Clinical Trials Register

Summary
EudraCT Number:	2013-000536-10
Sponsor's Protocol Code Number:	00103311
National Competent Authority:	Greece - EOF
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2014-01-21
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

Greece - EOF

A.2

EudraCT number

2013-000536-10

A.3

Full title of the trial

A Phase 3, Randomized, Open Label Study Investigating the Efficacy of the BiTE® Antibody Blinatumomab Versus Standard of Care Chemotherapy in Adult Subjects With Relapsed/Refractory B-precursor Acute Lymphoblastic Leukemia (ALL) (TOWER Study)

«Μία τυχαιοποιημένη, ανοιχτή κλινική μελέτη φάσης 3 για τη διερεύνηση
της αποτελεσματικότητας του αντισώματος BiTE® μπλινατουμομάμπη έναντι
συνήθους χημειοθεραπείας σε ενήλικους ασθενείς με
υποτροπιάζουσα/ανθεκτική πρόδρομη Β-οξεία λεμφοβλαστική λευχαιμία
(ΟΛΛ) (μελέτη TOWER)»

A.3.1

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

Clinical Phase 3 Study to evaluate the comparative efficacy of the bispecific antibody blinatumomab versus standard of care chemotherapy, in adult subjects with Acute Lymphoblastic Leukemia that did not respond to previous therapy or that relapsed after initially successful previous therapy

«Kλινική μελέτη φάσης 3 για την αξιολόγηση της συγκριτικής
αποτελεσματικότητας του αντισώματος BiTE® μπλινατουμομάμπη έναντι
συνήθους χημειοθεραπείας σε ενήλικους ασθενείς με
υποτροπιάζουσα/ανθεκτική πρόδρομη Β-οξεία λεμφοβλαστική λευχαιμία
(ΟΛΛ).»

A.3.2

Name or abbreviated title of the trial where available

TOWER Study

A.4.1

Sponsor's protocol code number

00103311

A.5.2

US NCT (ClinicalTrials.gov registry) number

NCT02013167

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	Amgen 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	Amgen 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	Amgen (EUROPE) GmbH
B.5.2	Functional name of contact point	IHQ medical Info-Clinical Trials
B.5.3	Address:
B.5.3.1	Street Address	Dammstrasse 23, P.O. Box 1557
B.5.3.2	Town/ city	Zug
B.5.3.3	Post code	CH-6300
B.5.3.4	Country	Switzerland
B.5.6	E-mail	MedinfoInternational@amgen.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/3/09/650
D.3 Description of the IMP
D.3.1	Product name	Blinatumomab
D.3.2	Product code	AMG 103, MT103
D.3.4	Pharmaceutical form	Powder for solution for infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Blinatumomab
D.3.9.1	CAS number	853426-35-4
D.3.9.2	Current sponsor code	AMG 103
D.3.9.3	Other descriptive name	BLINATUMOMAB
D.3.9.4	EV Substance Code	SUB35403
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	30.3 (clinical) to 38.5 (commercial)
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)	Yes
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.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

Adult patients with relapsed and/or refractory B-precursor Acute lymphoblastic leukaemia

Eνήλικοι ασθενείς με υποτροπιάζουσα/ανθεκτική (Υ/Α) πρόδρομη Β-ΟΛΛ

E.1.1.1

Medical condition in easily understood language

Adult patients with Acute lymphoblastic leukaemia - a cancer of the blood and marrow - which did not completely respond to treatment or has relapsed after first responding to therapy

παρακαλούμε όπως δείτε το άνωθεν πεδίο λόγω έλλεψης χώρου

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	19.0
E.1.2	Level	LLT
E.1.2	Classification code	10000845
E.1.2	Term	Acute lymphoblastic leukemia
E.1.2	System Organ Class	100000004864

E.1.2 Medical condition or disease under investigation

E.1.2	Version	19.0
E.1.2	Level	LLT
E.1.2	Classification code	10063625
E.1.2	Term	Acute lymphoblastic leukemia recurrent
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

evaluate the effect of blinatumomab on overall survival (OS) when compared to standard of care (SOC) chemotherapy

Η εκτίμηση της επίδρασης της μπλινατουμομάμπης στη συνολική
επιβίωση (OS) σε σύγκριση με τη συνήθη (SOC) χημειοθεραπεία

