Clinical Trials Register

Summary
EudraCT Number:	2018-004696-12
Sponsor's Protocol Code Number:	FACIALPARALYSIS
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:	2021-05-24
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

2018-004696-12

A.3

Full title of the trial

Clinical, Instrumental and Histological evaluation of the combined use of Onabotulinumtoxin A and hyaluronic acid fillers in patients with facial paralysis

Valutazione Clinica, Strumentale ed Istologica dell’applicazione combinata della Tossina Botulinica e dell’Acido Ialuronico in pazienti affetti da paralisi facciale

A.3.1

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

Evaluation of the combined use of Onabotulinumtoxin A and hyaluronic acid fillers in patients with facial paralysis

Valutazione dell'uso combinato della Tossina Botulinica e dell’Acido Ialuronico nel trattamento della paralisi facciale

A.3.2

Name or abbreviated title of the trial where available

Onabotulinumtoxin A and hyaluronic acid fillers in the treatment of facial paralysis

Tossina Botulinica e dell’Acido Ialuronico nel trattamento della paralisi facciale

A.4.1

Sponsor's protocol code number

FACIALPARALYSIS

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 UNIVERSITARIA INTEGRATA VERONA
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	AOUI Verona
B.4.2	Country	Italy
B.4.1	Name of organisation providing support	ALLERGAN PHARMACEUTICALS INTERNATIONAL LIMITED
B.4.2	Country	Ireland
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	AOUI Verona
B.5.2	Functional name of contact point	Unità Ricerca Clinica
B.5.3	Address:
B.5.3.1	Street Address	P.le Stefani, 1
B.5.3.2	Town/ city	Verona
B.5.3.3	Post code	37126
B.5.3.4	Country	Italy
B.5.4	Telephone number	0458127043
B.5.5	Fax number	0458122814
B.5.6	E-mail	supporto.noprofit@aovr.veneto.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	VISTABEX - 4 UNITA'/0.1 ML POLVERE PER SOLUZIONE INIETTABILE FLACONCINO DA 50 UNITA'
D.2.1.1.2	Name of the Marketing Authorisation holder	ALLERGAN S.P.A.
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	VISTABEX
D.3.2	Product code	[TOSSINA BOTULINICA DI TIPO A]
D.3.4	Pharmaceutical form	Powder for solution for injection
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intradermal use Intramuscular use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	TOSSINA BOTULINICA DI CLOSTRIDIUM BOTULINUM TIPO A
D.3.9.1	CAS number	93384-43-1
D.3.9.2	Current sponsor code	Tossina botulinica di tipo A
D.3.9.3	Other descriptive name	Onabotulinumtoxin A
D.3.10	Strength
D.3.10.1	Concentration unit	U unit(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	50
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	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

hemifacial paralysis (3 to 6 of the House-Brackmann scale)

paralisi emifacciale da 3 a 6 della scala House-Brackmann

E.1.1.1

Medical condition in easily understood language

hemifacial paralysis

paralisi emifacciale

E.1.1.2

Therapeutic area

Diseases [C] - Nervous System Diseases [C10]

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	10016060
E.1.2	Term	Facial palsy
E.1.2	System Organ Class	100000004852

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 functional (muscular enhancement) improvement of facial asymmetries due to facial nerve lesion after the treatment with OnabotulinumtoxinA and hyaluronic acid fillers compared with the untreated group. The evaluation will be performed analyzing the two groups at the baseline and at the end of the treatment period.

Valutare il miglioramento funzionale (miglioramento muscolare) delle asimmetrie facciali dovute alla lesione del nervo facciale dopo il trattamento con OnabotulinumtoxinA e acido ialuronico rispetto al gruppo non trattato. La valutazione verrà eseguita analizzando i due gruppi al baseline e al termine del periodo di trattamento.

E.2.2

Secondary objectives of the trial

Group A
- Evaluation of QoL, assessed through questionnaire before and after treatment (Visit 0 vs Visit 5)
- Quantify and evaluate the improvement facial symmetry obtained by treatments (Visit 0, Visit 1, Visit 4 and Visit 5).
- Aesthetic and Functionality, assessed through questionnaire, 3D photos, MRI, CBCT, US, Histological and EMG tests to underline treatment improvement on facial neuromuscular complex (Visit 0 vs Visit 5).
- Evaluate adverse events and safety of the treatments

Group A vs Group B
- Evaluation of QoL, assessed through questionnaire (Visit 5)
- Aesthetic and Functionality, assessed through questionnaire, 3D photos, MRI, CBCT, US, Histological and EMG tests on facial neuromuscular complex (Visit 5).

