Clinical Trials Register

Summary
EudraCT Number:	2014-005388-34
Sponsor's Protocol Code Number:	SOF
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:	2016-09-29
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

2014-005388-34

A.3

Full title of the trial

Single arm prospective clinical study to evaluate the efficacy of combination therapy sofosbuvir+ribavirin+peg-interferon in experienced patients with HCV-GT1

Studio clinico prospettico a braccio singolo di fase IV per la valutazione dell’efficacia e della sicurezza della terapia combinata Sofosbuvir + Ribavirina + Interferone Peghilato in pazienti con epatite cronica da HCV GT1 che hanno già fallito un precedente ciclo di duplice terapia con Ribavirina + Interferone Peghilato

A.3.1

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

Single arm prospective clinical study to evaluate the efficacy of combination therapy sofosbuvir+ribavirin+peg-interferon in experienced patients with HCV-GT1

A.3.2

Name or abbreviated title of the trial where available

IN-US-334-0141 - SOF

A.4.1

Sponsor's protocol code number

SOF

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	AZIENDA OSPEDALIERA DI PADOVA
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 S.R.L. - Italia
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	Medicina Generale
B.5.2	Functional name of contact point	U.O. TERAPIA EPATITI CRONICHE VIRAL
B.5.3	Address:
B.5.3.1	Street Address	via Giustiniani, 2
B.5.3.2	Town/ city	Padova
B.5.3.3	Post code	35128
B.5.3.4	Country	Italy
B.5.4	Telephone number	0498212293
B.5.5	Fax number	0498211826
B.5.6	E-mail	alfredo.alberti@unipd.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	SOVALDI - 400 MG - COMPRESSA RIVESTITA CON FILM - FLACONE (HDPE) - 28 COMPRESSE
D.2.1.1.2	Name of the Marketing Authorisation holder	GILEAD SCIENCES 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	SOVALDI
D.3.2	Product code	043196
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	SOFOSBUVIR
D.3.9.1	CAS number	1190307-88-0
D.3.9.2	Current sponsor code	SOF
D.3.9.3	Other descriptive name	SOFOSBUVIR
D.3.9.4	EV Substance Code	SUB121170
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	400
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	PEGASYS - 180MCG-SOLUZ. INIETTABILE-USO SOTTOCUT.-PENNA PRERIEMPITA-0.5 ML (360MCG/ML) 12 PENNE PRERIEMPITE
D.2.1.1.2	Name of the Marketing Authorisation holder	ROCHE REGISTRATION 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	PEGASYS
D.3.2	Product code	035683
D.3.4	Pharmaceutical form	Solution for injection
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Subcutaneous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	PEGINTERFERON ALFA-2A
D.3.9.1	CAS number	198153-51-4
D.3.9.2	Current sponsor code	PEG
D.3.9.4	EV Substance Code	SUB16452MIG
D.3.10	Strength
D.3.10.1	Concentration unit	µg microgram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	180
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	No
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	Yes
	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	Yes
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	Yes
D.2.1.1.1	Trade name	REBETOL - 200 MG 84 CAPSULE RIGIDE IN BLISTER
D.2.1.1.2	Name of the Marketing Authorisation holder	MERCK SHARP e DOHME 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	RIBAVIRINA
D.3.2	Product code	34459014
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	RIBAVIRINA
D.3.9.1	CAS number	36791-04-5
D.3.9.2	Current sponsor code	RIBA
D.3.9.3	Other descriptive name	RIBAVIRIN
D.3.9.4	EV Substance Code	SUB10297MIG
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	1000 to 1200
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

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

chronic hepatitis HCV GT1 who have already failed a prior course of dual therapy with pegylated interferon + ribavirin

epatite cronica da HCV GT1 che hanno già fallito un precedente ciclo di duplice terapia con Ribavirina + Interferone Peghilato

E.1.1.1

Medical condition in easily understood language

chronic hepatitis HCV GT1 already treated

epatite cronica da HCV GT1 già trattati

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	19.0
E.1.2	Level	HLT
E.1.2	Classification code	10057212
E.1.2	Term	Hepatitis viral infections
E.1.2	System Organ Class	10021881 - Infections and infestations

