Clinical Trials Register

Summary
EudraCT Number:	2015-000570-35
Sponsor's Protocol Code Number:	01-2015
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:	2021-01-26
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

2015-000570-35

A.3

Full title of the trial

Prophylaxis of Hepatitis B reactivation in patients with HBV occult infection and rheumatological diseases candidates to immune suppressive treatments of finite duration.

PROFILASSI DELLA RIATTIVAZIONE DELL¿EPATITE B NEI PAZIENTI CON INFEZIONE
OCCULTA AFFETTI DA MALATTIE REUMATOLOGICHE CANDIDATI A TERAPIA IMMUNOSOPPRESSIVA DI DURATA DEFINITA

A.3.1

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

Prevention of re-onset of HBV infection in patients apparently cured affected by rheumatological diseases requiring finite duration treatments with drugs that impair the immune systems.

Prevenzione del risveglio dell'infezione da virus epatitico B in pazienti apparentemente guariti dall'infezione da HBV e affetti da malattie reumatologiche che richiedono trattamento di durata definita con farmaci che deprimono le difese immunitarie

A.3.2

Name or abbreviated title of the trial where available

Prophylaxis of OBI reactivation

Profilassi della riattivazione di OBI

A.4.1

Sponsor's protocol code number

01-2015

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	DIPARTIMENTO DI MEDICINA CLINICA E CHIRURGIA - UNIVERSITÀ DEGLI STUDI DI NAPOLI FEDERICO II
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 Science
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	AOU FEDERICO II NAPOLI
B.5.2	Functional name of contact point	U.O.C. DI MALATTIE VIRALI INCLUSO A
B.5.3	Address:
B.5.3.1	Street Address	Via Sergio Pansini 5
B.5.3.2	Town/ city	Napoli
B.5.3.3	Post code	80131
B.5.3.4	Country	Italy
B.5.4	Telephone number	0817463082
B.5.5	Fax number	0817463094
B.5.6	E-mail	grazia.tosone@unina.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	VIREAD - 245 MG 30 COMPRESSE RIVESTITE CON FILM IN FLACONE USO ORALE
D.2.1.1.2	Name of the Marketing Authorisation holder	GILEAD SCIENCE INTERNATIONAL LIMITED
D.2.1.2	Country which granted the Marketing Authorisation	Italy
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	VIREAD 30 CPR 245 MG
D.3.2	Product code	35565011
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.3.11 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

Occult Hepatitis B virus Infection (OBI) in patients with rheumatologic diseases candidate to treatment a finite duration (less than 18 months) with potent immune suppressive drugs

Infezione Occulta da virus epatitico B (OBI) nei pazienti affetti da malattie reumatologiche che necessitano di trattamento per una durata definita di tempo (18 mesi) con farmaci immunosoppressori potenti

E.1.1.1

Medical condition in easily understood language

Patients recovered from hepatitis B may have occult Hepatitis B virus Infection (OBI). When they undergo treatment with potent immune suppressive drugs because of reumathological diseases may develop

Soggetti guariti dall¿epatite B (diventati HBsAg negativi) possono avere ancora tracce del virus B nascosto nelle cellule del fegato; tale fenomeno ¿ chiamato infezione occulta da virus epatitico B. F

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	20.0
E.1.2	Level	HLT
E.1.2	Classification code	10037163
E.1.2	Term	Psoriatic arthropathies
E.1.2	System Organ Class	100000004859

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.1
E.1.2	Level	HLT
E.1.2	Classification code	10057212
E.1.2	Term	Hepatitis viral infections
E.1.2	System Organ Class	100000004862

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.0
E.1.2	Level	HLT
E.1.2	Classification code	10039075
E.1.2	Term	Rheumatoid arthritis and associated conditions
E.1.2	System Organ Class	100000004870

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 prevent by prophlactic administration of tenofovir the risk of reactivation of HBV (namely the reappearance of serum markers of viral replication such as HBsAg and HBV DNA), that can lead to serious and often fatal outcomes, in a subject previously tested to be HBsAg negative, anti-HBc positive, HBV DNA negative (OBI) affected by prevention in a setting of patients with OBI affected by rheumatological disease,who are candidate to treatment of finite duration (less than 18 months) with potent immune suppressive drugs, followed by UOC di Malattie Virali incluso AIDS DH and UOC Reumatologia of AOU ¿Federico II¿ of Napoli"