E.2.2

Secondary objectives of the trial

• evaluate hematological response induced by blinatumomab when compared to SOC chemotherapy
• evaluate event free survival induced by blinatumomab when compared to SOC chemotherapy
• evaluate minimal residual disease (MRD) remissions induced by blinatumomab when compared to SOC chemotherapy
• estimate the effect of blinatumomab on patient reported outcomes, global health status/quality of life (QoL) using the EORTC QLQ-C30
• evaluate the incidence of allogeneic hematopoietic stem cell transplantation (alloHSCT) and 100-day mortality following HSCT in blinatumomab treated subjects when compared to SOC chemotherapy
• evaluate the safety of blinatumomab when compared to SOC chemotherapy
Exploratory:
• evaluate blinatumomab exposure-response relationships for efficacy and safety
• assess presence of ALL symptoms as measured by Acute Lymphoblastic Leukemia Symptom Scale (ALLSS)
• assess the potential for mutations in the tumor DNA to predict resistance to blinatumomab treatment

παρακαλούμε όπως δείτε το άνωθεν πεδίο λόγω έλλεψης χώρου

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Subjects with Philadelphia negative B-precursor ALL, with any of the following:
- refractory to primary induction therapy or refractory to salvage therapy,
- in untreated first relapse with first remission duration <12 months
- in untreated second or greater relapse
- or relapse at any time after allogeneic HSCT
2. Subject has received intensive combination chemotherapy for the treatment of ALL for initial treatment or subsequent salvage therapy.
3. Greater than 5% blasts in the bone marrow
4. Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2
5. Age ≥ 18 years at the time of informed consent
6. Subject has provided informed consent or subject’s legally acceptable representative has provided informed consent when the subject has any kind of condition that, in the opinion of the investigator, may compromise the ability of the subject to give written informed consent.

• Ασθενείς με πρόδρομη Β-ΟΛΛ αρνητική για το χρωμόσωμα
Φιλαδέλφειας, οι οποίοι παρουσιάζουν οποιαδήποτε από τα ακόλουθα
χαρακτηριστικά:
• εμφανίζουν αντοχή στη βασική εισαγωγική θεραπεία ή στη θεραπεία
διάσωσης,
• βρίσκονται σε πρώτη υποτροπή για την οποία δεν έχουν λάβει
θεραπεία με διάρκεια πρώτης ύφεσης <12 μήνες
• βρίσκονται σε δεύτερη ή μεταγενέστερη υποτροπή για την οποία δεν
έχουν λάβει θεραπεία
• ή εμφάνισαν υποτροπή σε οποιαδήποτε στιγμή μετά από αλλογενή
ΜΑΑΚ
• Ο ασθενής έχει λάβει εντατική συνδυασμένη χημειοθεραπεία για την
αντιμετώπιση της ΟΛΛ ως αρχική θεραπεία ή μεταγενέστερη θεραπεία
διάσωσης.
• Ποσοστό βλαστών στο μυελό των οστών >5%.
• Kατάσταση ικανότητας κατά ECOG (Συνεργαζόμενη Ογκολογική Ομάδα
της Ανατολικής Ακτής των ΗΠΑ) ≤ 2
• Ηλικία ≥ 18 ετών κατά το χρόνο παροχής της συγκατάθεσης κατόπιν
ενημέρωσης
• Παροχή συγκατάθεσης κατόπιν ενημέρωσης από τον ασθενή ή τον
νόμιμο εκπρόσωπό του όταν ο ασθενής πάσχει από οποιαδήποτε πάθηση η
οποία, κατά την κρίση του ερευνητή, ενδέχεται να μειώσει την ικανότητα
του ασθενή να παρέχει γραπτή συγκατάθεση κατόπιν ενημέρωσης.