E.1.2 Medical condition or disease under investigation

E.1.2	Version	19.0
E.1.2	Level	PT
E.1.2	Classification code	10019744
E.1.2	Term	Hepatitis C
E.1.2	System Organ Class	10021881 - Infections and infestations

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, as virological response at 12 weeks after the end of treatment (SVR-12), of the combined therapy Sofosbuvir + Ribavirin + pegylated interferon in patients with chronic hepatitis HCV genotype 1 who have failed a prior course of treatment with ribavirin and interferon alpha, assuming the achievement of an effectiveness of 71% according to what is predicted by the model FDA

Valutare l’efficacia, come risposta virologica a 12 settimane dal termine del trattamento (SVR-12), della terapia combinata Sofosbuvir + Ribavirina + Interferone Peghilato in soggetti affetti da epatite cronica HCV di genotipo 1, che abbiano fallito un precedente ciclo di trattamento con Ribavirina e Interferone alfa, ipotizzando il raggiungimento di una efficacia del 71% in base a quanto stimato dal modello FDA

E.2.2

Secondary objectives of the trial

Evaluate the effectiveness (SVR-12) of the combined treatment Sofosbuvir + pegylated interferon + ribavirin in relation to the viral response to the previous cycle of dual therapy (null-response, relapsers, partial responders).
• Evaluate the effectiveness (SVR-12) of the combined treatment Sofosbuvir + pegylated interferon + ribavirin in relation to the stage of liver disease (defined as METAVIR fibrosis stage) and the presence or absence of cirrhosis.
• Confirm the safety profile and tolerability of the combined treatment Sofosbuvir + pegylated interferon + ribavirin in patients with chronic hepatitis HCV genotype 1 who have failed at least six months a previous course of treatment with ribavirin and pegylated interferon and which do not show contraindications to the use of pegylated interferon and ribavirin.
• Evaluate the proportion of interruption of the course of treatment due to adverse events

Valutare l’efficacia (SVR-12) del trattamento combinato Sofosbuvir + Ribavirina + Interferone Peghilato in relazione alla risposta virale al ciclo precedente di duplice terapia (null-response, relapser, partial-responder).
• Valutare l’efficacia (SVR-12) del trattamento combinato Sofosbuvir + Ribavirina + Interferone Peghilato in relazione allo stadio della malattia epatica (definita come stadio di fibrosi METAVIR) e alla presenza o meno di cirrosi.
• Confermare il profilo di sicurezza e la tollerabilità del trattamento combinato Sofosbuvir + Ribavirina + Interferone Peghilato in soggetti affetti da epatite cronica HCV di genotipo 1, che abbiano fallito da almeno sei mesi un precedente ciclo di trattamento con Ribavirina e Interferone Peghilato e che non presentino controindicazioni all’uso di Interferone Peghilato e di Ribavirina.
• Valutare la proporzione d’interruzione del ciclo di trattamento a causa di eventi avversi

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Subjects, male or female, aged> 18 years.
2. Subjects infected with HCV genotype 1 chronic hepatitis or compensated cirrhosis (Child A).
3. Previous treatment with dual therapy (pegylated interferon + ribavirin) without obtaining SVR (relapsers, partial, null responders).
4. Positivity for serum HCV-RNA.
5. Evaluation recent (within 6 months) the degree of liver fibrosis with validated method (biopsy or Fibroscan).
6. Informed consent form with signed and dated

1. Soggetti, maschio o femmina, di età >18 anni.
2. Soggetti con infezione da HCV genotipo 1 con epatite cronica o cirrosi compensata (Child A).
3. Precedente trattamento con duplice terapia (Ribavirina+ Interferone Peghilato) senza ottenimento di SVR (Relapser, partial, null responder).
4. Positività sierica per HCV-RNA.
5. Valutazione recente (entro 6 mesi) del grado di fibrosi epatica con metodo validato (biopsia o Fibroscan).
6. Consenso informato con modulo firmato e datato