Gruppo A
- Valutazione della QoL tramite questionario prima e dopo il trattamento (Visita 0 vs Visita 5)
- Quantificare e valutare il miglioramento della simmetria facciale ottenuta dopo i trattamenti (Visita 0, Visita 1, Visita 4 e Visita 5).
- Estetica e funzionalità, valutate tramite questionario, foto 3D, risonanza magnetica, CBCT, US, test istologici ed EMG per sottolineare il miglioramento del trattamento sul complesso neuromuscolare facciale (Visita 0 vs Visita 5).
- Valutare gli eventi avversi e la sicurezza dei trattamenti

Gruppo A vs Gruppo B
- Valutazione della QoL valutata tramite questionario (visita 5)
- Estetica e funzionalità, valutate tramite questionario, foto 3D, RMN, CBCT, US, test istologici ed EMG sul complesso neuromuscolare facciale (visita 5).

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

- Adult patients (18-65) with hemifacial paralysis from 3 to 6 on the House-Brackmann scale, never treated with HA and BTX injection will be included in the study.
- Signed informed consent.
- Women of childbearing potential will only be included in the study if uptaking the following highly effective birth control measures: Women of childbearing potential will only be included in the study if uptaking the following highly effective birth control measures: - Combined hormonal contraception associated with inhibition of ovulation (Oral, Transdermal, Intravaginal), - Progesteron-only hormonal contraception associated with inhibition of ovulation (Oral, Injectable, Implantable), - Intrauterine devices, - Intrauterine hormone-releasing system, - Bilateral tubal occlusion, - vasectomized partner, - Sexual abstinence
- Patients will be included after a negative highly sensitive pregnancy test (blood test)

- Pazienti adulti (18-65) con paralisi emifacciale da 3 a 6 della scala House-Brackmann, mai trattati con iniezione di HA e BTX
- Consenso informato firmato.
- Donne in etá fertile che adottano misure contraccettive altamente efficaci: - Contraccezione ormonale combinata associata ad inibizione dell'ovulazione (orale, transdermica, intravaginale), - Contraccezione ormonale con solo progesterone associata ad inibizione dell'ovulazione (Orale, iniettabile, impiantabile), - Dispositivi intrauterini, - Sistema di rilascio dell'ormone intrauterino, - Occlusione tubarica bilaterale, - Partner vasectomizzato, - Astinenza sessuale
- Le pazienti saranno incluse dopo un test di gravidanza negativo (esame del sangue)

E.4

Principal exclusion criteria

- Hypersensitivity to any component of the products used
- Diabetes, systemic diseases, coronary artery disease, acute-chronic hepatitis C, autoimmune diseases and / or other diseases involving poor general health, clotting problem. Peripheric neuro-muscolars disorders, amyotrophic lateral sclerosis (ALS).
- Pregnant or lactating
- Patients <18 years and >65 years old

- Ipersensibilità ai prodotti o componenti di essi
- Diabete, patologie sistemiche, malattia coronarica, epatite C acuta-cronica, patologie autoimmuni e/o altre malattie che implicano una scarsa salute generale, problemi di coagulazione. Disturbi neuro-muscolari periferici, sclerosi laterale amiotrofica.
- Gravidanza o allattamento
- Età non compresa tra 18 e 65 anni

E.5 End points

E.5.1

Primary end point(s)

House-Brackmann scale score. La differenza di miglioramento di almeno 1 grado sulla scala House-Brackmann, rispetto al gruppo non trattato, sarà considerata clinicamente significativa

House-Brackmann scale score. Improvement difference of at least 1 grade on the House-Brackmann scale, compared with the untreated group, will be considered clinically significant

E.5.1.1

Timepoint(s) of evaluation of this end point

Visit 0 vs Visit 5

E.5.2

Secondary end point(s)