La riattivazione del virus B, spesso severa e fatale, viene favorita dalla condizione di
immunosoppressione iatrogena. E' necessario studiare le dimensioni del problema e la possibile prevenzione su una casistica di pazienti con OBI affetti da patologie reumatologiche, seguiti presso la AOU Federico II di Napoli dall¿UOC di Malattie Virali incluso AIDS DH e la Reumatologia.
Obiettivo generale dello studio sperimentale ¿ prevenire mediante profilassi con tenofovir il rischio di riattivazione di HBV (ossia della ricomparsa dei marcatori di replica virale quali HBsAg e di HBV DNA) che pu¿ esitare in quadri clinici severi e spesso fatali , nel sangue di soggetti precedentemente HBsAg negativi, anti-HBc positivi, HBV DNA negativi (pazienti con OBI) , affetti da malattie reumatologiche quali Artrite Reumatoide ed Artrite Psoriasica che richiedono schemi di terapia immunosoppressiva includenti i farmaci biologici per un periodo definito di tempo (18 mesi)

E.2.2

Secondary objectives of the trial

- Evaluate the rate of patients with OBI who reactivate HBV during the immune suppressive therapy
-Evaluate the rate of patients with OBI who reactivate HBV within 12month after end of immune suppressive therapy.
- Evaluate the rate of patients who withdraw protocol treatment because of HBV reactivation
- To prevent the severe ALT flares due to HBV reactivation, that cause premature discontinuation of immunesuppressive treatment and worsening of the rheumatological disease
- To compare the prophylaxis with tenofovir to the early therapy with antiviral drug soon after the onset of reactivation of hepatitis B .
-To prevent the risk of chronicity that is higher in this setting of patients respect to immune competent patients
- To charge the patient with HBV reactivation

-Valutare la percentuale di pazienti con riattivazione di OBI nel corso della terapia immunosoppressiva
-Valutare la percentuale di pazienti con riattivazione di OBI nell¿arco dei 12 mesi dopo sospensione della terapia immunosoppressiva
- Valutare la percentuale di pazienti che interrompono lo studio a causa di eventi avversi clinici e/o dei parametri di laboratorio legati alla riattivazione di HBV
- .Prevenire le forme severe di ipertransaminasemia dovute alla riattivazione di HBV, causa di prematura interruzione della terapia immunosoppressiva, con conseguente peggioramento della malattia reumatologica di base
- Comparare la profilassi con tenofovir versus l¿inizio della terapia antivirale solo dopo l¿avvenuta riattivazione ( replica virale e/o quadro di epatite acuta)
- Prevenire il rischio di cronicizzazione dell¿epatite B che ¿ maggiore nel paziente immunosoppresso
- Prendere in carico il paziente con riattivazione di HBV per la gestione diagnostico-terapeutica

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

- Age > 18 years;
- Patient affected by rheumatois arthrits and psoriasic arthrits, non responders to DMARDs (AR) or FANS/DMARDs (AP), candidates to immunesuppressive treatment with etanercept or adalimubab (finite therapy of 18 months)
- Written informed consent
- HBsAg negativity, anti-HBc positivity (with/without anti-HBs)
- HBV-DNA negativity (by Polymerase Chain Reaction)
- Normal liver tests (AST ed ALT <1,5 i valori max normali; PCHE, serum Albumin and Total Bilirubin levels within normal range)
- anti-HIV negativity
- anti-HCV negativity
- no Latent Tubercolosis infection (through IGRA test and skin test)
- Absence of controindications to Tenofovir
- Normal kidney function (ClCr > 80 ml/min, serum phospate > 2 mg/dl)
- No previous treatment with HBV drugs
- Adoption of adequate contraceptive measures in childbearing wowen

