Clinical Trials Register

Summary
EudraCT Number:	2019-002319-25
Sponsor's Protocol Code Number:	LOXO-RET-18037
National Competent Authority:	Italy - Italian Medicines Agency
Clinical Trial Type:	EEA CTA
Trial Status:	Trial now transitioned
Date on which this record was first entered in the EudraCT database:	2021-09-01
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

2019-002319-25

A.3

Full title of the trial

A Multi-Center Expanded Access Program (EAP) for the Treatment of Patients with Locally Advanced or Metastatic Solid Tumors with Rearranged During
Transfection (RET) Activation (LIBRETTO-201)

Programma di accesso allargato (EAP) multicentrico per il trattamento di pazienti affetti da tumori solidi localmente avanzati o metastatici con attivazione del gene riarrangiato durante la trasfezione (RET) (LIBRETTO-201)

A.3.1

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

A multiple center expanded access program (EAP) for the treatments of patients with advanced solid tumors

Programma di accesso allargato multicentrico per il trattamento di pazienti con tumori solidi in stadio avanzato.

A.3.2

Name or abbreviated title of the trial where available

LIBRETTO-201

A.4.1

Sponsor's protocol code number

LOXO-RET-18037

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	LOXO ONCOLOGY INCORPORATED
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	Loxo Oncology, 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	United BioSource Corporation, S.L.U.
B.5.2	Functional name of contact point	Clinical Trials Information
B.5.3	Address:
B.5.3.1	Street Address	Calle Monte Esquinza 30, Bajo izquierda
B.5.3.2	Town/ city	Madrid
B.5.3.3	Post code	28010
B.5.3.4	Country	Spain
B.5.6	E-mail	UBC.EURegulatory@ubc.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/3/18/2071
D.3 Description of the IMP
D.3.1	Product name	Selpercatinib
D.3.2	Product code	[LOXO-292 : liquid suspension]
D.3.4	Pharmaceutical form	Powder and solvent for oral solution
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	Selpercatinib
D.3.9.2	Current sponsor code	LOXO-292
D.3.9.4	EV Substance Code	SUB186998
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	20
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.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	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/3/18/2071
D.3 Description of the IMP
D.3.1	Product name	Selpercatinib
D.3.2	Product code	[LOXO-292 : 30% simple blend (40mg)]
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	Selpercatinib
D.3.9.2	Current sponsor code	LOXO-292
D.3.9.4	EV Substance Code	SUB186998
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	40
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.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	Yes
D.2.5.1	Orphan drug designation number	EU/3/18/2071
D.3 Description of the IMP
D.3.1	Product name	Selpercatinib
D.3.2	Product code	[LOXO-292 : 30% simple blend (80mg)]
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	Selpercatinib
D.3.9.2	Current sponsor code	LOXO-292
D.3.9.4	EV Substance Code	SUB186998
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	80
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

Advanced or metastatic solid tumors with activating Rearranged During Transfection (RET) alterations (and other evidence of RET activation)

Tumori solidi localmente avanzati o metastatici con attivazione del gene riarrangiato durante la trasfezione (RET), (e altra evidenza di attivazione di RET)

E.1.1.1

Medical condition in easily understood language

Advanced or metastatic solid tumors with activating RET alterations

Tumori solidi localmente avanzati o metastatici con alterazioni attivanti di RET

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	21.0
E.1.2	Level	LLT
E.1.2	Classification code	10049280
E.1.2	Term	Solid tumour
E.1.2	System Organ Class	10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)

E.1.2 Medical condition or disease under investigation

E.1.2	Version	21.1
E.1.2	Level	PT
E.1.2	Classification code	10061873
E.1.2	Term	Non-small cell lung cancer
E.1.2	System Organ Class	10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)

E.1.2 Medical condition or disease under investigation

E.1.2	Version	21.1
E.1.2	Level	PT
E.1.2	Classification code	10027105
E.1.2	Term	Medullary thyroid cancer
E.1.2	System Organ Class	10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)

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 provide access to Selpercatinib for patients with locally advanced or metastatic solid tumors with activating RET alterations (and other evidence of RET activation) who are 18 years of age or older.

