Clinical Trials Register

Summary
EudraCT Number:	2010-024423-24
Sponsor's Protocol Code Number:	AB10015
National Competent Authority:	Italy - Italian Medicines Agency
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2014-02-04
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

Italy - Italian Medicines Agency

A.2

EudraCT number

2010-024423-24

A.3

Full title of the trial

Studio prospettico, multicentrico, randomizzato, in doppio cieco, controllato verso placebo, a gruppi paralleli, di fase 2/3 sull'efficacia e la sicurezza di masitinib a confronto con placebo nel trattamento di pazienti affetti da Sclerosi Laterale Amiotrofica (SLA)

A prospective, multicenter, randomized, double-blind, placebocontrolled,parallel groups, phase 2/3 study to compare the efficacy and safety of masitinib versus placebo in the treatment of patients suffering from Amyotrophic Lateral Sclerosis (ALS)

A.3.1

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

Evaluation of masitinib in Amyotrophic Lateral Sclerosis (ALS)

Valutazione di masitinib nella Sclerosi Laterale Amiotrofica (SLA)

A.3.2

Name or abbreviated title of the trial where available

AB10015

A.4.1

Sponsor's protocol code number

AB10015

A.5.4

Other Identifiers

Name:

AB10015

Number:

AB10015

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	AB SCIENCE
B.1.3.4	Country	Italy
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	Azienda Farmaceutica: AB Scienc
B.4.2	Country	France
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	AB Science
B.5.2	Functional name of contact point	Vincent Arnold
B.5.3	Address:
B.5.3.1	Street Address	3 avenue George V
B.5.3.2	Town/ city	Parigi
B.5.3.3	Post code	75008
B.5.3.4	Country	France
B.5.4	Telephone number	0033 1 47 20 23 11
B.5.5	Fax number	0033 1 47 20 23 11
B.5.6	E-mail	a.moussy@ab-science.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.2.1.2	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	Masitinib
D.3.2	Product code	AB1010
D.3.4	Pharmaceutical form	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	Masitinib Mesylate
D.3.9.1	CAS number	790299-79-5
D.3.9.2	Current sponsor code	AB1010
D.3.9.3	Other descriptive name	MASITINIB MESYLATE
D.3.9.4	EV Substance Code	SUB126308
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	100
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Masitinib Mesylate
D.3.9.1	CAS number	790299-79-5
D.3.9.2	Current sponsor code	AB1010
D.3.9.3	Other descriptive name	MASITINIB MESYLATE
D.3.9.4	EV Substance Code	SUB126308
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	100
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
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Tablet
D.8.4	Route of administration of the placebo	Oral use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

patients suffering from Amyotrophic Lateral Sclerosis (ALS)

pazienti affetti da Sclerosi Laterale Amiotrofica (SLA)

E.1.1.1

Medical condition in easily understood language

ALS

SLA

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	18.0
E.1.2	Level	PT
E.1.2	Classification code	10002026
E.1.2	Term	Amyotrophic lateral sclerosis
E.1.2	System Organ Class	10029205 - Nervous system disorders

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

The objective is to compare the efficacy and safety of masitinib versus placebo in the treatment of patients suffering from Amyotrophic Lateral Sclerosis (ALS).

L'obiettivo dello studio consiste nel confrontare l'efficacia e la sicurezza di masitinib in combinazione con riluzolo a confronto con placebo in combinazione con riluzolo nel trattamento di pazienti affetti da Sclerosi Laterale Amiotrofica (SLA)

E.2.2

Secondary objectives of the trial

non applicabile

E.2.3

Trial contains a sub-study

Yes

E.2.3.1

Full title, date and version of each sub-study and their related objectives

PharmacoKinetic (PK) study:
A Pharmacokinetic study, in up to 10 patients, to evaluate PK parameters of riluzole will be conducted

Studio di Farmacocinetica (PK):
verrà condotto uno studio di Farmacocinetica su un massimo di 10 pazienti per valutare i parametri di Farmacocinetica del Riluzolo

