Clinical Trials Register

Summary
EudraCT Number:	2020-004805-30
Sponsor's Protocol Code Number:	CLN-PXT3003-06
National Competent Authority:	Italy - Italian Medicines Agency
Clinical Trial Type:	EEA CTA
Trial Status:	Prematurely Ended
Date on which this record was first entered in the EudraCT database:	2021-08-02
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

2020-004805-30

A.3

Full title of the trial

A Multi-Center, Randomized, Double-Blind, Placebo-Controlled Phase III Study to Assess the Efficacy, Safety, and Tolerability of PXT3003 in Charcot-Marie-Tooth type 1A (CMT1A)

Studio di fase III multicentrico, randomizzato, in doppio cieco, controllato con placebo, per valutare l'efficacia, la sicurezza e la tollerabilità di PXT3003 nella malattia di Charcot-Marie-Tooth di tipo 1A (CMT1A)

A.3.1

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

Phase 3 trial of PXT3003 in Charcot-Marie-Tooth (CMT) Type 1A patients

Studio di fase 3 di PXT3003 in pazienti affetti da malattia di Charcot-Marie-Tooth di tipo 1A

A.3.2

Name or abbreviated title of the trial where available

A.4.1

Sponsor's protocol code number

CLN-PXT3003-06

A.5.4

Other Identifiers

Name:

IND number

Number:

122505

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	Pharnext SA
B.1.3.4	Country	France
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	Pharnext SA
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	Pharnext SA
B.5.2	Functional name of contact point	Clinical Operations
B.5.3	Address:
B.5.3.1	Street Address	46 rue Saint Lazare
B.5.3.2	Town/ city	Parigi
B.5.3.3	Post code	7009
B.5.3.4	Country	France
B.5.4	Telephone number	0019178853598
B.5.5	Fax number	0033141092231
B.5.6	E-mail	misrael@pharnext.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/3/14/1260
D.3 Description of the IMP
D.3.1	Product name	PXT3003
D.3.2	Product code	[PXT3003]
D.3.4	Pharmaceutical form	Oral solution in sachet
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	BACLOFENE
D.3.9.1	CAS number	1134-47-0
D.3.9.2	Current sponsor code	na
D.3.9.4	EV Substance Code	SUB05667MIG
D.3.10	Strength
D.3.10.1	Concentration unit	µg/µl microgram(s)/microlitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	600
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	NALTREXONE CLORIDRATO
D.3.9.1	CAS number	16590-41-3
D.3.9.2	Current sponsor code	na
D.3.9.3	Other descriptive name	naltrexone hydrochloride
D.3.9.4	EV Substance Code	SUB09143MIG
D.3.10	Strength
D.3.10.1	Concentration unit	µg/µl microgram(s)/microlitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	70
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	SORBITOLO
D.3.9.1	CAS number	50-70-4
D.3.9.2	Current sponsor code	na
D.3.9.3	Other descriptive name	D-SORBITOL
D.3.9.4	EV Substance Code	SUB20837
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	21
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
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Oral solution in sachet
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

Charcot Marie Tooth Type 1A

Charcot-Marie-Tooth di tipo 1A

E.1.1.1

Medical condition in easily understood language

Hereditary Motor and Sensory Neuropathy

Neuropatia motoria e sensoriale ereditaria

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	20.0
E.1.2	Level	LLT
E.1.2	Classification code	10008414
E.1.2	Term	Charcot-Marie-Tooth disease
E.1.2	System Organ Class	100000004850

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

To evaluate the efficacy of treatment with PXT3003 (a fixed-dose combination of (RS)-baclofen, naltrexone hydrochloride, and D-sorbitol) compared to placebo in subjects with CMT1A

Valutare l'efficacia del trattamento con PXT3003 (una combinazione a dose fissa di (RS)-baclofene, naltrexone cloridrato (HCl), e D-sorbitolo) rispetto al placebo nei soggetti con malattia di Charcot-Marie-Tooth tipo 1 (CMT1A)

E.2.2

Secondary objectives of the trial

To evaluate the safety and tolerability of PXT3003 treatment in subjects with CMT1A