E.4

Principal exclusion criteria

1. History of malignancy other than ALL within 5 years prior to start of protocol-specified therapy with the exception of:
− Malignancy treated with curative intent and with no known active disease present for 5 years before enrollment and felt to be at low risk for recurrence by the treating physician
− Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease
− Adequately treated cervical carcinoma in situ without evidence of disease
− Adequately treated breast ductal carcinoma in situ without evidence of disease
− Prostatic intraepithelial neoplasia without evidence of prostate cancer.
2. Diagnosis of Burkitt´s Leukemia according to WHO classification
3. History or presence of clinically relevant CNS pathology such as epilepsy, childhood or adult seizure, paresis, aphasia, stroke, severe brain injuries, dementia, Parkinson’s disease, cerebellar disease, organic brain syndrome, or psychosis with the exception of history of CNS leukemia that is controlled with intrathecal therapy
4. Active ALL in the CNS (confirmed by CSF analysis) or testes (no clinical sign tehreof)
5. Isolated extramedullary disease
6. Current autoimmune disease or history of autoimmune disease with potential CNS involvement
7. Autologous HSCT within 6 weeks before the start of protocol-specified therapy
8. Allogeneic HSCT within 12 weeks before the start of protocol-specified therapy
9. Any active acute Graft-versus-Host Disease (GvHD), grade 2-4 according to the Glucksberg criteria or active chronic GvHD requiring systemic treatment
10. Any systemic therapy against GvHD within 2 weeks before start of protocol-specified therapy
11. Known exclusion criteria to investigator choice of SOC chemotherapy (as per product insert).
12. Cancer chemotherapy within 2 weeks before start of protocol-specified therapy (intrathecal chemotherapy and dexamethasone are allowed until start of protocol-specified therapy). In addition, any subject whose organ toxicity (excluding hematologic) from prior ALL treatment has not resolved to no more than CTCAE grade 1
13. Radiotherapy within 2 weeks before the start of protocol-specified therapy
14. Immunotherapy (e.g., rituximab) within 4 weeks before start of protocol-specified therapy
15. Subject received prior anti-CD19 therapy
4.2.16 Abnormal screening laboratory values as defined below:
− AST (SGOT) and/or ALT (SGPT) and/or ALP ≥ 5 x upper limit of normal (ULN)
− Total bilirubin (TBL) ≥ 1.5 x ULN (unless related to Gilbert´s or Meulengracht disease)
− Creatinine ≥ 1.5 ULN or Creatinine clearance < 60 ml/min (calculated)
17. Known infection with human immunodeficiency virus (HIV) or chronic infection with hepatitis B virus (HBsAg positive) or hepatitis C virus (anti-HCV positive)
18. Subject is pregnant or breast feeding, or might become pregnant
within 24 hours after the last dose of protocol-specified therapy
19. Woman of childbearing potential and is not willing to use a highly
effective method of contraception while receiving protocol-specified
therapy and for an additional 24 h after the last dose of protocolspecified
therapy.
20. Currently receiving treatment in another investigational device or
drug study or less than 30 days since ending treatment on another
investigational device or drug study(s). Thirty days is calculated from
Day 1 of protocol-specified therapy.
21. Other investigational procedures while participating in this study are
excluded (except for participation in optional sub-studies to this
protocol).
22. Subject has known sensitivity to immunoglobulins or any of the
products or components to be administered during dosing.
23. Subject previously has randomized into this study or previous
treatment with blinatumomab.
24. Subject likely to not be available to complete all protocol-required
study visits or procedures, including follow-up visits, and/or to comply
with all required study procedures to the best of the subject and
Investigator's knowledge.
25. History or evidence of any other clinically significant disorder,
condition or disease (with the exception of those outlined above) that, in
the opinion of the Investigator or Amgen physician, if consulted, would
pose a risk to subject safety orinterfere with the study evaluation,
procedures or completion.

παρακαλούμε όπως δείτε το άνωθεν πεδίο λόγω έλλεψης χώρου

E.5 End points

E.5.1

Primary end point(s)

Overall survival

Συνολική επιβίωση

E.5.1.1

Timepoint(s) of evaluation of this end point

Assessment when the 330th death is reported in the clinical trial
database, 12 months after the last subject is randomized if only 300 to
329 deaths have been reported, or when the 300th death is reported if
the study duration exceeds 12 months from the last subject randomized.