E.3

Principal inclusion criteria

1. Female or male patient aged between 18 and 75 years of age, with a weight > 50 kg and BMI between 18 and 35 kg/m².
2. Familial or sporadic ALS
3. Patient diagnosed with laboratory supported, clinically probable or definite ALS according to the World Federation of Neurology Revised El
Escorial criteria (Brooks, 1994)
4. Disease duration from symptoms onset no longer than 36 months at the screening visit
5. Patient treated with a stable dose of riluzole (100 mg/day) for at least 30 days prior to screening
6. Patient with a FVC (Forced Vital Capacity) equal to or more than 60% predicted normal value for gender, height, and age at the screening visit
7. Patient with life expectancy ≥ 6 months
8. Patient with adequate organ function at screening and baseline:
• Absolute Neutrophils Count (ANC) ≥ 2 x 109/L
• Hemoglobin ≥ 10 g/dL
• Platelets (PTL) ≥ 100 x 109/L
• AST/ALT ≤ 3 ULN
• Bilirubin ≤ 1.5 ULN
• Albuminemia > 1 x LLN
• Creatinine clearance > 60 mL/min (Cockcroft and Gault formula)
• Proteinuria < 30 mg/dL (1+) on dipstick; in case of the proteinuria ≥ 1+ on the dipstick, 24 hours proteinuria must be < 1.5g/24 hours
9. Male patient or female patient of child bearing potential, who must agree to use two methods (one for the patient and one for the partner) of medically acceptable forms of contraception (with failure rate < 1%) during the study and for three months after the last treatment intake
10. Female patient of childbearing potential must have a negative pregnancy test at screening and baseline
11. Patient able and willing to comply with study procedures as per protocol
12. Patient able to understand, and willing to sign, and date the written informed consent form at screening visit prior to any protocol-specific
procedures
13. Patient able to understand, and willing to follow the safety procedures mentioned on the patient card in case of signs or symptoms of severe neutropenia or severe cutaneous toxicity, during the first two months of treatment

1. Paziente maschio o femmina, di età compresa tra i 18 e i 75 anni, peso > 50 kg e BMI compreso tra 18 e 35 kg/m².
2. SLA familiare o sporadica
3. Paziente affetto da SLA definita o clinicamente probabile supportata da analisi di laboratorio secondo i criteri World Federation of Neurology
Revised El Escorial (Brooks, 1994)
4. Durata della malattia dalla comparsa dei sintomi non superiore a 36 mesi alla visita di screening
5. Paziente trattato con dose stabile di riluzolo (100 mg/giorno) per almeno 30 giorni prima dello screening
6. Paziente con FVC (Capacità vitale forzata) pari o superiore al 60% del valore normale previsto per sesso, altezza ed età alla visita di screening
7. Paziente con aspettativa di vita ≥ 6 mesi
8. Paziente con adeguate funzioni degli organi allo screening e al basale:
• Conta assoluta dei neutrofili (ANC) ≥ 2 x 109/L
• Emoglobina ≥ 10 g/dL
• Piastrine (PTL) ≥ 100 x 109/L
• AST/ALT ≤ 3 ULN
• Bilirubina ≤ 1,5 ULN
• Albuminemia > 1 x LLN
• Clearance della creatinina > 60 mL/min (formula di Cockcroft-Gault)
• Proteinuria < 30 mg/dL (1+) su striscia reattiva; in caso di proteinuria ≥ 1+ sulla striscia reattiva, la proteinuria delle 24 ore deve essere < 1,5g/24 ore
9. Donne in età fertile (che comincerà lo studio dopo un ciclo mestruale e che dovrà sottoporsi a un test di gravidanza con esito negativo) che acconsentirà all'utilizzo di due metodi (uno per il paziente e uno per il partner) contraccettivi in forma accettabile da un punto di vista medico durante lo studio e per tre mesi dopo l'ultima somministrazione del trattamento.
10. Uomini in età fertile devono utilizzare un'accettabile metodo contraccettivo qualora la partner sia in gravidanza, dal giorno della
prima somministrazione del farmaco in studio fino a tre mesi dopo l'ultima somministrazione. I pazienti di sesso maschile devono utilizzare
due accettabili metodi anticoncezionali ad alta efficienza (uno per sé stessi, l'altro per la partner) durante lo studio e fino a tre mesi dopo
l'ultima dose di trattamento assunta.
11. La paziente donna in età fertile dovrà sottoporsi a un test di gravidanza con esito negativo allo screening e al basale
12. Paziente disposto e in grado di attenersi alle procedure dello studio come definite nel protocollo
13. Paziente in grado di comprendere, e disposto a firmare e datare il modulo del consenso informato durante la visita di screening prima di
qualsiasi procedura specifica del protocollo
14. Paziente in grado di comprendere, e disposto a seguire le procedure di sicurezza riportate sulla scheda del paziente in caso di segni o sintomi
di grave neutropenia o tossicità cutanea acuta durante i primi due mesi di trattamento