Valutare la sicurezza e la tollerabilità del trattamento con PXT3003 in soggetti affetti da CMT1A

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1) Male and non-pregnant female subjects, aged 16 to 65 years with a genetically proven diagnosis of CMT1A
2) Able to provide written informed consent/assent and comply with study procedures
3) Mild-to-moderate severity assessed by CMTNS-v2 score >2 and =18
4) Muscle weakness in at least foot dorsiflexion on clinical assessment
5) Ulnar nerve motor conduction time of at least 15m/s
6) Stable dose of prescribed psychoactive drugs (e.g. antidepressants, stimulants, tranquilizers, anti-epileptics) for at least 4 weeks prior to randomization, which is not planned to be changed
7) Stable dose of prescribed or 'over-the-counter' (OTC) analgesic medications (e.g. paracetamol/acetaminophen, nonsteroidal antiinflammatory drugs [NSAIDs]) for at least 2 weeks prior to randomization, which is not planned to be changed
8) If female, subject must be: (a) Surgically sterilized via hysterectomy, bilateral oophorectomy, or bilateral tubal ligation; or (b) Of childbearing potential and using a birth control method such as:
• Combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation:
o Oral
o Intravaginal
o Transdermal
• Progestogen-only hormonal contraception associated with inhibition of ovulation:
o Oral
o Injectable
o Implantable
• Intrauterine device (IUD)
• Intrauterine hormone-releasing system (IUS)
• Bilateral tubal occlusion
• Vasectomized partner
• Sexual abstinence;
or (c) Of non-childbearing potential (i.e., postmenopausal for at least 1 year)
9) If male, the subject must have had a vasectomy or must use a reliable method of birth control with their partner or total abstinence from sexual intercourse. The subject must agree to continue using their selected method of birth control with their sexual partner during the study and for 120 days after study completion.

1. Soggetti di sesso maschile e di sesso femminile non in gravidanza, di età compresa tra i 16 e i 65 anni con una diagnosi geneticamente provata di CMT1A.
2. In grado di fornire il consenso/assenso informato scritto e di rispettare le procedure dello studio.
3. Gravità da lieve a moderata valutata con un punteggio CMTNS-V2 >2 e =18.
4. Debolezza muscolare almeno nella dorsiflessione del piede in base alla valutazione clinica.
5. Tempo di conduzione motorio del nervo ulnare di almeno 15 m/s.
6. Dose stabile di farmaci psicoattivi prescritti (ad esempio, antidepressivi, stimolanti, tranquillanti, antiepilettici) per almeno 4 settimane prima della randomizzazione, che non si prevede di modificare.
7. Dose stabile di farmaci analgesici prescritti o da banco (ad esempio, paracetamolo/acetaminofene, farmaci antinfiammatori non steroidei) per almeno 2 settimane prima della randomizzazione, che non si prevede di modificare.
8. Se di sesso femminile il soggetto deve essere: (a) sterilizzato chirurgicamente mediante isterectomia, ooforectomia bilaterale o legatura bilaterale delle tube; oppure (b) potenzialmente fertile che utilizza un metodo contraccettivo, ad esempio:
• contraccettivo ormonale combinato (contenente estrogeni e progestinici) associato a inibizione dell'ovulazione:
o orale
o intravaginale
o transdermico
• Contraccezione ormonale basata solo su progestinici, associata a inibizione dell'ovulazione:
o orale
o iniettabile
o impiantabile
• Dispositivo intrauterino
• Sistema intrauterino a rilascio di ormoni
• Occlusione bilaterale delle tube
• Partner vasectomizzato
• Astinenza sessuale
oppure (c) non potenzialmente fertili (cioè, in menopausa post-menopausa da almeno 1 anno)
9. Se di sesso maschile, il soggetto deve aver subito una vasectomia o deve utilizzare un metodo affidabile di contraccezione con la partner o praticare astinenza totale dal rapporto sessuale. Il soggetto deve accettare di continuare a utilizzare il metodo di contraccezione selezionato con la partner sessuale durante lo studio e per 120 giorni dopo il completamento dello studio.

