Clinical Trials Register

Summary
EudraCT Number:	2022-002464-75
Sponsor's Protocol Code Number:	534
National Competent Authority:	France - ANSM
Clinical Trial Type:	EEA CTA
Trial Status:	Trial now transitioned
Date on which this record was first entered in the EudraCT database:	2022-12-06
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

France - ANSM

A.2

EudraCT number

2022-002464-75

A.3

Full title of the trial

Glucocorticoids versus placebo for the treatment of acute exacerbation of idiopathic pulmonary fibrosis: a randomized controlled trial

Glucocorticoïdes contre placebo pour le traitement de l'exacerbation aiguë de la fibrose pulmonaire idiopathique : un essai contrôlé randomisé

A.3.1

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

Glucocorticoids versus placebo for the treatment of acute exacerbation of idiopathic pulmonary fibrosis: a randomized controlled trial

Glucocorticoïdes contre placebo pour le traitement de l'exacerbation aiguë de la fibrose pulmonaire idiopathique : un essai contrôlé randomisé

A.3.2

Name or abbreviated title of the trial where available

EXAFIP2

A.4.1

Sponsor's protocol code number

534

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	Groupe Hospitalier Paris Saint-Joseph
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	Groupe Hospitalier Paris Saint-Joseph
B.4.2	Country	France
B.4.1	Name of organisation providing support	PHRC
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	Groupe Hospitalier Paris Saint-Joseph
B.5.2	Functional name of contact point	Clinical Research Project Manager
B.5.3	Address:
B.5.3.1	Street Address	185 rue Raymond Losserand
B.5.3.2	Town/ city	Paris
B.5.3.3	Post code	75014
B.5.3.4	Country	France
B.5.4	Telephone number	144123362+33
B.5.5	Fax number	144123252+33
B.5.6	E-mail	esacco@ghpsj.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	Yes
D.2.1.1.1	Trade name	PREDNISONE
D.2.1.1.2	Name of the Marketing Authorisation holder	Sanofi
D.2.1.2	Country which granted the Marketing Authorisation	France
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	PREDNISONE
D.3.2	Product code	SUB10020MIG
D.3.4	Pharmaceutical form	Oral solution in bottle
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	Prednisone
D.3.9.1	CAS number	53-03-2
D.3.9.2	Current sponsor code	21003706002
D.3.9.3	Other descriptive name	Prednisonum micronisatum
D.3.9.4	EV Substance Code	SUB10020MIG
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	5
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.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	Yes
D.2.1.1.1	Trade name	METHYLPREDNISOLONE SODIUM HEMISUCCINATE
D.2.1.1.2	Name of the Marketing Authorisation holder	Pfizer
D.2.1.2	Country which granted the Marketing Authorisation	France
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	METHYLPREDNISOLONE SODIUM HEMISUCCINATE
D.3.2	Product code	SUB03255MIG
D.3.4	Pharmaceutical form	Infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Methylprednisolone
D.3.9.1	CAS number	83-43-2
D.3.9.2	Current sponsor code	Methylprednisolone
D.3.9.3	Other descriptive name	METHYLPREDNISOLONE HEMISUCCINATE
D.3.9.4	EV Substance Code	SUB03256MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg/kg milligram(s)/kilogram
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	10
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	Oral solution in bottle
D.8.4	Route of administration of the placebo	Oral use
D.8 Placebo: 2
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Infusion
D.8.4	Route of administration of the placebo	Infusion (Noncurrent)

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Acute exacerbation of idiopathic pulmonary fibrosis

Exacerbation aiguë de la fibrose pulmonaire idiopathique

E.1.1.1

Medical condition in easily understood language

Acute exacerbation of idiopathic pulmonary fibrosis

Exacerbation aiguë de la fibrose pulmonaire idiopathique

E.1.1.2

Therapeutic area

Diseases [C] - Respiratory Tract Diseases [C08]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	21.1
E.1.2	Level	PT
E.1.2	Classification code	10021240
E.1.2	Term	Idiopathic pulmonary fibrosis
E.1.2	System Organ Class	10038738 - Respiratory, thoracic and mediastinal disorders

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 assess the efficacy of glucocorticoids compared to placebo on mortality at Day 30 among patients with IPF-AE.

Evaluer l’efficacité des glucocorticoïdes comparée au placebo sur la mortalité à 30 jours des Exacrebation Aigue des Fibroses Pulmonaires Idiopathiques.

