaco
- Valutare i livelli di aderenza alle terapie antiretrovirali
- Valutare i livelli di DNA provirale dell' HIV
- Valutare l¿ HIV-1 RNA e l¿ HIV-1 DNA decay rates
- Valutare il cambiamento della BMD mediante DXA scan e markers del turnover osseo
- Valutare la funzionalit¿ renale (e-GFR e eGFRcys), marcatori urinari di danno tubulare (a1-microglobulin, ¿2-microglobulin, RBP) e l¿ albumina-creatinina ratio (ACR)
- Valutare la qualit¿ della vita dei pazienti
- Valutare le performance neuro cognitive
- Valutare lo sviluppo di resistenze in soggetti con fallimento virologico

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

• Age>18 years
• Diagnosis of HIV-1 infection during PHI as determined by at least one of the following criteria: a) positive HIV viral load (2000 copies/mL) and negative HIV Ab/Ag Combo or Western Blot test, b) positive HIV Ab/Ag Combo test and negative or undetermined Western Blot test; c) positive HIV Ab/Ag Combo test and incomplete Western Blot test (no p31 protein reactivity); d) recent infection confirmed by a positive HIV-1 EIA or Western Blot test and a documented negative HIV-1 EIA within the previous 6 months
• Being on first-line treatment of primary HIV-1 infection with either DRV/RTV or DRV/C +TDF/FTC + RAL treatment; minimum time on treatment is the time elapsed between start of ARV and first available HIV RNA <40 copies/ml
• Plasma HIV-1 RNA <40 copies/mL at least one HIV RNA test
• To have Genotyping Resistance Test before start of ARV without resistance mutations to any antiretroviral drug class
• A female subject is eligible to enter the study if it is confirmed that she is:
- Not pregnant confirmed by a negative serum pregnancy test
- Not breastfeeding
- Of non-childbearing potential (eg women who have had a hysterectomy or both ovaries removed or are postmenopausal women >54years of age with cessation for >12 months of previously occurring menses)
- Of childbearing potential (as defined in Appendix **) and agrees to utilize the protocol specified method of contraception or be non-heterosexually active or practice sexual abstinence (as defined in Appendix **) from screening throughout the duration of study treatment and for 30 days following discontinuation of study drugs.
- Female subjects who utilize hormonal contraceptive as one of their birth control methods must have used the same method for at least three months prior to study dosing.
• Written Informed consent

• Età >18 anni
• Diagnosi di infezione da HIV-1 durante l’ infezione primaria determinata da uno dei seguenti criteri:
a) carica virale positiva (2000 cp/ml) e test HIV Ab/Ag Combo o Western Blot test negativo; b) HIV Ab/Ag Combo test positivo o Western Blot test indeterminato; C) HIV Ab/Ag Combo test positivo e Western Blot test incompleto (no p31 protein reactivity); D) infezione recente confermata da positività a HIV-1 EIA o Western Blot test e un documentato HIV-1 EIA negativo nei precedenti 6 mesi
• Essere in trattamento di prima linea per infezione primaria da HIV-1 con DRV/RTV oppure DRV/C +TDF/FTC + RAL , il tempo minimo di trattamento è il tempo trascorso tra l' inizio dell' ARV e i primi valori di HIVRNA<40 copie/ml disponibili
• HIV-1RNA plasmatico <40 copie/ml in almeno un test HIVRNA
• Avere un test di resistenza genotipica privo di resistenze a quasialsi classe di farmaco antiretrovirale
• Un soggetto femminile è eleggibile se è confermato che è:
- Non in gravidanza, confermato da un test di gravidanza sierologico negativo
-Non in allattamento
-Potenzialmente non fertile (donne che hanno subito un intervento di isterectomia o hanno rimosso entrambe le ovaie oppure sono in postmenopausa >54 anni con ultima mestruazione precedente a 12 mesi
-In età fertile e si impegna ad utilizzare uno specifico metodo contraccettivo o dichiara di essere non eterosessualmente attiva oppure pratica l' astinenza sessuale dallo screening per tutta la durata dello studio e per 30 giorni dopo la sospensione dei farmaci in studio
-soggetti di sesso femminile che utilizzano contraccettivi ormonali come uno dei loro metodi di controllo delle nascite deve aver utilizzato lo stesso metodo per almeno tre mesi prima del dosaggio di studio
• Soggetti di sesso maschile devono accettare uno specifico metodo di contraccezione durante il rapporto eterosessuale o essere non eterosessuali oppure praticare l' astinenza sessuale dalla prima dose di farmaco di studio fino alla fine dello studio e per 90 giorni dopo l' ultima dose di farmaco
• Firma consenso informato