E.4

Principal exclusion criteria

1) Subjects previously enrolled in any PXT3003 study
2) Subjects living in the same household and enrolled in a PXT3003 study (due to potential lack of adequate storage for study material, risk of mixing treatments and potential unblinding)
3) CMT of any subtype other than 1A
4) ONLS score of 0
5) Known clinically significant motor or sensory abnormalities secondary to a different neurological cause (e.g. diabetes, alcohol, vascular, autoimmune, neoplastic, neurodegenerative, HIV, etc.)
6) Subjects who have had any surgery or have a concomitant disorder (e.g. severe arthrosis) that reduces the mobility of the ankle making it, in the opinion of the investigator, difficult to assess the efficacy of the treatment.
7) Known peripheral neuropathy, myopathy, or neuromuscular disorder of any other kind
8) Any other clinically significant and/or uncontrolled medical condition that, in the opinion of the investigator, could be a confound or may preclude successful participation or completion of the study
9) Known hypersensitivity or intolerance to baclofen, naltrexone, or sorbitol
10) Concomitant treatments including but not limited to baclofen, naltrexone, sorbitol (pharmaceutical form), opioids, and potentially neurotoxic drugs such as amiodarone, chloroquine, and chemotherapeutics capable of inducing peripheral neuropathy. Subjects able to stop these medications at least 2 weeks before randomization and for the study duration may be included
11) History of porphyria
12) Diagnosis or history of substance use disorder by DSM-V criteria within the past 12 months
13) Medical or recreational use of marijuana in the 3 months prior to the Screening Visit
14) Active suicidality (e.g. any suicide attempts within the past 12 months or any current suicide intent, including a plan, as assessed by the Columbia Suicide Severity Rating Scale (C-SSRS) score of "YES" on questions 4 or 5; and/or based on clinical evaluation by the investigator)
15) Currently active major depression, as determined by a Beck Depression Inventory (BDI-II) score = 20
16) Currently lactating, pregnant, or planning on becoming pregnant during the study
17) Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) levels greater than 2 times the upper limit of normal (ULN)
18) Significant renal impairment as determined by Glomerular Filtration Rate (GFR) of less than 50 mL/min
19) Subject has participated in an investigational drug or device study within 30 days prior to the Screening Visit or plans to participate in an investigational drug or device study during the course of this study
20) Subject is a dependent and/or relative of the Sponsor or investigator.