E.2.2

Secondary objectives of the trial

To evaluate among patients with IPF-AE the efficacy of glucocorticoids compared to placebo on:
1. Time to death
2. Overall mortality rate at Day 90
3. Death or transplantation at Day 90
4. Respiratory disease-specific mortality rate at Day 30 and 90
5. Time to worsening
6. Percentage of patients admitted to ICU
7. Percentage of patients requiring invasive ventilation
8. Length of hospital stay
9. Radiological evolution
10. Pulmonary function tests evolution
Secondary Safety objectives
To evaluate among patients with IPF-AE the safety of glucocorticoids compared to placebo in particular on the occurence of:
1. Infectious disease
2. Diabetes mellitus
3. Cardiovascular disorder
4. Neuropsychological disturbances
5. Clinical laboratory evaluation
Other secondary objectives (exploratory)
To compare both arms in terms of:
1. Dyspnea
2. Anxiety
3. Depression
4. Clinical status at day 15 as assessed on a 7-category ordinal scale

Evaluer l’efficacité des glucocorticoïdes par rapport au placebo sur :
- Délai jusqu'au décès
- Mortalité globale à 90 jours
- Transplantation à 90 jours
- Mortalité spécifique à une maladie respiratoire à 30 jours et 90 jours
- Délai jusqu’à l’aggravation
- Pourcentage de patients admis en soins intensifs
- Pourcentage de patients nécessitant une ventilation invasive
- Durée de l'hospitalisation
- Évolution radiologique de la fibrose pulmonaire
- Évolution des explorations fonctionnelles respiratoires (EFR)

Objectifs secondaires de sécurité
Comparer la sécurité des glucocorticoïdes par rapport au placebo sur la survenue de :
- Maladies infectieuses
- Diabète
- Problèmes cardiovasculaires
- Perturbations neuropsychologiques
- Modifications des bilans biologiques

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1) Patient is ≥ 18 years of age
2) IPF or IPF (likely) diagnosis defined on 2018 international recommendations (See Appendix 1) (1)
3) Definite or suspected Acute Exacerbation defined by the international working group (2) criteria after exclusion of alternative diagnoses of acute worsening* (see below)
4) For women of childbearing age: efficient contraception for the duration of the study*
*Effective contraception is defined as any contraceptive method that is used consistently and appropriately and has a low failure rate (i.e., less than 1% per year)
Birth control methods which may be considered as highly effective :
• 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
• vasectomised partner
• sexual abstinence (highly effective method only if defined as refraining from heterosexual intercourse during the entire period of risk associated with the study treatments)
Post-menopausal women : A postmenopausal state is defined as no menses for 12 months without an alternative medical cause. A high follicle stimulating hormone (FSH) level in the postmenopausal range may be used to confirm a post-menopausal state in women not using hormonal contraception or hormonal replacement therapy. However in the absence of 12 months of amenorrhea, a single FSH measurement is insufficient.
5) Affiliation to the social security
6) Patient able to understand and sign a written informed consent form
*The criteria of IPF-AE are as follows:
- Previous or concurrent diagnosis of IPF (a)
- Acute worsening or development of dyspnea typically < 1-month duration
- Computed tomography with new bilateral ground-glass opacity and/or consolidation superimposed on a background pattern consistent with usual interstitial pneumonia pattern (b)
- Deterioration not fully explained by cardiac failure or fluid overload
Patients who fail to meet all 4 criteria due to missing computed tomography should be considered as having “suspected Acute Exacerbation”.
(a)If the diagnosis of IPF is not previously established, this criterion can be met by the presence of radiologic and/or histopathologic changes consistent with usual interstitial pneumonia pattern on the current evaluation.
(b)If no previous computed tomography is available, the qualifier “new” can be dropped from the third criterion.

1) Patient dont l’âge est ≥ 18 ans
2) Patient avec un diagnostic de fibrose pulmonaire idiopathique défini suivant les recommandations internationales de 2018
3) Patient avec une exacerbation aigüe certaine ou probable définie par les critères internationaux après l’exclusion des diagnostics alternatifs d’aggravation aigüe
4) Pour les femmes en âge de procréer : contraception efficace* pendant la durée du traitement et jusqu’à 5 semaines après l’arrêt
* Tout moyen de contraception utilisé de manière régulière et appropriée dont le taux d’échec est faible (c’est à-dire inférieur à 1% par an)
Méthodes de contrôle des naissances qui peuvent être considérées comme très efficaces :
- contraception hormonale combinée (contenant des œstrogènes et des progestatifs) associée à une inhibition de l'ovulation :
o orale
o intravaginale
o transdermique
- contraception hormonale à base de progestatifs seuls associée à l'inhibition de l'ovulation :
o orale
o injectable
o implantable
- dispositif intra-utérin (DIU)
- système intra-utérin à libération d'hormones (SIU)
- occlusion tubaire bilatérale
- partenaire vasectomisé
- abstinence sexuelle (méthode hautement efficace uniquement si elle est définie comme l'abstention de tout rapport hétérosexuel pendant toute la période de risque associée aux traitements de l'étude).
Femmes ménopausées : L'état post-ménopausique est défini comme l'absence de règles pendant 12 mois sans autre cause médicale. Un taux élevé d'hormone folliculo-stimulante (FSH) dans la fourchette post-ménopausique peut être utilisé pour confirmer un état post-ménopausique chez les femmes n'utilisant pas de contraception hormonale ou de traitement hormonal de substitution. Cependant, en l'absence de 12 mois d'aménorrhée, une seule mesure de FSH est insuffisante.
5) Patient affilié à un régime d’assurance maladie
6) Patient francophone
7) Patient ayant donné son consentement libre, éclairé et écrit