Number and type of adverse events; Evaluation of QoL assessed through FACE-Q questionnaire in both groups; Facial aesthetic will be evaluated in both groups through:
- the analysis of 3D-photography implemented with a face grid and the Arnett’s aesthetic analysis. Arnett’s aesthetic analysis evaluate the different areas of the face as “flat”, “soft”, “normal” and “protruded”
-MRI provides quantitative data on the thickness of soft tissue (millimetric quantification of the thickness of the different areas)
-CBCT provides quantitative data on the thickness of hard tissue (millimetric quantification of the thickness of the different areas)
-US provides quantitative data on the thickness of soft tissue (millimetric quantification of the thickness of the different areas) and qualitative data on the tropism of muscules (Atrophy, hypotrophy, eutrophy, hypertrophy)
-Histological analysis provides a qualitative analysis of patho-physiological condition of injected and not-injected tissue and specifically the effects on the fiber muscles.
Histological and imaging (SEM and/or TEM) analysis should provide a through examination of tissue changes due to the physical introduction of the products, comparing different conditions in injected and not-injected tissue and eventually any effect on the fiber muscles. Possible physical and mechanical effect on treated tissues will be evaluated by histological evaluation to characterize tissue and cells involved in the modification, including the emergence and/or change of resident populations via the application of straightforward approaches. Histological evidence is then supported and completed with TEM and /or SEM.
-EMG provides electric potentials of the facial neuromuscular complex in order to evaluate the activity and symmetry of their function (quantification of the electric potential of the different areas will be reported in the both relax and movement position); Evaluation of QoL through FACE-Q questionnaire before and after treatment. “FACE-Q Social Function”, “FACE-Q Psychological Function” and “FACE-Q”; The measurements of facial symmetry will be performed through the analysis of 3D-photography implemented with a face grid, that allows the quantification of symmetry of the face. The face grid permits to calculate the distance in millimeters of two points from the midline (both in vertical and horizontal direction); Facial aesthetic will be evaluated through:
- the analysis of 3D-photography implemented with a face grid and the Arnett’s aesthetic analysis. Arnett’s aesthetic analysis evaluate the different areas of the face as “flat”, “soft”, “normal” and “protruded”
-MRI provides quantitative data on the thickness of soft tissue (millimetric quantification of the thickness of the different areas)
-CBCT provides quantitative data on the thickness of hard tissue (millimetric quantification of the thickness of the different areas)
-US provides quantitative data on the thickness of soft tissue (millimetric quantification of the thickness of the different areas) and qualitative data on the tropism of muscules (Atrophy, hypotrophy, eutrophy, hypertrophy)
-Histological analysis provides a qualitative analysis of patho-physiological condition of injected and not-injected tissue and specifically the effects on the fiber muscles.
Histological and imaging (SEM and/or TEM) analysis should provide a through examination of tissue changes due to the physical introduction of the products, comparing different conditions in injected and not-injected tissue and eventually any effect on the fiber muscles. Possible physical and mechanical effect on treated tissues will be evaluated by histological evaluation to characterize tissue and cells involved in the modification, including the emergence and/or change of resident populations via the application of straightforward approaches. Histological evidence is then supported and completed with TEM and /or SEM.
-EMG provides electric potentials of the facial neuromuscular complex in order to evaluate the activity and symmetry of their function (quantification of the electric potential of the different areas will be reported in the both relax and movement position)