Garantire l’accesso a Selpercatinib a pazienti di età pari o superiore a 18 anni affetti da tumori solidi localmente avanzati o metastatici con alterazioni attivanti di RET (e altra evidenza di attivazione di RET)

E.2.2

Secondary objectives of the trial

To determine the safety profile and tolerability of Selpercatinib.

Determinare il profilo di sicurezza e la tollerabilità di Selpercatinib

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

Major Inclusion Criteria:
1. Patients with a locally advanced or metastatic solid tumor with RET activation who:
• Are not eligible for an ongoing selpercatinib clinical trial (e.g., for clinical, geographic or financial reasons or due to cohort closure), but are deemed appropriate candidates to receive selpercatinib treatment by the Investigator and the Sponsor, and
• Have progressed on or are intolerant to standard therapy, or
• No standard therapy exists, or
• In the opinion of the Investigator, are not candidates for or who would be unlikely to derive significant clinical benefit from standard therapy
Patients eligible for LIBRETTO-001 and/ or Phase 3 trials who are being considered for the EAP must be discussed with the Medical Monitor prior to screening.
2. Evidence of an activating RET gene alteration from a laboratory with Clinical Laboratory Improvement Act (CLIA), International Organization for Standardization (ISO)/independent ethics committee (IEC), College of American Pathologists (CAP), or other similar certification.
3. Eighteen years of age or older at the time of consent.
4. Adequate hematologic, renal and hepatic function as defined in Section 6.1.
5. Ability to provide consent.
6. Provision of a signed informed consent prior to any protocol specific procedures. Patients already receiving selpercatinib who enroll in this protocol must be reconsented and sign the consent form for this expanded access protocol.
7. Patients who are deemed eligible by the Sponsor’s medical monitor.
8. Willingness of men and women of reproductive potential to observe double effective birth control methods, defined as one used by the patient and another by his/her partner, for the duration of treatment and for 3 months following the last dose of study treatment (refer to Section 1.6.3).

Principali criteri di inclusione:

1. Pazienti affetti da un tumore solido localmente avanzato o metastatico con attivazione di RET che:
• non sono eleggibili a partecipare a una sperimentazione clinica in corso su Selpercatinib (per es., per motivi clinici, geografici o economici o a causa della chiusura della coorte), ma sono ritenuti candidati idonei a ricevere un trattamento con Selpercatinib dallo sperimentatore e dallo sponsor, e
• hanno sviluppato progressione o sono intolleranti alla terapia standard, oppure
• non dispongono di alcuna terapia standard, oppure
• a giudizio dello sperimentatore, non sono candidati o verosimilmente non trarrebbero un beneficio clinico significativo dalla terapia standard.
I pazienti eleggibili allo studio LIBRETTO-001 e/o studio di Fase 3 vengono presi in considerazione per l’EAP devono essere esaminati con il responsabile del monitoraggio medico prima dello screening.
2. Evidenza di alterazione attivante del gene RET fornita da un laboratorio dotato di certificazione secondo la Legge per il miglioramento dei laboratori clinici (CLIA), la International Organization for Standardization (ISO)/il Comitato etico indipendente (CE indipendente), il College of American Pathologists (CAP) o altra certificazione simile.
3. Età pari o superiore a diciotto anni alla data del consenso.
4.Funzione ematologica, renale ed epatica adeguata come definito nella sezione 6.1.
5. Capacità di fornire consenso.
6. Sottoscrizione di un consenso informato prima di qualsiasi procedura specifica del protocollo. I pazienti già in terapia con selpercatinib che si arruolano in questo protocollo dovranno fornire un nuovo consenso e sottoscrivere il modulo di consenso per il presente protocollo di accesso allargato.
7. Pazienti giudicati eleggibili dal responsabile del monitoraggio medico dello sponsor.
8. Per gli uomini e le donne potenzialmente fertili, disponibilità ad attenersi a misure contraccettive doppiamente efficaci, definito come uno utilizzato dal paziente ed un altro dal partner per tutta la durata del trattamento e per 3 mesi dopo l’ultima dose di trattamento dello studio (fare riferimento alla sezione 4.1). .