E.4

Principal exclusion criteria

1. Patient with history of hematologic, hepatic, respiratory disorder that is clinically significant for his/her participation in the study
2. Patient who underwent tracheotomy and /or gastrostomy
3. Patient with a diagnosis of cancer or evidence of continued disease within five years before starting study treatment
4. Patient with significant sensory abnormalities, dementia, other neurologic diseases, uncompensated medical illness and psychiatric
illness
5. Patient who have participated in a clinical trial within 3 months prior to screening
6. Pregnant, or nursing female patient
7. Patient with a known diagnosis of human immunodeficiency virus
(HIV) infection
8. Patient with known hepatitis B, hepatitis C or tuberculosis
9. Patient with any severe and/or uncontrolled medical condition
10. Patient having cardiac disorders defined by at least one of the following conditions:
• Patient with recent cardiac history (within 6 months) of:
- Acute coronary syndrome
- Acute heart failure (class III or IV of the NYHA classification)
- Significant ventricular arrhythmia (persistent ventricular tachycardia, ventricular fibrillation, resuscitated sudden death)
• Patient with cardiac failure class III or IV of the NYHA classification
• Patient with severe conduction disorders which are not prevented by permanent pacing (atrio-ventricular block 2 and 3, sino-atrial block)
• Syncope without known aetiology within 3 months
• Uncontrolled severe hypertension, according to the judgment of the investigator, or symptomatic hypertension
11. Patient with history of poor compliance or history of drug/alcohol abuse, or excessive alcohol beverage consumption that would interfere with the ability to comply with the study protocol, or current or past psychiatric disease that might interfere with the ability to comply with the study protocol or give informed consent
PREVIOUS TREATMENTS WASH OUT
12. Patient treated with any investigational agent within 3 months prior to screening

1. Paziente con storia di disturbi ematologici, epatici, respiratori clinicamente significativi per la sua partecipazione allo studio
2. Paziente sottoposto a tracheotomia e/o gastrostomia
3. Paziente con diagnosi di tumore o evidenza di progressione di malattia negli ultimi cinque anni prima dell'inizio del trattamento dello studio
4. Paziente con anomalie sensoriali significative, demenza, altre patologie neurologiche, malattia scompensatae patologia psichiatrica
5. Paziente che abbia partecipato ad uno studio clinico nei 3 mesi precedenti lo screening
6. Gravidanza o allattamento in corso
7. Paziente con diagnosi nota di infezione da virus
dell'immunodeficienza umana (HIV)
8. Paziente con nota epatite B, epatite C o tubercolosi
9. Paziente affetto da condizione medica grave e/o non controllata
10. Paziente affetto da disturbi cardiaci definiti da almeno una delle seguenti condizioni:
• Paziente avente precedenti cardiaci recenti (ultimi 6 mesi) tra cui:
- Sindrome coronarica acuta
- Insufficienza cardiaca acuta (classe III o IV della classificazione
NYHA)
- Aritmia ventricolare significativa (tachicardia ventricolare sostenuta,
fibrillazione ventricolare, morte improvvisa rianimata)
• Paziente affetto da insufficienza cardiaca di classe III o IV della
classificazione NYHA
• Paziente affetto da gravi disturbi di conduzione non prevenuti con
pacemaker permanente (blocco atrioventricolare di 2° e 3° grado, blocco senoatriale)
• Sincope senza eziologia nota negli ultimi 3 mesi
• Grave ipertensione incontrollata secondo il giudizio dello sperimentatore, o ipertensione sintomatica
11. Paziente con storia di scarsa compliance o storia di abuso di sostanze stupefacenti/alcol, o consumo eccessivo di bevande alcoliche
che potrebbero interferire con la capacità di aderire al protocollo di studio, o patologia psichiatrica attuale o pregressa che potrebbe interferire con la capacità di aderire al protocollo di studio o prestare il consenso informato

E.5 End points

E.5.1

Primary end point(s)

Change from baseline to week 48 in Amyotrophic Lateral Sclerosis functional rating scale (ALSFRS)-Revised

Variazione della Scala di valutazione funzionale SLA (ALSFRS)-Revised dal baseline alla settimana 48.