Numero e tipologia di AE; Valutazione della QoL attraverso il questionario FACE-Q nei due gruppi; L'estetica del viso sarà valutata nei due gruppi attraverso:
- l'analisi della fotografia 3D implementata con una griglia facciale e l'analisi estetica di Arnett. L'analisi estetica di Arnett valuta le diverse aree del viso come "piatte", "morbide", "normali" e "sporgenti"
- MRI che fornisce dati quantitativi sullo spessore del tessuto molle (quantificazione millimetrica dello spessore delle diverse aree)
-CBCT che fornisce dati quantitativi sullo spessore del tessuto duro (quantificazione millimetrica dello spessore delle diverse aree)
-US che fornisce dati quantitativi sullo spessore del tessuto molle (quantificazione millimetrica dello spessore delle diverse aree) e dati qualitativi sul trofismo dei muscoli (atrofia, ipotrofia, eutrofia, ipertrofia)
-analisi istologica che fornisce un'analisi qualitativa della condizione patofisiologica del tessuto trattato e non trattato e in particolare degli effetti sulle fibre dei muscoli.
L'analisi istologica e di imaging (SEM e/o TEM) dovrebbe fornire un esame approfondito delle variazioni dei tessuti dovute all'introduzione fisica dei prodotti, confrontando le diverse condizioni nei tessuti iniettati e non iniettati e infine eventuali effetti sulle fibre muscolari. I possibili effetti fisici e meccanici sui tessuti trattati saranno valutati mediante valutazione istologica per caratterizzare i tessuti e le cellule coinvolti nella modifica, incluso l'emergere e / o il cambiamento delle popolazioni residenti attraverso l'applicazione di approcci semplici. Le prove istologiche sono quindi supportate e completate con TEM e/o SEM.
-EMG che fornisce i potenziali elettrici del complesso neuromuscolare facciale per valutare l'attività e la simmetria della loro funzione (la quantificazione del potenziale elettrico delle diverse aree sarà riportata sia nella posizione di rilassamento che di movimento); Valutazione della QoL attraverso il questionario FACE-Q prima e dopo il trattamento. "Funzione sociale FACE-Q", "Funzione psicologica FACE-Q" e "FACE-Q"; Le misure della simmetria facciale verranno eseguite attraverso l'analisi della fotografia 3D implementata con una griglia frontale, che consente la quantificazione della simmetria del volto. La griglia frontale consente di calcolare la distanza in millimetri di due punti dalla linea mediana (sia in direzione verticale che orizzontale); L'estetica del viso sarà valutata attraverso:
- l'analisi della fotografia 3D implementata con una griglia facciale e l'analisi estetica di Arnett. L'analisi estetica di Arnett valuta le diverse aree del viso come "piatte", "morbide", "normali" e "sporgenti"
- MRI che fornisce dati quantitativi sullo spessore del tessuto molle (quantificazione millimetrica dello spessore delle diverse aree)
-CBCT che fornisce dati quantitativi sullo spessore del tessuto duro (quantificazione millimetrica dello spessore delle diverse aree)
-US che fornisce dati quantitativi sullo spessore del tessuto molle (quantificazione millimetrica dello spessore delle diverse aree) e dati qualitativi sul trofismo dei muscoli (atrofia, ipotrofia, eutrofia, ipertrofia)
-analisi istologica che fornisce un'analisi qualitativa della condizione patofisiologica del tessuto trattato e non trattato e in particolare degli effetti sulle fibre dei muscoli.
L'analisi istologica e di imaging (SEM e/o TEM) dovrebbe fornire un esame approfondito delle variazioni dei tessuti dovute all'introduzione fisica dei prodotti, confrontando le diverse condizioni nei tessuti iniettati e non iniettati e infine eventuali effetti sulle fibre muscolari. I possibili effetti fisici e meccanici sui tessuti trattati saranno valutati mediante valutazione istologica per caratterizzare i tessuti e le cellule coinvolti nella modifica, incluso l'emergere e/o il cambiamento delle popolazioni residenti attraverso l'applicazione di approcci semplici. Le prove istologiche sono quindi supportate e completate con TEM e/o SEM.
- EMG che fornisce i potenziali elettrici del complesso neuromuscolare facciale per valutare l'attività e la simmetria della loro funzione (la quantificazione del potenziale elettrico delle diverse aree sarà riportata sia nella posizione di rilassamento che di movimento)

E.5.2.1

Timepoint(s) of evaluation of this end point

Visit 0, Visit 1, Visit 2, Visit 3, Visit 4 and Visit 5; Visit 5; Visit 5; Visit 0 and Visit 5; Visit 0, Visit 1, Visit 4 and Visit 5; Visit 0, Visit 5

Visita 0, Visita 1, Visita 2, Visita 3, Visita 4 e Visita 5; Visita 5; Visita 5; visite 0 e 5; Visita 0, Visita 1, Visita 4 e Visita 5; Visita 0, Visita 5

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)

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

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 farmacologico

no pharmacological 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.8.6 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)

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

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)

Patients will be followed according to best clinical practice

I pazienti saranno seguiti secondo pratica clinica

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

2019-10-31

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2020-01-15

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

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