E.4

Principal exclusion criteria

1. decompensated liver disease, or a history of heart failure, ascites, encephalopathy, HCC.
2. Inadequate tolerability ribavirin and/or pegylated interferon therapy during the previous attempt.
3. Any known contraindication to ribavirin and / or pegylated interferon and / or Sofosbuvir.
4. Any severe comorbidities that in the opinion of Clinical Researcher may compromise the safety of the treatment.
5. Pregnancy ongoing or breastfeeding. Pregnancy is highly NOT recommended in these patients, and if it is programmed patients are excluded from the study. If sexually active, patients should use an effective method of birth control.
6. Other concomitant treatment against viral hepatitis HCV.
7. Patients taking medications that interfere with ribavirin, pegylated interferon and Sofosbuvir (cytochrome P450, azathioprine, methadone, telbivudine and anti-HIV agents).

1. Malattia epatica scompensata, o precedenti episodi di scompenso, ascite, encefalopatia, HCC.
2. Inadeguata tollerabilità a Ribavirina e/o Interferone Peghilato durante il precedente tentativo terapeutico.
3. Qualsiasi controindicazione nota a Ribavirina e/o Interferone Peghilato e/o a Sofosbuvir.
4. Qualsiasi comorbilità severa che a giudizio del Ricercatore Clinico possa compromettere la sicurezza del trattamento.
5. Gravidanza in corso o l'allattamento al seno. La gravidanza è altamente sconsigliata in queste pazienti e se è programmata le pazienti sono esclusi dallo studio. Se sessualmente attivi, i pazienti devono utilizzare un efficace metodo di controllo delle nascite.
6. Altro trattamento concomitante contro l’epatite virale HCV.
7. I pazienti che assumono farmaci che interferiscono con Ribavirina, Interferone Peghilato e Sofosbuvir (inibitori del citocromo P450, azatioprina, metadone, telbivudina e agenti anti-HIV).

E.5 End points

E.5.1

Primary end point(s)

virological response at 12 weeks after the end of treatment (proportion of SVR-12, or negative viremia) of combination therapy pegylated interferon + ribavirin + Sofosbuvir

Risposta virologica a 12 settimane dal termine del trattamento (proporzione di SVR-12, ovvero negativizzazione della viremia) della terapia combinata Sofosbuvir + Ribavirina + Interferone Peghilato

E.5.1.1

Timepoint(s) of evaluation of this end point

at 12 weeks after the end of treatment

12 settimane dal termine del trattamento

E.5.2

Secondary end point(s)

1.SVR-12 combined treatment of pegylated interferon + ribavirin + Sofosbuvir in relation to the viral response to the previous cycle of dual therapy (null-response, relapsers, partial responders)
2.SVR-12 combined treatment of pegylated interferon + ribavirin + Sofosbuvir in relation to the stage of liver disease (fibrosis / cirrhosis).
3.Adverse events and serious adverse events and tolerability of the combined treatment Sofosbuvir + pegylated interferon + ribavirin.
4Proportion of interruption of the course of treatment due to adverse events.

1.SVR-12 del trattamento combinato Sofosbuvir + Ribavirina + Interferone Peghilato in relazione alla risposta virale al ciclo precedente di duplice terapia (null-response, relapser, partial-responder).
2.SVR-12 del trattamento combinato Sofosbuvir + Ribavirina + Interferone Peghilato in relazione allo stadio della malattia epatica (fibrosi/cirrosi).
3.Eventi avversi ed eventi avversi seri e la tollerabilità del trattamento combinato Sofosbuvir + Ribavirina + Interferone Peghilato.
4.Proporzione d’interruzione del ciclo di trattamento a causa di eventi avversi.

E.5.2.1

Timepoint(s) of evaluation of this end point

1)at 12 weeks EOT
2)at 12 weeks EOT
3)EOT
4)EOT

1)12 settimane dalla fine del trattamento
2)12 sett EOT
3)EOT
4)EOT

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

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)

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

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

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.8.6 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

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:

100

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

120

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)

Patients who fail to reach the SVR-12 will come into treatment protocols with new antiviral drugs, when available.

I soggetti che non raggiungeranno la SVR-12 entreranno in protocolli terapeutici con nuovi farmaci antivirali, quando disponibili.

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

2015-05-20

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2015-02-12

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

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