1. Soggetti precedentemente arruolati in qualsiasi studio su PXT3003.
2. Soggetti che vivono nella stessa abitazione e che sono stati arruolati in uno studio su PXT3003 (a causa della potenziale mancanza di un'adeguata conservazione del materiale dello studio, del rischio di mischiare i trattamenti e della potenziale apertura del cieco).
3. CMT di qualsiasi sottotipo diverso da 1A.
4. Punteggio ONLS di 0.
5. Note anomalie motorie o sensoriali clinicamente significative secondarie ad una diversa causa neurologica (ad esempio, diabete, alcool, vascolare, autoimmune, neoplastica, neurodegenerativa, virus dell'immunodeficienza umana, ecc.)
6. Soggetti che hanno subito un intervento chirurgico o che presentano un disturbo concomitante (es. artrosi grave) che riduce la mobilità della caviglia rendendo difficile, a parere dello sperimentatore, valutare l'efficacia del trattamento.
7. Nota neuropatia periferica, miopatia o disturbo neuromuscolare di qualsiasi altro tipo.
8. Qualsiasi altra condizione medica clinicamente significativa e/o incontrollata che, secondo l'opinione dello sperimentatore, potrebbe essere un fattore di confusione o potrebbe precludere la partecipazione o il completamento dello studio.
9. Nota ipersensibilità o intolleranza a baclofene, naltrexone o sorbitolo.
10. Trattamenti concomitanti che includono, ma non sono limitati a, baclofene, naltrexone, sorbitolo (forma farmaceutica), oppioidi e farmaci potenzialmente neurotossici come amiodarone, clorochina e chemioterapia in grado di indurre neuropatie periferiche. Possono essere inclusi i soggetti in grado di interrompere questi farmaci almeno 2 settimane prima della randomizzazione e per la durata dello studio.
11. Anamnesi di porfiria.
12. Diagnosi o anamnesi di disturbo da abuso di sostanze come definito dai criteri del Manuale diagnostico e statistico dei disturbi mentali,5a Edizione negli ultimi 12 mesi.
13. Uso medico o ricreativo di marijuana nei 3 mesi precedenti la Visita di screening.
14. Suicidalità attiva (per es., qualsiasi tentativo di suicidio negli ultimi 12 mesi o qualsiasi intento suicida attuale, compreso un piano, come valutato dal punteggio C-SSRS di "SÌ" alle domande 4 o 5; e/o sulla base della valutazione clinica da parte dello sperimentatore).
15. Depressione grave attualmente attiva, come determinato da un punteggio del Questionario della Depressione di Beck–II (BDI-II) =20.
16. Attualmente in allattamento, in gravidanza o con l'intenzione di iniziare una gravidanza durante lo studio.
17. Alanina aminotransferasi o aspartato aminotransferasi 2 volte maggiori rispetto al limite superiore della norma.
18. Danno renale significativo, determinato da una velocità di filtrazione glomerulare inferiore a 50 ml/min.
19. Il soggetto ha partecipato a uno studio su un farmaco o dispositivo sperimentale entro 30 giorni prima della Visita di screening o prevede di partecipare a uno studio su un farmaco o dispositivo sperimentale durante il corso di questo studio.
20. Il soggetto è un dipendente e/o parente dello Sponsor o dello Sperimentatore principale.

E.5 End points

E.5.1

Primary end point(s)

The change in the modified Overall Neuropathy Limitation Scale (ONLS) between baseline and the Month 15 visit.

Variazione nel punteggio ONLS modificato tra la Baseline e la Visita del Mese 15.

E.5.1.1

Timepoint(s) of evaluation of this end point

Month 15 visit

Visita del Mese 15

E.5.2

Secondary end point(s)

The change from baseline to month 15 in the following outcome measures in hierarchical order:
1) 10-Meter Walk Test (10mWT)
2) Quantified Muscular Testing (bilateral foot dorsiflexion dynamometry)
3) Patient Global Impression of Severity (PGI-S)
4) Patient Global Impression of Change (PGI-C)*
5) Charcot-Marie-Tooth Neuropathy Score, version 2 (CMTNS-v2)
6) Quantified Muscular Testing (hand grip)
* Because the PGI-C is already a change assessment, the change from Baseline is not needed for this endpoint.

Variazione dalla Baseline al Mese 15 nelle seguenti misure di esito in ordine gerarchico:
1. 10mWT
2. Test muscolare quantificato (QMT) (dinamometria bilaterale della dorsiflessione del piede)
3. Impressione globale di gravità del paziente (PGI-S)
4. Impressione globale di cambiamento del paziente (PGI-C)1
5. CMTNS-V2
6. QMT (impugnatura con la mano)
1 Poiché PGI-C è già una valutazione della variazione, la variazione rispetto alla Baseline non è necessaria per questo endpoint.

E.5.2.1

Timepoint(s) of evaluation of this end point

Month 15 visit

Visita del Mese 15

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

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

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

Yes

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

Canada

Israel

United States

Belgium

Denmark

France

Germany

Italy

Netherlands

Spain

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

LVLS - completion of the Month 15 Visit by the last subject

LVLS - completamento della Visita al mese 15 dell'ultimo soggetto

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

Yes

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)

Yes

F.1.1.6.1

Number of subjects for this age range:

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

271

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

Yes

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

Yes

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

F.3.3.6

Subjects incapable of giving consent personally

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

F.4.2

For a multinational trial

F.4.2.1

In the EEA

130

F.4.2.2

In the whole clinical trial

350

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.

Nessuno.

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

2021-05-19

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2021-05-05

P. End of Trial
P.	End of Trial Status	Prematurely Ended
P.	Date of the global end of the trial	2023-12-11

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