E.5.1.1

Timepoint(s) of evaluation of this end point

48 weeks

48 settimane

E.5.2

Secondary end point(s)

Combined Assessment of Function and Survival (CAFS) • Survival defined as the time from randomisation to the date of documented death or first tracheotomy • Time to first tracheotomy defined as the time from randomisation to the time of the first tracheotomy • Change of Forced Vital Capacity (FVC) from baseline to each time point (week 4, 8, 12, 24, 36, 48) • Number of failure defined as a 9-point drop in ALSFRS-R or death from baseline • Change from baseline to each time point (week 4, 8, 12, 24 and 36) in Amyotrophic Lateral Sclerosis functional rating scale (ALSFRS)- Revised • Survival rate defined as the rate of patients alive without tracheotomy at each time point (week 12, 24, 36 and 48) • Change in cystatin C level from baseline to each time point • Time to first gastrectomy defined as the time from randomisation to the time of the first gastrectomy • Absolute and relative change in ALSAQ- 40 at each time point • Safety: occurrence of Adverse Events (AE), changes on clinical examination including vital signs and weight, ECG and laboratory exams(biochemistry, hematology and urinalysis)

Valutazione combinata di Funzione e Sopravvivenza (CAFS) • Sopravvivenza intesa come il tempo intercorso tra la randomizzazione e la morte documentata o la prima tracheotomia • Tempo della prima tracheotomia, inteso come periodo intercorso tra la randomizzazione e la prima tracheotomia • Variazione della capacità vitale forzata (FVC) dal basale ad ogni timepoint (settimana 4, 8, 12, 24, 36, 48) • Numero di declini definiti come diminuzione di 9 punti nella scala di valutazione funzionale (ALSFRS-R) rispetto al basale oppure morte • Variazione del punteggio della scala di valutazione funzionale (ALSFRS)-Revised dal basale ad ogni timepoint (settimana 4, 8, 12, 24,36, 48) Tasso di sopravvivenza inteso come il numero di pazienti vivi non tracheotomizzati ad ogni timepoint (settimana 12, 24, 36 e 48) • Variazione del livello di Cistatina C rispetto al basale ad ogni timepoint • Tempo della prima gastrectomia intesa come periodo intercorso tra la randomizzazione e la prima gastrectomia • Variazione assoluta e relativa nella Qualità della vita ALSAQ-40 dal basale ad ogni timepoint • Sicurezza: Eventi Avversi (EA), variazioni all'esame clinico compresi parametri vitali e peso, ECG ed esami di laboratorio (analisi biochimiche,ematologiche e analisi delle urine)

E.5.2.1

Timepoint(s) of evaluation of this end point

week 4, 8, 12, 24, 36

4, 8, 12, 24, 36 settimane

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

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

Yes

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)

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

E.8.1.3

Single blind

E.8.1.4

Double blind

Yes

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

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

Argentina

Colombia

France

Germany

Greece

Italy

Mexico

Romania

Serbia

Spain

United Kingdom

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:

300

F.1.3

Elderly (>=65 years)

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

100

F.4.2

For a multinational trial

F.4.2.1

In the EEA

240

F.4.2.2

In the whole clinical trial

381

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)

Maximum treatment exposure of 96 weeks.
At Week 96 patient visit, patients will be proposed to carry on their study treatment at the same dose level.
As soon as the treatment groups will be known, patients receiving placebo will be withdrawn from the study.

La durata massima del trattamento sarà di 96 settimane.
Alla visita della settimana 96, ai pazienti verrà proposto di continuare il trattamento in studio alla stessa dose assunta.
Non appena i gruppi di trattamento saranno noti, i pazienti che ricevono placebo saranno sospesi dallo studio.

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

2015-05-05

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2015-03-20

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2017-11-01

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IMP with orphan designation in the indication
Orphan Designation Number:
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