•Età superiore a 18 anni
•Paziente affetto da malattia articolare attiva, progressiva, non responder ai DMARDs (AR) o ai FANS/DMARDs (AP), eleggibile a terapia con etanercept o adalimubab per una durata di 18 mesi
•Consenso informato scritto
•HBsAg negatività, anti-HBc positività (con o senza anti-HBs positività)
•HBV-DNA negatività (testato mediante Polymerase Chain Reaction)
•Normali parametri di funzionalità epatica (AST ed ALT <1,5 i valori max normali; PCHE, Albumina sierica e Bilirubina totale nel range dei valori normali)
•Assenza di anticorpi contro il virus dell’immunodeficienza umana (HIV)
•Assenza di anticorpi contro il virus epatitico C (HCV)
•Assenza di TBC Latente (IGRA, TST)
•Assenza di controindicazioni al tenofovir
•Normali parametri di funzionalità renale (clearance della creatinina > 80 ml/min, fosfato sierico > 2 mg/dl)
•Nessun precedente trattamento con farmaci antivirali per l’epatite B
•Adozione di adeguati mezzi contraccettivi di barriera nei pazienti di sesso femminile

E.4

Principal exclusion criteria

- Age < 18 years;
- Patient not affected by rheumatois arthrits and psoriasic arthrits and not candidate to immunesuppressive treatment including
etanercept or adalimubab (finite therapy of 18 months)
- No written informed consent
- Previous succesfull HBV vaccination
- HBsAg positivity
- Anti-HBc negativity
- Abnormal liver tests (AST ed ALT >1,5 max normal values; PCHE, serum Albumin and Total Bilirubin levels outside normal range)
- anti-HIV positivity
- anti-HCV positivity
- Latent Tubercolosis infection
- Controindications to Tenofovir
- Abnormal kidney function ( creatinine clearance < 80 ml/min, serum phosphate < 2 mg/dl)
- Previous treatment with HBV drugs
- Refusal of adoption of adequate contraceptive measures in childbearing wowen
- Pregnancy
- Breastfeeding

•Età inferiore ai 18 anni
•Paziente non affetto da malattia articolare attiva, progressiva e non eleggibile a terapia con etanercept o adalimubab per una durata di 18 mesi
•Assenza di consenso scritto informato
•Pregressa vaccinazione anti-epatite B
•Positività per HBsAg
•Negatività per anti-HBc
•Alterati parametri di funzionalità epatica (AST ed ALT >1,5 i valori max normali; PCHE, Albumina sierica e Bilirubina totale al di fuori del range dei valori normali)
•Alterazioni dei parametri di funzionalità renale (clearance della creatinina < 80 ml/min, fosfato sierico < 2 mg/dl)
•Anti-HIV positività
•Anti-HCV positività
•Presenza di Tbc latente
•Pregressa terapia antivirale per l’epatite B
•Presenza di controindicazioni al tenofovir
•Rifiuto di adottare adeguate misure contracettive nelle donne in età fertile
-Gravidanza
-Allattamento

E.5 End points

E.5.1

Primary end point(s)

Percentage of patients with serum HBVDNA levels below 20 UI/L (PCR negative) and HBsAg- negativity at the end of the study

Percentuale di pazienti con livelli sierici di HBV DNA < 20 UI/ml e con HBsAg negativo alla fine dello studio

E.5.1.1

Timepoint(s) of evaluation of this end point

30 months (namely 12 months after the withdrawal of immune suppressive therapy)

30 mesi (ossia 12 mesi dopo la sospensione della terapia immunosoppressiva)

E.5.2

Secondary end point(s)

Percentage of patients with normal AST and ALT levels (serum aminotransferase) <1,5 max normal value at the end of the study; Percentage of patients with normal PCHE levels (5400-13200 U/L) at the end of the study; Percentage of patients with normal Albumin levels (3,6 -. 5,2 g/dL) at the end of the study; Percentage of patients with normal Total Bilirubin levels (0,2 ¿ 1,1 mg/dL) at the end of the study; Percentage of patients with creatinine clearance in the normal range (> 80 ml/min) at the end of the study; Percentage of patients with serum phophaste levels in the normal range (>2 mg/dl) at the end of the study; Percentage of patients with at least a 6% decrease from baseline in bone mineral density at the end of the study; Percentage of patients who withdraw immune suppressive therapy because of events related to HBV reactivation; Percentage of patients in whom HBV reactivation progress to chronicity; Percentage of patients charged by UOC Malattie Virali incluso AIDS DH because of HBV-related events