παρακαλούμε όπως δείτε το άνωθεν πεδίο λόγω έλλεψης χώρου

E.5.2

Secondary end point(s)

Key Secondary Efficacy Endpoints (in order of hierarchical testing)
1. CR within 12 weeks of treatment initiation
2. CR/CRh*/CRi within 12 weeks of treatment initiation
3. Event Free Survival (EFS)
Secondary Efficacy Endpoints
4. Duration of CR
5. Duration of CR/CRh*/CRi
6. MRD remission (defined as MRD level below 10-4 by PCR or flow
cytometry) within 12 weeks of treatment initiation
7. Time to a 10 point decrease from baseline in global health status and QoL scale using EORTC QLQ-C30, or EFS event
8. AlloHSCT with or without blinatumomab treatment
Secondary Safety Endpoints
9. Incidence of adverse events
10. 100-day mortality after alloHSCT
11. Incidence of anti-blinatumomab antibody formation
12. Changes in select vital sign and laboratory parameters
Exploratory Endpoints
13. Blinatumomab steady state concentration (Css)
14. ALLSS score at measured time points
15. Investigation for mutations in the tumor DNA to predict resistance to blinatumomab treatment

παρακαλούμε όπως δείτε το άνωθεν πεδίο λόγω έλλεψης χώρου

E.5.2.1

Timepoint(s) of evaluation of this end point

1+2: after 12 weeks; samples are taken at the end of cycles 1 and 2
3: at the time of relapse, death or EOS
4+5+15: throughout the study; samples are taken at the end of each cycle, at the safety follow-up visit and every 3 months during long-term follow-up
6: within 12 weeks of treatment initiation
7+12+14: troughout treatment and at the safety follow-up visit
8+9: throughout the study
10: 100 days after alloHSCT
11: before first dose, after cycle 2 and at the safety follow-up visit
13: day 1 and 15 of cycle 1

1+2: μετά από 12 εβδομάδες, δείγματα παίρνονται στα τέλη των κύκλων 1
και 2
3: στην στιγμή υποτροπής, θανάτου ή EOS
4+5+15: καθ΄ όλη τη διάρκεια της δοκιμής, δείγματα παίρνονται στο
τέλος του κάθε κύκλου, στην επίσκεψη παρακολούθησης ασφάλειας και
κάθε 3 μήνες κατά την μακροπρόθεσμη παρακολούθηση
6: στα τέλη των κύκλων 1 και 2
7+12+14: καθ΄ όλη τη διάρκεια της δοκιμής και στην επίσκεψη
παρακολούθησης ασφάλειας
8+9: καθ΄ όλη τη διάρκεια της δοκιμής
10: 100 ημέρες μετά την alloHSCT
11: πριν από την πρώτη δόση, μετά τον δεύτερο κύκλο και στην επίσκεψη
παρακολούθησης ασφάλειας
13: ημέρες 1 και 15 του πρώτου κύκλου

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

Yes

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

Yes

E.6.10

Pharmacogenetic

Yes

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

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)

Yes

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

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

Austria

Belgium

Bulgaria

Canada

Czech Republic

France

Germany

Greece

Ireland

Israel

Italy

Korea, Republic of

Mexico

Poland

Russian Federation

Spain

Taiwan

Turkey

United Kingdom

United States

E.8.7

Trial has a data monitoring committee

Yes

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

End of study (primary completion): when the last subject is is assessed or receives an intervention for the purposes of final collection of data for the primary endpoint.

End of study (end of trial): when the last subject is assessed or receives an intervention for evaluation in the study; including survival assessments.

Ως αρχική ολοκλήρωση ορίζεται ο χρόνος κατά τον οποίο ο τελευταίος ασθενής θα ξιολογηθεί ή θα υποβληθεί σε μία διαδικασία για τους σκοπούς της τελικής συλλογής δεδομένων για την κύρια ανάλυση

Ως τέλος της κλινικής δοκιμής ορίζεται ο χρόνος κατά τον οποίο ο τελευταίος ασθενής θα αξιολογηθεί ή θα υποβληθεί σε μία διαδικασία για τους σκοπούς της τελικής συλλογής δεδομένων για τη μελέτη.

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:

308

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

Yes

F.3.3.6.1

Details of subjects incapable of giving consent

If the subject has any kind of condition that, in the opinion of the Investigator, may compromise the ability of the subject to give written informed consent, the subject's legally acceptable representative can provide written informed consent.

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

253

F.4.2.2

In the whole clinical trial

400

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)

none

Κανένα Σχέδιο

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

2014-03-14

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2014-02-25

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2017-03-14

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Orphan Designation Number:
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