E.4

Principal exclusion criteria

Exclusion criteria
• Presence of an opportunistic infection or an AIDS-defining illness, unless they are directly attributable to the acute seroconversion illness
• Receipt of investigational research agents within 30 days prior to study entry
• Receipt of prior experimental HIV vaccines. Individuals who received a saline placebo in a prior HIV vaccine trial are not excluded, provided that they did not receive a sham vector or an adjuvant.
• Receipt of immunosuppressive medications or immune-modulators (e.g., cytokine therapy) within the past 6 months.
• Current anti-tuberculosis prophylaxis or therapy
• Serious illness other than acute HIV infection requiring systemic treatment or hospitalization until either therapy is completed or patient is clinically stable on therapy
• Hepatitis C (HCV Ab positive) or hepatitis B infection (Positive hepatitis B surface antigen, HBsAg)
• Women who are pregnant or breastfeeding
• Renal function with CrCl below 50 mL/min
• Severe hepatic impairment
• Known hypersensitivity to the study drug, the metabolites or formulation excipients.

• Presenza di una infezione opportunistica o AIDS correlata, a meno che non sia attribuibile a malattia acuta da sieroconversione
• Aver partecipato a studi sperimentali nei 30 giorni precedenti l’ ingresso nello studio
• Aver ricevuto precedenti vaccini sperimentali contro l' HIV. Gli individui che hanno ricevuto un placebo salino in un precedente trial su vaccino contro l'HIV non sono esclusi, a condizione che non abbiano ricevuto un vettore o un coadiuvante.
• Aver ricevuto farmaci immunosoppressori o immuno-modulatori (ad esempio, la terapia con citochine) negli ultimi 6 mesi.
• Corrente profilassi anti-tubercolosi o terapia antitubercolare
• Malattia grave, diversa da infezione acuta da HIV, che richiede un trattamento sistemico o il ricovero in ospedale fino al termine del trattamento o il paziente è clinicamente stabile in terapia
• Infezione da epatite C (HCV Ab positivo) infezione da Epatite B (HBsAg positivo)
• Le donne incinta o che allattano
• La funzione renale con clearance della creatinina inferiore a 50 ml / min
• Insufficienza epatica grave
• Ipersensibilità nota ai farmaci in studio, ai metaboliti o agli eccipienti

E.5 End points

E.5.1

Primary end point(s)

• Percentage of subjects with Ultrasensitive HIV RNA <5 copies/mL at week 48 (FDA Snapshot algorithm)

Percentuale di soggetti con Ultrasensitive HIV RNA <5 copie / ml alla settimana 48 (FDA Snapshot algorithm)

E.5.1.1

Timepoint(s) of evaluation of this end point

48 weeks

48 settimane

E.5.2

Secondary end point(s)