Percentuale di pazienti con livelli di AST ed ALT (transaminasi sieriche) <1,5 i valori max normali alla fine dello studio; Percentuale di pazienti con livelli sierici di PCHE nel range dei valori normali (5400-13.200 U/L) alla fine dello studio; Percentuale di pazienti con livelli sierici di Albumina nel range dei valori normali (3,6 -. 5,2 g/dL) alla fine dello studio; Percentuale di pazienti con livelli sierici di bilirubina totale nel range dei valori normali (0,2 ¿ 1,1 mg/dL) alla fine dello studio; Percentuale di pazienti con valori di clearance della creatinina nei limiti della norma (> 80 ml/min) alla fine dello studio; Percentuale di pazienti con valori di fosfato sierico nei limiti della norma (>2 mg/dl) alla fine dello studio; Percentuale di pazienti con diminuzione della densit¿ minerale ossea (almeno 6%) alla fine dello studio rispetto al valore baseline; Percentuale di pazienti che interrompono la terapia immunosoppressiva per eventi correlati alla riattivazione di HBV; Percentaule di pazienti in cui l'infezione da HBV riattivata va incontro a cronicizzazione; Percentuale di pazienti presi in carico presso l'UOC di Malattie Virali incluso AIDS DH per eventi HBV-correlati

E.5.2.1

Timepoint(s) of evaluation of this end point

30 months (namely 12 months after the withdrawal of immune suppressive therapy); 30 months (namely 12 months after the withdrawal of immune suppressive therapy); 30 months (namely 12 months after the withdrawal of immune suppressive therapy); 30 months (namely 12 months after the withdrawal of immune suppressive therapy); 30 months (namely 12 months after the withdrawal of immune suppressive therapy); 30 months (namely 12 months after the withdrawal of immune suppressive therapy); 30 months (namely 12 months after the withdrawal of immune suppressive therapy); 30 months (namely 12 months after the withdrawal of immune suppressive therapy); 30 months (namely 12 months after the withdrawal of immune suppressive therapy); 30 months (namely 12 months after the withdrawal of immune suppressive

30 mesi (ossia 12 mesi dopo la sospensione della terapia immunosoppressiva); 30 mesi (ossia 12 mesi dopo la sospensione della terapia immunosoppressiva)

; 30 mesi (ossia 12 mesi dopo la sospensione della terapia immunosoppressiva); 30 mesi (ossia 12 mesi dopo la sospensione della terapia immunosoppressiva); 30 mesi (ossia 12 mesi dopo la sospensione della terapia immunosoppressiva); 30 mesi (ossia 12 mesi dopo la sospensione della terapia immunosoppressiva); 30 mesi (ossia 12 mesi dopo la sospensione della terapia immunosoppressiva); 30 mesi (ossia 12 mesi dopo la sospensione della terapia immunosoppressiva)

; 30 mesi (ossia 12 mesi dopo la sospensione della terapia immunosoppressiva); 30 mesi (ossia 12 mesi dopo la sospensione della terapia immunosoppressiva)

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

E.6.4

Safety

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

Yes

E.8.1.3

Single blind

E.8.1.4

Double blind

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

E.8.2.3

Other

Yes

E.8.2.3.1

Comparator description

Nessun trattamento

No treatment

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

Yes

E.8.4

The trial involves multiple sites in the Member State concerned

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)

At the end of the study all the patients will continue to be monitored according to a schedule of clinical and laboratory and imaging examinations as stated by national and international guidelines in the rheumatological setting for patients with OBI
undergoing immune suppression drug-induced, including also tets for serum markers of HBV replication. Patients developing HBV reactivation will be charged at our UOC di di Malattie Virali incluso AIDS DH

Al termine della partecipazione allo studio tutti i pazienti continueranno ad essere sottoposti ad un calendario di controlli clinici, laboratoristici e strumentali che prevede oltre ai routinari esami di controllo previsti periodicamente in ambito reumatologico, anche la determinazione periodica dei marcatori di replica virale di HBV come raccomandato dalle linee guida Italiane ed internazionali nei pazienti con OBI sottoposti ad immunodepressione iatrogena. I pazienti che avranno eventualmente

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

2015-11-06

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2016-02-10

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

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