E.4

Principal exclusion criteria

Major Exclusion Criteria:
1. Investigational agent (via clinical trial) or anticancer therapy within 5 half-lives or 2 weeks (whichever is shorter) prior to planned start of selpercatinib unless considered by the Investigator to be safe, within the best interest of the patient and with prior Sponsor approval.
2. Clinically significant active cardiovascular disease (including NYHA class III/IV heart failure, stroke, severe valvular disease or uncontrolled hypertension defined as = 140/80 sustained over multiple readings) or history of myocardial infarction within 6 months prior to Cycle 1, Day 1 (C1D1); ongoing cardiomyopathy; or current prolongation of the QT interval corrected for heart rate using Fridericia’s formula (QTcF) interval > 470 msec. Patients who meet this criteria may be enrolled (with a modified dosing strategy) if a clinical rationale exists which is reviewed and agreed upon by the Sponsor.
3. Current treatment with strong cytochrome P450 3A4 (CYP3A4) inhibitors or inducers (refer to Section 1.6.3).
4. Current treatment with proton-pump inhibitors (PPIs). Note: Treatment with PPIs must be stopped 1 or more weeks prior to the first dose of selpercatinib.
Complete EAP eligibility criteria are presented in Section 4.

Principali criteri di esclusione:
1. Agente sperimentale (ricevuto attraverso la partecipazione a una sperimentazione clinica) o terapia antitumorale entro 5 emivite o 2 settimane (a seconda di quale sia il periodo più breve) prima dell’avvio programmato di selpercatinib, salvo laddove lo sperimentatore li ritenga sicuri e nel miglior interesse del paziente e previa approvazione dello sponsor.
2. Malattia cardiovascolare clinicamente significativa in fase attiva (tra cui insufficienza cardiaca di classe III/IV secondo la New York Heart Association [NYHA], ictus, valvulopatia grave o ipertensione non controllata, definita come valori pressori =140/80 mantenuti nell’arco di più letture) o anamnesi di infarto miocardico entro 6 mesi prima del Ciclo 1, Giorno 1 (C1G1); cardiomiopatia in corso; o attuale prolungamento dell’intervallo QT corretto per la frequenza cardiaca utilizzando la formula di Fridericia (QTcF) a un valore >470 msec. I pazienti che soddisfano questo criterio possono essere arruolati (con una strategia di dosaggio modificata) se esiste un razionale clinico che venga esaminato e approvato dallo sponsor.
3. Attuale trattamento con inibitori o induttori forti del citocromo P450 3A4 (CYP3A4) (fare riferimento alla Sezione 1.6.1).
4. Attuale trattamento con inibitori della pompa protonica (IPP). Nota: Il trattamento con IPP deve essere interrotto 1 o più settimane prima della prima dose di selpercatinib.
I criteri di eleggibilità completi dell’EAP sono presentati nella Sezione 4.

E.5 End points

E.5.1

Primary end point(s)

As an expanded access program (EAP), this program is not designed to assess the effectiveness of selpercatinib. Data collection will be limited to information needed to determine eligibility, describe patient demographics and exposure, collect safety information, and meet regulatory reporting requirements.

Trattandosi di un EAP, questo programma non è disegnato per valutare l’efficacia di selpercatinib. La raccolta dati sarà limitata alle informazioni necessarie per determinare l’idoneità, descrivere i dati demografici e l’esposizione dei pazienti, raccogliere informazioni di sicurezza e soddisfare i requisiti regolatori di segnalazione. Le statistiche saranno riassunte in maniera descrittiva.

E.5.1.1

Timepoint(s) of evaluation of this end point

Not Applicable

Non applicabile

E.5.2

Secondary end point(s)

Not Applicable

Non applicabile

E.5.2.1

Timepoint(s) of evaluation of this end point

Not Applicable

Non applicabile

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

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)

Yes

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

Yes

E.7.1.3.1

Other trial type description

Expanded Access Program

Programma ad accesso allargato

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

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

Yes

E.8.1.7.1

Other trial design description

programma di accesso allargato

expanded access program

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

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

Information not present in EudraCT

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

Hong Kong

Israel

Japan

New Zealand

Singapore

United States

France

Germany

Italy

Poland

Spain

Switzerland

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

Marketing Authorization in all countries

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:

350

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

100

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

150

F.4.2.2

In the whole clinical trial

450

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)

Routine standard of care

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

2019-12-31

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2019-11-07

P. End of Trial
P.	End of Trial Status	Trial now transitioned

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IMP with orphan designation in the indication
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