Clinical Trials Register

Summary
EudraCT Number:	2015-002125-19
Sponsor's Protocol Code Number:	9494
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:	2016-05-18
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

2015-002125-19

A.3

Full title of the trial

A phase IIb, prospective, multicentre, double-blind, triple-arm, randomized versus placebo trial, to assess the efficacy of a single injection of either 2 or 10 x 106 autologous adipose derived mesenchymal stromal cells (ASC) in the treatment of mild to moderate osteoarthritis (OA) of the knee, active and unresponsive to conservative therapy for at least 12 months.

Studio di fase IIb, prospettico, multicentrico, in doppio cieco, a tre bracci, randomizzato verso placebo, per valutare l’efficacia di una singola iniezione di 2 o 10 x 106 cellule stromali mesenchimali derivate da tessuto adiposo autologo (ASC) nel trattamento dell’artrosi di ginocchio da lieve a moderata , in fase acuta e non responsiva ad almeno 12 mesi di terapia standard

A.3.1

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

A phase 2b Study Evaluating the Efficacy of a Single Injection Autologous Adipose Derived Mesenchymal Stromal Cells in Patients with Knee Osteoarthritis

“Singola iniezione nell'articolazione del ginocchio di pazienti affetti da artrosi moderata
(malattia delle articolazioni che peggiora nel tempo caratterizzata dalla formazione di nuovo tessuto attorno alla zona interessata) di cellule capaci di trasformarsi in diversi altri tipi di cellule del corpo derivate dal tessuto adiposo prelevato precedentemente dallo stesso paziente ricevente”

A.3.2

Name or abbreviated title of the trial where available

ADIPOA 2

A.4.1

Sponsor's protocol code number

9494

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	CHU MontpellierCentre administratif André Benech,
B.1.3.4	Country	France
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	H2020-PHC-2014-single-stage
B.4.2	Country	European Union
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	CHU Montpellier
B.5.2	Functional name of contact point	Christian JORGENSEN
B.5.3	Address:
B.5.3.1	Street Address	Hôpital Lepyronie, 191, avenue du Doyen gaston Giraud
B.5.3.2	Town/ city	Montpellier cedex 5
B.5.3.3	Post code	34295
B.5.3.4	Country	France
B.5.4	Telephone number	330467337796
B.5.5	Fax number	330467337227
B.5.6	E-mail	c-jorgensen@chu-montpellier.fr

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	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	autologous adipose derived mesenchymal stromal cells
D.3.4	Pharmaceutical form	Suspension for injection
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intraarticular use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	NA
D.3.9.1	CAS number	NA
D.3.9.3	Other descriptive name	EXPANDED HUMAN AUTOLOGOUS MESENCHYMAL ADULT STEM CELLS EXTRACTED FROM ADIPOSE TISSUE (EASCS)
D.3.9.4	EV Substance Code	SUB30158
D.3.10	Strength
D.3.10.1	Concentration unit	million organisms/ml million organisms/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	2000000
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)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	Yes
D.3.11.3.1	Somatic cell therapy medicinal product	Yes
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	Yes
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.IMP: 2
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	No
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	Autologous adipose derived mesenchymal stromal cells
D.3.4	Pharmaceutical form	Suspension for injection
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intraarticular use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	NA
D.3.9.1	CAS number	NA
D.3.9.3	Other descriptive name	EXPANDED HUMAN ALLOGENEIC MESENCHYMAL ADULT STEM CELLS EXTRACTED FROM ADIPOSE TISSUE
D.3.9.4	EV Substance Code	SUB30305
D.3.10	Strength
D.3.10.1	Concentration unit	million organisms/ml million organisms/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	10000000
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)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	Yes
D.3.11.3.1	Somatic cell therapy medicinal product	Yes
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	Yes
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	Suspension for injection
D.8.4	Route of administration of the placebo	Intraarticular use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Active knee Osteoarthritis (mild to moderate)

Artrosi in fase acuta da lieve a moderata

E.1.1.1

Medical condition in easily understood language

Osteoarthritis

Malattia delle articolazioni che peggiora nel tempo caratterizzata dalla formazione di nuovo tessuto attorno alla zona interessata

E.1.1.2

Therapeutic area

Diseases [C] - Musculoskeletal Diseases [C05]

MedDRA Classification

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

Evaluate the efficacy of a single intra-articular injection of ASC in mild to moderate knee OA (KL 2-3) based on improvement of WOMAC pain and function subscore at 6 month, compared to placebo (vehic: 0.5% glucose in saline with 4% alb)

Valutare l’efficacia di una singola iniezione intra-articolare di ASC nell’artrosi di ginocchio da lieve a moderata OA (Kellgren Lawrence 2-3) basata sull’incremento del numero dei pazienti strettamente responsivi (strict responders) definiti tali mediante i miglioramenti rispetto al baseline del dolore e della funzionalità fisica secondo il sottopunteggio 50% WOMAC (Western Ontario and McMaster Universities Osteoarthritis Index), con variazioni assolute di 20 mm a 6 mesi, comparata con placebo (veicolo 0.5% glucosio in soluzione salina con 4.5% alb).