E.4

Principal exclusion criteria

Identified etiology for acute worsening (i.e.: infectious disease)
2) Known hypersensitivity to glucocorticoids or to any component of the study treatment
3) Patient requiring or on mechanical ventilation
4) Active bacterial, viral, fungal or parasitic infection. On swab collected, only positive for SARS-CoV-2, Influenzae A, Influenzae B and Respiratory Syncytial Virus (RSV) result, are considered active viral infection. The others viruses (i.e. Rhinovirus, Adenovirus…) are not considered to be responsible of pneumonia.
5) Active cancer
6) Patient on a lung transplantation waiting list
7) Treatment with glucocorticoids > 1 mg/kg/d from more than 7 days in the last 15 days
8) Patient participating to another interventional clinical trial
9) Documented pregnancy or lactation
10) Patient under tutorship or curatorship
11) Patient deprived of liberty
12) Patient under court protection

1) Étiologie identifiée pour l'aggravation aiguë (par exemple : maladie infectieuse)
2) Hypersensibilité connue aux glucocorticoïdes ou à tout composant du traitement à l'étude.
3) Patient sous ou nécessitant une ventilation mécanique
4) Infection bactérienne, virale, fongique ou parasitaire active.
Sur les écouvillons prélevés, seuls les résultats positifs pour le SARS-CoV-2, l'influenzae A, l'influenzae B et le virus respiratoire syncytial (VRS) sont considérés comme une infection virale active. Les autres virus (Rhinovirus, Adenovirus...) ne sont pas considérés comme responsables de pneumonie
5) Patient avec un cancer actif
6) Patient inscrit sur une liste d'attente de transplantation pulmonaire
7) Patient sous traitement par glucocorticoïdes > 1 mg/kg/jour pendant plus de 7 jours au cours des 15 derniers jours
8) Patient déjà inclus dans un protocole de recherche interventionnelle à risques (RIPH1)
9) Femme enceinte ou allaitante
10) Patient sous tutelle ou curatelle
11) Patient privé de liberté
12) Patient sous sauvergarde de justice

E.5 End points

E.5.1

Primary end point(s)

Parameter: all-cause mortality rate; Timetable: Day 30.
The choice of all cause-mortality rate at Day 30 as the primary endpoint, has been driven by the results of our previous trial, EXAFIP.

Taux de mortalité toute cause à 30 jours.

E.5.1.1

Timepoint(s) of evaluation of this end point

30 days

30 jours

E.5.2

Secondary end point(s)

Secondary Efficacy endpoints
1. Parameter: Time to death
Methods: vital status assessment at Day 30 and Day 90 with time (in days) between randomization and death
2. Parameter: Overall mortality at Day 90
Methods: vital status assessment at Day 90
3. Parameter: Death or transplantation at Day 90
Methods: vital status and transplantation at Day 90
4. Parameter: Mortality linked to the respiratory disease at Day 30 and Day 90
Methods: cause of death assessment at Day 30 and Day 90
5. Parameter: Time to worsening
Methods: Time (in days) from randomization to worsening* (see below)
Timetable: From Day 4 to Day 30 (end of study treatment)

Statut vital à 30 jours et 90 jours avec le délai entre la randomisation et le décès
Statut vital à 90 jours
Transplantation à 90 jours
Causes de décès et mortalité liée à une maladie respiratoire à 30 jours et 90 jours
Temps en jours entre la randomisation et l’aggravation
Nombre de patients admis en soins intensifs sur les 110 patients inclus et randomisés
Nombre de patients ayant nécessité une ventilation invasive sur les 110 patients inclus et randomisés
Durée en jours du séjour hospitalier
Comparaison des scanners entre celui réalisé avant l’EA-FPI (si disponible) et celui réalisé à 90 jours.
Comparaison des résultats d’EFR entre celles réalisées avant l’EA-FPI (si disponible) et celles réalisées à 90 jours

Critères de jugement secondaires de sécurité
Suivi pendant les 90 jours de participation des patients : de l’inclusion/randomisation à la sortie de l’hôpital, à 30 jours et à 90 jours.

E.5.2.1

Timepoint(s) of evaluation of this end point

30 days or 90 days

30 jours ou 90 jours

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

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

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

The end of the trial corresponds to the last visite of the last subject.

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

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

Yes

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

Yes

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

F.3.3.6

Subjects incapable of giving consent personally

Yes

F.3.3.6.1

Details of subjects incapable of giving consent

The investigator proposes to the relative in case of incapacity of the patient, to participate in the study, informs relative orally. The relative confirms his interest in the study, he is asked to sign the consent form in duplicate .

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

110

F.4.2

For a multinational trial

F.4.2.1

In the EEA

110

F.4.2.2

In the whole clinical trial

110

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)

After discontinuation of the study treatment, patients will benefit form the usual management.

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

2022-12-06

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2022-10-20

P. End of Trial
P.	End of Trial Status	Trial now transitioned

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Orphan Designation Number:
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