¿ Percentage of subjects with HIV RNA <50 copies/mL at week 48 (FDA Snapshot algorithm); Percentage of subjects with Ultrasensitive HIV RNA <5 copies/mL at week 24 (FDA Snapshot algorithm); ¿ Discontinuation of any drug in the treatment combination
¿ WHO grade 3-4 toxicity at any laboratory exam
¿ Change in CD4+ T-cells in the peripheral blood (absolute and %)
; ¿ Total proviral HIV-1 DNA in peripheral blood mononuclear cells (PBMCs) at baseline and at 6 and 12 months
¿ HIV antibody levels and Ab avidity test at baseline and 6 months
¿ Lymphocyte activation markers in PBMCs at baseline and at 6 and 12 months
¿ Inflammation markers (soluble CD14, IL-6, D-Dimer, vCam, C Reactive Protein) at baseline and 6 and 12 months
¿ Urinary tubular damage markers (¿1-microglobulin, ¿2-microglobulin, RBP) and albumin-creatinine ratio (ACR) at baseline and 6 and 12 months
¿ BMD change by DXA scan at baseline and at 12 months
¿ Bone turn-over markers (BMT) (CTX, P1NP) at baseline and at 6 and 12 months
; INSTI-mutations in genotypic resistance testing (GRT) at baseline and at virologic failure; Percentage of subjects discontinuing study drug

Percentuale di soggetti con HIV RNA <50 copie / ml alla settimana 48 (FDA Snapshot algorithm);
¿ Percentuale di soggetti con Ultrasensitive HIV RNA <5 copie / ml alla settimana 24 (FDA Snapshot algoritmo)
; ¿L'interruzione di qualsiasi farmaco in combinazione al trattamento
¿ WHO grado di tossicit¿ 3-4 in qualsiasi esame di laboratorio
¿ Variazione di cellule T CD4+ nel sangue periferico (assoluto e %)
; ¿ HIV-1 DNA provirale totale nelle cellule mononucleari del sangue periferico (PBMC) al basale e
a 6 e 12 mesi
¿ i livelli di anticorpi HIV e Ab avidity test al basale e 6 mesi
¿ marker di attivazione linfocitaria in PBMC al basale ea 6 e 12 mesi
¿ marcatori di infiammazione (soluble CD14, IL-6, D-dimero, VCAM, Proteina C reattiva) al basale e 6 e 12 mesi
¿ Marcatori urinari di danno tubulare (¿1-microglobulin, ¿2-microglobulin, RBP) e rapporto albumina-creatinina (ACR) al basale e 6 e 12 mesi
¿ Variazione della BMD al DXA scan al basale e dopo 12 mesi
¿ marcatori turn-over Osso (BMT) (CTX, P1NP) al basale e alla 6 e 12 mesi
; INSTI-mutations nel test di resistenza genotipica (TSL) al basale e al fallimento virologico; Percentuale di soggetti che hanno interrotto il farmaco di studio

E.5.2.1

Timepoint(s) of evaluation of this end point

48 weeks; 24 weeks; nd; 6 and 12 months; baseline and virologic failure; nd

48 settimane; 24 settimane; nd; 6 e 12 mesi; basale e fallimento virologico; nd

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

E.8.1.1

Randomised

E.8.1.2

Open

Yes

E.8.1.3

Single blind

E.8.1.4

Double blind

E.8.1.5

Parallel group

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

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.8.5.1

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

E.8.6.2

Trial being conducted completely outside of the EEA

Information not present in EudraCT

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

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:

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

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

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

F.4.2.2

In the whole clinical trial

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 patient, at the end of his participation in the study, will continue on a regular clinical follow-up care. The doctor will establish, according to the guidelines of good clinical practice, the possible continuation of therapy and the specific deadlines of execution of laboratoristic and clinical evaluations

Il paziente, al termine della sua partecipazione allo studio, proseguir¿ il regolare follow up clinico assistenziale, presso il proprio Centro di appartenenza. Il Curante stabilir¿, secondo le regole della buona pratica clinica, l¿eventuale prosieguo della terapia in atto e le specifiche tempistiche di effettuazione di valutazioni laboratoristiche e cliniche.

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

2016-09-15

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2016-11-14

P. End of Trial
P.	End of Trial Status	Ongoing

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IMP with orphan designation in the indication
Orphan Designation Number:
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