E.2.2

Secondary objectives of the trial

- Kellgren-Lawrence scores assessment on the basis of X-rays
- Progression of affected knee joints by quantitative MRI
- Disability and life quality assessment
- OARSI response assessment
- Paracetamol (Acetaminophen) medication assessment

- Valutazione punteggio Kellgren Lawrence sulla base degli esami radiografici;
- Progressione del ginocchio interessato definita mediante RMN;
- Valutazione della disabilità e della qualità della vita;
- Valutazione della risposta OARSI;
- Valutazione dell’uso del paracetamolo e di altri antidolorifici.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Symptomatic mild to moderate osteoarthritis (OA) of the index knee as defined by the American college of Rheumatology (ACR):
- History of pain in the index knee ≥ 6 months, AND
- Kellgren-Lawrence (K-L) Grade 2 or 3 only, on plain radiographs of the index knee (including fixed flexion), AND
- Swelling of the index knee evaluated by the investigator
2. Must meet the following pain criteria at the time of screening/baseline visit since at least half of the days in the previous month:
- Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain subscores ≥ 40 mm on the 0-100 normalised scale
- Visual Analogic Scale (VAS) pain rating of at least 40 on a 100-mm scale
- Subject’s global assessment of arthritis status must be fair, poor, or very poor
-Subject’s global assessment of the contralateral knee <20 mm by 100-mm using Visual Analogic Scale (VAS)
3. NSAID washout of at least 2 days before screening/baseline
4. BMI between 20-35 kg/m2

1. Precedenti trattamenti che agiscono sulla cartilagine o sul metabolismo osseo (es bifosfonati orali o endovena <1 anno precente, denosumab < 6 mesi, ranelato di stronzio o teriparatide o raloxifene <7 giorni prima dallo screening)
2. Glucosamina orale ≥1500 mg/die e condroitinsolfato ≥1000 mg/die <3 mesi prima
3. Pazienti che abbiano ricevuto iniezioni intra-articolari di corticosteroidi, piastrine ricche di plasma o acido ialuronico nei 6 mesi precedent la visita di screening.
4. Traumi significativi o operazioni chirurgiche nel ginocchio interessato nel corso dell’ultimo anno o artroscopia del ginocchio entro 12 mesi dallo screening.
5. Kellgren-Lawrence di grado 1 o 4 nel ginocchio interessato e in qualunque proiezione.
6. Artrosi causante dolore significativo in qualunque altra sede diversa dal ginocchio interessato, ad esempio dolore all’anca o al ginocchio controlaterale (≥ 20 mm sulla scala del dolore) come confermato dal VAS al baseline per ogni altra articolazione interessata dal dolore .

7. Storia di protesi del ginocchio o dell’anca nei 12 mesi precedenti.

8. Diagnosi di una o più dei seguenti:
 Artriti infiammatorie come l’artrite reumatoide, disordini autoimmuni, spondiloartrite sieronegativa, gotta o pseudogotta (definita come attacco acuto di gonfiore, dolore articolare in pazienti con condrocalcinosi o cristalli CPPD ai raggi X); storia o evidenza di artriti infettive, malattia di Paget, Ocronosi, sindrome di Wilson, Osteocondromatosi primaria
 Storia di fratture articolari nel ginocchio interessato
 Storia di disordini ereditari (es ipermobilità) e mutazioni del gene del collagene
 Patologie da immunodeficienza
 Alcolismo non trattato e ancora in corso (+14 bevande alcoliche a settimana)
 Soggetti con diabete mellito scarsamente controllato (HbA1C > 8%) o problemi vascolari concomitanti noti
 Programmati soggiorni prolungati fuori regione che impediscono la compliance per le visite programmate previste
 Grave disallineamento del ginocchio (eccessivamente varo o valgo ≥ 8°) all’esame obiettivo, e alla radiografia standard.
Grave osteoporosi con precedenti e sintomatiche fratture vertebrali o del femore

E.4

Principal exclusion criteria

1. Previous treatments acting on cartilage or bone metabolism (eg, oral or intravenous bisphosphonates <1 year previously, strontium ranelate or teriparatide or raloxifene <7 days prior to selection, and oral glucosamine ≥1500 mg/day and chondroitin sulphate <3 months previously)
2. Prior to the screening visit, has received intra-articular injection of corticosteroids, platelet rich plasma or hyaluronic acid within the previous 6 months,
3. Significant trauma or surgery to the index knee within the last year or arthroscopy of the index knee within 12 months of screening.
4. Kellgren-Lawrence Grade 1 or 4 in the index knee.
5. Osteoarthritis causing significant pain in any joint other than the identified knee, i.e., pain in hip, back, or contralateral knee (≥ 20 mm pain) as confirmed by a separate VAS at baseline for any other painful joint concerned
6. History of joint replacement of the knee or hip within the  previous 12 month
7. Diagnosis of one or more of the following:
- Inflammatory arthritis such as rheumatoid arthritis, autoimmune disorder, seronegative spondyloarthritis, gout or pseudogout (defined as acute episodic attacks of swollen, painful joint in a patient with X-Ray chondrocalcinosis or CPPD crystals);
- Severe misalignment of the knee (excessive varus or valgus ≥ 8°) at physical examination, as confirmed by standard radiograph
- Severe osteoporosis with previous fractures

1. Artrosi del ginocchio sintomatica da lieve a moderata come definita dai criteri diagnostici dell’ American college of Rheumatology (ACR):
 Storia di dolore nel ginocchio interessato ≥ 6 mesi, E
 Kellgren-Lawrence (K-L) di grado 2 o 3, alle radiografie del ginocchio interessato (inclusa la proiezione in flessione fissa), E
 Tumefazione del ginocchio interessato valutato dallo sperimentatore.

2. I seguenti requisiti relativi al dolore devono essere soddisfatti al momento della prima visita di screening/baseline da almeno la metà dei giorni del mese precedente:
 Punteggio del dolore ≥ 40 mm su una scala normalizzata da 0-100 mm secondo l’Indice WOMAC
 Valutazione del dolore di almeno 40 mm su una scala fino a 100 mm secondo la Visual Analogic Scale (VAS)
 La valutazione globale del ginocchio controlaterale <20 mm secondo la Visual Analogic Scale (VAS) fino a 100 mm
3. Washout di FANS da almeno 2 giorni prima sia dello screening che basale.

E.5 End points

E.5.1

Primary end point(s)

Primary Efficacy Analysis:
- Improvement from baseline to month 6 in WOMAC pain score of the index knee.
-Improvement from baseline to month 6 in WOMAC physical function score of the index knee.

Aumento del numero di pazienti veramente rispondenti OMERACT/OARSI definiti attraverso il miglioramento rispetto al baseline del dolore e della funzionalità fisica secondo il sottopunteggio 50% WOMAC con variazioni assolute di 20 mm a 6 mesi

E.5.1.1

Timepoint(s) of evaluation of this end point

Month 6

A 6 mesi

E.5.2

Secondary end point(s)

- Changes from baseline to months 1, 3, 6, 12 and 24 in OARSI scores of the index knee.
- Changes from baseline to months 1, 3, 6, 12 and 24 in VAS pain scores of the index knee.
- Changes from baseline to months 1, 3, 6, 12 and 24 in WOMAC stiffness scores of the index knee
- Changes from baseline to months 1, 3, 6, 12 and 24 in WOMAC global scores of the index knee
- Changes from baseline to months 1, 3, 12 and 24 in WOMAC pain and function scores of the index knee
- Changes from baseline to months 1, 3, 6, 12 and 24 in KOOS scores of the index knee
- Changes from baseline to months 1, 3, 6, 12 and 24 in SAS scores of the index knee
- Changes from baseline to months 1, 3, 6, 12 and 24 in SF-36
- Changes from baseline to months 12 and 24 in cartilage volume/thickness of the index knee MRI (MOAKS score).
- Changes from baseline to months 12 and 24 in femorotibial joint space of the index knee on X-ray

 Cambiamenti dal baseline ai mesi 1, 3, 6, 12 e 24 dei punteggi OARSI al ginocchio interessato.
 Cambiamenti dal baseline ai mesi 1, 3, 6, 12 e 24 dei punteggi del dolore sulla scala VAS al ginocchio interessato.
 Cambiamenti dal baseline ai mesi 1, 3, 6, 12 e 24 dei punteggi di rigidità WOMAC al ginocchio interessato
 Cambiamenti dal baseline ai mesi 1, 3, 6, 12 e 24 dei punteggi generali WOMAC al ginocchio interessato
 Cambiamenti dal baseline ai mesi 1, 3, 6, 12 e 24 dei punteggi di dolore e funzionalità WOMAC al ginocchio interessato
 Cambiamenti dal baseline ai mesi 1, 3, 6, 12 e 24 dei punteggi KOOS al ginocchio interessato.
 Cambiamenti dal baseline ai mesi 1, 3, 6, 12 e 24 dei punteggi SAS al ginocchio interessato
 Cambiamenti dal baseline ai mesi 1, 3, 6, 12 e 24 in SF-36
 Cambiamenti dal baseline ai mesi 1, 3, 6, 12 e 24 nell’uso degli analgesici.
 Cambiamenti dal baseline ai mesi 12 e 24 in punteggio MOAKS e del volume e dello spessore della cartilagine nel ginocchio interessato alla risonanza magnetica.
 Cambiamenti dal baseline ai mesi 12 e 24 nello spazio articolare femoro-tibiale ai raggi X del ginocchio interessato

E.5.2.1

Timepoint(s) of evaluation of this end point

Months 1, 3, 6, 12 and 24

A 1, 3, 6, 12 e 24

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

Yes

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

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

E.8.6.2

Trial being conducted completely outside of the EEA

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

LVLP

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

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)

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

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

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

153

F.4.2.2

In the whole clinical trial

153

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

G. Investigator Networks to be involved in the Trial
G.4 Investigator Network to be involved in the Trial: 1
G.4.1	Name of Organisation	ECRIN European Correspondent for France
G.4.3.4	Network Country	France

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2016-06-01

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2016-06-20

P. End of Trial
P.	End of Trial Status	Completed

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